1. Chronic Renal Failure (CKI)

2. Objectives Definition. Pathophysiology. Causes Presentation.
Complications and Treatment.
Prevention

3. Definition
Chronic kidney disease (CKD) refers to an irreversible deterioration in renal function which classically develops over a period of years. Initially, it is manifest only as a biochemical abnormality (Azotemia).
Eventually, loss of the excretory, metabolic and endocrine functions of the kidney leads to the clinical symptoms and signs of renal failure, which are referred to as Uraemia.

4. The term chronic renal failure applies to the process of continuing significant irreversible reduction in nephron number, and typically corresponds to CKD stages 3–5.
The dispiriting term end-stage renal disease represents a stage 5 of CKD where the accumulation of toxins, fluid, and electrolytes normally excreted by the kidneys results in the uremic syndrome.
The normal annual mean decline in GFR with age from the peak GFR (~120 mL/min per 1.73 m2) attained during the third decade of life is ~1 mL/min per year per 1.73 m2, reaching a mean value of 70 mL/min per 1.73 m2 at age 70.

5. Classification of Chronic Kidney Disease (CKD)
GFR (ml/min/1.73m2
Description
Stage
≥90a
> 90b
Kidney damage with normal or high GFR 1
60–89
Kidney damage with slightly low GFR 2
30–59
Moderately low GFR 3
15–29
Severe low GFR 4
<15
Kidney failure 5
aWith risk factors for CKD.
bWith demonstrated kidney damage (e.g., persistent proteinuria, abnormal urine sediment, abnormal blood and urine chemistry, abnormal imaging studies).

6. Common causes of end-stage renal failure%
Disease
20-40
Diabetes mellitus
20-30
Interstitial diseases
10-20
Glomerular diseases
5-20
Hypertension
5-10
Systemic inflammatory diseases 5
Renal artery stenosis
5-20%
Unknown

7. Pathophysiology and Biochemistry of Uremia
In summary, the pathophysiology of the uremic syndrome can be divided into manifestations in three spheres of dysfunction:
(1)Those consequent to the accumulation of toxins normally undergoing renal excretion, including products of protein metabolism;
(2) Those consequent to the loss of other renal functions, such as fluid and electrolyte homeostasis and hormone regulation; and
(3) Progressive systemic inflammation and its vascular and nutritional consequences.

8. Clinical assessment
Chronic kidney disease may present as a raised blood urea and creatinine found during routine examination, often accompanied by hypertension, proteinuria or anaemia. The great majority of patients with slowly progressive disease are asymptomatic until GFR falls below 30 mL/min/1.73 m2 (stage 4 or 5).
In ESRD (stage 5) there may be pruritus, anorexia, nausea and vomiting. Later, hiccups, unusually deep respiration related to metabolic acidosis (Kussmaul's respiration), muscular twitching, fits, drowsiness and coma ensue.

9. Suggested Screening Tests in Chronic Renal Failure
Full blood count.
Urea, electrolytes and creatinine: dietary restriction of potassium. Calcium, phosphate and albumin: dietary restriction of phosphate, calorie maintenance in advanced renal impairment
Parathyroid hormone: treatment of secondary hyperparathyroidism with 1-α-hydroxylated vitamin D
Lipids, glucose ± HbA1c: aggressive metabolic control
Hepatitis and HIV serology: if dialysis is needed (vaccination against hepatitis B if no previous infection; isolation of dialysis machine if positive)

10. Suggested Screening Tests in Chronic Renal Failure (Cont.)
Renal ultrasound: to confirm/refute two equal-sized unobstructed kidneys
Chest X-ray: heart size, pulmonary oedema
ECG: if > 40 years or there are risk factors for cardiac disease
Renal artery imaging: if renovascular disease is suspected
Tissue typing
Cytomegalovirus, Epstein-Barr virus, varicella zoster virus

11. Retarding the progression of CRF
Once the plasma creatinine exceeds about 300 μmol/l (3.4 mg/dl), there is usually progressive deterioration in renal function, irrespective of aetiology. The rate of deterioration is very variable between patients but is relatively constant for an individual patient.

12. Signs and symptoms of chronic renal failure

13. General Considerations
Blood pressure control: maximum target 130/80 mmHg, reduced to 125/75 mmHg in diabetes mellitus, and anyone with an elevated PCR or ACR
Use of ACE inhibitors or ARBs in those with proteinuria
Lipid management
Lifestyle advice: smoking, exercise, diet and weight e.g. 'Restriction of dietary protein intake delays the progression of chronic renal failure.

14. Complications and treatment
Fluid, Electrolyte and Acid-Base Disorders
Sodium and Water Homeostasis: Hyponatremia is not commonly seen in CKD patients but, when present, can respond to water restriction. Thiazide diuretics have limited utility in stages 3–5 CKD, such that administration of loop diuretics, including furosemide, bumetanide, or torsemide, may also be needed. The combination of loop diuretics with metolazone, can help effect renal salt excretion.

15. Fluid, Electrolyte and Acid-Base Disorders
Potassium Homeostasis: hyperkalemia may be precipitated in certain settings. These include increased dietary potassium intake, protein catabolism, hemolysis, hemorrhage, transfusion of stored red blood cells, and metabolic acidosis, (ACE) (ARBs), and spironolactone and other potassium-sparing.
Metabolic Acidosis: Hyperkalemia, if present, further depresses ammonia production. Alkali supplementation be considered when the serum bicarbonate concentration falls below 20–23 mmol/L.

16. Disorders of Calcium and Phosphate Metabolism
Different types of bone disease occur with chronic kidney disease, as follows: (1) high turnover bone disease due to high parathyroid hormone (PTH) levels; (2a) low turnover bone disease (adynamic bone disease); (2b) defective mineralization (osteomalacia); (3) mixed disease; and (4) beta-2-microglobulin associated bone disease.
Secondary hyperparathyroidism develops because of hyperphosphatemia, hypocalcemia, decreased renal synthesis of 1,25-dihydroxycholecalciferol

17. Disorders of Calcium and Phosphate Metabolism
Hyperphosphatemia develops from the inability of the kidneys to excrete the excess dietary intake.
Calciphylaxis: is a devastating condition seen almost exclusively in patients with advanced CKD. It is heralded by livedo reticularis and advances to patches of ischemic necrosis, especially on the legs, thighs, abdomen, and breasts.

18. Disorders of Calcium and Phosphate Metabolism
Phosphate binders are calcium acetate and calcium carbonate. A major side effect of calcium-based phosphate binders is total-body calcium accumulation and hypercalcemia, especially in patients with low-turnover bone disease.
Sevelamer, a non-calcium-containing polymer, also functions as a phosphate binder; it does not predispose CKD patients to hypercalcemia, and may attenuate calcium deposition in the vascular bed.

19. Cardiovascular Abnormalities
Ischemic Vascular Disease: Traditional risk factors include hypertension, hypervolemia, dyslipidemia, sympathetic overactivity, and hyperhomocysteinemia. The CKD-related risk factors comprise anemia, hyperphosphatemia, hyperparathyroidism, sleep apnea, and generalized inflammation.
Heart Failure: Secondary to myocardial ischemia, left ventricular hypertrophy, and frank cardiomyopathy, in combination with the salt and water retention that can be seen with CKD, often results in heart failure or even episodes of pulmonary edema.
Hypertension and Left Ventricular Hypertrophy: Are thought to be related primarily, but not exclusively, to prolonged hypertension and ECFV overload. In addition, anemia and the placement of an arteriovenous fistula for hemodialysis can generate a high cardiac output state and consequent heart failure. Low blood pressure actually carries a worse prognosis than does high blood pressure.

20. Cardiovascular Abnormalities
Management of Hypertension: In CKD patients with diabetes or proteinuria > 1 g per 24 h, blood pressure should be reduced to 125/75, The ACE inhibitors and ARBs slow the rate of decline of kidney function, even in dialysis patients, but their use may be complicated by the development of hyperkalemia. Potassium-sparing diuretics should be used with caution or avoided altogether in most patients.
Management of Cardiovascular Disease: Lifestyle changes, including regular exercise, Hyperhomocysteinemia may respond to vitamin therapy, Hyperlipidemia in patients with CKD should be managed according to national guidelines.

21. Pericardial Disease
Rarely lead to tamponade. However, the pericardial effusion can be asymptomatic. Pericarditis is observed in advanced uremia. It is now more often observed in underdialyzed, nonadherent patients than in those starting dialysis.
Treatment: Uremic pericarditis is an absolute indication for the urgent initiation of dialysis or for intensification of the dialysis prescription in those already receiving dialysis. Because of the propensity to hemorrhage in pericardial fluid, hemodialysis should be performed without heparin. A pericardial drainage procedure should be considered in patients with recurrent pericardial effusion.

22. Hematologic Abnormalities
Anemia: Causes of Anemia in CKD
Erythropoietin deficiency.
Diminished red blood cell survival
Bleeding diathesis
Iron deficiency
Folate or vitamin B12 deficiency
Hyperparathyroidism/bone marrow fibrosis
Chronic inflammation
Hemoglobinopathy
Comorbid conditions: hypo/hyperthyroidism, pregnancy, etc.

23. Anemia
Treatment: Adequate bone marrow iron stores should be available before treatment with Erythropoietin (EPO) is initiated. Oral iron supplementation should be attempted.
Epoetin alfa (Epogen): Induces release of reticulocytes from bone marrow into blood stream. Before starting Epogen, iron stores should be checked, and the aim is to keep iron saturation at 30-50% and ferritin at
Darbepoetin: Mechanism of action is similar to that of endogenous erythropoietin, has longer half-life than epoetin alfa (may be administered weekly or biweekly).
Iron Salts: Ferrous sulfate, Iron dextran (When oral administration is unfeasible or ineffective), Iron sucrose (Used to treat iron deficiency in conjunction with erythropoietin due to chronic hemodialysis), Ferric gluconate.

24. Anemia resistant to recommended doses of EPO
May be due to some combination of the following:
Acute or chronic inflammation.
Chronic blood loss or hemolysis.
Chronic infection.
Inadequate dialysis.
Severe hyperparathyroidism, or
Malignancy.

25. Abnormal Hemostasis
Prolonged bleeding time, decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption. CKD patients also have a greater susceptibility to thromboembolism.
Abnormal bleeding time and coagulopathy in patients with renal failure may be reversed temporarily with desmopressin (DDAVP), cryoprecipitate, IV conjugated estrogens, blood transfusions, and EPO therapy.

26. Neuromuscular Abnormalities
Early manifestations of CNS complications include mild disturbances in memory and concentration and sleep disturbance. Neuromuscular irritability, including hiccups, cramps, and fasciculations or twitching of muscles, becomes evident at later stages. Asterixis, myoclonus, seizures, and coma can be seen in advanced cases. Peripheral neuropathy initially, sensory nerves are involved more than motor.
Evidence of peripheral neuropathy without another cause (e.g., diabetes mellitus) is a firm indication for starting renal replacement therapy.

27. Gastrointestinal and Nutritional Abnormalities
Uremic fetor, a urine-like odor on the breath, derives from the breakdown of urea to ammonia in saliva and is often associated with an unpleasant metallic taste (dysgeusia). Gastritis, peptic disease, and mucosal ulcerations at any level of the GI tract. These patients are also prone to constipation, which can be worsened by the administration of calcium and iron supplements. The retention of uremic toxins also leads to anorexia, nausea, and vomiting. Patient at risk for malnutrition. Protein-energy malnutrition.

28. Endocrine-Metabolic Disturbances
Fasting blood glucose is usually normal or only slightly elevated. Because the kidney contributes to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic patients, both in the fasting and postprandial states. Many hypoglycemic agents require dose reduction in renal failure, and some, such as metformin, are contraindicated when the GFR is less than half of normal.
In women with CKD, estrogen levels are low, and menstrual abnormalities and inability to carry pregnancies to term are common, a high rate of spontaneous abortion. Men with CKD have reduced plasma testosterone levels, and sexual dysfunction and oligospermia may supervene.

29. Dermatologic Abnormalities
Pruritus is quite common. In advanced CKD, even on dialysis, patients may become more pigmented, and this is felt to reflect the deposition of retained pigmented metabolites, or urochromes. EPO therapy was initially reported to improve uremic pruritus, although that is not always the case. Local moisturizers, mild topical glucocorticoids, oral antihistamines, and ultraviolet radiation have been reported to be helpful.
Nephrogenic fibrosing dermopathy has recently been reported in which progressive subcutaneous induration, especially on the arms and legs, is described. Seen in patients with CKD, most commonly on dialysis. Recent reports suggest that exposure to the magnetic resonance contrast agent, gadolinium, may precipitate this syndrome.

30. Prognosis of CKD
Patients with chronic kidney disease generally progress to ESRD. The rate of progression depends on the underlying diagnosis, on the successful implementation of secondary preventative measures, and on the individual patient.
Patients on chronic dialysis have a high incidence of morbidity and mortality.
Patients with ESRD who undergo renal transplantation survive longer than those on chronic dialysis.

31. Renal Replacement Therapy
Unlike other forms of end-stage organ failure, renal failure is unique in having three modalities of therapy:
(1) Hemodialysis,
(2) Peritoneal dialysis, and
(3) Renal transplantation.

32. Intermittent haemodialysis
This modality offers the best rate of small solute clearance. In previously undialysed patients with ARF and elevated plasma urea, haemodialysis should be started gradually because of the risk of confusion and convulsions due to cerebral oedema (dialysis disequilibrium). Typically, 1 hour of treatment should be prescribed. Subsequently, patients with ARF who are haemodynamically stable can be treated by 3-4 hours of haemodialysis on alternate days, or 2-3 hours every day if they are severely catabolic.
For patients at risk of bleeding, epoprostenol may be used instead of heparin for anticoagulation but can cause hypotension. For short dialyses or patients with abnormal clotting, it may be possible to avoid anticoagulation.

33. Intermittent haemodialysis
Haemodialysis is started when the patient has symptomatic advanced renal failure but before the development of serious complications, often with a plasma creatinine of μmol/l ( mg/dl). Vascular access is required. Haemodialysis is usually carried out for 3-5 hours three times weekly. Plasma urea and creatinine are lowered by each treatment but do not return to normal.

34. Flow Scheme Hemodialysis
Blood Pump
Dialyzer
Anti-Coagulation
Blood to the Patient
Fresh Dialysate
Used Dialysate
Blood from the Patient

35. Haemofiltration
This may be either intermittent, with litres of plasma ultrafiltrate exchanged for replacement fluid over 3-5 hours (high-volume haemofiltration), or continuous with 1-2 litres/hour of filtrate replaced (equivalent to a GFR of ml/min); higher rates of filtration may be of benefit in patients with sepsis and multi-organ failure.

36. Peritoneal dialysis
In ARF, this technique is rarely used. It is less efficient than haemodialysis, and seldom achieves adequate biochemical control in catabolic patients. It requires an intact peritoneal cavity and is not feasible after recent abdominal surgery

37. Peritoneal dialysis
In peritoneal dialysis, 1.5–3 L of a dextrose-containing solution is infused into the peritoneal cavity and allowed to dwell for a set period of time, usually 2–4 h. The rate of peritoneal solute transport varies from patient to patient and may be altered by the presence of infection (peritonitis), drugs, and physical factors such as position and exercise.
Continuous ambulatory peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), or a combination of both. CAPD used during the day and exchanged three to five times daily. In CCPD, exchanges are performed in an automated fashion, usually at night.

38. Haemodialysis Peritoneal dialysis
Efficient
Less efficient
4 hours three times per week usually adequate
Four exchanges per day usually required, each taking minutes (continuous ambulatory peritoneal dialysis) or 8-10 hours each night (automated peritoneal dialysis)
2-3 days between treatments
A few hours between treatments
Requires visits to hospital (although home treatment possible for some patients)
Performed at home
Requires adequate venous circulation for vascular access
Requires an intact peritoneal cavity without major scarring from previous surgery
Careful compliance with diet and fluid restrictions required between treatments
Diet and fluid less restricted
Fluid removal compressed into treatment periods; may cause symptoms and haemodynamic instability
Slow continuous fluid removal, usually asymptomatic
Infections related to vascular access may occur
Peritonitis and catheter-related infections may occur
Patients are to some extent dependent on others
Patients can take full responsibility for their treatment

39. Complications during Hemodialysis
Hypotension: . Numerous factors appear to increase the risk of hypotension, including excessive ultrafiltration with inadequate compensatory vascular filling, impaired vasoactive or autonomic responses, osmolar shifts, overzealous use of antihypertensive agents, and reduced cardiac reserve.
Muscle cramps : common complication of the procedure use of low-sodium–containing dialysate.
Anaphylactoid reactions to the dialyzer.
Headache.
Haemorrhage
Cardiac arrhythmias

40. Complications during Peritoneal Dialysis
Peritonitis.
Hypoproteinemia.
Hyperglycemia and weight gain.
Complications of insulin resistance, including hypertriglyceridemia.

41. Renal Transplantation
Renal transplantation offers the best chance of long-term survival in patients with end-stage renal disease. It can restore normal kidney function and correct all the metabolic abnormalities of CRF. All patients should be considered for transplantation unless there are active contraindications.
Kidney grafts may be taken from a cadaver or from a living donor.
ABO (blood group) compatibility between donor and recipient is essential, and the degree of matching for major histocompatability (MHC) antigens-particularly HLA-DR-influences the incidence of rejection.

42. Renal Transplantation

43. CONTRAINDICATIONS TO RENAL TRANSPLANTATION
Absolute:
Active Malignancy
Active vasculitis or anti-GBM disease, with positive serology-at least 1 year of remission is recommended prior to transplantation
Severe IHD
Severe occlusive aorto-iliac vascular disease .
Relative
Age: not routinely offered to very young children (< 1 year) or older people (> 75 years)
High risk of disease recurrence in the transplant kidney.
Disease of the lower urinary tract-in patients with impaired bladder function, an ileal conduit may be considered
Significant comorbidity.

44. Renal Transplantation
All transplant patients require regular life-long clinic follow-up to monitor renal function and immunosuppression.
Immunosuppressive therapy is required to prevent rejection. Different therapeutic regimens are used; a commonly used one is triple therapy consisting of prednisolone, plus ciclosporin or tacrolimus and azathioprine. Newer immunosuppressive drugs such as mycophenolate mofetil and rapamycin are increasing in use.

45. Thanks for Listening