1. Lecture Five—March 4, 2013

3. “Acute Kidney Injury” Sudden decrease in renal function  inability to maintain acid- base balance Inability to maintain fluid balance Inability to maintain electrolyte balance Inability to excrete nitrogenous wastes Serum Creatinine is a convenient marker

4. RIFLE Criteria—3 progressive levels of acute kidney injury based on elevation in serum Cr or decline in urinary output with two outcome measures (loss and ESRD) Risk—1.5-fold increase in serum Cr or urine output < 0.5 mL/kg/h × 6 h Injury—2-fold increase in serum Cr or urine output < 0.5 mL/kg/h x 12 h Failure—3-fold increase in serum Cr or urine output <0.5 mL/kg/h x 24 h AKIN Criteria—similar, also mention serum Cr >0.3 mg/day is risk for acute kidney injury Serum Cr increases 1-1.5 mg/dL if no renal function 5% of hospital admissions and 30% of ICU admissions have a diagnosis of acute kidney injury/acute renal failure ARF will develop in 25% of hospitalized patients ARF of any type  higher risk for all-cause mortality

6. Nonspecific Often due uremia or underlying cause Uremia—N/V, malaise, altered sensorium Hypertension Hypovolemia or hypervolemia Hypervolemia  rales Pericardial effusions/friction rub Cardiac tamponade Arrhythmias (hyperkalemia) Abdominal pain and ileus Bleeding and clotting disorders Encephalopathy and seizures

7. Elevated BUN/Cr Hyperkalemia impaired K+ excretion ECG—peaked T waves, long PR, wide QRS, long QT if hypocalcemia is also present Metabolic Acidosis decreased organic and nonorganic acid clearance Hyperphosphatemia impaired phosphate excretion Anemia decreased erythropoetin production platelet dysfunction

8. Most common reason for ARF (40-80%) Prerenal azotemia – due to renal hypoperfusion Decreased intravascular volume Changes in vascular resistance Low cardiac output—low effective renal arterial flow BUN:Cr ratio typically >20:1 (increased urea reabsorption) Low fractional excretion percent of sodium High urine osmolality Urinary sediment—benign or hyaline casts Treatment—CORRECTION OF UNDERLYING CAUSE Maintain euvolemia Maintain normal K+ levels Avoid nephrotoxic drugs

9. Least common reason for ARF (5-10%); Reversible Post renal azotemia—urinary flow from both kidneys (or a single functional kidney) is obstructed Elevated intraluminal pressure  parenchymal damage Urethral obstruction, bladder dysfunction or obstruction, obstruction of both ureters or renal pelvises Initially—high urine osmolality, low urine sodium, high BUN:Cr (>20:1)—similar to prerenal ARF After several days—low urine sodium, low osmolality Treatment—CORRECTION OF UNDERLYING CAUSE Avoid post-treatment volume depletion Prompt treatment can result in partial or complete reversal

11. Up to 50% of all cases of ARF Exclude prerenal and postrenal causes of ARF Major injury sites—tubules, interstitium, vasculature, glomeruli Acute Tubular Necrosis—ischemia, nephrotoxins Acute Glomerulonephritis— immune complex-mediated, pauci- immune, anti-GBM Acute Interstitial Nephritis— allergic reaction, drug reaction, infection, collagen vascular disease

12. 85% of intrinsic acute renal failure Ischemia—tubular damage from states of low perfusion Inadequate GFR and inadequate blood flow to maintain parenchymal cellular formation Nephrotoxins—exogenous more commonly cause damage than endogenous Exogenous—aminoglycosides, amphotericin B, vancomycin, acycovir, cephalosporins, radiographic contrast media, cycosporine, antineoplastics, mercury, cadmium, arsenic Endogenous—heme-containing products, uric acid, paraproteins

13. Aminoglycosides—up to 25% on therapeutic levels; medication can remain in renal tissues for up to 1 month Amphotericin B—can cause hypokalemia and nephrogenic diabetes insipidus Radiographic contrast media—contrast nephropathy is 3 rd leading cause of new ARF in hospitalized pts Combination of DM and kidney dysfunction poses greatest risk Can reduce risk by using less contrast and IV infusion of NS before and after contrast Others—vancomycin, IV acyclovir, cephalosporins, cyclosporine, antineoplastics, heavy metals

14. Myogobinuria—from rhabdomyolysis mainly when CK >20,000-50,000 False + urine dip for hemoglobin (dark brown but NO RBCs) ↑ K+, Phosphate, uric acid; ↓ Calcium Volume repletion Hemoglobin—hemolysis Hyperuricemia—cell lysis Bence Jones Protein—seen with multiple myeloma Dark urine in Rhabdomyolysis Bence Jones protein

15. Signs/Symptoms—see general ARF S/S Labs—BUN:Cr < 20:1 (tubular function not intact) ↑ K+, phosphate, urine Na may see brown urine +/- oliguria Pigmented granular casts or “muddy brown casts” Renal tubular epithelial cells or epithelial cell casts

16. 1. Bland sediment 2. Renal tubular epithelial cells 3. Renal tubular epithelial cell cast 4. Finely granular casts 5. Muddy brown casts with necrotic debris Muddy brown cast in ATN

17. Treatment—avoid volume overload and hyperkalemia Loop diuretics—often used at high doses; controversial Restrict dietary protein to 0.6 g/kg/d to prevent metabolic acidosis Improve ↑ Ca and phosphate with diet and phosphate-binding agents; Dialysis—if life-threatening electrolyte disturbances, volume overload unresponsive to diuresis, worsening acidosis, or uremic complications Prognosis—initial injury, maintenance, and recovery maintenance phase—1-3 weeks—cellular repair and removal of tubular debris recovery phase—GFR begins to rise and BUN/Cr begin to fall Mortality—20-50% in hospitalized settings, can be up to 70% Leading causes of death—infections, fluid/electrolyte imbalance, worsening of underlying disease

18. 10-15% of intrinsic ARF; 70% of cases 2 o drugs Other causes—infections, immunologic disorders, idiopathic Interstitial inflammatory response with edema and possible tubular cell damage Signs/Symptoms—fever (>80%), transient maculopapular rash (25-50%), eosinophilia (80%) Urine—RBCs (95%), WBCs, WBC casts, eosinophils Treatment—removal of cause; supportive; steroids Recovery in weeks-months May need urgent dialysis for up to 1/3 of pts Often good prognosis; rarely progress to ESRD

19. Rare—5% of ARF; inflammatory glomerular lesions on pathology Immune complex deposition—IgA nephropathy (Berger disease), post-infectious glomerulonephritis, endocarditis, lupus nephritis, cryoglobulinemic, MPGN Anti-GBM—confined to kidney or associated with pulmonary hemorrhage; autoantibodies against GBM Pauci-immune—small vessel vasculitis associated with ANCAs (granulomatosis with polyangiitis/Wegener granulomatosis) Other causes—HTN emergencies, Hemolytic-uremic syndrome, Thrombotic thrombocytopenic purpura

20. Signs/Symptoms—hypertensive, edematous Labs—elevated BUN/Cr (usually >20:1 ratio)—not reliable marker of kidney function Urine—hematuria, proteinuria (<3 g/d), RBCs, RBC casts, WBCs Other tests—complement, ASO, anti-GBM, ANCAs, ANA, hepatitis panel, blood culture, renal US, renal bx Treatment—depends on underlying cause steroids, cytotoxic agents plasma exchange if Goodpasture disease or pauci-immune

22. > 20 million Americans 1 in 9 adults Over 70% of stage 5 CKD and ESRD—DM or HTN Rarely reversible— progressive decline in function even after the inciting event is removed Independent risk factor for cardiovascular disease Read – Table 22-5 p. 884— stages of CKD

23. Signs/Symptoms—asymptomatic for most of course S/S manifest usually when CKD well advanced ( GFR <10-15) Build up of metabolic waste/uremic toxins  uremic syndrome (Table 22-7) Most common physical finding—HTN Other findings—sallow skin, easy bruising, uremic fetor, cardiopulmonary signs, altered mental status S/S of uremia—immediate admission and nephro consult ID and correct reversible causes or exacerbating factors Imaging—small echogenic kidneys bilaterally supports dx Labs—documented ↑ BUN/Cr over at least 3 mo, or persistent proteinuria or abnormal renal imaging (even if GFR is normal) Urine sediment—broad, waxy casts may be present Proteinuria—if present, quantify

24. Death from CV disease—45% of all pts on dialysis 80-90% of CKD pts die before reaching need for dialysis HTN—most common complication of CKD Nonpharmacologic therapy—decrease salt intake to 3 g/d (2g/d if persistent HTN or CHF); weight loss; exercise; treat OSA Pharmacologic therapy—diuretics; ACE/ARB (Monitor Cr and K+) Second line drugs—CCBs, BBs; often need adjunct drugs Goal of <130/80 mmHg CAD—aggressively treat risk factors CHF—fluid and salt restriction; diuretics; ACE Pericarditis—rare—uremic pericarditis  mandatory hospitalization and hemodialysis

25. Typical: ↑ phosphate, ↓ Ca and vit D, secondary hyperparathyroidism due to first 3 abnormalities Increased fracture risk; now also noted increased vascular calcification Renal Osteodystrophy—common—includes osteitis fibrosa cystica; metastatic calcifications; adyamic bone disease; osteomalacia Bone pain, proximal muscle weakness, higher risk for fractures Correct calcium, phosphorus, and vitamin D levels as well as hyperparathyroidism Dietary phosphorus restriction, phosphorus binders, vitamin D replacement therapy

26. Anemia—mainly due to decreased erythropoetin Erythropoetin-like agents approved for goal Hgb of 10-12 if no other treatable causes of anemia present Higher Hgb—increased risk of stroke and other CV events HTN—complication of erythropoietin or darbepoetin in 20% Iron deficiency—impaired GI iron absorption Ferritin <100-200 or iron saturation <20% is abnormal Check iron studies, thyroid, vitamin B12, folate and fecal occult blood before starting erythropoetin Coagulopathy—platelet dysfunction Treatment—only if symptomatic Raising Hgb to 9-10 Desmopressin—short-lived but effective (surgery) Conjugated estrogens—can help for several weeks but rarely used Dialysis—improves beeding time but does not normalize Cryoprecipitate—lasts <24 hrs—rarely used

27. Hyperkalemia—CKD stages 4-5 but can occur earlier cardiac monitoring if EKG changes or >6.0-6.5 mEq/L sodium polystyrene sulfonate; β- agonists, insulin + glucose, calcium gluconate Chronically elevated K+ - dietary K+ restriction (2 g/d), adjust medications, loop diuretics Acid-Base Disorders—inability to excrete acid from dietary proteins mainly due to loss of renal mass treat with sodium bicarbonate Neurologic Complications— uremic encephalopathy (GFR <5-10)—improves with dialysis neuropathy—65% of stage 5 and ESRD pts—varied presentations Endocrine Complications— Diabetics—higher circulating insulin levels; may need to adjust meds discontinue metformin if GFR <60 due to increased risk of lactic acidosis Sexual dysfunction—decreased testosterone and anovulation faster progression of CKD during pregnancy if Cr >1.4 Infertility common and pregnancies often have poor outcomes renal transplant is best option for ESRD pts wishing to have children

28. Protein Restriction—may slow progression to ESRD but low serum albumin at dialysis initiation is a strong predictor of mortality Salt and Water Restriction—2 g/d sodium; 2 L/d of fluid Potassium Restriction—GFR <10-20 or once pt becomes hyperkalemic; <50-60 mEq/d Phosphorus Restriction–dietary intake 800-1000 mg/d below GFR 20-30, phosphorus binders usually needed Magnesium Restriction—dangerously high levels rare unless received in medication or IV

29. GFR 10 mL/min or Cr 8 mg/dL (GFR 15 mL/min / Cr 6 mg/dL in DM) Other indications—uremic symptoms, fluid overload unresponsive to diuresis, refractory hyperkalemia, severe metabolic acidosis (pH <7.2) Hemodialysis—semipermeable membrane with constant flow of blood along one side and diasylate on the other usually 3 sessions/wk, 3-5 hrs each Peritoneal dialysis—diasylate instilled into peritoneal cavity and exchanged periodically improved autonomy minimizes symptomatic volume and electrolyte shifts less dietary restrictions lower overall cost preferred by patients Cons – removes large amounts of albumin, peritonitis is a risk

31. Up to 50% of all pts with ESRD are suitable for transplant 2/3 from deceased donors, 1/3 from living donors 1-yr survival—95% (living), 89% (deceased) 3-yr survival—88% (living), 78% (deceased) Immunosuppressive regimens required Higher risk for certain cancers and infections

32. Mortality higher in dialysis than transplant patients Overall 5-year survival for CKD pts—36% Average life expectancy for dialysis pts—3-5 yrs Most common cause of death—cardiac disease (45%) infection (14%), cerebrovascular disease (6%), cancer (4%) Mortality predictors—DM, advanced age, low albumin, low socioeconomic status, inadequate dialysis ESRD without dialysis—death in days-weeks Uremia, arrhythmias, volume overload, dyspnea