Chronic Kidney Disease: Management of Complications

Chronic Kidney Disease: Management of Complications
Pharmacotherapy II Second Semester 2017

References Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl ; 3: Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney inter., Suppl. 2012; 2: 279–335. KDIGO Clinical Practice Guidelines for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)

CKD complications Complications begin to develop as kidney disease progresses, most often when patients reach to eGFR is <60 mL/minute/1.73 m2 (G3a-G5). Among these complications are: fluid and electrolyte abnormalities, anemia, hyperphosphatemia, hyperparathyroidism, metabolic acidosis, cardiovascular complications, poor nutritional status. Often, these complications go unrecognized or are inadequately managed during the earlier stages of CKD, leading to poor outcomes by the time a patient is in need of dialysis therapy.

Metabolic Effects of Progressive Kidney Disease
Cardiovascular Hypertension Congestive heart failure Pericarditis Atherosclerosis Arrhythmias Metastatic calcifications Dermatologic Altered pigmentation Pruritus Endocrine Calcium-phosphorous imbalances Hyperparathyroidism Metabolic bone disease Altered thyroid function Altered carbohydrate metabolism Hypophyseal-gonadal dysfunction Decreased insulin metabolism Erythropoietin deficiency Fluid, Electrolyte, and Acid-Base Effects Fluid retention Hyperkalemia Hypermagnesemia Hyperphosphatemia Hypocalcemia Metabolic acidosis Gastrointestinal Anorexia Nausea, vomiting Delayed gastric emptying GI bleeding Ulcers Hematologic Anemia Bleeding complications Immune suppression Musculoskeletal Renal bone disease Amyloidosis Neurologic Lethargy Depressed sensorium Tremor Asterixis Muscular irritability and cramps (i.e., restless legs syndrome) Seizures Motor weakness Peripheral neuropathy Coma Psychological Depression Anxiety Psychosis Miscellaneous Reduced exercise tolerance These manifestations certainly may develop in the earlier stages of CKD, underscoring the importance of early intervention, but become more prominent as the disease worsens. The pathogenesis of these disorders has been attributed, in part, to the accumulation of uremic toxins. The search for uremic toxins has led to the identification of nitrogenous compounds that are consistently observed in the serum of patients with kidney disease. A cause-and-effect relationship between these compounds and the clinical manifestations of uremia has not been clearly established, however. Asterixis (also called the flapping tremor, or liver flap) is a tremor of the hand when the wrist is extended, Sensorium: The totality of those parts of the brain that receive, process and interpret sensory stimuli. The sensorium is the supposed seat of sensation, the place to which impressions from the external world are conveyed and perceived.

1) Fluid And Electrolyte Abnormalities:
Sodium and Water Patient with CKD or ESKD maintain sodium balance but are volume expanded the most common manifestation of increased intravascular volume is systemic hypertension The goal in managing sodium and water balance is to maintain a normal serum sodium concentration while preventing fluid overload or volume depletion (i.e., maintaining hemodynamic stability). By achieving these goals, the risk of developing hypertension secondary to volume overload is also reduced, although hypertension is already present in many patients at G3 and G4. Early in the course of CKD, glomerular and tubular adaptive processes develop, such as an increase in the fractional excretion of sodium (FENa). These mechanisms enable patients to maintain relatively normal sodium and water homeostasis Eventually, however, patients with advanced kidney dysfunction exhibit signs of sodium and fluid retention, because sodium balance is maintained at the expense of increased extracellular volume, which results in hypertension. Expansion of blood volume, if not controlled, can cause peripheral edema, heart failure, and pulmonary edema. To achieve control, most patients with more advanced kidney disease will be placed on sodium restriction (~2 to 4 g/day) and fluid restriction (~2 L/day). These restrictions will depend on the current dietary intake, extent of volume overload, and urine output and should be altered according to the special needs of the patient

secondary to the defect in urinary concentrating ability
Sodium and Water In persons with normal kidney function, sodium balance is maintained at a sodium intake of 120 to 150 mEq/day. The fractional excretion of sodium (FeNa) is approximately 1% to 3%. Water balance is also maintained, with a normal range of urinary osmolality of 50 to 1,200 mOsm/kg (average range 500 to 800 mOsm/kg). An osmotic diuresis occurs with an increase in FeNa leading to obligatory water losses and impairment in the kidney’s ability to dilute or concentrate urine (urinary osmolality is often fixed at that of plasma or approximately 300 mOsm/L). Nocturia is present relatively early in the course of CKD (stage 3) secondary to the defect in urinary concentrating ability. In patients with severe CKD (stages 4 and 5), serum sodium concentration is generally maintained as the result of an increase in FeNa by as much as 30%, but results in a volume-expanded state. Total renal sodium excretion decreases despite an increase in sodium excretion by remaining nephrons. Volume overload with pulmonary edema can result, but the most common manifestation of increased intravascular volume is systemic hypertension. Volume overload — Sodium and intravascular volume balance are usually maintained via homeostatic mechanisms until the GFR falls below 10 to 15 mL/min. However, the patient with mild to moderate chronic kidney disease, despite being in relative volume balance, is less able to respond to rapid infusions of sodium and is therefore prone to fluid overload. Patients with chronic kidney disease and volume overload generally respond to the combination of dietary sodium restriction and diuretic therapy, usually with a loop diuretic given daily. Some investigators have also claimed that limiting sodium intake may also help decrease progression of chronic kidney disease by lowering intraglomerular pressure [36]. as the result of an increase in FeNa = plasma

Management The ability of the kidney to adjust to abrupt changes in sodium intake is greatly diminished in patients with ESKD. Sodium restriction beyond a no-added-salt diet should not be recommended except in the face of hypertension or edema.(2-4 g/day). Saline-containing IV solutions should be used cautiously in patients with CKD because the kidney’s ability to excrete a salt load is impaired and such patients are prone to volume overload Fluid restriction is generally unnecessary provided sodium intake is controlled, although fluid intake between dialysis sessions is generally limited for hemodialysis patients (avoid < 2 L/d) (depends on urine output).

Diuretic therapy is often necessary to control edema or blood pressure.
Loop diuretics, particularly when administered by continuous infusion, increase urine volume and renal sodium excretion. Thiazide diuretics are ineffective in patients with a GFR below 30 mL/min. The possible exception is use of the thiazide-like diuretic, metolazone, which may retain its effect at reduced eGFRs. As kidney failure progresses, manifestations of excess fluid accumulation develop that are resistant to more conventional interventions, and dialysis will be required to control volume status. The maximum effective diuretic dose is higher in patients with heart failure, advanced cirrhosis, or renal failure. In these settings, decreased renal perfusion (and therefore decreased drug delivery to the kidney), diminished proximal secretion (due to the retention of competing anions in renal failure), and enhanced activity of sodium-retaining forces (such as the renin-angiotensin-aldosterone system) combine to diminish the diuretic effect

2) Potassium Homeostasis (Hyperkalemia):
Hyperkalemia can result from a combination of factors, including: diminished renal potassium excretion, redistribution of potassium into the extracellular fluid owing to metabolic acidosis, excessive potassium intake. Rare if GRF >15 without an endogenous or exogenous load of potassium. Hyperkalemia is defined as a serum potassium concentration greater than 5.5 mEq/L. It can be further classified according to its severity: mild hyperkalemia (serum potassium 5.5 to 6 mEq/L); moderate hyperkalemia (6.1 to 6.9 mEq/L); severe hyperkalemia (>7 mEq/L). The chronic goal is to maintain potassium concentrations of approximately 4.5 to 5.5 mEq/L Hyperkalemia — The ability to maintain potassium excretion at near normal levels is generally maintained in patients with renal disease as long as both aldosterone secretion and distal flow are maintained [37,38]. Thus, hyperkalemia generally develops in the patient who is oliguric or who has an additional problem such as a high potassium diet, increased tissue breakdown, or hypoaldosteronism (due in some cases to the administration of an ACE inhibitor or ARB) [39]. Impaired cell uptake of potassium also may contribute to the development of hyperkalemia in advanced chronic kidney disease. (See "Causes of hyperkalemia".) Hyperkalemia due to ACE inhibitor or ARB therapy is most likely to occur in patients in whom the serum potassium concentration is elevated or in the high normal range prior to therapy. This is discussed in detail separately. (See "Treatment and prevention of hyperkalemia".) In addition to treating hyperkalemia, there are several measures that can help prevent hyperkalemia in patients with chronic kidney disease. These include ingestion of a low potassium diet (eg, less than 40 to 70 meq/day [1500 to 2700 mg/day]) and avoiding, if possible, the use of drugs that raise the serum potassium concentration such as nonsteroidal antiinflammatory drugs [40]. Nonselective beta-blockers make the postprandial rise in the serum potassium concentration but do not produce persistent hyperkalemia. (See "Sympathetic activity and potassium balance" and "Patient information: Low potassium diet".)

Hyperkalemia – Clincal presentation
Frequently asymptomatic; however, the patient may complain of heart palpitations or skipped heartbeats. The earliest ECG change (serum potassium 5.5 to 6 mEq/l) is peaked T waves. The sequence of change with further increases is: prolongation of the PR interval , widening of the QRS complex, loss of the P wave, merging of the QRS complex with the T wave resulting in a sine-wave pattern. Hyperkalemic ECG changes are uncommon at potassium concentrations of <7 mEq/L, but occur regularly at concentrations >8 mEq/L. Ventricular arrhythmias or cardiac arrest may ensue if no effort to lower serum potassium Treatment of hyperkalemia depends on the serum concentration of potassium as well as the presence or absence of symptoms and electrocardiographic (ECG) changes. Manifestations of hyperkalemia include weakness, confusion, and muscular or respiratory paralysis. These symptoms may be absent, however, especially if hyperkalemia develops rapidly. Early ECG changes include peaked T waves, followed by a decreased R-wave amplitude, widened QRS complex, and a prolonged PR interval. These changes may progress to complete heart block with absent P waves and, finally, a sine wave. Ventricular arrhythmias or cardiac arrest may ensue if no effort to lower serum potassium is initiated. Hyperkalemic ECG changes are uncommon at potassium concentrations of <7 mEq/L, but occur regularly at concentrations >8 mEq/L.

The most serious manifestations of hyperkalemia are muscle weakness or paralysis, cardiac conduction abnormalities, and cardiac arrhythmias. These manifestations usually occur when the serum potassium concentration is ≥7.0 meq/L with chronic hyperkalemia or possibly at lower levels with an acute rise in serum potassium. Patients with skeletal muscle or cardiac manifestations typically have one or more of the characteristic ECG abnormalities associated with hyperkalemia. Other manifestations in hyperkalemic patients may be related to the cause of the hyperkalemia, such as polyuria and polydipsia with uncontrolled diabetes. Hyperkalemia interferes with renal ammonium (NH4+) excretion, thereby limiting acid excretion and possibly leading to the development of metabolic acidosis

The earliest ECG change (serum potassium 5
The earliest ECG change (serum potassium 5.5 to 6 mEq/l) is peaked T waves. The sequence of change with further increases is: prolongation of the PR interval , widening of the QRS complex, loss of the P wave, merging of the QRS complex with the T wave resulting in a sine-wave pattern.

Hyperkalemia - Management
Generally, treatment is unnecessary if the potassium concentration is <6.5 mEq/L and there are no ECG changes. If potassium concentrations rise above 6.5 mEq/L, and especially if they are accompanied by neuromuscular symptoms or changes in the ECG, treatment should be instituted. Chronic management involves prevention of hyperkalemia by: limiting potassium intake to 50 to 80 mEq/day Homework: what constitutes a low potassium diet? avoiding the use of agents that could elevate potassium levels. Homework: what are these agents? Constipation in patients with CKD can interfere with colonic potassium excretion; therefore a good bowel regimen is important. Homework: What is good bowel regimen?

HW: low-potassium diet
Grains Foods prepared with white flour (eg, pasta, bread), white rice Beverages Non-dairy creamer, fruit punch, drink mixes (eg, Kool-Aid), tea (<2 cups or 16 ounces per day), coffee (<1 cup or 8 ounces per day) Sweets Angel or yellow cake, pies without chocolate or high-potassium fruit, cookies without nuts or chocolate Fruits Apples (1), apple juice, applesauce, apricots (canned), blackberries, blueberries, cherries, cranberries, fruit cocktail (drained), grapes, grape juice, grapefruit (½), mandarin oranges, peaches (½ fresh or ½ cup canned), pears (1 small fresh or ½ cup canned), pineapple and juice, plums (1 whole), raspberries, strawberries, tangerine (1 whole), watermelon (1 cup) Vegetables Alfalfa sprouts, asparagus (6 spears), green or wax beans, cabbage (cooked), carrots (cooked), cauliflower, celery (1 stalk), corn (½ fresh ear or ½ cup), cucumber, eggplant, kale, lettuce, mushrooms (fresh), okra, onions, parsley, green peas, green peppers, radish, rhubarb, water chestnuts (canned, drained), watercress, spinach (raw, 1 cup), squash (yellow), zucchini Proteins Chicken, turkey (3 ounces), tuna, eggs, baloney, shrimp, sunflower or pumpkin seeds (1 ounce), raw walnuts, almonds, cashews, or peanuts (all 1 ounce), flax seeds (2 tablespoons ground), unsalted peanut butter (1 tablespoon) Dairy products Cheddar or Swiss cheese (1 ounce), cottage cheese (½ cup) HW: low-potassium diet These foods have a low level of potassium (less than 250 mg potassium per serving on average). You can eat these low-potassium foods, but be sure to watch your portion size since potassium can quickly add up if you eat a large portion. Unless noted, one serving is ½ cup (4 ounces)

Agents that can cause hyperkalemia.
Medication that interferes with urinary excretion: ACE inhibitors and angiotensin receptor blockers Potassium-sparing diuretics (e.g. amiloride and spironolactone) NSAIDs such as ibuprofen, naproxen, or celecoxib The calcineurin inhibitor immunosuppressants cyclosporine and tacrolimus The antibiotic trimethoprim The antiparasitic drug pentamidine In constipation use: potassium-binding resins such as sodium polystyrene sulfonate (Kayexalate) Treatment of constipation in these patients is similar to that used in the general population and includes stool softeners, lubricants, laxatives, and enemas. Enemas that contain magnesium and phosphate should be avoided to prevent the development of hypermagnesemia and hyperphosphatemia, and to prevent further loss of residual renal function.

Hyperkalemia - Management
Acute management involves: reversal of cardiac effects with calcium administration (antagonize membrane effects of potassium) reduction of serum potassium which can be achieved by shifting potassium intracellularly with administration of: glucose and insulin, β-adrenergic agonists, alkali therapy (if metabolic acidosis is a contributing factor) Removing excess potassium from the body Loop or thiazide diuretics exchange resins to remove potassium dialysis using a low-potassium dialysate bath Stabilize cardiac membranes with calcium: Give only for hyperkalemia with significant ECG findings (eg, widening of the QRS complex or loss of P waves, but not peaked T waves alone) or severe arrhythmias thought to be caused by hyperkalemia Give adults calcium chloride 500 to 1000 mg (5 to 10 mL of 10 percent solution) by IV infusion slowly over 2 to 3 minutes, preferably via a central line; or give calcium gluconate 1000 mg (10 mL of 10 percent solution) also infused slowly; may be given peripherally in large vein; time to onset is immediate Calcium treatment may be repeated after 5 minutes if ECG changes persist; patient must be on cardiac monitor when receiving calcium; calcium can exacerbate digoxin toxicity Give children calcium gluconate (10 percent solution) 0.5 mL/kg Since the effect of calcium is transient, patients with hyperkalemia also require treatments to shift potassium into cells and to remove potassium Shift potassium into cells: Give insulin and glucose to hyperkalemic patients with ECG changes OR serum potassium ≥6.5 to 7 meq/L Insulin and glucose: Give IV bolus of regular insulin 10 units with 50 mL of a 50 percent glucose solution; give children regular insulin 0.2 units per gram of glucose, give glucose 1 g/kg; time to onset is 10 to 20 minutes; after insulin and glucose bolus therapy, start dextrose infusion; monitor fingerstick glucose closely Beta 2 agonist: May give albuterol 10 to 20 mg in 4 mL saline nebulized over 10 minutes (may use metered dose inhaler); pediatric dose 0.1 to 0.3 mg/kg; time to onset is 20 to 30 minutes; IV albuterol or epinephrine are alternatives Sodium bicarbonate: Provides minimal effect on shifting potassium intracellularly, even in acidemic patients; may give 150 meq in one liter of 5 percent dextrose in water at 250 mL/hour; do not give in same IV as calcium Since the effect of shifting potassium into the cells is transient, treatments to remove potassium are also required Remove potassium Cation exchange resin (sodium polystyrene sulfonate): Give 15 to 30 grams of sodium polystyrene sulfonate (without sorbitol) orally; pediatric dose is 1 g/kg; although less preferable, sodium polystyrene sulfonate may be given as a retention enema (dose is 50 g) without sorbitol; time to onset is approximately 1 to 2 hours; may repeat dose after 4 to 6 hours based upon repeat serum potassium; Sorbitol can cause intestinal necrosis and should be avoided; Do not give sodium polystyrene sulfonate or sorbitol to post-operative or renal transplant patients Loop or thiazide diuretic: Provides only limited short-term effect; May give furosemide 20 to 40 mg IV; pediatric dose is 1 to 2 mg/kg IV; higher dose may be required with renal insufficiency; fluid losses must be replaced unless the patient is volume expanded Hemodialysis: Can be used if the conservative measures listed above fail, if hyperkalemia is severe, if the patient has renal failure, or if the patient has marked tissue breakdown and is releasing large amounts of potassium from injured cells

Therapeutic alternatives for the management of hyperkalemia
In the gut, sodium polystyrene sulfonate takes up potassium (and calcium and magnesium to lesser degrees) and releases sodium. Each gram of resin may bind as much as 1 meq of potassium and release 1 to 2 meq of sodium. Thus, a potential side effect is exacerbation of edema due to sodium retention. Calcium polystyrene sulfonate, available outside the United States, does not have significant sodium content.

3) Metabolic Acidosis: A clinically significant metabolic acidosis is commonly seen when the GFR drops below ml/min. The major factors responsible for development of metabolic acidosis in advanced kidney disease: Reduced bicarbonate reabsorption impaired production of ammonia by the kidneys Consequences of metabolic acidosis include: renal bone disease (bone buffering of some of the excess hydrogen ions is associated with the release of calcium and phosphate from bone, i.e. promoting bone resorption), Fatigue and decreased exercise tolerance, reduced cardiac contractility, increased vascular irritability , protein catabolism (Uremic acidosis can increase skeletal muscle breakdown and diminish albumin synthesis) The goals of therapy for patients with CKD are: to normalize the pH of the blood (pH of approximately 7.35 to 7.45) maintain the serum bicarbonate within the normal range (22 to 28 mEq/L). Normal buffering of hydrogen ions by the bicarbonate and carbonic acid system as well as other extracellular and intracellular buffers, including proteins, phosphates, and hemoglobin, is essential for maintaining normal acid-base balance (i.e., normal pH). Metabolic acidosis — There is an increasing tendency to retain hydrogen ions among patients with chronic kidney disease [41-43]. This can lead to a progressive metabolic acidosis with the serum bicarbonate concentration tending to stabilize between 12 and 20 meq/L, and rarely falling below 10 meq/L [42,44]. Previously, exogenous alkali was not usually given to treat the generally mild metabolic acidosis (arterial pH generally above 7.25) in asymptomatic adults with chronic kidney disease. This was primarily due to concerns related to the exacerbation of volume expansion and hypertension. However, these concerns appear to be overstated. There are three major reasons why treatment of the acidemia may be desirable in patients with chronic kidney disease. (See "Pathogenesis and treatment of metabolic acidosis in chronic kidney disease".) Bicarbonate supplementation may slow the progression of chronic kidney disease [45]. Bone buffering of some of the excess hydrogen ions is associated with the release of calcium and phosphate from bone, which can worsen the bone disease. (See 'Renal osteodystrophy' below.) Uremic acidosis can increase skeletal muscle breakdown and diminish albumin synthesis, leading to loss of lean body mass and muscle weakness. The administration of bicarbonate increases serum albumin and the lean body mass [45]. We recommend alkali therapy to maintain the serum bicarbonate concentration above 23 meq/L [45-50]. If alkali is given, sodium bicarbonate (in a daily dose of 0.5 to 1 meq/kg per day) is the agent of choice. Sodium citrate (citrate is rapidly metabolized to bicarbonate) may be used in patients who are unable to tolerate sodium bicarbonate, since it does not produce the bloating associated with bicarbonate therapy [47]. Sodium citrate should be avoided in the rare patient who may be taking aluminum-containing antacids since it markedly enhances intestinal aluminum absorption [51,52]. The K/DOQI clinical practice guidelines for nutrition in CRF, as well as other K/DOQI guidelines, can be accessed through the National Kidney Foundation's web site at

Metabolic acidosis - Management
Asymptomatic patients with mild acidosis (bicarbonate of 12 to 20 mEq/L; pH of 7.2 to 7.4) generally do not require emergent therapy and gradual correction over days to weeks is appropriate. When plasma bicarbonate ↓< 20 mEq/L, give NaHCO3 orally Each 650-mg tablet of sodium bicarbonate provides 8 mEq of sodium and 8 mEq of bicarbonate. Dose (mEq)= 0.5 x WT x (24 – Serum bicarbonate) The calculated amount of bicarbonate replacement therapy (in milliequivalents [or in mmols]) should be administered over several days to prevent volume overload from excessive sodium intake. Should be administered over several days to avoid volume overload from Na. Daily dose should not exceed 0.5 mEq/kg/day and should be given in divided doses GI distress from carbon dioxide production Homework: what are Bicitra and Polycitra and what are their uses. Patients with severe acidosis (serum bicarbonate <8 mEq/L; pH <7.2) may require IV therapy Serum bicarbonate concentrations less than 22 mmol/l are associated with increased risk of CKD progression and increased risk of death. Conversely, high serum bicarbonate concentrations greater than 32 mmol/l are associated with increased risk of death irrespective of the level of kidney function. In patients with stage 4 or 5 CKD, the use of alkalinizing salts, such as sodium bicarbonate or citrate/citric acid preparations, is useful to replenish depleted body bicarbonate stores. Sodium bicarbonate tablets are manufactured in 325- and 650-mg strengths (a 650-mg tablet contains 7.6 mEq [7.6 mmol] sodium and 7.6 mEq [7.6 mmol] bicarbonate). Shohl solution and Bicitra contain 1 mEq/mL (1 mmol/mL) of sodium and the equivalent of 1 mEq/mL (1 mmol/mL) of bicarbonate as sodium citrate/citric acid. Citrate is metabolized in the liver to bicarbonate, and citric acid is metabolized to CO2 and water. Polycitra, which contains potassium citrate (1 mEq/mL [1 mmol/mL] of sodium, 1 mEq/mL [1 mmol/mL] of potassium, and 2 mEq/mL [2 mmol/mL] of bicarbonate) should not be used in patients with severe CKD because of the risk of hyperkalemia. The replacement dose of alkali (base) needed to restore the serum bicarbonate concentration to normal (24 mEq/L [24 mmol/L]) can be approximated by multiplying the volume of distribution of bicarbonate (0.5 L/kg) by the patient's body weight (in kilograms) and the patient's base deficit (difference between the patient's serum bicarbonate value and the normal value of 24 mEq/L [24 mmol/L]). The calculated amount of bicarbonate replacement therapy (in milliequivalents [or in mmols]) should be administered over several days to prevent volume overload from excessive sodium intake. After the serum bicarbonate has normalized, a maintenance regimen of bicarbonate to neutralize daily acid production may be all that is necessary (12 to 20 mEq/day [12 to 20 mmol/day] in divided doses). Doses are subsequently titrated to maintain normal plasma bicarbonate concentrations. Patients with renal tubular acidosis may require higher doses of alkalinizing agents (see Chap. 61). Fluid balance should be monitored carefully because of the sodium content of these agents. Citrate-containing solutions should not be used in combination with aluminum-containing compounds because they can enhance aluminum absorption and increase the risk of aluminum intoxication. Excessive doses of alkalinizing agents may cause metabolic alkalosis, as well as lethargy or cardiac depression secondary to a decrease in ionized serum calcium concentration. Gastrointestinal distress characterized by gastric distension and flatulence is relatively common with high doses of oral sodium bicarbonate. Patients with severe acidemia (serum bicarbonate <8 mEq/L [<8 mmol/L]; pH <7.2) will likely require IV therapy (see Chap. 61). Metabolic acidosis in both adult and pediatric patients undergoing dialysis is usually managed by tailoring the patient's dialysis prescription. Increasing the concentration of bicarbonate (or acetate) in the dialysate to values above the serum bicarbonate concentration causes diffusion of the bicarbonate across the dialyzer and is an effective chronic treatment for metabolic acidosis in the dialysis population (see Chap. 54). Administration of oral bicarbonate salts may also be necessary for some dialysis patients.

Bicitra contain 1 mEq/mL (1 mmol/mL) of sodium and the equivalent of 1 mEq/mL (1 mmol/mL) of bicarbonate as sodium citrate/citric acid. Citrate is metabolized in the liver to bicarbonate, and citric acid is metabolized to CO2 and water. Polycitra, which contains potassium citrate (1 mEq/mL [1 mmol/mL] of sodium, 1 mEq/mL [1 mmol/mL] of potassium, and 2 mEq/mL [2 mmol/mL] of bicarbonate) should not be used in patients with severe CKD because of the risk of hyperkalemia.

Other Electrolyte and Metabolic Disturbances of CKD
Hypermagnesemia is due to decreased elimination of magnesium by the kidney. Magnesium is eliminated by the kidney to the extent required to achieve normal serum magnesium concentrations (1.7 to 2.2 mg/dL) until eGFR is <30 mL/minute/1.73 m2. Serum magnesium concentrations <5 mEq/L rarely cause symptoms. Higher concs can lead to nausea, vomiting, lethargy, confusion, and diminished tendon reflexes, Severe hypermagnesemia may depress cardiac conduction. The risk of hypermagnesemia can be reduced by avoiding magnesium-containing antacids and laxatives use of magnesium-free dialysate in patients with stage 5 CKD requiring dialysis. 1.7 to 2.2 mg/dL

Other Electrolyte and Metabolic Disturbances of CKD
Hyperphosphatemia is a result of decreased phosphorus elimination by the kidneys patients should reduce dietary phosphorus to 800 to 1,000 mg/day while maintaining adequate nutritional needs. Phosphorus-containing laxatives and enemas should also be avoided. Hyperphosphatemia is associated with low serum calcium concentrations. Asymptomatic Hyperuricemia. Happen due to diminished urinary excretion of uric acid. In the absence of a history of gout or urate nephropathy, asymptomatic hyperuricemia does not require treatment.

4) Anemia: Anemia appears as early as G3 stage
Usually is normochromic & normocytic The primary cause of anemia in patient with CKD or ESKD is erythropoietin (EPO) deficiency. Other factors include: decreased lifespan of red blood cells secondary to uremia, blood loss from frequent phlebotomy and HD, GI bleeding, severe hyperparathyroidism, protein malnutrition, severe infections, and inflammatory conditions uremic toxins may inhibit the production of EPO, the bone marrow response to EPO, and the synthesis of heme. iron deficiency  microcytic hypochromic pattern vitamin B12 & folate deficiency, occurs more frequently in dialyzed patients since folic acid is removed by dialysis (rare in other stages of CKD)  macrocytic anemia Aluminum intoxication (RBCs are typically microcytic). The major source is aluminium-containing antacids. Approximately 90% of the total EPO is produced in the peritubular cells of the kidney; the remainder is produced by the liver. Other factors that contribute to anemia include a shortened RBC life span secondary to uremia, blood loss from frequent phlebotomy and HD, GI bleeding, severe hyperparathyroidism, protein malnutrition, accumulation of aluminum, severe infections, and inflammatory conditions.85 Substances present in the plasma of patients with CKD, collectively termed “uremic toxins,” may inhibit the production of EPO, the bone marrow response to EPO, and the synthesis of heme. The negative effects of these substances on RBC production are supported by improvement in erythropoiesis with dialysis, which removes these uremic toxins. This uremic environment also causes a decrease in the RBC life span, from a normal life span of 120 days to approximately 60 days in patients with severe CKD. A shortened RBC life span has been observed in uremic patients transfused with RBC from individuals with normal kidney function, whereas RBC from uremic individuals have a normal survival time when transfused into patients without kidney failure.90

Definition and identification of anemia in CKD
The recommended thresholds for diagnosis and evaluation of anemia should not be interpreted as being thresholds for treatment of anemia but simply for the identiﬁcation of this complication. Practice preferences with respect to treatment strategies should be directed according to local resources. Evaluation of anemia in people with CKD To identify anemia in people with CKD measure Hb concentration: when clinically indicated in people with GFR<60 ml/min/1.73 m2 (GFR categories G1-G2); at least annually in people with GFR ml/min/1.73 m2 (GFR categories G3a-G3b); at least twice per year in people with GFR <30 ml/min/1.73 m2 (GFR categories G4-G5). at least every 3 months in patients with CKD 5HD and CKD 5PD The anemia observed with chronic kidney disease is largely diagnosed by excluding non-renal causes of anemia in the patient with a suitably decreased GFR. The evaluation of patients should therefore include red blood cell indices, absolute reticulocyte count, serum iron, total iron binding capacity, percent transferrin saturation, serum ferritin, white blood cell count and differential, platelet count, B12 and folate concentrations, and testing for blood in stool. The content of hemoglobin in reticulocytes can also be assessed. This work-up should be performed prior to administering ESA therapy. Frequency of testing for anemia 1.1.1: For CKD patients without anemia measure Hb concentration when clinically indicated and (Not Graded): at least annually in patients with CKD 3 at least twice per year in patients with CKD 4–5ND at least every 3 months in patients with CKD 5HD and CKD 5PD For CKD patients with anemia not being treated with an ESA, measure Hb concentration when clinically indicated and (Not Graded): at least every 3 months in patients with CKD 3–5ND and CKD 5PD at least monthly in patients with CKD 5HD

Anemia - Clinical presentation and diagnosis
Pallor and fatigue are the earliest clinical signs, with other manifestations (exertional dyspnea, dizziness, headache) developing as anemia worsens progressively with declining kidney function A significant consequence of anemia is development of left ventricular hypertrophy (LVH), further contributing to cardiovascular complications and mortality in patients with CKD  CHF, angina Early and aggressive treatment of anemia of CKD before the development of stage 5 CKD is important. A more complete and regular workup for anemia of CKD is recommended for patients with an eGFR of <60 mL/minute/1.73 m2. This workup includes: monitoring of hemoglobin and hematocrit, assessment of iron indices with correction if iron deficiency is present, evaluation for sources of blood loss, such as bleeding from the GI tract. The anemia observed with chronic kidney disease is largely diagnosed by excluding non-renal causes of anemia in the patient with a suitably decreased GFR. The evaluation of patients should therefore include red blood cell indices, absolute reticulocyte count, serum iron, total iron binding capacity, percent transferrin saturation, serum ferritin, white blood cell count and differential, platelet count, and testing for blood in stool. The content of hemoglobin in reticulocytes can also be assessed. This work-up should be performed prior to administering epoetin alfa (EPO) or darbepoetin alfa therapy.

Laboratory tests in the evaluation of anemia
The Roche ECLIA reference ranges for ferritin are 30–400 ng/mL for males, and 13–150 ng/mL for females. Other tests are in usage that rely on different methods and may have different reference ranges.

% Transferrin saturation = (Serum iron/TIBC) x 100
MCV=(Hct/RBC Count) MCHC=(Hgb/Hct) MCH=(Hgb/RBC Count) % Transferrin saturation = (Serum iron/TIBC) x 100 RBC Distribution Width = (Standard deviation of MCV ÷ mean MCV) × 100 fL  1 femtolitre is equal to: m³

Anemia – Goals of therapy
The desired outcomes of anemia management are: to increase oxygen-carrying capacity, decrease signs and symptoms of anemia, improve the patient’s quality of life, decrease the need for blood transfusions. Achievement of these goals requires a combination of an ESA and iron supplementation to promote and maintain erythropoiesis. Hb is the preferred monitoring parameter for red blood cell production because, unlike Hct, its concentration is not affected by blood storage conditions and instrumentation used for analysis. Hematocrit is dependent on volume status, which can be problematic for patients with fluctuations in plasma water (e.g., dialysis, volume overload). In addition, a number of variables can affect the hematocrit value, including temperature, hyperglycemia, the size of the red blood cell, and the counters used for the test. These variables do not significantly affect hemoglobin, making it the preferred test for anemia.85

Do not use ESAs to maintain Hb above 11.5 g/dL
Parameter KDOQI KDIGO ND-CKD and PD-CKD HD-CKD ND-CKDa HD and PD-CKDa Hb Hb 11–12 g/dL Do not use ESAs to exceed Hb of 13 g/dL If Hb ≥10 g/dL, do not initiate an ESA If Hb <10 g/dL, consider rate of fall of Hb, prior response to iron, risk of needing a transfusion, risk of ESA therapy, and presence of anemia symptoms before initiating an ESA Do not use ESAs to maintain Hb above 11.5 g/dL Use ESAs to avoid drop in Hb to <9 g/dL by starting ESA when Hb is between 9 and 10 g/dL TSatb (goal during ESA therapy) >20% (>0.20) >30% (>0.30) Serum ferritinb (goal during ESA therapy) >100 ng/mL >200 ng/mL >500 ng/mL Of note, recommendations in the revised product labeling differ from the target of 11 to 12 g/dL (110 to 120 g/L; 6.83 to 7.45 mmol/L) recommended in the KDOQI guidelines for management of anemia of CKD and from the previous labeling that recommended a target of 10 to 12 g/dL (100 to 120 g/L; 6.21 to 7.45 mmol/L) in ESA-treated patients with CKD.103 KDIGO anemia guidelines from 2012 are shown in Table It is important to consider that in making the recommendations regarding Hb targets listed in Table 29-8, the KDIGO expert panel considered the quality of the evidence to be low or very low. Clinicians should always take into account trends in Hb when adjusting ESA doses. Before making treatment decisions, prescribers must weigh the risks of ESA use and higher Hb values against the benefit of fewer blood transfusions and ensure that patients understand these risks and benefits. Previous versions of the KDOQI anemia guidelines recommended an upper level for TSat of 50% (0.50) and serum ferritin of 800 ng/mL (800 mcg/L; 1,800 pmol/L) to reduce the risk of iron overload. No upper level for these iron indices has been established in the current recommendations; however, the guidelines state that there is insufficient evidence to recommend routine administration of IV iron if the patient’s serum ferritin level is greater than 500 ng/mL (500 mcg/L; 1,100 pmol/L).51 KDIGO guidelines do not suggest stringent iron indices, but do recommend that iron supplementation be administered if TSat is ≤30% (≤0.30) and serum ferritin is ≤500 ng/mL (≤500 mcg/L; ≤1,100 pmol/L) if the goal is to increase the Hb or decrease the ESA dose (Table 29-8).42 Since ferritin is an acute-phase reactant, the decision of whether to give IV iron in conditions of elevated ferritin must be based on objective parameters such as TSat and Hb in addition to the clinical condition of the patient (e.g., infection, inflammation). a The KDIGO expert panel considered the quality of the evidence to be low or very low. b If TSat and serum ferritin are below suggested levels, consider iron supplementation if goal is to increase Hb and/or decrease ESA dose. Note: Serum ferritin is an acute-phase reactant—use clinical judgment when above 500 ng/mL.

TABLE 29–8

Target Hemoglobin and Use of ESAs
Initiation of ESA therapy should be considered in all CKD patients when Hb is between 9 and 10 g/dL and in nondialysis patients when the following additional criteria are met: (a) the rate of Hb decline indicates the likelihood of requiring a RBC transfusion and (b) reducing the risk of alloimmunization and/or other RBC- transfusion-related risks is a goal. According to the labeling for the available ESAs, the ESA dose should be decreased or interrupted when Hb is above 10 g/dL in CKD patients not receiving dialysis or above 11 g/dL in patients receiving dialysis. This is in contrast to the KDOQI and more recent KDIGO recommendations. The target range for Hb in the CKD population is a topic of much debate. Observational studies and USRDS data have shown decreased hospitalizations, lower mortality, and improved quality of life with Hb levels above 11 g/dL. While these data support a higher Hb, targeting Hb levels above 13 g/dL with ESA therapy has resulted in increased risk of mortality and cardiovascular events compared with patients maintained in the 11 to 12 g/dL range. These conclusions were based on clinical trials (CHOIR and CREATE trials) that included individuals with early stage CKD and from previous data reported in the hemodialysis population (Normal Hematocrit Cardiac Trial [NHCT]). An increased risk of all-cause mortality with ESA treatment was also reported in a meta-analysis of nine randomized controlled trials that included over 5,100 CKD patients treated to Hb targets in the range of 12 to 16 g/dL There was also a higher risk of dialysis access thrombosis and uncontrolled blood pressure in the higher Hb group. Subsequent analysis of the CHOIR trial has also shown an association between targeting a higher Hb and increased rate of progression of CKD.

New KDIGO guidelines The 2012 KDIGO guidelines
suggested that ESAs not be started among adult non-dialysis CKD patients with Hgb concentrations ≥10 g/dL. For non-dialysis CKD patient with Hgb <10 g/dL, the decision to start ESAs should be individualized based upon: the rate of fall in Hgb concentration, prior response to iron therapy, risk of needing a transfusion, the risks related to ESA therapy the presence of symptoms. Among dialysis patients, KDIGO suggests initiating ESAs when the Hgb concentration is below 10 g/dL. The KDIGO 2012 guidelines suggest that ESAs should generally not be used to maintain Hgb concentrations above 11.5 g/dL, but that individualization of therapy will be necessary as some patients may have improvements in quality of life at Hgb ≥11.5 g/dL and will be prepared to accept the risks . The KDIGO guidelines recommended that ESAs not be used to maintain Hgb ≥13 g/dL. The 2012 KDIGO guidelines recommended that ESAs be used with great caution if at all in CKD patients with active malignancy, especially if cure is anticipated , or with a history of stroke or a history of malignancy. Dose is decreased or interuptted if reaching 11.5

Iron Status Iron supplementation is required by most CKD patients receiving an ESA because of the increased iron demand that results from stimulation of red blood cell production. As CKD worsens, a progressive decline in Hb despite ESA therapy may be observed. Iron indices that should be monitored include: TSat, an indicator of iron immediately available for delivery to the bone marrow (Transferrin is the carrier protein for iron and, as a protein, may be affected by nutritional status) serum ferritin, an indirect measure of storage iron. Serum ferritin is an acute-phase reactant, meaning it may be elevated under certain inflammatory conditions and give a false indication of storage iron. The content of hemoglobin in reticulocytes (CHr) is also recommended as a parameter to assess iron status in hemodialysis patients, although it is not commonly used in clinical practice..

Anemia - Management Nonpharmacologic Therapy Pharmacologic Therapy
Nonpharmacologic therapy for anemia of CKD includes maintaining adequate dietary intake of iron as well as folate and B12. Patients on hemodialysis or peritoneal dialysis should be routinely supplemented with water-soluble vitamins (vitamins B, C, and folic acid) as these vitamins are often depleted with dialysis therapy. A relatively small amount of dietary iron, approximately 1 to 2 mg (or approximately 10%), is absorbed each day, primarily in the duodenum. Although there is some debate as to whether GI absorption of iron is significantly altered in patients with severe CKD, it is clear that oral intake from dietary sources alone is insufficient to meet the increased iron requirements from initiation of ESA therapy. Pharmacologic Therapy Pharmacologic therapy for anemia of CKD is based on a foundation of ESA therapy to correct erythropoietin deficiency and iron supplementation to correct and prevent iron deficiency caused by ongoing blood loss and increased iron demands associated with the initiation of erythropoietic therapy. Iron supplementation is first-line therapy for anemia of CKD if iron deficiency is diagnosed, and for some patients the target Hb may be achieved without concomitant ESA therapy. For most individuals with advanced CKD, however, combined therapy with iron and an ESA is required.

Anemia - Management 1) Iron (Parenteral and Oral Form)
Anemia therapy in patients with CKD requires effective use of iron agents, guided by appropriate testing of iron status. Efficacy of iron therapy appears not to be limited to patients with evidence of iron deficiency. Thus, the goals of iron therapy are: to avoid storage iron depletion, prevent iron-deficient erythropoiesis, achieve and maintain target Hgb levels Iron status tests should be performed as follows: Every month during initial ESA treatment At least every 3 months during stable ESA treatment or in patients with HD-CKD not treated with an ESA Dietary intake is insufficient Iron supplementation is required for absolute iron deficiency, when whole-body iron stores are low, but may also be required in individuals with functional iron deficiency. In the latter condition the individual with anemia may have a low TSat, but a serum ferritin at or above goal. In this situation iron stores fail to release iron rapidly enough to satisfy the demands for erythropoiesis. It has been shown that anemic hemodialysis patients with a TSat less than 25% (0.25) and serum ferritin between 200 and 1,200 ng/mL (200 and 1,200 mcg/L; 450 and 2,700 pmol/L) had an improved response to ESAs when they also received a 1 g course of IV iron.

Iron preparations - Oral
Oral ferrous sulphate (glutamate, fumarate) 200mg/day of elemental iron taken on empty stomach in 2-3 doses Patients should be advised to take oral iron on an empty stomach to maximize absorption, unless side effects prevent this strategy. In case of GI complaints: oral iron can be taken with small snack /or ferrous sulphate solution, iron polysaccharide complex or sustained-release preparation may be used but with the latter two bioavailability is the problem Patients should be counseled on potential drug interactions with oral iron (e.g., antacids, quinolones) and GI side effects (e.g., nausea, abdominal pain, diarrhea, constipation, dark stools). Food and CaCO3 delay iron absorption  iron should be taken 1 hr before or 2 hr after CaCO3 Noncompliance with therapy is a primary cause of therapeutic failure with oral iron. Some preparations with ascorbic acid Iron requires acidic pH for absorption It reduces the absorption of quinolone containing antobiotics Adverse effects of oral iron are primarily GI in nature and include constipation, nausea, and abdominal cramping. These adverse effects are more likely as the dose is escalated and may be present in more than 50% of patients receiving 200 mg of elemental iron per day. These unfavorable effects often discourage patients from taking these medications on a chronic basis. Some of these GI side effects can be minimized if oral iron products are taken with food; however, food decreases absorption of oral iron. Patients should initially be instructed to take oral iron on an empty stomach; however, if side effects lead to intolerance and nonadherence these agents can be administered with food, or an alternative agent may be prescribed.

Oral Iron Preparations
Iron Product Common Agents and Available Units Elemental Iron per Unit Number of Units Per Daya Ferrous sulfate Fer-In-Sol (75 mg/0.6 mL) 75 mg 2–3 Feosol (200 mg) 65 mg 3–4 Ferrous sulfate, various preparations (325 mg) Slow FE (160 mg) 50 mg 4 Ferrous fumarate Ferrous fumarate, various preparations (300 mg) 99 mg 2 Femiron (63 mg) 20 mg 10 Nephro-Fer (350 mg) 115 mg Vitron-C ( mg) 3 Ferrous gluconate Ferrous gluconate, various (325 mg) 36 mg 5 Fergon (240 mg) 27 mg 6 Polysaccharide iron Niferex (50 mg) Hytinic (150 mg) 150 mg 1–2 Heme iron polypeptide Proferrin-ES (12 mg) 12 mg 17 Bioavailability. Approximately 10% of orally administered iron is absorbed in the duodenum and upper jejunum. Absorption of iron is decreased by food and achlorhydria. The heme form of oral iron binds to a different receptor in the GI tract than nonheme iron, is absorbed to a greater extent, and may be better tolerated. 57 Some oral iron formulations also include ascorbic acid to enhance iron absorption.

Differences between iron products
The ferrous form of iron is absorbed three times more readily than the ferric form. Although ferrous sulfate, ferrous gluconate, and ferrous fumarate are absorbed almost equally, each contains a different amount of elemental iron. ORAL IRON FORMULATIONS — Among patients who are selected for oral iron therapy, we suggest that iron be administered at a daily dose of at least 200 mg of elemental iron. Because of simplicity and cost issues, we suggest giving this as ferrous sulfate 325 mg (65 mg elemental iron per tablet) three times daily. Intestinal iron absorption may be normal or impaired in patients with renal failure, and may be reduced by food and antacids. Thus, oral iron should be given between meals, if tolerated. Giving one of the doses at bedtime may be a simple and effective expedient. Other iron preparations are also available but tend to be more expensive without greater efficacy or consistently fewer side effects. Intestinal iron absorption is intrinsically normal in renal failure, but may be reduced by food and antacids. Thus, oral iron should be given between meals, if tolerated. Giving one of the doses at bedtime may be a simple and effective expedient. Because of the decreased efficacy and other adverse factors associated with traditional oral iron, a new generation of oral iron products has been developed. For example, heme iron polypeptide is absorbed in the gastrointestinal tract via different mechanisms from nonheme iron, resulting in absorption kinetics and side effects that differ from traditional iron products. In a six-month prospective trial of hemodialysis patients, heme iron polypeptide adequately maintained both hemoglobin levels and serum iron indices after substituting for intravenous iron [19]. Although further study is needed, these results suggest that this oral formulation may become a viable option for iron delivery

Iron-drug interactions
a proton pump inhibitor, is thought to inhibit serum iron absorption by increasing the pH of the stomach and decreasing the solubility of ferrous salts  should be advised to take her iron at least 1 hour before or 3 hours after the proton pump inhibitor dose. antacids can increase stomach pH and certain anions (carbonate and hydroxide) also are thought to form insoluble complexes when combined with iron (the clinical significance of this is undetermined), the absorptions of both iron and tetracycline are decreased when administered concomitantly, the iron should be taken 3 hours before or 2 hours after the tetracycline dose.

Iron preparation - Parenteral
Parenteral iron therapy: The IV iron preparations currently available are: iron dextran (INFeD and Dexferrum), ferric gluconate (Ferrlecit), iron sucrose (Venofer). Ferumoxytol (Feraheme) Iron dextran 100mg during each HD session by IV push over 2 min for 10 session  50 mg each week during dialysis for 10 weeks ADR: Arthralgias, myalgias, serum sickness-like syndrome, hypotension. A one-time dose of 25mg in adults should be administered IV before initiating therapy to detect small risk of anaphylaxis ferric gluconate and iron sucrose and ferumoxytol have less ADR  no need for test dose Administration of IV iron also introduces a risk of iron overload. (How can this be prevented and treated?) Not directly IV – worry about iron overload. (managed with deferoxamine or phlebotomy) For hypotension: reduce rate of infusion Intravenous iron preparations are colloids that consist of an iron-containing core that is surrounded by a carbohydrate shell to stabilize the iron complex. Available agents differ in the size of the core and the composition of the surrounding carbohydrate. These differences affect the rate of dissociation of iron from the complex to phagocytes within the reticuloendothelial system where iron is either stored or released to the extracellular carrier protein transferrin, which transports iron to the bone marrow for red blood cell production. The half-lives of the available IV iron formulations differ: ferric gluconate (1 hour), iron sucrose (6 hours), ferumoxytol (15 hours), and iron dextran (40 to 60 hours). 54,56,58 Adverse effects of IV iron include allergic reactions, hypotension, dizziness, dyspnea, headaches, lower back pain, arthralgia, syncope, and arthritis. Some of these reactions, in particular hypotension, can be minimized by decreasing the dose or rate of infusion of iron. The most concerning potential consequence of IV iron administration is anaphylaxis. Anaphylactoid reactions to iron dextran have been reported in up to 1.8% of patients, with serious reactions including respiratory complications and cardiovascular collapse occurring in approximately 0.6%. 60 Such reactions are believed to be partly a response to antibody formation to the dextran component. Adverse reactions have been reported two to eight times more frequently in those receiving Dexferrum compared with INFeD. 61 Based on the labeling for all iron dextran products clinicians should (a) administer a test dose of 25 mg prior to the first therapeutic dose; if there are no signs or symptoms of an anaphylactic-type reaction then administer the full therapeutic dose; (b) observe for signs or symptoms of anaphylactic-type reactions during and after every administration; and (c) note that patients with a history of drug allergies may be at increased risk of anaphylactic-type reactions. 62,63 The potential for increased risk of reactions with concomitant use of angiotensin-converting enzyme inhibitors and iron dextran is also highlighted in the labeling for iron dextran, and a statement is included to clarify that there are differences in the chemical characteristics and clinical effects of available iron dextran products (e.g., Dexferrum and INFeD) since these agents are often erroneously considered interchangeable. 63 The risk of adverse events with iron dextrans was particularly influential in product selection prior to the availability of sodium ferric gluconate, iron sucrose, and ferumoxytol. These IV iron formulations have a better safety record than either of the iron dextran products, based on their history of use in Europe over the last 4 decades (sodium ferric gluconate and iron sucrose) and data in the United States since these products were approved. 61,64 These newer agents do not require administration of a test dose prior to administration of the full dose. As a precaution with all IV preparations, patients should be observed during and immediately following administration for any adverse reactions. Administration of IV iron also introduces a risk of iron overload. Deposition of excess iron may affect several organ systems, leading to hepatic, pancreatic, and cardiac dysfunction. Bone marrow biopsy provides the most definitive diagnosis of iron overload, but because it is an extremely invasive procedure, it is not widely employed in most clinical settings. Maintaining serum ferritin and TSat values that demonstrate efficacy in preventing iron deficiency yet are safe is the most reasonable approach to minimize the risk of iron toxicity. The challenge is in defining these upper limits, particularly for serum ferritin, which may be elevated in inflammatory conditions and not reflective of true iron stores in such situations. If symptomatic overload does occur, deferoxamine (Desferal) or phlebotomy may be necessary.

TABLE 29–10 More recent than the next two slides

Parenteral Iron Preparations
Iron Compounds FDA-Approved Indications FDA-Approved Dosing Warnings Dose Rangesa Iron Dextran (INFeD, Watson Pharma Inc., Morrisontown, NJ, and DexFerrum, American Regent, Inc.. Shirley, NY)b Patients with iron deficiency in whom oral iron is unsatisfactory IV push: 100 mg over 2 min (25-mg test dose required) Black box (risk of anaphylactic reactions) 25–1,000 mg Sodium ferric gluconate (Ferrlecit, Sanofi-Aventis, Dagenham, Essex, England)c Adult and pediatric HD patients age 6 years and older receiving ESA therapy IV push (adult): 125 mg over 10 min IV infusion (adult): 125 mg in 100 mL of 0.9% NaCl over 60 min IV infusion (pediatric): 1.5 mg/kg in 25 mL of 0.9% NaCl over 60 min; maximum dose 125 mg General 62.5–1,000 mg a Small doses (e.g., 25–150 mg/wk) generally used for maintenance regimens. Larger doses (e.g., 1 g) should be administered in divided doses. b Supplied in 1-mL (Dexferrum) and 2-mL (Dexferrum and InFeD) single-dose vials containing 50 mg of elemental iron/mL. c Available in 5-mL glass ampules or vials containing 62.5 mg elemental iron. d Supplied in 2.5-, 5-, and 10-mL single-dose vials containing 20 mg/mL. e Supplied as a 17-mL single-use vial containing 510 mg elemental iron (30 mg/mL). a Small dosing ranges (e.g., 25–150 mg per week) generally used for maintenance regimens. Larger doses (e.g., 1 g) should be administered in divided doses. b Supplied in 2-mL single-dose vials containing 50 mg of elemental iron per mL. c Available in colorless glass ampules containing 62.5 mg elemental iron (12.5 mg/mL).

Parenteral Iron Preparations-cont’d
Iron Compounds FDA-Approved Indications FDA-Approved Dosing Warnings Dose Rangesa Iron sucrose (Venofer, American Regent, Inc., Shirley, NY)d Adult and pediatric HD patients age 2 years and older IV push: 100 mg over 2–5 min IV infusion: 100 mg in maximum of 100 mL of 0.9% NaCl over 15 min General 25–1,000 mg Adult and pediatric ND-CKD patients age 2 years and older IV push: 200 mg over 2–5 min on 5 different occasions within 14-day period IV infusion: 2 infusions, 14 days apart, of 300 mg in a maximum of 250 mL of 0.9% NaCl over 1.5 h, followed by 1 infusion, 14 days later, of 400 mg in a maximum of 250 mL of 0.9% NaCl over 2.5 h Ferumoxytol (Feraheme, AMAG Pharmaceuticals, Lexington, MA)e Adult patients with iron-deficiency anemia associated with chronic kidney disease IV: 510 mg (17 mL) as a single dose, followed by a second 510 mg dose 3–8 days after the initial dose (rate of 1 mL or 30 mg/second) 510 mg Adverse effects of IV iron include allergic reactions, hypotension, dizziness, dyspnea, headaches, lower back pain, arthralgia, syncope, and arthritis. Some of these reactions, in particular hypotension, can be minimized by decreasing the dose or rate of infusion of iron. The most concerning potential consequence of IV iron administration is anaphylaxis. Anaphylactic reactions to iron dextran have been reported in up to 1.8% of patients, with serious reactions including respiratory complications and cardiovascular collapse occurring in approximately 0.6% to 0.7% of patients.42 Such reactions are believed to be partly a response to antibody formation to the dextran component. Adverse reactions have been reported more frequently in those receiving Dexferrum compared with INFeD.42 + Sodium ferric gluconate, iron sucrose, and ferumoxytol have a better safety record than either of the iron dextran products, based on their history of use in Europe over the last 4 decades (sodium ferric gluconate and iron sucrose) and data in the United States since these products were approved. A comparison of adverse event rates reported to the FDA for IV iron products revealed that ferumoxytol had higher rates of adverse events than sodium ferric gluconate or iron sucrose.113 Serious adverse events including anaphylactic-type reactions and cardiac arrest prompted a change in the product labeling postmarketing.110 As a superparamagnetic oxide, ferumoxytol may affect the diagnostic ability of magnetic resonance imaging studies; therefore, these imaging studies should be done prior to administration of ferumoxytol when possible. These effects may persist for up to 3 months following administration of ferumoxytol. Ferumoxytol will not interfere with x-ray, computed tomography, positron emission tomography, single photon emission computed tomography, ultrasonography, or nuclear medicine imaging.110 Administration of IV iron also introduces a risk of iron overload. Deposition of excess iron may affect several organ systems, leading to hepatic, pancreatic, and cardiac dysfunction. Bone marrow biopsy provides the most definitive diagnosis of iron overload, but because it is an extremely invasive procedure, it is not widely employed in most clinical settings. Maintaining serum ferritin and TSat values that demonstrate efficacy in preventing iron deficiency, yet are safe, is the most reasonable approach to minimize the risk of iron toxicity. The challenge is in defining these upper limits, particularly for serum ferritin, which may be elevated in inflammatory conditions and not reflective of true iron stores in such situations. If symptomatic overload does occur, deferoxamine (Desferal), deferiprone (Ferriprox), or phlebotomy may be necessary. d Supplied in 5-mL single-dose vials containing 100 mg elemental iron (20 mg/mL). e Supplied as a 17-mL single-use vial containing 510 mg elemental iron (30 mg/mL).

Dosing and admiration of iron
If oral therapy is initiated, the recommended dose is 200 mg of elemental iron per day. With numerous oral agents to choose from, the best option is one that provides adequate elemental iron with the fewest number of dosage units required per day. KDIGO guidelines suggest a 1- to 3-month trial of oral therapy in the nondialysis CKD population. For the hemodialysis population, administration of 1 g of IV iron is recommended to initially replete patients with an absolute iron deficiency. : Typical repletion dosing regimens for IV iron are 100 mg as iron sucrose or iron dextran over 10 dialysis sessions, or 125 mg of sodium ferric gluconate over 8 dialysis sessions (see Table 29-10). Ferumoxytol is administered as 510 mg at a rate not to exceed 30 mg/s (1 mL/s) with a second dose given within 3 to 8 days, a higher dose and administration rate compared with other available IV iron formulations. Without ongoing iron supplementation, many patients quickly become iron deficient. To prevent iron deficiency, maintenance doses of IV iron are administered in hemodialysis patients (e.g., iron sucrose or iron dextran 25 to 100 mg/wk; sodium ferric gluconate 62.5 to 125 mg/wk) based on evidence of improved Hb and lower ESA doses with these regimens. Dipiro 9th If not resposnign to oral…change to IV

According to the labeling for the available ESAs, the ESA dose should be decreased or interrupted when Hb is above 10 g/dL in CKD patients not receiving dialysis or above 11 g/dL in patients receiving dialysis Dipiro 2014….9th edition According to the labeling for the available ESAs, the ESA dose should be decreased or interrupted when Hb is above 10 g/dL in CKD patients not receiving dialysis or above 11 g/dL in patients receiving dialysis. This is in contrast to the KDOQI and more recent KDIGO recommendations. Dipiro 9th DOSING AND ADMINISTRATION for iron If oral therapy is initiated, the recommended dose is 200 mg of elemental iron per day. With numerous oral agents to choose from, the best option is one that provides adequate elemental iron with the fewest number of dosage units required per day. KDIGO guidelines suggest a 1- to 3-month trial of oral therapy in the nondialysis CKD population.42 For the hemodialysis population, administration of 1 g of IV iron is recommended to initially replete patients with an absolute iron deficiency. Typical repletion dosing regimens for IV iron are 100 mg as iron sucrose or iron dextran over 10 dialysis sessions, or 125 mg of sodiumferric gluconate over 8 dialysis sessions (see Table 29-10). Ferumoxytol is administered as 510 mg at a rate not to exceed 30 mg/s (1 mL/s) with a second dose given within 3 to 8 days, a higher dose and administration rate compared with other available IV iron formulations.110 Without ongoing iron supplementation, many patients quickly become iron deficient. To prevent iron deficiency, maintenance doses of IV iron are administered in hemodialysis patients (e.g., iron sucrose or iron dextran 25 to 100 mg/wk; sodium ferric gluconate 62.5 to 125 mg/wk) based on evidence of improved Hb and lower ESA doses with these regimens.42,51 Administration of a 25 mg test dose is required for all iron dextran products. This test dose should be administered over at least 30 seconds for InFeD and 5 minutes for Dexferrum.107,108 It is recommended that a period of ≥1 hour lapse before administering the remainder of the dose. Patients receiving any of the non-dextran IV iron agents should be closely observed for signs of hypersensitivity during and for at least 30 minutes after administration.109–111 KDIGO guidelines advocate monitoring for 60 minutes following an infusion of any available IV iron product, with a stronger emphasis on this recommendation for iron dextran products.42 The safety and efficacy of high-dose IV iron regimens have been evaluated. Iron dextranhas been safely administered to dialysis patients in total-dose infusions ranging from 400 mg to 2 g and to patients with stage 3 or 4 CKD at doses of up to 500 mg.114,115 Sodiumferric gluconate has been safely administered at doses of 250 mg infused over 1 hour (4.2 mg/min).116 Iron sucrose at doses of up to 500 mg administered over 3 hours on consecutive days has been successful in maintaining iron stores without causing serious adverse events.117 Higher-dose regimens for iron sucrose have been approved in patients with early stage CKD and peritoneal dialysis patients (see Table 29-10), populations in whom administration of higher doses is more convenient as these patients are seen less frequently by healthcare providers than the hemodialysis population.111 As a general practice, if IV iron doses higher than those currently approved are used in practice, they should be administered over at least 2 to 4 hours depending on the dose due to the risk of hypersensitivity reactions, hypotension, dizziness, and nausea. Although there are conflicting reports, most clinicians believe that exposure to iron may contribute to the risk of bacterial infection because iron is used by microorganisms for metabolic functions. The association of IV iron with oxidative stress, acceleration of atherosclerosis, and other cardiovascular conditions has also been suggested.118 These potential long-term risks of IV iron therapy are not clearly defined, and there are no data confirming unequivocally that aggressive use of IV iron in CKD patients treated with ESA therapy increases patient morbidity or mortality. KDIGO guidelines suggest that IV iron be avoided in patients with active systemic infections.42 Dipior 9th: DOSING AND ADMINISTRATION of ESA Recommended starting doses of ESA are listed in Table Less frequent dosing ofepoetin alfa (e.g., every 1 to 2 weeks) is effective and may be preferred for stage 3 and 4 CKD patients since these patients are seen in the outpatient clinical setting on a relatively infrequent basis.122 Subcutaneous dosing is also more convenient in this population and in peritoneal dialysis patients who do not have regular IV access. Conversion tables for patients who are to be switched from epoetin alfa (units per week) to darbepoetin alfa(micrograms per week) are available in the labeling information for darbepoetin.101 When starting an ESA, Hb levels should be monitored at least weekly until stable and then at least monthly. Dose adjustments should be made based on Hb response with consideration of data on risks associated with higher Hb levels and rate of rise in Hb. An acceptable rate of increase in Hb is 1 to 2 g/dL (10 to 20 g/L; 0.62 to 1.24 mmol/L) per month. As a general rule, ESA doses should not be increased more frequently than every 4 weeks, although decreases in dose may occur more frequently in response to a rapid rate of rise in Hb. Based on labeling for ESAs, the dose should be reduced by at least 25% if the Hb increases by more than 1 g/dL (10 g/L; 0.62 mmol/L) in a 2-week period. The dose should be reduced or temporarily discontinued if the Hb level approaches or exceeds 11 g/dL (110 g/L; 6.83 mmol/L) in dialysis patients (all ESAs) or 10 g/dL (100 g/L; 6.21 mmol/L) in patients with CKD not requiring dialysis. KDIGO recommendations advocate a decrease in dose as opposed to withholding the ESA when a decrease in Hb concentration is desired.42 A 25% increase in dose may be considered if the Hb has not increased by 1 g/dL (10 g/L; 0.62 mmol/L) after 4 weeks of ESA treatment and if no causes of resistance to the ESA have been identified. For patients who do not respond adequately over a 12-week escalation period, an increase in ESA dose is unlikely to improve response and may increase risks. Initial hyporesponsiveness to ESAs should be considered when there is no increase in Hb from baseline after the first month of appropriate weight-based dosing. Acquired ESA hyporesponsiveness may be suspected when patients previously on a stable ESA dose require two increases in ESA doses up to 50% beyond the stable dose.42In these situations repeat escalations in ESA dose beyond double the initial weight-based dose should be avoided. The lowest dose of ESA should be used to maintain a Hb level sufficient to reduce the need for RBC transfusions.99–101Figure 29-6 provides an approach to management of anemia using ESAs and iron therapy in patients with CKD.

Anemia – Management (cont’d)
2) Folic Acid 1 mg/day 3) Blood Transfusion Is no longer the main therapy due to risk of iron overload, infections, suppression of erythropoietin. Only use in case of persistent anemia, severe symptoms and substantial blood loss(acute bleeding). 4) Erythropoiesis-Stimulating Agent (ESA) The erythropoietin deficiency evident in patients with CKD can be corrected by the exogenous administration of erythropoiesis- stimulating agents. Two such agents are currently available: Epoetin alfa (recombinant human erythropoietin [rHuEPO - Epogen™ or Procrit™]) Darbepoetin alfa (Aranesp™), a unique molecule that stimulates erythropoiesis with a longer half-life than rHuEPO Initial dose is u/kg IV or SC, 3 times weekly increase in steps of 25u/kg Q4 weeks. Maintenance dose is u/kg/week SC. The erythropoietin dose should be approximately 50 to 100 U/kg per week. The 2006 guidelines suggest that the initial erythropoietic agent dose and dose adjustment be given based upon the initial and target hemoglobin level, the clinical setting, and the rate of increase of the hemoglobin level [62]. Epoetin alfa stimulates the proliferation and differentiation of erythroid progenitor cells, increases hemoglobin synthesis, and accelerates the release of reticulocytes from the bone marrow. Extended dosing intervals for SC administration of epoetin alfa have been evaluated in patients with CKD who are not having dialysis.108,109 Doses of 10,000 U once weekly to 40,000 U once every 4 weeks have been shown to maintain target hemoglobin values for those patients with CKD not on dialysis.110,111 Such dosing strategies may provide more convenient therapy for these patients who are not yet on dialysis, but must come to the clinic for erythropoietic therapy.

Dosing and administration of ESA
Recommended starting doses of ESA are listed in Table Less frequent dosing ofepoetin alfa (e.g., every 1 to 2 weeks) is effective and may be preferred for stage 3 and 4 CKD patients since these patients are seen in the outpatient clinical setting on a relatively infrequent basis.Subcutaneous dosing is also more convenient in this population and in peritoneal dialysis patients who do not have regular IV access. Conversion tables for patients who are to be switched from epoetin alfa (units per week) to darbepoetin alfa(micrograms per week) are available in the labeling information for darbepoetin. When starting an ESA, Hb levels should be monitored at least weekly until stable and then at least monthly. Dose adjustments should be made based on Hb response with consideration of data on risks associated with higher Hb levels and rate of rise in Hb. An acceptable rate of increase in Hb is 1 to 2 g/dL (10 to 20 g/L; 0.62 to mmol/L) per month.

Dosing and administration of ESA
As a general rule, ESA doses should not be increased more frequently than every 4 weeks, although decreases in dose may occur more frequently in response to a rapid rate of rise in Hb. Based on labeling for ESAs, the dose should be reduced by at least 25% if the Hb increases by more than 1 g/dL (10 g/L; 0.62 mmol/L) in a 2-week period. The dose should be reduced or temporarily discontinued if the Hb level approaches or exceeds 11 g/dL (110 g/L; 6.83 mmol/L) in dialysis patients (all ESAs) or 10 g/dL (100 g/L; mmol/L) in patients with CKD not requiring dialysis. KDIGO recommendations advocate a decrease in dose as opposed to withholding the ESA when a decrease in Hb concentration is desired. A 25% increase in dose may be considered if the Hb has not increased by 1 g/dL (10 g/L; 0.62 mmol/L) after 4 weeks of ESA treatment and if no causes of resistance to the ESA have been identified. For patients who do not respond adequately over a 12-week escalation period, an increase in ESA dose is unlikely to improve response and may increase risks. Initial hyporesponsiveness to ESAs should be considered when there is no increase in Hb from baseline after the first month of appropriate weight-based dosing. Acquired ESA hyporesponsiveness may be suspected when patients previously on a stable ESA dose require two increases in ESA doses up to 50% beyond the stable dose. in these situations repeat escalations in ESA dose beyond double the initial weight-based dose should be avoided. The lowest dose of ESA should be used to maintain a Hb level sufficient to reduce the need for RBC transfusions. Figure 29-6 provides an approach to management of anemia using ESAs and iron therapy in patients with CKD. Kidifo..reduce dose if reaching 11.5

TABLE 29–11 The pharmacodynamics of ESAs is important to consider when evaluating response to therapy. With initiation of ESA therapy or a change in dose, the Hb may begin to rise as the result of demargination of reticulocytes; however, it takes approximately 10 days before erythrocyte progenitor cells mature and are released into the circulation. The Hb continues to increase until the life span of the cells stimulated by ESA therapy is reached (mean 2 months; range 1 to 4 months in patients with ESRD). At this point a new steady state is achieved (i.e., the rate at which red blood cells are being produced equals the rate at which they are leaving the circulation). For this reason it is important to evaluate the Hb response over several weeks.

Improvement of anemia with erythropoiesis-stimulating agents is associated with some clinical benefits. These include: improvements in quality of life increased energy levels greater capacity for work and exercise restored sexual function improved appetite and participation in social activities reduced depression and fatigue Human ERYthropoetin-Epoetin Alfa SC administration is preferred because lower doses can be administered less frequently and cost is lower than with IV administration Based on the half-life of epoetin alfa (8.5 hours IV, 24.4 hours SC), the total weekly dose is usually divided into smaller doses, administered one to three times per week with SC administration and three times per week for IV administration in patients on HD RHuEPO, which provides effective treatment for anemia in patients with CKD when administered once weekly in patients not on dialysis, has become the standard of care. However, the need for weekly doses can place a considerable burden on both patients and healthcare staff. Studies also reveal that insufficient numbers of patients with CKD are being treated for anemia. (See "Overview of the management of chronic kidney disease in adults".) A molecule with enhanced biological activity and an extended dosing interval could potentially simplify the management of anemia in patients with CKD. Darbepoetin alfa, one such erythropoietic agent, is also indicated for the treatment of anemia associated with CKD. The three-fold longer half-life and greater biological activity of darbepoetin alfa, compared with rHuEPO, enables this agent to effectively maintain target Hb levels with less frequent dosing [12,13]. However, this may not be a unique feature.

ESA: Darbepoetin alfa: The newer erthropoietic agent, has a longer half life and prolonged biological activity therefore, doses are administered less frequently, starting at once a week or every other week when administered IV or SC. Starting dose in patients not previously receiving epoietin-alpha therapy is mcg/kg IV or SC once weekly. For patients previously receiving epoietin alpha: conversion doses is listed in table (2-3 x/week  weekly, weekly every other week) Extended dosage interval – up to 4 weeks shown to be successful In dialysis and nondialysis patients with CKD receiving ESA therapy, the selected Hgb target should generally be in the range of 11.0 to 12.0 g/dL and not be greater than 13g/dL. favors subcutaneous administration in non-hemodialysis-CKD patients and intravenous (IV) administration in HD (hemodialysis)-CKD patients Starting dose in patients not previously receiving epoietin-alpha therapy is 0.45 mcg/kg IV or SC once weekly.

Estimated starting dose schedule of darbepoetin alfa according to the previous rHuEPO regimen in patients with CKD. Efficacy following switch from rHuEPO to darbepoetin alfa — Several large trials have confirmed that patients stabilized on either subcutaneous or intravenous rHuEPO can be successfully switched to darbepoetin alfa given at extended dosing intervals of once weekly or once every two weeks, with maintenance of a constant Hb (mean change of –0.08 to 0.16 g/dL) after 28 to 36 weeks of treatment.

ADR of ESA Adverse Effects.
Hypertension is the most common adverse event reported with epoetin alfa and darbepoetin alfa and may be associated with the rate of rise in Hb. 53 Protocols established in some clinical settings, primarily in outpatient dialysis clinics, sometimes recommend withholding ESA therapy if blood pressure is above a defined threshold. K/DOQI guidelines for anemia do not recommend withholding ESA therapy for elevated blood pressure, but instead advocate more judicious use of antihypertensive agents and dialysis to control blood pressure; however, according to FDA-approved product labeling ESAs should not be used in those with uncontrolled blood pressure. 74,76,82 Seizures have occurred in patients treated with epoetin, particularly within the first 90 days of starting therapy. Vascular access thrombosis may also be more frequent during ESA therapy. 76,83 The potential for these adverse effects calls for close monitoring of the rate of rise in Hb, changes in blood pressure, and monitoring neurologic symptoms following initiation of therapy or a change in ESA dose. Data demonstrating a higher risk of adverse outcomes in CKD patients treated more aggressively to Hb targets above 12 g/dL (120 g/L; 7.45 mmol/L) with ESAs prompted the FDA to issue a warning in March 2007 about safety concerns of higher Hb targets. Manufacturers revised the ESA product labeling to include updated warnings, a new boxed warning, and modifications to the dosing instructions. The new boxed warning advises healthcare providers to monitor Hb and to adjust the ESA dose to maintain the lowest hemoglobin level needed to avoid blood transfusions. Of note the Hb target in the product labeling for ESAs is 10 to 12 g/dL (100–120 g/L; 6.21–7.45 mmol/L), 74,76,82 An FDA-approved medication guide describing the risks of ESA use must also be given to patients receiving ESA therapy. Neutralizing antibodies to ESAs have been identified in a relatively small number of patients treated with ESAs; approximately 200 cases were reported between 1998 and These patients develop antibody-mediated pure red cell aplasia (PRCA), which results in an absolute resistance to ESA therapy and reliance on blood transfusions as the primary therapeutic option. Cases were mostly reported between 1998 and 2002 and occurred in parallel with the increase in SC administration, primarily with one epoetin alfa product manufactured outside the United States, Eprex (Johnson & Johnson, Manati, Puerto Rico). Differences in this formulation that were noted at the time of the increase in PRCA cases were the substitution of human albumin with polysorbate 80 and use of uncoated rubber stoppers in the single-dose syringes, factors that in combination may have increased the immunogenicity of SC-administered epoetin alfa. Changes in packaging of these syringes led to a decrease in PRCA case reports. Although the case reports of antibody-associated PRCA are relatively few in number, further evaluation for PRCA should be considered for patients receiving ESA therapy who develop a rapid decrease in Hb level (rate of 0.5–1.0 g/dL/wk [5–10 g/L/wk; 0.31–0.62 mmol/L/wk]), become transfusion dependent, and have an absolute reticulocyte count of less than 10,000/L (10 x 109/L) with a normal platelet and white blood cell count. Discontinuation of ESA therapy is recommended in antibody-mediated PRCA because antibodies are cross-reactive and continued exposure may lead to anaphylactic reactions. Immunosuppressive therapy has been effective in up to 50% of patients with PRCA. 84 A peptide-based erythropoietin-receptor agonist, hematide, an investigational agent that has a different amino acid sequence than native or recombinant erythropoietin, has been shown to stimulate erythropoiesis in patients with PRCA or hyporesponsiveness due to antierythropoietin antibodies and may provide another option in the future for individuals with PRCA. 85 Drug–Drug Interactions. No significant drug interactions have been reported with the available ESAs.

The most common causes of resistance are iron deficiency, acute illness, catheter insertion, hypoalbuminemia, elevated C-reactive protein, chronic bleeding, aluminum toxicity, malnutrition, hyperparathyroidism, cancer and chemotherapy, AIDS, inflammation, and infection. According to the labeling for the available ESAs, the ESA dose should be decreased or interrupted when Hb is above 10 g/dL in CKD patients not receiving dialysis or above 11 g/dL in patients receiving dialysis Dipiro 2014….9th edition According to the labeling for the available ESAs, the ESA dose should be decreased or interrupted when Hb is above 10 g/dL in CKD patients not receiving dialysis or above 11 g/dL in patients receiving dialysis. This is in contrast to the KDOQI and more recent KDIGO recommendations. The most common causes of resistance are iron deficiency, acute illness, catheter insertion, hypoalbuminemia, elevated C-reactive protein, chronic bleeding, aluminum toxicity, malnutrition, hyperparathyroidism, cancer and chemotherapy, AIDS, inflammation, and infection.

ESA Causes of ESA resistance:
Fe deficiency Inflammation ↓Fe delivery to BM response AL toxicity Folate and vit B 12 Deficiency Hyperparathyrodism Possibly ACEIs Before patient starts EPA following tests should be done: RBC indices Hct or Hgb Reticulocyte count Iron parameter Occult blood in the stool The most common causes of resistance are iron deficiency, acute illness, catheter insertion, hypoalbuminemia, elevated C-reactive protein, chronic bleeding, aluminum toxicity, malnutrition, hyperparathyroidism, cancer and chemotherapy, AIDS, inflammation, and infection. Erythropoietic therapy may be continued in the infected or postoperative patient, even though increased doses are often required to maintain or slow the rate of decline in Hb. Deficiencies in folate and vitamin B12 should also be considered as potential causes of resistance to ESA therapy, as both are essential for optimal erythropoiesis

Peginesatide (withdrawn)
Peptides that mimic the action of erythropoietin may eliminate the need for recombinant EPO in renal failure. Peginesatide is a synthetic peptide that activates the EPO receptor. Peginesatide stimulates erythroid colony growth, reticulocyte count and hematocrit in animal models, but, because its amino acid sequence is unrelated to erythropoietin, does not cross react with erythropoietin antibodies. March  The US Food and Drug Administration has approved peginesatide for intravenous or subcutaneous administration to treat anemia in adult dialysis patients with CKD but not in CKD patients who are not on dialysis February 2013  Peginesatide has been withdrawn from the market due to serious hypersensitivity reactions reported in approximately 0.2 percent of patients following the first dose of intravenous administration with death occurring in 0.02 percent of patients. Peginesatide, a synthetic, pegylated peptide that has no amino acid sequence homology to erythropoietin, was available in March 2012 and approved for use in dialysis patients, but was withdrawn from the market in early 2013 due to reports of serious adverse events

Evaluation of therapeutic outcomes
Iron status should be assessed at least every 3 months in patients receiving a stable ESA regimen or for those hemodialysis patients not treated with an ESA to detect iron deficiency as a cause for anemia. Iron status should be monitored more frequently (e.g., every month) when initiating or increasing the ESA dose, following a course of IV iron, or when other factors put the patient at risk for iron loss (e.g., bleeding). For all ESAs, the initial dose and subsequent adjustments should be determined by the patient’s Hb level and the observed rate of increase in Hb. In patients with anemia not treated with an ESA, Hb levels should be monitored at least every 3 months in stage 3 to 5 CKD patients not requiring hemodialysis and at least monthly in hemodialysis patients. Hb should be monitored at least monthly (weekly preferred) in patients started on ESA therapy until the Hb is stable. Once Hb is stable, the recommended frequency of monitoring is monthly in dialysis patients and every 3 months in nondialysis CKD patients (see Fig. 29-6).

Key points for the management of anemia in CKD patients
Work-up for anemia in CKD should include assessment of secondary causes including iron deficiency. Iron replacement is often effective in anemia of CKD as initial therapy and routes of administration (intravenous or oral) will be determined by clinicians, patient preferences, and local available resources. ESA therapy is not recommended in those with active malignancy, or recent history of malignancy. In most people with CKD, ESAs should not be used to intentionally increase the Hb concentration above 11.5 g/dl (115 g/l) For pediatric patients, the selection of Hb concentration at which ESA therapy is initiated should be individualized after taking into account the potential benefits (e.g., improvement in QOL, school attendance/ performance, and avoidance of transfusion) and potential harms.

Case: Anemia in CKD Note: Refer to the case in the previous lecture

CKD-Mineral and Bone Disorder (MBD)
CKD-MBD is a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism Abnormalities in bone turnover, mineralization, volume, linear growth, or strength Vascular or other soft tissue calcification Hyperphosphatemia, hypocalcemia, hyperparathyroidism,decreased production of active vitamin D, and resistance to vitamin D therapy are all frequent problems in CKD that can lead to the secondary complications of CKD-MBD. Although the interrelationships among phosphorus, calcium, vitamin D, and PTH have been reviewed extensively, fibroblast growth factor 23 (FGF23), a phosphaturic hormone discovered within the last decade, has added some new insight. Increased dietary phosphorus intake stimulates FGF23 secretion. FGF23 increases phosphorus excretion via the proximal tubules, inhibits vitamin D activation, increases activated vitamin D catabolism, and is associated with kidney disease progression.

Homeostatic mechanisms to maintain serum Ca concentration
6) Secondary Hyperparathyroidism and Renal Osteodystrophy (mineral and bone disorders) Calcium and phosphorus homeostasis is mediated through the effects of four hormones on bone, the GI tract, kidney, and parathyroid gland. These hormones include PTH, the precursor form of vitamin D known as 25- hydroxyvitamin D (25-OHD), active vitamin D or 1,25-dihydroxyvitamin D (calcitriol), and fibroblast growth factor-23 (FGF-23). Homeostatic mechanisms to maintain serum Ca concentration Disorders of mineral and bone metabolism are common in the CKD population and include abnormalities in parathyroid hormone (PTH), calcium, phosphorus, the calcium-phosphorus product, vitamin D and bone turnover, as well as soft tissue calcifications. Historically these abnormalities have been described as classic characteristics of secondary hyperparathyroidism and renal osteodystrophy (ROD). Recently the term CKD-mineral and bone disorder (CKD-MBD) has been advocated to encompass the abnormalities in mineral and bone metabolism as well as associated calcifications. 18 The pathophysiology of CKD-MBD is complex (Fig. 53–2). Calcium and phosphorus homeostasis is mediated through the effects of four hormones on bone, the GI tract, kidney, and parathyroid gland. These hormones include PTH, the precursor form of vitamin D known as 25-hydroxyvitamin D (25-OHD), active vitamin D or 1,25-dihydroxyvitamin D (calcitriol), and fibroblast growth factor-23 (FGF-23). As kidney function declines there is a decrease in phosphorus elimination, which results in hyperphosphatemia and a reciprocal decrease in serum calcium concentration. Hypocalcemia is the primary stimulus for secretion of PTH by the parathyroid glands. PTH secretion is suppressed by the interaction of ionized calcium with the calcium-sensing receptor on the chief cells of the parathyroid gland. Hyperphosphatemia also increases PTH synthesis and release through its direct effects on the parathyroid gland and production of prepro-PTH messenger RNA. 19 In an attempt to normalize ionized calcium, PTH decreases phosphorus reabsorption and increases calcium reabsorption by the proximal tubules of the kidney (at least until the GFR falls to less than approximately 30 mL/min) and also increases calcium mobilization from bone. FGF-23 production in bone also increases and promotes phosphate excretion by the kidney. The result is a resetting of the calcium and phosphorus homeostasis set point, at least in the early stages of CKD; however, this occurs at the expense of an elevated PTH ("the trade-off hypothesis"). With advanced kidney disease the kidney fails to respond to PTH or to FGF-23. The increase in PTH is most notable when GFR is less than 60 mL/min/1.73 m2 (0.58 mL/s/m2) (stage 3 CKD) and worsens as kidney function further declines. 20 Elevated PTH levels have been reported in approximately 21% of patients with an estimated GFR between 60 and 69 mL/min/1.73 m2 (0.58 and 0.66 mL/s/m2)and in 56% of patients with stage 3, 4, or 5 CKD. 20

T M V Renal Osteodystrophy Turnover High Normal Low Mineralization
Renal osteodystrophy is an alteration of bone morphology in patients with CKD. It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by histomorphometry of bone biopsy. It can be classified as follows: T M V Turnover High Normal Low Mineralization Normal Abnormal Volume High Normal Low Slide courtesy of Susan Ott

2ry Hyperparathyroidism and Renal Osteodystrophy
As kidney disease progresses renal activation of vitamin D is impaired, which reduces gut absorption of calcium. Low blood calcium concentration stimulates secretion of PTH  As renal function declines, serum calcium balance can be maintained only at the expense of increased bone resorption, ultimately resulting in renal osteodystrophy. Pathogenesis of 2ry Hyperparathyroidism and Renal Osteodystrophy: Bone mineral density testing is not generally recommended in patients with advanced CKD since this test has not been shown to predict fracture risk and does not indicate the type of renal osteodystrophy. Abnormalities in mineral metabolism are highly associated with vascular and soft-tissue calcifications, known risk factors for mortality; therefore, diagnostic testing for calcifications should be considered in the evaluation for CKD-MBD. Electron-beam computed tomography (EBCT) is a noninvasive and sensitive method available for detecting cardiovascular calcifications and has been used clinically and in studies in the CKD population. Other methods advocated include lateral abdominal radiographs to detect vascular calcification and echocardiogram to detect valvular calcification. KDIGO suggests these tests are reasonable alternatives to EBCT based on the sensitivity to detect calcifications and lower cost. 18

Renal Osteodystrophy:
Secondary hyperparathyrodism can cause complication such as: osteitis fibrosa cystica (high bone formation rate - bones turn soft and become deformed) Osteomalacia (softening of the bones) adynamic bone disease (under active bone) altered lipid metabolism, altered insulin secretion, resistance to erythropietic therapy, impaired neurological and immune function increased mortality. Renal osteodystrophy progresses insidiously for several years before the onset of symptoms such as bone pain and fractures, when symptoms appear, the disease is not easily amenable to treatment. Renal osteodystrophy (ROD) is the term used to describe the skeletal manifestations that occur as kidney function declines. Collectively, ROD refers to specific bone abnormalities that include osteitis fibrosa (most common pattern), osteomalacia, osteosclerosis, and osteopenia. Hyperphosphatemia, hypocalcemia, hyperparathyroidism, decreased production of active vitamin D, and resistance to vitamin D therapy are all frequent problems in CKD that can lead to the secondary complication of ROD. Adynamic bone disease Adynamic bone disease has only been recognised in the last few years, and is not fully understood. Although the bones may have normal strength and overall appearance, they are under active. Normally bone is quite active, with constant reabsorption of bone and laying down of bone. In adynamic bone disease, both the reabsorption and laying down processes are slow. This may not be harmful to the bones themselves. Certainly in the short term, severe problems do not seem to develop. However, the bones cannot help keep blood levels of calcium normal by soaking up calcium from the blood when levels are high. Therefore people with adynamic bone disease are prone to high calcium levels, and may be at increased risk of calciphylaxis. It is therefore necessary to monitor the levels of calcium and phosphate very carefully in this condition. PTH levels are normal.

Lab findings and monitoring
There are no substantial differences between KDOQI and KDIGO with regard to recommendations for serum calcium (corrected for serum albumin) and phosphorus. Both KDOQI and KDIGO recommend maintaining serum phosphorus within the normal range for stage 3 to 4 CKD patients and lowering phosphorus toward the normal range for dialysis patients. KDIGO recommends that the corrected serum calcium be maintained within the normal range for all CKD patients; however, KDOQI recommends a more conservative range in stage 5 CKD patients based on an increased risk of soft-tissue and vascular calcifications. The most appropriate strategy is to evaluate trends in corrected calcium to predict if hypercalcemia is a concern that warrants changes in therapy. KDIGO did not specify a particular PTH target, but rather advocated looking at trends in serum PTH to make treatment decisions. KDIGO did not specify a particular PTH target, but rather advocated looking at trends in serum PTH to make treatment decisions. For the dialysis population, KDIGO recommends a PTH range of two to nine times the upper limit of the normal range for the assay (corresponds to a PTH of approximately 130 to 600 pg/mL or 130 to 600 ng/L [14 to 64 pmol/L]).43 This approach proposed by KDIGO is advocated to control hyperparathyroidism, yet prevent oversuppression of PTH and reduce the risk of adynamic bone disease. Corrected calcium (mg/dL) = measured total Ca (mg/dL) (4.0 - serum albumin [g/dL]), where 4.0 represents the average albumin level in g/dL. in other words, each 1 g/dL decrease of albumin will decrease 0.8 mg/dL in measured serum Ca and thus 0.8 must be added to the measured Calcium to get a corrected Calcium value. PTH levels — The K/DOQI practice guidelines suggested the following target plasma levels of intact PTH at different stages of chronic renal failure to achieve adequate control of secondary hyperparathyroidism [3]: 35 to 70 pg/mL for patients with an estimated GFR of 30 to 59 mL/min per 1.73 m2 (stage 3 chronic kidney disease) 70 to 110 pg/mL for patients with an estimated GFR of 15 to 29 mL/min per 1.73 m2 (stage 4 chronic kidney disease) 150 to 300 pg/mL for patients on dialysis or with an estimated GFR of less than 15 mL/min per 1.73 m2 (stage 5 chronic kidney disease) (See "Overview of the management of chronic kidney disease in adults", section on 'Definitions and classification'.) Calcium and phosphate levels — In addition to the guidelines to attain PTH target levels, the 2003 K/DOQI guidelines also recommend more stringent control of calcium and phosphate in the attempt to lower the risk of vascular calcification. For those with stage 3 CKD (GFR 30 to 59 mL/min) and stage 4 CKD (GFR 15 to 29 mL/min), the following treatment goals were recommended: Serum level of phosphate should be maintained between 2.7 mg/dL (0.87 mmol/L) and 4.6 mg/dL (1.49 mmol/L) The serum levels of corrected total calcium should be maintained within the "normal" range for the laboratory used. The serum calcium-phosphorus product should be maintained at <55 mg2/dL2. For those with stage 5 CKD, the following are recommended: Serum levels of phosphate should be maintained between 3.5 and 5.5 mg/dL (1.13 to 1.78 mmol/L) Serum levels of corrected total calcium should be maintained between 8.4 and 9.5 mg/dL (2.10 to 2.37 mmol/L) The serum calcium-phosphate product should be maintained at less than 55 mg2/dL2. Assessment and monitoring — To attain goal levels, serum levels of PTH, phosphate, and calcium must be measured frequently. As recommended by the KDIGO guidelines, phosphate and calcium levels should be measured approximately every 1 to 3 months and every 3 to 6 months for PTH levels [5]. 25(OH) vitamin D levels should also be measured. All of these levels should be assessed more frequently in response to changes in therapeutic measures that affect these levels. Corrected calcium (mg/dL) = measured total Ca (mg/dL) (4.0 - serum albumin [g/dL]),

Calcium and Phosphorus
Recommended Frequency of Monitoring Calcium, Phosphorus, PTH , and 25 OHD by Stage of CKD (KDIGO Guidelines) CKD Stage Calcium and Phosphorus PTH 25-Hydroxyvitamin D KDOQI KDIGO 3 Annually Every 6–12 months Baseline, and then based on level and CKD progression If PTH above target Baseline level; correct deficiencies as in general population 4 Every 3 months Every 3–6 months 5 Monthly Every 1–3 months Not measured The KDIGO guidelines also recommend monitoring bone-specific alkaline phosphatase annually in stage 4 and 5 CKD patients. The frequency of monitoring these parameters may increase once a diagnosis of CKD-MDB is made and further information is needed to assess the patient's response to treatment and to guide decisions about changes in therapy. In addition to monitoring for biochemical abnormalities that define CKD-MBD, evaluation of bone architecture is also necessary in some cases. The gold standard test for diagnosing bone manifestations of CKD-MBD is a bone biopsy for histologic analysis; however, this is an invasive test that is not easily performed. KDOQI and KDIGO guidelines recommend bone biopsy only in patients in whom the etiology of symptoms is not clear or in individuals with more unique biochemical abnormalities.43,52 This includes patients experiencing unexplained fractures, persistent hypercalcemia, and possible aluminum toxicity. If aluminum concentrations are elevated (60 to 200 mcg/L [2.2 to 7.4 μmol/L]), a deferoxamine test should be done. KDIGO also suggests a bone biopsy be considered in CKD patients prior to beginning treatment with bisphosphonates since adynamic bone disease is a contraindication to the use of these agents. Bone biopsy findings are described on the basis of turnover rate, mineralization, and volume. Bone mineral density testing is not generally recommended in patients with advanced CKD since this test has not been shown to predict fracture risk and does not indicate the type of ROD.43 ++ Abnormalities in mineral metabolism are highly associated with vascular and soft-tissue calcifications, known risk factors for mortality; therefore, diagnostic testing for calcifications should be considered in the evaluation for CKD-MBD. Electron-beam computed tomography (EBCT) is a noninvasive and sensitive method available for detecting cardiovascular calcifications and has been used clinically and in studies in the CKD population. Other methods advocated include lateral abdominal radiographs to detect vascular calcification and echocardiogram to detect valvular calcification. KDIGO suggests these tests are reasonable alternatives to EBCT based on the sensitivity to detect calcifications and lower cost.43 The KDIGO guidelines also recommend monitoring bone-specific alkaline phosphatase annually in stage 4 and 5 CKD patients. The frequency of monitoring these parameters may increase once a diagnosis of CKD-MDB is made and further information is needed to assess the patient's response to treatment and to guide decisions about changes in therapy.

Monitoring In addition to monitoring for biochemical abnormalities that define CKD- MBD, evaluation of bone architecture is also necessary in some cases. The gold standard test for diagnosing bone manifestations of CKD-MBD is a bone biopsy for histologic analysis; however, this is an invasive test that is not easily performed. KDOQI and KDIGO guidelines recommend bone biopsy only in patients in whom the etiology of symptoms is not clear or in individuals with more unique biochemical abnormalities. This includes patients experiencing unexplained fractures, persistent hypercalcemia, and possible aluminum toxicity. If aluminum concentrations are elevated (60 to 200 mcg/L, a deferoxamine test should be done. KDIGO also suggests a bone biopsy be considered in CKD patients prior to beginning treatment with bisphosphonates since adynamic bone disease is a contraindication to the use of these agents.

Monitoring Bone biopsy findings are described on the basis of turnover rate, mineralization, and volume. Bone mineral density testing is not generally recommended in patients with advanced CKD since this test has not been shown to predict fracture risk and does not indicate the type of ROD.

Monitoring Abnormalities in mineral metabolism are highly associated with vascular and soft-tissue calcifications, known risk factors for mortality; therefore, diagnostic testing for calcifications should be considered in the evaluation for CKD-MBD. Electron-beam computed tomography (EBCT) is a noninvasive and sensitive method available for detecting cardiovascular calcifications and has been used clinically and in studies in the CKD population. Other methods advocated include: lateral abdominal radiographs to detect vascular calcification echocardiogram to detect valvular calcification. KDIGO suggests these tests are reasonable alternatives to EBCT based on the sensitivity to detect calcifications and lower cost.

Management of Renal Osteodystrophy:
The optimal approach for treating secondary hyperparathyroidism and mineral metabolism abnormalities in predialysis patients with stage 3, 4, and 5 CKD is unclear. The current management of secondary hyperparathyroidism in patients with stage 3 to 5 CKD not yet on dialysis principally involves the administration of some combination of: dietary phosphate restriction, phosphate binders (either calcium or non-calcium containing binders), vitamin D analogues, calcium supplementation and/or (possibly) a calcimimetic (NOT currently approved for patients with CKD not yet undergoing dialysis). To help guide preventive measures, parathyroid hormone levels should therefore be assessed among such patients, as hormonal abnormalities are one of the earliest markers of abnormal bone mineral metabolism with progressive chronic kidney disease. Prevention and/or treatment of osteitis fibrosis in patients with predialysis chronic kidney disease are primarily based upon dietary phosphate restriction, the administration of oral phosphate binders, and the administration of calcitriol (or vitamin D analogs) to directly suppress the secretion of parathyroid hormone. Calcitriol (1,25-dihydroxyvitamin D), the most active metabolite of vitamin D, is principally synthesized in the kidney. Circulating calcitriol levels begin to fall when the GFR is less than 40 mL/min and are typically markedly reduced in subjects with end-stage renal disease. In addition to the loss of functioning renal mass, calcitriol production is also reduced by phosphate retention. (See "Pathogenesis of renal osteodystrophy".) Calcimimetics are agents that allosterically increase the sensitivity of the calcium-sensing receptor in the parathyroid gland to calcium. The calcium-sensing receptor is the principal factor regulating parathyroid gland parathyroid hormone secretion and hyperplasia. The separate target offers the potential to suppress parathyroid hormone secretion by mechanisms complementary and potentially synergistic with vitamin D analogues that target the vitamin D receptor. Although not approved for patients with CKD not yet on dialysis, cinacalcet, the only currently available calcimimetic, is an emerging option in the treatment of secondary hyperparathyroidism in predialysis patients with CKD. Target serum levels for PTH as well as the approach to the management of this issue are discussed separately. (See "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in adult predialysis patients with chronic kidney disease".)

1) Dietary Phosphate Restriction
In general, serum phosphorus should be lowered toward near normal levels. KDIGO recommends normal levels for all stages of CKD, whereas K/DOQI allows a more liberal phosphorus management in stage 5 of 3.5 to 5.5 mg/dL. Dietary phosphorus restriction can prevent hyperphosphatemia and maintain target phosphorus concentrations. Dietary phosphorus should not exceed 800 to 1,000 mg/day. Predominate sources of phosphorus are protein rich foods, which presents a challenge in tailoring a diet that lowers dietary phosphorus intake while providing adequate nutrition. However, efforts should be made to distinguish between organic (e.g., plant seeds, nuts, legumes, and meats) and inorganic phosphorus (e.g., preservatives and additive salts found in processed foods) sources. Inorganic phosphorus sources are absorbed to a greater extent than organic phosphorus (90% vs.50%, respectively) and should be minimized in the diet. 1) Dietary Phosphate Restriction Start restriction when GFR <60ml/min. Restrict to mg/day (meat, milk, dried beans, nuts, colas, peanut butter, beer) Protein retraction is helpful as protein rich food is usually phosphate rich with dialysis, diet phosphate can be increased up to 1200 mg/day as dialysis remove phosphate

1) Dietary Phosphate Restriction (cont’d)
Dark carbonated beverages are a common culprit for elevated phosphorus levels; their consumption should be discouraged, and the beverages should be removed from vending machines in dialysis clinics. Although phosphorus is removed to some extent by dialysis, neither HD nor PD removes adequate amounts to warrant complete liberalization of phosphorus in the diet (diet phosphate can be increased up to 1200 mg/day) Regular dietary counseling by a kidney specialist dietitian is necessary to reinforce the importance of phosphorus restriction and other dietary recommendations.

2) Phosphate Binding Agent:
A significant reduction of serum phosphorus is difficult to achieve with dietary intervention alone, particularly in patients with more advanced kidney disease (eGFR<30 mL/minute/1.73 m2). In these patients, the use of phosphate binding agents is also necessary. These agents decrease phosphorus absorption from the gut and should be administered with meals to maximize this effect (A) Oral calcium compounds are first-line agents for controlling both serum phosphorus and calcium concentration, elemental calcium should not exceed 1500 mg/day. Correction of hypocalcemia is an added beneficial effect of the calcium-containing preparations; Before initiating Ca therapy and during it, the Ca-P product (Ca x P) should be determined. If >55, patient is at risk for Ca deposition in soft tissues and patient should be switched to other binders. A “corrected” serum calcium and the “Ca-P product” should be determined before therapy is started and at regular intervals thereafter. (Note: KDIGO guidelines is different – check the next slide) Among patients with calcium levels between 8.4 and 9.5 mg/dL (2.10 and 2.37 mmol/L), management varies based upon the presence of adynamic bone disease, low PTH levels, and/or vascular calcification: - Among those without such comorbidities, we suggest a calcium-based phosphate binder. The dose of calcium-containing phosphate binders is generally increased until the serum phosphate falls to normal values or hypercalcemia ensues. The safe dose of calcium is not known in stage 3 and 4 CKD but likely exceeds the 1500 mg/day limit in end stage renal disease patients suggested by the K/DOQI work group. - Among those with adynamic bone disease, low PTH levels, and/or vascular calcification, we suggest a non-calcium based phosphate binder rather than a calcium-containing phosphate binder. Either sevelamer or lanthanum carbonate can be given in this setting. Magnesium-containing antacids are also effective phosphate binders and may decrease the amount of calcium-containing binders necessary for control of phosphorus; however, their use is limited by the frequent occurrence of GI side effects (i.e., diarrhea) and the potential for magnesium accumulation.

Comment on Ca×P product
Traditionally, the calculated calcium–phosphorus product(Ca×P) value is used as an indication as to when calcium and phosphate may precipitate and deposit into soft tissue, leading to calcific uremic arteriolopathy (CUA). CUA, or calciphylaxis, is characterized by calcification of the arterioles and small arteries with intimal proliferation and endovascular fibrosis and manifests visually as necrosis of the skin. K/DOQI guidelines set a target goal of the Ca×P to be less than 55 mg2/dL2, whereas a Ca×P greater than 60 to 70 mg2/dL2 suggests an increased risk of CUA. However, KDIGO suggests the Ca×P provides no additional clinical information than the individual values of calcium and phosphorus and is not recommended for guiding therapy.

Phosphate-Binding Agents Used for the Treatment of Hyperphosphatemia in CKD Patients
Compound Trade Name Compound Content (mg) Dose Titrationa Starting Doses Comments Calcium carbonate (40% elemental calcium) Tums Oscal-500 Caltrate 600 500, 750, 1,000, 1,250 1,500 Increase or decrease by 500 mg per meal (200 mg elemental calcium) 0.5–1 g (elemental calcium) three times a day with meals First-line agent; dissolution characteristics and phosphate binding may vary from product to product Approximately 39 mg phosphorus bound per 1 g calcium carbonate Calcium acetate (25% elemental calcium) PhosLo 667 Increase or decrease by 667 mg per meal (168 mg elemental calcium) First-line agent; comparable efficacy to calcium carbonate with half the dose of elemental calcium Approximately 45 mg phosphorus bound per 1 g calcium acetate By prescription only Sevelamer carbonate *Available as tablet and powder for oral suspension Renvela 800 Increase or decrease by 800 mg per meal 800–1,600 mg three times a day with meals First-line agent; lowers low-density lipoprotein cholesterol More expensive than calcium products; consider in patients at risk for extraskeletal calcification Associated with a lower risk of acidosis and GI adverse events than Renagel. Sevelamer Hydrochloride Renagel 400, 800 Increase or decrease by 1 tablet per meal Same as Renvela Same as Renvela, plus acidosis Lanthanum carbonate Fosrenol 500, 750, 1,000 Increase or decrease by 750 mg per day 750–1,500 mg daily in divided doses with meals First-line agent; Available as chewable tablets Aluminum hydroxide Alterna GEL 600 mg/5 mL – 300–600 mg three times a day with meals Not a first line agent; do not use concurrently with citrate-containing products Reserve for short-term use (4 weeks) in patients with hyperphosphatemia not responding to other binders Drugs that bind dietary phosphorous in the GI tract form insoluble phosphate compounds that are excreted in feces, thus reducing phosphorus absorption and serum phosphorus concentrations. A variety of phosphate-binding agents are available, including elemental calcium-, lanthanum-, aluminum-, and magnesium-containing compounds, and the nonelemental agent sevelamer carbonate (Table 53–8). Patients must be instructed to take these agents with meals to maximize the binding of phosphorus in the GI tract. Calcium carbonate is more soluble in an acidic medium and therefore should be administered prior to meals when stomach acidity is highest. In addition, acid-suppressing agents such as ranitidine and proton pump inhibitors may reduce the phosphate-binding activity of calcium carbonate by increasing gastric pH. Calcium acetate binds approximately twice as much phosphorus as calcium carbonate at comparable doses of elemental calcium. Adverse effects of all phosphate binders are generally limited to GI side effects, including constipation, diarrhea, nausea, vomiting, and abdominal pain. The risk of hypercalcemia may necessitate restriction of calcium-containing binders use and/or a reduction in dietary intake. Aluminum binders have been associated with CNS toxicity and the worsening of anemia, whereas magnesium binder use may lead to hypermagnesemia and hyperkalemia. Drug–Drug and Drug–Food Interactions. Calcium-containing phosphate-binding agents interfere with the absorption of several oral medications that are commonly prescribed for CKD patients, including iron, zinc, and quinolone antibiotics. No drug interaction studies have been performed with sevelamer carbonate; however, studies with sevelamer hydrochloride have shown no drug interactions with digoxin, warfarin, metoprolol, enalapril, or iron. Coadministration with ciprofloxacin did, however, result in a 50% decrease in bioavailability of the antibiotic. This information is reported in the labeling for the newer formulation sevelamer carbonate. 97 Potential interactions between sevelamer and cyclosporine (decreased bioavailability of cyclosporine) and altered phosphorus binding in the presence of agents that increase gastric pH (e.g., omeprazole) have been reported. 98,99 Drug interaction studies with lanthanum, although limited, have shown that coadministration with warfarin, digoxin, and metoprolol did not affect the bioavailability of those agents. 100 In general, it is rational to separate the administration time of oral medications for which a reduction in bioavailability has a clinically significant effect (e.g., quinolones) from phosphate binders by at least 1 hour before or 3 hours after administration of the phosphate binder. This is a key patient-counseling recommendation as patients are often switched from one phosphate binder to another, and it is easier for them to remember this general concept regarding phosphate binders and other medications. Many phosphate binders are marketed as antacids or calcium supplements, and often CKD patients do not know why they have been prescribed these agents. Regular patient counseling is essential to improve adherence and minimize the potential for drug interactions. Dosing and Administration. Initial dosing regimens for phosphate-binding agents and suggested dose titration schemes are shown in Table 53–8. Doses should be titrated to achieve the recommended serum phosphorus concentrations based on the patient's stage of CKD. The daily dose of elemental calcium should be limited in individuals with elevated calcium levels.

TABLE 29–13

3) Vitamine D Therapy: (what are its benefits?)
Calcium (less than 9.5 mg/dL) and phosphorus (less than 4.6 mg/dL) must be controlled before Vitamin D therapy is initiated. Ergocalciferol In stage 3 and 4 If the 25-hydryoxyvitamin D level is less than 30 ng/mL, a vitamin D precursor (e.g., ergocalciferol) is recommended To prevent vitamin D insufficiency, doses of 600 to 800 units per day of ergocalciferol are recommended Calcitriol, (1,25-Dihydroxyvitamine D3) Has been used for the management of secondary hyperparathyroidism Directly suppresses PTH synthesis and secretion and appears to upregulate vitamin D receptors which ultimately may reduce parathyroid hyperplasia. If hypercalcemia develops, the decision to withhold therapy orto switch to a vitamin D analog. The comparative effects of the different active oral vitamin D analogs in predialysis patients with CKD have not been established. As a result, any one of the available active oral agents (calcitriol, alfacalcidol, doxercalciferol, or paricalcitol) may be administered. If the serum level of corrected total calcium exceeds 10.2 mg/dL (2.54 mmol/L), ergocalciferol therapy and all forms of vitamin D therapy should be discontinued. Vitamin D therapy should also be discontinued if intact PTH levels become persistently low. Several studies have shown that native vitamin D (i.e., ergocalciferol or cholecalciferol) administration benefits extend beyond bone and mineral metabolism. Reduction in ESA doses, improved glycemic control, reduced activated vitamin D administration, and inflammation modulation are benefits observed from native vitamin D supplementation in dialysis patients. Although some effects have been repeated in different studies, randomized control trials are needed to confirm these benefits. Vitmin D Therapy Vitamin D compounds include ergocalciferol (vitamin D2 ) and cholecalciferol (vitamin D3 ) that must be converted to the active form in the kidney. Calcitriol (1,25-dihydroxyvitamin D3) is the most active form of vitamin D and is available as an oral formulation (Rocaltrol) as well as an IV formulation (Calcijex). The currently available vitamin D analogs include paricalcitol (19-nor-1,25-dihydroxyvitamin D2; Zemplar) and doxercalciferol (1-hydroxyvitamin D2; Hectorol). Calcitriol or one of the vitamin D analogs is required for patients with severe kidney disease because these agents do not require conversion by the kidney to the biologically active form. Pharmacology and Mechanism of Action. Active vitamin D suppresses PTH secretion by stimulating absorption of serum calcium by intestinal cells and through direct activity on the parathyroid gland to decrease PTH synthesis. As a result, the serum calcium concentration is raised and the parathyroid glands decrease the rate of secretion and formation of PTH. The set point for calcium (i.e., the calcium concentration at which PTH secretion is decreased by 50%), which is generally raised in CKD-MBD, is lowered when active vitamin D therapy is initiated. This indicates that a lower ionized calcium concentration is effective at suppressing secretion of PTH. All of these actions are mediated by the interaction of vitamin D with vitamin D receptors, which are located in many organs, including the parathyroid gland, GI tract, and kidney. Calcitriol also upregulates vitamin D receptors, which ultimately may reduce parathyroid hyperplasia. Unfortunately, the enhanced GI absorption of calcium and phosphorus with calcitriol therapy frequently leads to hypercalcemia and hyperphosphatemia. There is also evidence that hyperphosphatemia results in resistance to the PTH-suppressing effects of vitamin D and directly stimulates PTH release. These actions contribute to the increase in the Ca x P product, which is associated with soft-tissue and vascular calcifications. 22,25 Consequently, reasonable control of calcium and phosphorus must be achieved before initiation and during continued vitamin D therapy. This does not mean that vitamin D therapy should be withheld or discontinued in patients with a Ca x P product greater than 55 mg2/dL2 (4.4 mmoL2/L2). Rather interventions with agents with a lower risk of hypercalcemia and hyperphosphatemia, and more prudent use of phosphate binders to lower calcium and phosphorus, may be necessary in such patients. The unique interactions of vitamin D with the vitamin D receptors have been a focus of research and have led to the development of vitamin D analogs, which vary in their affinity for these receptors and result in less hypercalcemia while retaining the positive physiologic actions on bone and parathyroid tissue. Paricalcitol and doxercalciferol are D2 compounds that effectively lower PTH. 101 Paricalcitol differs from calcitriol by the absence of the exocyclic carbon 19 and the fact that it is a vitamin D2 derivative. Doxercalciferol is a prohormone that needs to be hydroxylated in the liver to 1,25-dihydroxyvitamin D2. These agents are available in an IV formulation for use in patients with stage 5 CKD and in oral forms that are approved for use in those with stage 3 to 5 CKD. Pharmacokinetics. Calcitriol can be administered orally as well as by IV injection. Oral absorption occurs rapidly; therefore oral and IV therapies are both reasonable options for treatment of CKD-MBD. When paricalcitol is administered IV, its half-life is similar to that of calcitriol (up to 30 hours). The half-life of paricalcitol after oral administration is 17 to 20 hours in patients with stage 3 and 4 CKD. 102 Doxercalciferol has a slightly prolonged half-life of 45 hours. 103 Efficacy. Administration of calcitriol by either the oral or the IV route may be based on conventional dosing (usually 0.25–0.5 mcg/day) or pulse dosing (0.5–2 mcg two to three times per week). Logistically, IV dosing is more practical in hemodialysis patients, whereas oral therapy is more practical for nondialysis CKD and peritoneal dialysis patients. Conventional daily oral doses of calcitriol may be more frequently associated with hypercalcemia and hyperphosphatemia, because vitamin D receptors are located in intestinal mucosa where direct stimulation can occur. Although hypercalcemia is less likely with the newer analogs (paricalcitol and doxercalciferol), elevated calcium concentrations have been observed with these agents in patients with ESRD. However, some of these cases were associated with excessive dosing of these agents and oversuppression of PTH, a condition more likely to promote hypercalcemia. When administered at doses 10 times that of calcitriol and at a dose equivalent to doxercalciferol, paricalcitol has been less frequently associated with hypercalcemia in animal studies and in human trials. 104,105 Intestinal calcium absorption was 14% lower in paricalcitol-treated hemodialysis patients compared with those treated with calcitriol. 106 Doxercalciferol and paricalcitol have also been evaluated in patients with stages 3 and 4 CKD. They are effective in reducing PTH to target levels; however, differences in the magnitude of elevations of calcium and phosphorus have not been directly compared in this population. 107,108 Although comparisons between vitamin D analogs are relatively limited the incidence of hyperphosphatemia with paricalcitol was lower than with doxercalciferol when administered at high doses to hemodialysis patients. 105 A more rapid suppression of PTH was also observed in paricalcitol-treated patients compared to those who received calcitriol. The more clinically significant finding from this study was the decrease in incidence of hypercalcemia and elevated Ca x P in the paricalcitol-treated patients. 109 Nontraditional effects of vitamin D, including a potential survival benefit, have also been reported. 101 An improvement in 3-year survival in a large dialysis population receiving paricalcitol was observed compared with a historic cohort that received calcitriol. 110 This survival advantage was also observed for hemodialysis patients who received vitamin D (either calcitriol or paricalcitol) compared with no vitamin D and was independent of calcium, phosphorus, and PTH. 111 The relationship between all available vitamin D agents (calcitriol, doxercalciferol, and paricalcitol) and mortality was further evaluated in a retrospective analysis of more than 7,700 hemodialysis patients. 112 After a median follow-up of 37 weeks, all-cause mortality and atherosclerotic cardiovascular mortality were similar for doxercalciferol- and paricalcitol-treated patients and similar to the calcitriol-treated patients when adjusted for laboratory values (e.g., calcium, PTH, albumin, phosphorus) and standardized mortality for the dialysis clinics included in this study. Vitamin D therapy, regardless of agent, was associated with lower mortality. It must be noted that these are observational studies and that prospective, randomized, controlled trials are required to better understand survival benefits associated with vitamin D therapy. Antiproteinuric effects of paricalcitol have also been reported in patients with stages 3 and 4 CKD. 113 These findings are of interest when considering other potential effects of vitamin D beyond suppression of PTH. Adverse Effects. Although all agents are effective in suppressing PTH levels, they differ in the degree to which they cause other metabolic abnormalities. Adverse effects of note with vitamin D therapy in patients treated for CKD-MBD include hypercalcemia and hyperphosphatemia. Differences in calcitriol and vitamin D analogs have been demonstrated in animal studies and in clinical trials evaluating their effect on reduction of PTH while minimizing the risk of these adverse consequences. 105,106 Drug–Drug and Drug–Food Interactions. Cholestyramine may reduce the absorption of orally administered calcitriol and doxercalciferol. In vitro data suggest that paricalcitol is metabolized by the hepatic enzyme CYP3A4 and has the potential to interact with other agents that are metabolized by this enzyme. When ketoconazole, a CYP3A4 inhibitor, was given concomitantly, paricalcitol serum concentrations doubled. 114 Caution is also advised when CYP3A4 inhibitors are given to those receiving doxercalciferol. No other significant interactions have been reported. Dosing and Administration. Recommendations for vitamin D therapy differ based on the stage of CKD. Because deficiency in the vitamin D precursor, 25-hydroxyvitamin D, is common in patients with CKD, K/DOQI guidelines recommend measuring 25-hydroxyvitamin D levels in patients with stage 3 or 4 CKD who have PTH values above the upper recommended ranges (see Table 53–4). If the 25-hydryoxyvitamin D level is less than 30 ng/mL (75 nmol/L), a vitamin D precursor (e.g., ergocalciferol or cholecalciferol) is recommended. The dose and duration of treatment are dependent on the severity of the deficiency. To prevent vitamin D insufficiency, doses of 600 to 800 units per day of ergocalciferol are recommended. Calcitriol, doxercalciferol, or paricalcitol should be administered orally when PTH remains elevated despite the achievement of adequate 25-hydroxyvitamin D levels. Initial oral doses of vitamin D recommended in patients with stage 3 or 4 CKD are 0.25 mcg calcitriol, 1 mcg doxercalciferol, or 1 mcg paricalcitol administered daily. 115 For paricalcitol the recommended daily dose is 2 mcg if the PTH is greater than 500 pg/mL (500 ng/L). If these agents are administered intermittently (generally three times per week), the recommended initial oral dose is twice the daily dose. Higher starting doses may be required based on the severity of CKD-MBD. Prior to starting therapy the serum calcium and phosphorus should be within the normal range to minimize the risk of hypercalcemia and an elevated Ca x P. In patients with ESRD there is a clearly defined role for treatment with active vitamin D or a vitamin D analog because the conversion of precursors to active vitamin D is impaired. The active vitamin D agents available in the United States vary markedly with regard to the oral and IV dosage regimens that are recommended for CKD patients (Table 53–9). Serum calcium and Ca x P should be monitored regularly while the patient is receiving therapy. Dose adjustments should be made every 2 to 4 weeks based on PTH concentrations. 22 For patients who need to be converted from calcitriol to paricalcitol, a dosing conversion ratio of 1:4 of IV calcitriol to paricalcitol has been proposed; however, some clinicians suggest a ratio of 1:3 to avoid oversuppression of PTH.

reasonable control of calcium and phosphorus must be achieved before initiation and during continued vitamin D therapy. This does not mean that vitamin D therapy should be withheld or discontinued in patients with a Ca x P product greater than 55 mg2/dL2 (4.4 mmoL2/L2). Rather interventions with agents with a lower risk of hypercalcemia and hyperphosphatemia, and more prudent use of phosphate binders to lower calcium and phosphorus, may be necessary in such patients.

Available Vitamin D Agents
Generic Name Trade Name Form of Vitamin D Dosage Range Dosage Forms Frequency of Administration Vitamin D precursor Ergocalciferol Vitamin D2 D2 400–50,000 IU PO Daily (doses of 400–2000 IU) Cholecalciferol Vitamin D3 D3 Weekly or monthly for higher doses (50,000 IU) Active vitamin D Calcitriol Calcijex 0.5–5 mcg IV Three times per week Rocaltrol 0.25–5 mcg Daily, every other day, or three times per week Vitamin D analogs Paricalcitol Zemplar 1–4 mcg Daily or three times per week 2.5–15 mcg Doxercalciferol = 1-hydroxyvitamin D2 Hectorol 5–20 mcg 2–8 mcg Vitamin D compounds include ergocalciferol (vitamin D2 ) and cholecalciferol (vitamin D3 ) that must be converted to the active form in the kidney. Calcitriol (1,25-dihydroxyvitamin D3) is the most active form of vitamin D and is available as an oral formulation (Rocaltrol) as well as an IV formulation (Calcijex). The currently available vitamin D analogs include paricalcitol (19-nor-1,25-dihydroxyvitamin D2; Zemplar) and doxercalciferol (1-hydroxyvitamin D2; Hectorol). Calcitriol or one of the vitamin D analogs is required for patients with severe kidney disease because these agents do not require conversion by the kidney to the biologically active form. Calcitriol (1,25- dihydroxyvitamin D3) suppresses PTH secretion by stimulating absorption of serum calcium by intestinal cells and through direct activity on the parathyroid gland to decrease PTH synthesis. As a result, the serum calcium concentration is raised and the parathyroid glands decrease the rate of formation and secretion of PTH. The set point for calcium (i.e., the calcium concentration at which PTH secretion is decreased by 50%), which is generally raised in CKD-MBD, is lowered when active vitamin D therapy is initiated. This indicates that a lower ionized calcium concentration is effective at suppressing secretion of PTH. All of these actions are mediated by the interaction of vitamin D with vitamin D receptors, which are located in many organs, including the parathyroid gland, GI tract, and kidney. Calcitriol also upregulates vitamin D receptors, which ultimately may reduce parathyroid hyperplasia. Unfortunately, the enhanced GI absorption of calcium and phosphorus with calcitriol therapy frequently leads to hypercalcemia and hyperphosphatemia and an increase in the Ca × P product, which is associated with soft-tissue and vascular calcifications.52 ++The unique interactions of vitamin D with the vitamin D receptors have led to the development of vitamin D analogs that vary in their affinity for the vitamin D receptors. Paricalcitol and doxercalciferol retain activity with vitamin D receptors on the parathyroid gland to effectively lower PTH, but have less risk of hypercalcemia and hyperphosphatemia. Paricalcitol differs from calcitriol by the absence of the exocyclic carbon 19 and the fact that it is a vitamin D2 derivative (19-nor-1,25-dihydroxyvitamin D2). Doxercalciferol is a prohormone that is activated by CYP27 in the liver to form the major active D2 metabolite 1,25-dihydroxyvitamin D2. These analogs are available in IV and oral forms.

TABLE 29–14

Some data suggest dosing ergocalciferol according to the following formula: the serum 25(OH)D level is raised 0.7 ng/mL for every 100 IU of ergocalciferol supplemented per day. As an example, a patient with a measured serum 25(OH)D level of 20 ng/mL would need to raise this by at least 10 ng/mL to be above the lower limits of normal. This would require 1428 IU ergocalciferol per day, or 10,000 IU per week. Therefore, an average recommended dose is 8,000 to 10,000 IU per week.

4) Calcimimetics: Acts on Ca-sensing receptor on the surface of chief cell of PT gland to mimic effect of extracellular ionized Ca & increase sensitivity of Ca-sensing receptor to Ca  decrease PTH secretion within hours after administration. The calcimimetic cinacalcet (Sensipar): is the first agent in this class to be approved by the FDA. demonstrated efficacy in lowering PTH concentrations and Ca-P product in patients on HD with sHPT and a higher proportion of patients achieved recommended targets for PTH, calcium, phosphorus, and Ca-P product. No data are found on survival rates for patients receiving cinacalcet versus those treated with vitamin D. Cinacalcet, however, offers an additional choice of agent to lower PTH when vitamin D cannot be increased because of elevated calcium, phosphorus, or calcium-phosphorus product. Initiated at a dose of 30 mg daily with dosage titrations occurring every 2 to 4 weeks to 60, 90, 120 or a maximum of 180 mg daily to achieve target iPTH levels. (given with meals) Because cinacalcet lowers serum calcium and may cause hypocalcemia, this agent should not be started if the serum calcium is less than the lower limit of normal, approximately 8.4 mg/dL Serum calcium and phosphorous levels should be drawn within 1 week after initiation or dosage increase, and plasma PTH levels drawn within 4 weeks after initiation of therapy or dosage adjustment. Cinacalcet is metabolized by the liver, specifically by the cytochrome P450 isoenzymes CYP3A4, CYP2D6, and CYP1A2  drug interactions Cinacalcet is also a potent inhibitor of the enzyme CYP2D6. Extracellular calcium-sensing receptors (CaSR) have been identified in the parathyroid gland, thyroid, nephron, brain, intestine, bone, lung, and other tissues. Calcimimetics Pharmacology and Mechanism of Action. Cinacalcet hydrochloride (Sensipar) is a calcimimetic agent approved for treatment of secondary hyperparathyroidism in ESRD patients and for treatment of hypercalcemia in patients with parathyroid carcinoma. Cinacalcet is the first agent in this class to receive FDA approval. This compound acts on the calcium-sensing receptor on the surface of the chief cells of the parathyroid gland to mimic the effect of extracellular ionized calcium and increase the sensitivity of the calcium-sensing receptor to calcium, subsequently reducing PTH secretion. Cinacalcet does not increase intestinal calcium and phosphorus absorption. In fact, the reduction in PTH with cinacalcet is associated with a decrease in serum calcium. 116 Pharmacokinetics. The maximum plasma concentration of cinacalcet is achieved in approximately 2 to 6 hours following oral administration. The half-life is approximately 30 to 40 hours. Cinacalcet has a large volume of distribution (approximately 1,000 L), and is 93% to 97% bound to plasma proteins, both characteristics indicating that removal by dialysis is negligible. Cinacalcet is metabolized by the liver, specifically by the cytochrome P450 isoenzymes CYP3A4, CYP2D6, and CYP1A2. 117 Efficacy. In placebo-controlled clinical trials conducted in dialysis patients (predominantly those receiving hemodialysis) cinacalcet significantly decreased PTH and the Ca x P product within the 6-month study period, regardless of the severity of secondary hyperparathyroidism. 116 The starting dose of 30 mg per day was titrated every 3 or 4 weeks to a maximum dose of 180 mg per day to achieve the target PTH of 250 pg/mL (250 ng/L) and avoid hypocalcemia. Approximately 66% and 93% of patients in the clinical trials were receiving concurrent vitamin D and phosphate binders, respectively. If a patient experienced symptoms of hypocalcemia or had a serum calcium <8.4 mg/dL (<2.10 mmol/L), calcium supplements and/or calcium-based phosphate binders could be increased. If ineffective, the vitamin D dose could be increased. The median dose required to achieve the desired PTH by the end of the study period was 90 mg. This agent is not approved for use in patients with early stage CKD (stages 3–5 CKD not requiring dialysis) due to the risk of hypocalcemia. Because cinacalcet was approved after the K/DOQI guidelines on bone disease became available, the challenge to clinicians is in deciding how to most effectively use cinacalcet in conjunction with other therapies to manage CKD-MBD. KDIGO guidelines endorse the use of cinacalcet alone or in conjunction with vitamin D therapy to lower PTH in the dialysis population. 18 There are no studies evaluating the effect of cinacalcet on vascular calcification in humans. Adverse Effects. The most frequently reported adverse events with cinacalcet were nausea and vomiting. Although nausea and vomiting occurred more frequently with cinacalcet, these events were generally transient, mild to moderate in nature, and infrequently led to withdrawal from clinical trials. 117 Because cinacalcet lowers serum calcium and may cause hypocalcemia, this agent should not be started if the serum calcium is less than the lower limit of normal, approximately 8.4 mg/dL (2.10 mmol/L). Serum calcium should be measured within 1 week after initiation or following a dose adjustment of cinacalcet. Once the maintenance dose is established, serum calcium should be measured approximately monthly. Potential manifestations of hypocalcemia include paresthesia, myalgia, cramping, tetany, and convulsions. Drug–Drug and Drug–Food Interactions. Because cinacalcet is metabolized by multiple hepatic enzymes there is potential for drug interactions. Cinacalcet is also a potent inhibitor of the enzyme CYP2D6. As a result, dose adjustments of concomitant medications that are predominantly metabolized by this enzyme and have a narrow therapeutic index, such as flecainide, thioridazine, vinblastine, and most tricyclic antidepressants (e.g., amitriptyline) may be required. 117 Several agents commonly used in the CKD population have been evaluated for interactions with cinacalcet. Coadministration of calcium carbonate or sevelamer did not affect the pharmacokinetics of cinacalcet. Pantoprazole did not alter the pharmacokinetics of cinacalcet. This is an important finding because pantoprazole alters gastric pH, and the solubility of cinacalcet decreases as the gastric pH rises over 5.5. Coadministration of cinacalcet with warfarin also did not affect the pharmacokinetics of warfarin. Coadministration of cinacalcet and ketoconazole, a strong inhibitor of cytochrome P450 (CYP) 3A4, resulted in an increase in the area under the curve and maximum concentration of 2.3 and 2.2 times, respectively. Concurrent administration of cinacalcet with amitriptyline increased amitriptyline exposure and nortriptyline (active metabolite) exposure by approximately 20% in CYP2D6-extensive metabolizers. 117 Food has been shown to increase absorption of cinacalcet by up to 81% compared with fasting; therefore this medication should be taken with meals to achieve the maximal effect. Dosing and Administration. The recommended starting oral dose of cinacalcet is 30 mg once daily. The dose should be titrated every two to four weeks to a maximum dose of 180 mg once daily to achieve the desired PTH levels and to maintain near-normal serum calcium concentrations. Patients with hepatic disease may require lower doses, as studies have shown a decrease in metabolism of cinacalcet in this patient population. Cinacalcet is available as a film-coated tablet containing 30, 60, or 90 mg.

Stepped approach for the management of renal osteodystrophy
The initial focus in managing sHPT should be the management of hyperphosphatemia. Among patients with hyperphosphatemia  restricting dietary phosphate intake. Step 2 Among patients with hyperphosphatemia despite dietary phosphorus restriction after two to four months  administration of phosphate binders For patients with an initial serum calcium levels less than 9.5 mg/dL (<2.37 mmol/L), a calcium containing phosphate binder should be administered as long as hypercalcemia does not develop. For patients with an initial serum calcium level greater than 9.5 mg/dL (<2.37 mmol/L), a non-calcium based phosphate binder rather than a calcium-containing phosphate binder. Either sevelamer or lanthanum carbonate can be given in this setting.

Treatment with ergocalciferol should be initiated if vitamin D deficiency exists, as demonstrated by a 25(OH)-vitamin D (calcidiol) level of less than 30 ng/mL. If elevated PTH levels remain despite ergocalciferol and phosphate binder therapy over a six-month period  administering a low dose active oral vitamin D analog. If the serum level of corrected total calcium exceeds 10.2 mg/dL (2.54 mmol/L)  ergocalciferol therapy and all forms of vitamin D therapy should be discontinued Step 3 Decide whether phosphate binder therapy is sufficient or whether a vitamin D analogue should be added. This is based upon calcium, phosphate, and PTH levels that are measured when administering optimal phosphate binder therapy. Step 4 Among predialysis patients with sHPT, the use of cinacalcet is controversial. Some experts and the KDIGO working group recommend NOT giving cinacalcet given the paucity of data concerning efficacy and safety in predialysis patients with CKD.

Case: Renal Osteodystrophy

New! Feb 2017 The US Food and Drug Administration (FDA) has approved the novel calcimimetic etelcalcetide (Parsabiv, Amgen) for the treatment of secondary hyperparathyroidism in adults on hemodialysis. Etelcalcetide reduces the PTH level by binding to and activating the calcium-sensing receptor on the parathyroid gland. It offers an advantage over the current standard calcimimetic treatment, cinacalcet (Sensipar, Amgen), in that it can be administered intravenously by the dialysis healthcare team at the end of each hemodialysis session. The approval was based largely on the results from the two 26-week randomized, double-blind, phase 3, placebo-controlled pivotal trials, which enrolled a total of 1023 hemodialysis patients with moderate to severe secondary hyperparathyroidism (PTH > 400 pg/mL). Patients received intravenous etelcalcetide or placebo at the end of their thrice-weekly dialysis sessions, in addition to standard care that could include administration of vitamin D and /or phosphate binders. Both studies met the primary endpoint, with 77% and 79% of patients achieving 30% PTH reduction from baseline during weeks 20 to 27 in the first and second studies, compared with 11% with placebo in both studies, and PTH levels of 300 pg/mL or less, which was achieved by 52% and 56% of patients, respectively, vs just 6% and 5% for patients receiving placebo. Adverse events in the two studies combined included more frequent asymptomatic reductions in serum calcium levels and symptomatic hypocalcemia with etelcalcetide compared to placebo. Other adverse events – none of which occurred in more than 12% of patients ― included muscle spasms, diarrhea, nausea, vomiting, headache, and parathesia/hypoesthesia.

6) Hyperlipidemia: Treatment with a statin should not be initiated in patients with type 2 diabetes on maintenance hemodialysis who do not have a specific cardiovascular indication for treatment (Strong evidence) – see next slide. Lipid profile should be reassessed at least annually and 2 to 3 months after changing treatment. HMG-CoA reductase inhibitors may have some other advantages that may help to reduce kidney disease progression in addition to lipid reduction, such as: reduction of monocyte infiltration, mesangial cell proliferation, mesangial matrix expansion, and tubulointerstitial inflammation and fibrosis New phosphate-binding agent sevelamer hydrochloride appears to lower lipid levels by mechanisms similar to those of bile acid sequestrants. Statins in Early-Stage CKD. Statins are effective agents in patients with early-stage CKD, although there is little documented clinical trial data. 3 Atorvastatin therapy targeted to achieve an LDL of 80 mg/dL (2.07 mmol/L) or a maximum dose of 80 mg per day decreased cardiovascular risk in individuals with coronary heart disease and stage 3 CKD. 121 This effect was similar to that achieved in individuals without CKD. These results are similar to those from the Treating to New Targets trial, which evaluated atorvastatin (80 mg vs 10 mg per day) on cardiovascular events in patients with (n = 3,107) and without (n = 6,549) CKD. 122 Atorvastatin 80 mg reduced the relative risk of major cardiovascular events by 32% in patients with CKD over the median follow-up period of 5 years. Thus statin therapy clearly can reduce cardiovascular risk for patients with stage 3 CKD. Evidence of these benefits for those with stage 4 CKD, however, is lacking.

KDIGO Management of dyslipidemia in patients with CKD has been guided by recommendations from the National Cholesterol Education Program and the KDOQI guidelines for dyslipidemia. Based on evidence of risk reduction and the benefits of lipid-lowering therapy in the general population, the consensus was that CKD patients should be treated aggressively to an LDL cholesterol goal below 100 mg/dL. However, the KDIGO guidelines for lipid management in CKD published in do not support this goal since clinical trials have not proven the strategy of targeting a specific LDL level to be beneficial. KDIGO recommends that a lipid profile be done for all adults with CKD to include LDL, HDL, and triglycerides. Follow up lipid levels are not recommended unless the information may alter management (e.g., assessing adherence to therapy or assessing cardiovascular risk in a patient <50 years of age and not currently on a statin). Patients should also be evaluated for other conditions that are known to cause dyslipidemias (e.g., liver disease). KDIGO acknowledges that reduction in the risk of adverse cardiovascular events in patients with CKD has only been demonstrated with regimens that include a statin or statin plus ezetimibe combination and recommendations focus on these agents for individuals at risk of cardiovascular events. Follow ATP IV

KDIGO Based on the available evidence, the KDIGO guidelines for lipid management in CKD recommend treatment with a statin in adults aged 50 and older with stage 1 to 5 CKD (not on dialysis). The statin/ezetimibe combination may also be an option in patients in this age group in stage 3 to 5 CKD (not on dialysis). KDIGO only recommends statins in adults aged 18 to 49 years with stage 1 to 5 CKD (not on dialysis) who have one or more of the following: known coronary disease, diabetes mellitus, prior ischemic stroke, and an estimated 10- year incidence of coronary death or nonfatal myocardial infarction >10%. It is not recommended that statins or statin/ezetimibe be initiated in patients with stage 5 CKD on dialysis; however, therapy with these agents may be continued if patients were receiving these medications at the time of dialysis initiation. Due to the risk of adverse events with statins and absence of safety data in patients with stage 3 to 5 CKD, KDIGO recommends using statins at doses shown to be beneficial in randomized studies conducted in this population (e.g., atorvastatin 20 mg, fluvastatin 80 mg, rosuvastatin 10 mg, simvastatin 20 mg).

Atorvastatin treatment in patients with type 2 diabetes on maintenance hemodialysis treatment does not improve cardiovascular outcomes. (Strong evidence) Results from a 4-year study evaluating the effect of atorvastatin therapy on cardiac mortality in more than 1,200 hemodialysis patients with type 2 diabetes showed no significant benefit in the composite end point compared with the placebo group. 124 In fact, there was a significantly greater relative risk of fatal stroke in the atorvastatin-treated patients. These findings do not support initiation of statin therapy in ESRD patients, especially those with type 2 diabetes Statins in the ESRD Population. Data on statin use in the ESRD population are not consistently favorable as they are in early CKD. Although observational studies in hemodialysis patients receiving statins indicated a significant benefit: 31% relative risk reduction in overall mortality and a 23% reduction in cardiac causes of death, 123 the findings from prospective studies have not been encouraging. 124,125 Results from a 4-year study evaluating the effect of atorvastatin therapy on cardiac mortality in more than 1,200 hemodialysis patients with type 2 diabetes showed no significant benefit in the composite end point compared with the placebo group. 124 In fact, there was a significantly greater relative risk of fatal stroke in the atorvastatin-treated patients. These findings do not support initiation of statin therapy in ESRD patients, especially those with type 2 diabetes. The AURORA trail assessed the impact of rosuvastatin 10 mg daily or placebo on the primary end points of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. Despite a 43% reduction in cholesterol in the rosuvastatin group there was no difference in the primary end points. 125 It is evident from these trials that information from the general population regarding statin therapy cannot be directly extrapolated to the ESRD population. Results from an ongoing trial known as the Study of Heart and Renal Protection (SHARP) trial will provide additional information on the use of the combination of simvastatin and ezetimibe both in those with early-stage CKD as well as in hemodialysis patients. 126 Sidebar: Clinical Controversy While observational studies have reported decreased mortality associated with statin use in the dialysis population, this has not been demonstrated in prospective trials (4D and AURORA trials). Critics of these prospective trials argue that these trials included patients with preexisting cardiovascular disease (e.g., history of MI) and speculate whether a study designed for primary prevention of cardiovascular events would have yielded positive results. There is also the argument that LDL cholesterol levels in the populations studied were relatively low and the effect of statins in individuals with higher LDL cholesterol levels (above 150 mg/dL [3.88 mmol/L]) was not adequately studied. For these reasons some practitioners support use of statins for primary prevention of cardiovascular events in the dialysis population and for individuals with LDL cholesterol levels well above 150 mg/dL (3.88 mmol/L

Avoiding agents that increase the blood levels of statins
A number of medications may interact with the metabolism of statins and thereby increase statin blood levels. Medications known to increase statin blood levels should either be avoided, or, if necessary, the statin should be reduced or stopped. While this is true for all patients, it is especially true for patients with CKD Stages 4-5, since some statin levels tend to be high in Stage 4-5 CKD patients. It is even more critical for interactions to be avoided among kidney transplant patients receiving cyclosporine (and possibly tacrolimus), since cyclosporine often increases statin levels through mechanisms that may be exacerbated by the addition of a third interacting agent.

7) Hypertension: The pathogenesis of hypertension in patient with CKD is multifactorial. Multiple factors are involved in the development of hypertension in the CKD population, including extracellular volume expansion from salt and water retention and activation of the renin-angiotensin-aldosterone system.123 Increased sympathetic tone also has been observed with an increase in norepinephrine activity.

Treatment of hypertension in chronic kidney disease patients, nondialysis ND-CKD without diabetes mellitus. Strategy for treatment of hypertension based on urine albumin excretion and target blood pressure

8) Anorexia & Malnutrition
Limited data defining CKD stage where malnutrition develops Malnutrition is common in patients with advanced chronic renal disease because of: a lower food intake (principally due to anorexia), decreased intestinal absorption and digestion, and metabolic acidosis Studies have shown a strong correlation between malnutrition and death in maintenance dialysis patients It is desirable to monitor the nutritional status of patients with chronic kidney disease. NKF K/DOQI guidelines: evaluate for signs of malnutrition when GFR < 60 mL/min/1.73 m2 A low plasma concentration of albumin and/or creatinine (which varies with muscle mass as well as GFR) may be indicative of malnutrition. Nutrition assessment dietary protein calorie intake serum albumin urine protein Nutritional Status Protein-energy malnutrition is very common among patients with advanced CKD (stages 4 and 5). 9 Causes of malnutrition in these patients include inadequate food intake secondary to anorexia, altered taste sensation, and the unpalatability of prescribed diets. Other factors in the ESRD population, such as the effect of the dialysis procedure on removal of nutrients, hypercatabolism induced by other inflammatory conditions, and blood loss are also contributory. Protein restriction as an intervention to potentially delay progression of kidney disease in patients with stage 3 or 4 CKD may also lead to protein malnutrition by the time a patient reaches ESRD; therefore the risks versus the benefits of this intervention must be considered on an individual basis (see Chap. 52) as hypoalbuminemia and malnutrition have a strong association with mortality in chronic dialysis patients. Patients with ESRD have increased nutritional needs relative to the general population, based on the effect of the disease state and the dialysis procedure on nutritional status. The recommended dietary protein intake in chronic hemodialysis patients is 1.2 g/kg body weight per day. 9 The recommended intake for chronic peritoneal dialysis patients is at least 1.2 to 1.3 g/kg body weight per day, based on the increased protein loss that occurs with this dialysis modality. Protein requirements are higher in patients who are acutely ill (see Chap. 149). The recommended total daily energy intake in both hemodialysis and peritoneal dialysis patients is 35 kcal/kg (147 kJ/kg) body weight per day. For peritoneal dialysis patients, this includes intake from both diet and the glucose absorbed from peritoneal dialysate. For patients older than 60 years of age this criterion differs, because increasing age is generally associated with reduced physical activity and lean body mass. Daily energy intake for these patients is 30 to 35 kcal/kg (126–147 kJ/kg) body weight per day. Nutritional support should be considered for those patients who cannot achieve these goals with oral intake alone. Another option for nutritional supplementation in patients on hemodialysis includes interdialytic parenteral nutrition (see Chap. 151). Vitamin requirements for ESRD patients receiving dialysis differ from those of a healthy person because of dietary modifications, kidney dysfunction, and dialysis therapy. The plasma concentrations of vitamins A and E are elevated in ESRD, whereas those of the water-soluble vitamins (B1, B2, B6, B12, niacin, pantothenic acid, folic acid, biotin, and vitamin C) tend to be low in large part because many are dialyzable. The goal for vitamin supplementation should be to prevent subclinical and frank deficiency and to avoid pathology from overdosage. Special vitamin supplements have been formulated for the dialysis population, which primarily include B vitamins with C and folic acid. Supplementation with L-carnitine has been advocated for its potential benefits in patients with ESRD, including management of hypertriglyceridemia, hypercholesterolemia, and anemia. 128 Although some of these benefits have been demonstrated, the evidence does not strongly support routine supplementation. Cost and the addition of yet another medication to the already complex regimen prescribed for many of these patients also mitigate against the routine use of this agent.

Malnutrition: Protein-energy malnutrition is common in patients with stage 4 or 5 CKD Daily protein intake should be 1.2g/kg for patient undergoing hemodialysis and 1.2 to 1.3 g/kg for those undergoing peritoneal dialysis Daily energy intake should be 35 kcal/kg for patients undergoing any type of dialysis ,the intake should be lowered to kcal/kg for patients older than 60 years. Water-soluble vitamins should be supplemented to replace dialysis-induced loss L-carnitine is not recommended for patients with ESKD unless the disorders for which it has shown benefit (eg: hpertriglyceridemia, hypercholesterimia, and anemia) do not respond to standard therapies. The desire to maintain adequate nutrition among patients with chronic renal failure clearly competes with attempts to slow the progression of renal dysfunction with the use of a low protein diet. Although the benefits of slowing progressive chronic kidney disease with marked dietary protein restriction remain controversial, it is probably reasonable to restrict intake to 0.8 to 1.0 g/kg of high biologic value protein since this level of restriction avoids protein malnutrition and may slow progressive disease. In addition, since symptoms and signs of uremic toxicity are enhanced with high intakes of protein, it is reasonable to prescribe this diet to all patients with a GFR below 20 mL/min per 1.73 m2

The nutritional intake is adjusted based upon individual needs
* The nutritional intake is adjusted based upon individual needs. This is particularly important for the carbohydrate, lipid, and mineral contents of the diet. GFR <70 mL/min/1.73 m2 with evidence for progression. Some recommend 0.56 to 0.75 g/kg/day, with 0.35 g/kg/day of high biological value protein. The protein intake is increased by 1.0 g/day of high biological value protein for each gram per day of urinary protein loss. This is performed under close supervision and dietary counseling. Phosphate binders often are also needed to maintain normal serum phosphorus levels. § 10 mg/day for males and nonmenstruating females, 18 mg/day for menstruating females.

9) Other complications Self reading:
Management of other complications: Uremic bleeding Pericarditis Uremic neuropathy Thyroid dysfunction Reference: UpToDate: Overview of the management of chronic kidney disease in adults Uremic bleeding — An increased tendency to bleeding is present in both acute and chronic kidney disease. This appears to correlate most closely with prolongation of the bleeding time, due primarily to impaired platelet function. (See "Platelet dysfunction in uremia".) No specific therapy is required in asymptomatic patients. However, correction of the platelet dysfunction is desirable in patients who are actively bleeding or who are about to undergo a surgical or invasive procedure (such as a renal biopsy). A number of different modalities can be used in this setting, including the correction of anemia, the administration of desmopressin (dDAVP), cryoprecipitate, estrogen, and the initiation of dialysis. (See "Platelet dysfunction in uremia".) Pericarditis — Advances in management have decreased the incidence of pericarditis in patients with chronic kidney disease, but this problem is still associated with significant morbidity and occasional mortality. (See "Pericarditis in renal failure".) Fever, pleuritic chest pain, and a pericardial friction rub are the major presentations of uremic pericarditis. One relatively characteristic feature of uremic pericarditis is that the electrocardiogram does not usually show the typical diffuse ST and T wave elevation, presumably because this is a metabolic pericarditis and epicardial injury is uncommon. Thus, the finding of these abnormalities suggests some other cause for the pericarditis. The occurrence of pericarditis in a patient with mild to moderate chronic kidney disease is another clue that the renal disease is probably not responsible. The development of otherwise unexplained pericarditis in a patient with advanced renal failure is an indication to institute dialysis (providing there is no circulatory compromise or evidence of impending tamponade) (see below). Most patients with uremic pericarditis respond rapidly to dialysis with resolution of chest pain as well as a decrease in the size of the pericardial effusion. (See "Pericarditis in renal failure".) Uremic neuropathy — Dysfunction of the central and peripheral nervous system, including encephalopathy (impaired mental status progressing if untreated to seizures and coma), polyneuropathy, and mononeuropathy are important complications of end-stage renal disease. They have become much less common because of the current tendency to earlier initiation of dialysis. Sensory dysfunction, characterized by the restless leg or burning feet syndromes, are frequent presentations of uremic neuropathy. These complications are usually absolute indications for the initiation of dialysis. The extent of recovery from uremic neuropathy is directly related to the degree and extent of dysfunction prior to the initiation of dialysis. (See "Uremic polyneuropathy".) Thyroid dysfunction — The kidney normally plays an important role in the metabolism, degradation, and excretion of several thyroid hormones. It is not surprising therefore that impairment in kidney function leads to disturbed thyroid physiology. However, the overlap in symptomatology between the uremic syndrome and hypothyroidism requires a cautious interpretation of the tests of thyroid function. It is usually possible in the individual patient with chronic renal disease to assess thyroid status accurately by physical diagnosis and thyroid function testing. The disturbances that can occur include low serum free and total T3 concentrations and normal reverse T3 and free T4 concentrations. The serum thyrotropin (TSH) concentration is normal and most patients are euthyroid. (See "Thyroid function in chronic kidney disease".)

Prescribing in people with CKD

Chronic Kidney Disease: Management of Complications

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