Acute Tubular Necrosis

1. Acute Tubular Necrosis Resident’s conference Presented by Dr Gagandeep K Heer, MD (PGY-2)

2. Background • Definition: ARF is defined as an abrupt or rapid decline in the renal function. • A rise in serum BUN or creatinine concentration, with or without decrease in urine output, usually is evidence of ARF. • ARF is often transient and completely reversible.

3. Background • The causes of ARF are divided into 3 categories: Prerenal Renal Postrenal • ATNis the most common cause of ARF in the renalcategory. • ATN is the 2nd most common cause of all categories of ARF in hospitalized patients, with only prerenal azotemia occurring more frequently. • In outpatients, obstruction (ureteric, bladder neck or urethral) is the 2nd most common cause of ARF after prerenal azotemia. • Other causes of ARF include acute interstitial nephritis, acute glumerulonephtitis, vasculitis, HUS, TTP, DIC, accelerated HTN, radiation nephritis, acute on chronic renal failure, renovascular obstruction (bilateral or unilateral in the setting of single functioning kidney), renal allograft rejection, intratubular deposition and obstruction (myeloma proteins, urate, oxalate crystals, etc.)

4. Pathophysiology • ATN usually occurs after an acute ischemic or toxic event, and it has a well-defined sequence of events. • Initiation phase characterized by acute decrease in GFR to very low levels, with a sudden increase in serum Cr and BUN concentrations. • Maintenance phase is characterized by sustained severe reduction in GFR and the BUN and Cr continue to rise. • Recovery phase, in which the tubular function is restored, is characterized by an increase in urine volume (if oliguria was present) and gradual decrease in Cr and BUN to their pre-injury level.

5. Ischemic ATN • Ischemic ATN is often described as a continuum of prerenal azotemia. Response to fluid repletion can help distinguish between the two: return of renal function within 24-72 hours usually indicate prerenal disease although short-lived ATN can recover within similar timeframe (e.g. self limited insult such as transient aortic clamping during suprarenal aortic aneurysm surgery). • Initiation phase: Hypoperfusion initiates cell injury that often leads to cell death. It is most prominent in straight portion of the proximal tubules and thick ascending limb of loop of Henle. The reduction in the GFR occurs not only from reduced filtration due to hypoperfusion but also from casts and debris obstructing the lumen, causing back leak of filtrate through the damaged epithelium (ineffective filtration). In addition, ischemia leads to decreased production of vasodilators (i.e. nitric oxide, prostacyclin) by tubular epithelial cells, leading to further vasoconstriction and hypoperfusion.

6. Ischemic ATN • Maintenance phase is characterized by stabilization of GFR at a very low level, and it typically lasts 1-2 weeks. Uremic complications typically develop during this phase. In addition to the above mentioned mechanism of injury, tubulo-glomerular feedback also plays a role by causing constriction of afferent arterioles by the macula densa cells, which detect and increased salt load in the distal tubules. • During Recovery phase, there is regeneration of tubular epithelial cells. An abnormal diuresis sometimes occurs, causing salt and water loss and volume depletion. The mechanism of the diuresis is not completely understood, but it may in part be due to delayed recovery of tubular cell function in the setting of increased glomerular filtration. In addition, continued use of diuretics (often administered during initiation and maintenance phases) may also add to the problem.

7. Nephrotoxic ATN • Most of the pathophysiological features of ischemic ATN are shared by the nephrotoxic forms and it has the same three phases. • Nephrotoxic injury to tubular cells occurs by multiple mechanisms including direct toxicity, intrarenal vasoconstriction, and intratubular obstruction.

9. At cellular level… • Ischemic ATN: Cellular ischemia results in series of alterations in energetics, ion transport and membrane integrity that ultimately leads to cell injury or necrosis. These changes include depletion of ATP, inhibition of active sodium transport and transport of other solutes, impairment of cell volume regulation, cytoskeletal disruption and loss of cell polarity, cell-cell and cell-matrix attachment, accumulation of intracellular calcium, altered phospholipid metabolism, oxygen free radical formation and peroxidation of membrane lipids. A characteristic feature of ischemic ATN is the absence of widespread necrosis of tubular epithelial cells. Necrosis is more subtle and is reflected in individual necrotic cells within some proximal or distal tubules. These single cells shed into tubular lumen, with resulting focal denudation of the tubular basement membrane. Interstitial edema is common.

10. Ischemic ATN

11. Histology (continued…) • Toxic ATN: The morphology differs from ischemic ATN in that the former is characterized by more extensive necrosis of the tubular epithelium. In most cases, however, the necrosis is limited to certain segments that are most sensitive to the toxin. ATN caused by hemoglobin or myoglobin has added feature of numerous red-brown tubular casts, colored by heme pigments. • During the recovery phase of ATN, the tubular epithelium regenerates, leading to the appearance of mitoses, increased size of cells and nuclei, and cell crowding. Survivors eventually display complete restoration of normal renal architecture.

12. Nephrotoxic ATN

13. Frequency • In the US: ARF is seen in 5% of all hospital admissions and upto 30% of patients admitted to the ICU. Prerenal causes account for about half of all cases. • ATN is most common cause out of the intrinsic renal diseases.

14. History • A good history is very important in diagnosis of ATN. • Find out about: Recent hypotension Sepsis Muscle necrosis (e.g. h/o seizure, cocaine use) Exposure to contrast or nephrotoxic medications Hypovolumia Other risk factors for development of ATN like underlying renal disease from DM, HTN, etc.

15. Physical Exam • Physical exam may be unremarkable because ARF is often found incidentally during routine laboratory studies (i.e. elevated BUN and Cr). • Look for pericardial friction rub (pt may have pericarditis), asterixis and/or excoriation marks related to uremic pruritis. • Hypertension or edema may be noted. • Physical findings related to the underlying disease.

16. Causes of ATN ATN is usually caused by an acute event, either ischemic or toxic.

17. Causes of Ischemic ATN It may be considered part of the spectrum of prerenal azotemia and they have the same causes and risk factors • Hypovolumic states – hemorrhage, volume depletion from GI or renal losses, burns, fluid sequestration. • Low cardiac output states – CHF and other diseases of the myocardium, valvulopathy, arrhythmia, pericardial diseases, tamponade.

18. Causes of Ischemic ATN • Systemic vasodilation – sepsis, anaphylaxis • DIC • Renal vasoconstriction – cyclosporine, norepinephrine, epinephrine, amphotericin B, etc • Hyperviscosity syndrome • Impaired renal autoregulatory responses – cyclooxygenase inhibitors

19. Causes of Nephrotoxic ATN The kidney is a good target for toxins. Not only does it have a rich blood supply, receiving 25% of CO, but it also helps in the excretion of these toxins by glomerular filtration and tubular secretion.

20. Exogenous toxins Aminoglycosides: • 10-30% of patients getting aminoglycosides develop ATN. • Risk factors include preexisting liver disease, renal disease, concomitant use of other nephrotoxins, advanced age, shock, female sex and a higher level 1 hr after the dose. • Toxicity presumably more common with 3 doses/day than a single daily dose (as the drug uptake by tubules is saturable phenomenon). Amphotericin B: The likelihood of toxicity is in direct proportion to the total dose administered and is more common if > 3 grams is administered.

21. Exogenous Toxins Radiocontrast media: • Contrast-induced nephropathy has become a frequent occurrence with increased number of studies requiring contrast media like angiography, CT scan, etc • Iodinated contrast media causes vasoconstriction as well as a direct toxic effects on tubular cells. • Patients at increased risk include diabetes, baseline renal insufficiency, large contrast load, history of HTN, older age and presence of proteinuria. Cyclosporine and tacrolimus: Can cause ARF as well as chronic interstitial nephritis. Sulfa drugs, acyclovir and indinavir cause ARF by tubular obstruction due to crystal formation in the tubular lumen Others: Cisplatin, methotrexate and foscarnet, etc.

22. Endogenous toxins Myoglobinuria • The breakdown of muscle (rhabdomyolysis), leading to myoglobinuria, occurs in many clinical settings like crush injuries, viral illness, cocaine, heavy exercise, alcoholism, seizures and certain medications. ATN can develop in small proportion of these patients. • The exact mechanism of renal failure is not clearly understood, but several theories include direct toxic injury, development of DIC, mechanical tubular obstruction by the pigment and intrarenal ischemia from vasomediator release. • Factors that increase the risk of ATN in this setting include extracellular fluid volume depletion, liver dysfunction and hypotension. Hemoglobinuria ARF is a rare complication of hemolysis and hemoglobinuria and is most often associated with transfusion reactions. Hemoglobin has no apparent direct toxicity on the cells and the renal failure in this setting is probably related to hypotension and decrease renal perfusion.

23. Endogenous Toxins Crystals: Acute crystal-induced nephropathy is encountered in conditions where crystals are produced endogenously due to high cellular turnover (i.e. uric acid, calcium phosphate), as seen in certain malignancies or the treatment of these malignancies (tumor lysis syndrome). However, this condition is also associated with ingestion of certain toxic substances, such as ethylene glycol. Multiple myeloma: This condition causes renal failure by several mechanisms, such as prerenal azotemia due to volume contraction, cast nephropathy due to increased light chain proteins precipitated into the tubular lumen, hypercalcemia and uric acid nephropathy.

24. Workup Lab studies • Serum chemistries: By definition, BUN and serum Cr concentrations are increased. In addition, hyponatremia, hyperkalemia, hypermagnesemia, hypocalcemia, hyperphosphatemia and metabolic acidosis may be present. Remember that hypercalcemia and hyperuricemia may suggest a malignant condition as a cause. • CBC: Pt may be anemic. Not only is erythropoietin production decreased but platelet dysfunction from uremia also makes bleeding more likely. • Urinalysis: May reveal muddy brown, granular casts and epithelial cell casts. In addition, checking urine lytes may also help differentiate ATN from prerenal azotemia.

27. Laboratory Findings Used to Differentiate Prerenal Azotemia from ATN

29. Lab (continued…) • Loss of concentrating ability is an early and almost universal finding in ATN. • None of the above criteria for the diagnosis of prerenal disease may be present in a patient with underlying renal disease. Hence, a cautious trial of fluids may be given.

30. Imaging Studies • Abdominal radiograph is of limited benefit in ARF except in diagnosing (or excluding) nephrolithiasis. • Ultrasound, CT scan, or MRI very useful, both to exclude obstructive uropathy and measure renal size and cortical thickness. • Renal US is a simple, relatively inexpensive and non-invasive imaging modality and should be done in all patients presenting with ARF.

31. Renal biopsy • Biopsy is rarely necessary. It should only be performed when the exact renal cause of ARF is unclear, the course is protracted and knowing the exact cause is possibly going to change the management. • Needless to say, prerenal and postrenal causes must be ruled out before subjecting a patient to this invasive procedure. The diagnosis of ATN is made on a clinical basis, i.e. with the help of detailed and accurate history, thorough physical exam, and pertinent lab tests and imaging studies. • A more urgent indication for renal biopsy is in the setting of clinical and urinary findings suggestive of renal vasculitis rather than ATN and the diagnosis needs to be established quickly so that appropriate immunomodulatory therapy can be initiated. • Biopsy may also be more critically important in a renal transplant patient to rule out rejection. • Other indications for biopsy include suspected glomerulonephritis, HUS, TTP and acute interstitial nephritis. • The biopsy is performed under ultrasound or CT guidance after ascertaining the safety of the procedure.

32. Complications Patients with ATN can have several complications. • Electrolyte abnormalities • Hyperkalemia: Higher levels are associated with ECG abnormalities (e.g. peaked T waves, prolonged PR interval, P wave flattening, widened QRS) and risk of developing life-threatening arrhythmias (e.g. ventricular tachycardia or fibrillation, complete heart block, bradycardia, asystole). Arrhythmias have been reported in up to 30% of patients. In addition to these worrisome cardiac effects, hyperkalemia can also lead to neuromuscular dysfunction and, potentially, respiratory failure. • Hyponatremia • Hyperphosphatemia • Hypermagnesemia • Hypocalcemia: Hypocalcemia may be secondary to both deposition of calcium phosphate and reduced levels of 1,25 dihydroxyvitamin D. It is usually asymptomatic, but hypocalcemia may result in nonspecific ECG changes, muscle cramps, or seizures. • Metabolic acidosis

33. Complications • Intravascularvolume overload: It is characterized by weight gain, raised jugular venous pressure and dependent edema. In its most severe manifestation, this may lead to respiratory failure from pulmonary edema. • Hypertension: Hypertension is suspected to mainly be due to salt and water retention. About 25% of patients with ARF develop some hypertension. • Uremic syndrome/Uremia: Uremia results from the accumulation of nitrogenous waste. It is a potentially life-threatening complication associated with ARF. • Platelet dysfunction is common and can lead to life-threatening hemorrhage. • This may manifest as pericardial disease (uremic pericarditis…listen for a rub on exam) • GI symptoms (i.e. nausea, vomiting, cramping) • Neurological symptoms (i.e. lethargy, confusion, asterixis, seizures). • Anemia: Anemia may develop from many possible causes. Erythropoiesis is reduced in ARF, but platelet dysfunction is also observed in the setting of uremia, which may predispose to hemorrhage. In addition, volume overload may lead to hemodilution, and red cell survival time may be decreased.

34. Complications • Polyuric phase of ATN: This complication can lead to hypovolemia and create a setting for prerenal azotemia and perpetuation of ATN. • Infections: Infections is the leading cause of morbidity and mortality and can occur in 30-70% of patients with ARF. Infections are more likely in these patients because of an impaired immune system and because of increased use of indwelling catheters and intravenous needles.

35. Prevention • Ischemic ATN: Be attentive to optimizing cardiovascular function as well as maintaining intravascular volume, especially in patients with preexisting risk factors or those taking nephrotoxic medications. Medicines that reduce systemic resistance (e.g. afterload reducers) may cause renal vasoconstriction or affect the kidney’s autoregulatory response (e.g. ACE inhibitors, cyclooxygenase inhibitors) and also should be used with caution. • Dopamine, mannitol and furosemide, etc have been tried within 24 hrs of ischemic insult to prevent progression to ATN, but have no proven benefit.

36. Prevention • Nephrotoxic ATN • Aminoglycosides: Once daily dosing of aminoglycosides decreases the incidence of nephrotoxicity. • Amphotericin B: Minimize the use of this drug and assure that ECF volume is adequate. • Cyclosporin and tacrolimus: Regular monitoring of blood levels. • Alkalinization of the urine should be tried in patients with marked myoglobinuria and hemoglobinuria.

37. Prevention • Radiocontrast dye: Out of all the agents/modalities that have been investigated for prevention of CIN, only the following have been shown to be of some benefit: 1.Hydration with isotonic saline infusion has proven benefits in prevention of contrast-induced nephropathy. Typically, half isotonic sodium chloride solution (0.45%) administered at a rate of 50-100 mL/h 12 hours before and 12 hours after the administration of the dye load is most effective, especially in the setting of prior renal insufficiency and diabetes mellitus. 2. Low osmolal and iso-osmolalnonionic contrast media are also associated with lower incidence of CIN. 3. N-acetylcysteine has been used with success in high-risk patients to prevent contrast-induced nephrotoxicity. 4. Using lower doses of contrast media, avoiding volume depletion and NSAIDs,both of which can cause renal vasoconstriction are some other useful measures. 5. A new modality recently investigated is use of prophylactichemofiltration in patients who need contrast and have baseline renal insufficiency.

38. The Prevention of Radiocontrast-Agent–Induced Nephropathy by Hemofiltration Giancarlo Marenzi, M.D., et al. NEJM October 2nd, 2003. 114 consecutive patients with chronic renal failure (serum creatinine concentration, >2 mg/dl, who were undergoing coronary interventions, were Randomly assigned to either hemofiltration in an intensive care unit (ICU) or isotonic-saline hydration at a rate of 1 ml per kilogram of body weight per hour given in a step-down unit. Hemofiltration and saline hydration were initiated 4 to 8 hours before the coronary intervention and were continued for 18 to 24 hours after the procedure was completed. Results: Compared with intravenous saline, hemofiltration was associated with the following significant benefits   1. A lesser likelihood of an increase in the serum creatinine concentration of greater than 25 percent from baseline values (5 versus 50 percent) 2. A lesser likelihood of requirement for temporary renal replacement therapy (3 versus 25 percent) 3. A reduction in both in-house mortality (2 versus 14 percent) and one-year mortality (10 versus 30 percent). 4. Greatest benefit was seen in patients with higher Cr (>4 mg/dl).Until additional data are available, routine use of hemofiltration for prevention of CIN is not recommended. However, consideration should be given to the use of hemofiltration (in combination with other preventive measures) among patients at highest risk of contrast nephropathy, particularly the diabetic patient with a baseline serum creatinine concentration of 4 mg/dL or greater.

39. Treatment • General treatment • The main goal of treatment is to prevent further injury to the kidney. ECF volume should be assessed promptly, either on clinical grounds or by invasive means (Swan-Ganz catheter), and repletion of any deficit should be initiated promptly. A renal ultrasound should be performed to exclude obstruction. • All possible nephrotoxic drugs should be stopped. • In general, an attempt is made to increase the urine output if oliguria is present, by using loop diuretics, although there is some controversy about this in the literature. One retrospective study showed that diuretics may even increase the risk of death and non-recovery of renal function. Only use diuretics if ECF volume and cardiac function are first carefully assessed and found adequate. • The only true indication for diuretic use is volume overload. Furosemide and bumetanide are the commonly used diuretics.

40. Treatment • Aggressively treat any complications that develop. Remember that sepsis is a common cause of death with severe ARF, so aggressive treatment of infections is prudent. However, prophylactic antibiotic has not been proven to be of any benefit. • Also, adjust doses of all medications if the kidney eliminates them. • Various agents have been studied for their possible role in hastening tubular regeneration and functional recovery in ATN including growth factors (IGF-I), low dose DA, combination of DA and ANP and anaritide (a synthetic form of ANP) but have shown no benefit in recovery or survival.

41. Treatment • Dialysis treatment • In general, no clear consensus is established on when or how often to perform hemodialysis in the setting of ARF. Some studies have suggested that early initiation may be beneficial, but, in one prospective trial, aggressive dialysis did not improve recovery or survival rates. However, hemodialysis is still considered standard therapy in severe ARF. In addition, continuous hemodialysis (continuous venovenous hemofiltration [CVVHD] and continuous arteriovenous hemofiltration with dialysis (CAVHD) and peritoneal dialysis are also available. No compelling studies suggest that one mode is better than another. In general, patients with multiorgan failure and hemodynamic instability may benefit from a continuous mode because it is typically less taxing on the hemodynamics. • Indications for dialysis: Clinical evidence of uremia, intractable intravascular volume overload, hyperkalemia or severe acidosis resistant to conservative measures.

42. Treatment of Complications • Volume overload: Salt and water restriction, diuretics. Dialysis for refractory cases. • Hyperkalemia: Restrict potassium intake, glucose and insulin, sodium bicarbonate, kayexalate, calcium gluconate, dialysis. • Metabolic acidosis: Sodium bicarb (only if HCO3 <15mmol/L or pH<7.2) or dialysis. • Hypocalcemia: Calcium carbonate, calcium gluconate. • Infections: Antibiotics, assess the IV sites. • Hyponatremia: Free water restriction. • Hyperphosphatemia: Restrict phosphate intake, phosphate binding agents. • Hypermagnesemia: Avoid Mg containing antacids. • Anemia: Blood transfusion may be required.

43. Nutrition • Clearly, the maintenance of fluid and electrolyte balance is critical. Aggressive and early nutritional support also improves survival rates. Adequate caloric intake is essential to avoid catabolism and starvation ketoacidosis, while minimizing production of nitrogenous waste. This is best achieved by restricting dietary protein to approximately 0.6g/kg/day of protein of high biologic value (rich in essential amino acids) and provide most calories as carbohydrate (approximately 100 g/day). • Enteral hyperalimentation or parenteral nutrition if recovery prolonged or if patient very catabolic.

44. The in-hospital survival rate of patients with ATN is about 50%, with 30% surviving for 1 year. Factors associated with increased mortalityinclude: poor nutrition status, male sex, the presence of oliguria, need for mechanical ventilation, chronic immunosuppression, acute MI, stroke or seizures. The presence of renal failure itself seems to be a prognostic factor in survival since it weakens immune system and impairs platelet function thus predisposing the patient to sepsis and bleeding. Mortality and Morbidity

45. Mortality and Morbidity • Infections remain the leading cause of death. • For ARF the mortality rate is 20-50% in patients with underlying medical illnesses, but the mortality rate is as high as 60-70% with patients in a surgical setting or with severe trauma. If multiorgan failure is present, especially severe hypotension or acute respiratory distress syndrome, the mortality rate ranges from 50-80%. • With dialysis intervention, the frequency of uremia, hyperkalemia, and volume overload as causes of death have decreased. The most common causes of death now are sepsis, cardiovascular and pulmonary dysfunction, and withdrawal of life support. • The type of dialysis membrane utilized during HD may also affect prognosis.

46. Prognosis • Patients with oliguric ATN have a worse prognosis than patients with nonoliguric ATN. This probably is related to more severe necrosis and more significant disturbances in electrolyte balance. • Rapid increase in serum creatinine (i.e. >3 mg/dL) probably also indicates a poorer prognosis. Again, this probably reflects more serious underlying disease. • Of the survivors of ATN, approximately 50% have residual subclinical impairment of renal function, about 5%continue to undergo a decline in renal function following an initialrecovery phase and about 5% never recoverkidney function and require dialysis.