Pigment nephropathy

Nephrology

1. Pigment Nephropathy Salwa Ibrahim MD FRCP Cairo University Navigate AKI Comprehensive Course September 2018

2. Topics Definition Causes Rhabdomylosis Intravascular Hemolysis Bile cast nephropathy

3. Introduction Pigment nephropathy is an abrupt decline in renal function as a result of the toxic action of pigment on the kidney It includes myoglobin , released from skeletal muscle in rhabdomyolysis , hemoglobin , released during intravascular hemolysis and Bile cast nephropathy induced by high serum bilirubin levels

4. Rhabdomyolysis

5. Muscle injury leading to myoglobinuria was reported in victims of WW II who died of uremia and postmortem exam revealed extensive muscle necrosis and pigment nephropathy

6. Traumatic muscle injury : crush injury, grand mal seizure, electric shock, prolonged coma Electrolyte disturbance : hypokalemia, hypophosphatemia Toxins and drugs : alcohol, statin , CsA , erthyromycin Infections : influenza and Varicella zoster Heat stroke and severe hypothermia Hypothyroidism Rhabdomyolysis

7. Case 26-year-old female was admitted to with severe bilateral thigh pain persisting for 5 days after heavy exercise On the physical examination, the bilateral thigh muscles were tender and slightly swollen Blood work showed a raised CK level of 55235 U/L, ALT of 314 U/L , AST of 974 U/L (0–32), LDH of 1508 U/L (135–214), and myoglobin of 3984 ng / mL Urine analysis, reddish with no RBCs

8. Pathogenesis

9. Myoglobin, a heme pigment present in the skeletal muscle, is released upon injury Due to its small size, myoglobin is readily filterable and is excreted in urine

10. Three basic mechanisms underlie myoglobin toxicity Renal hypoperfusion and vasoconstriction Tubular cast formation causing tubular obstruction Direct myoglobin Induced nephrotoxicity

11. Hyperphosphatemia can markedly potentiate ischemic and nephrotoxic renal damage Hyperuricemia contributes to intratubular obstruction Hypovolemia is a crucial factor in development of myoglobinuric ARF As much as 18 liters of fluid may extravagate into damaged limbs The formation of thrombi in the glomerular capillary tufts due to DIC be triggered in rhabdomyolysis .

12. Biochemical findings in rhabdomyolysis Elevation of serum CK and LDH (>5000) Myoglobin in urine Hyperkalemia Hypocalcemia Hyperphosphatemia High creatinine/BUN ratio Serum CK begins to rise 2 to 12 hours following the onset of muscle injury and reaches maximum within 24 to 72 hours

13. Fluid Resuscitation Expansion of extracellular volume is the cornerstone of treatment Support of intravascular volume increases the glomerular filtration rate and oxygen delivery and dilutes myoglobin and other renal tubular toxins

14. Management of rhabodomyloysis NSS should be infused at a rate of 1.5 liters per hour Urinary alkalization should be considered in patients with acidemia and dehydration to achieve a urine pH higher than 6.5-7.0 Sodium bicarbonate is used with caution because it may potentiate hypocalcemia

15. The Renal Association Guideline 3.4-AKI* advise fuid resuscitation with 0.9% sodium chloride at a rate of 10-15ml/kg/hr to achieve high urinary flow rates (>100ml/hr) with the cautious addition of sodium bicarbonate 1.4% to maintain urinary pH> 6.51

16. Mannitol An osmotic agent that causes shift of fluid from the interstitial compartment leading to decreased muscular swelling and correcting hypovolaemia A study by   Bragadottir et al (2012)  has shown that mannitol can redistribute blood flow to the kidneys, induce renal vasodilatation and increase renal blood flow by up to 61 %

17. Dialysis may be needed for hyperkalemia in the oliguric phase and hypercalcemia in the diuretic phase Myoglobin, because of size, is poorly removed by hemofiltration or peritoneal dialysis

18. HEME NEPHROPATHY

19. Massive intravascular hemolysis Paroxysysmal nocturnal hemoglobinuria (PNH) Hemolytic transfusion reactions as a result of ABO incompatibility Mechanical damage to the erythrocytes during cardiopulmonary bypass

20. Pathogenesis Free hemoglobin immediately bound to haptoglobin and cleared by hepatocytes by the formation of bilirubin, iron, and amino acids If haptoglobin is saturated, hemoglobin dimers accumulate in the plasma and pass through the glomerulus

21. Renal Biopsy ATN secondary to haemosiderin deposition

22. Management of Heme Nephropathy Volume repletion with NSS Alkaline Diuresis involves IV NaHCO3 with either mannitol or loop diuretics The alkaline pH of urine promotes the solubility of pigments and limits the formation of casts and crystals The aim is to reach a urine pH above 6.5

23. Mannitol an osmolar diuretic acts by improving renal perfusion, promoting the excretion of heme , and iron and decreasing the oxidative stress in the PCT cells Furosemide prevents the accumulation of pigments in DCT

24. Bile Cast Nephropathy

25. The association of hyperbilirubinemia and kidney failure was first described in 1899

26. HRS

27. DD of AKI in liver Disease HRS Bile Cast Nephropathy ATN

28. Risk Factors The risk of acute tubular injury increases when serum bilirubin levels are greater than 20 mg/dl Low serum albumin decrease binding of bile acid and bilirubin to albumin allowing them to be filtered by the glomeruli with subsequent increased tubular exposure

29. Pathogenesis It causes oxidative damage of tubular cell membrane It is caused by uncoupling of mitochondrial phosphorylation deceasing ATPase activity Greenish yellow discoloration of kidney with BCN

30. Pathology Bile casts within tubular lumina with tubular epithelial injury The tubules contain cellular debris and detached epithelial cells

31. Casts containing bilirubin and bile salts in renal tubules

32. Urine analysis Urinary sediment of epithelial cells containing granular or crystalline bilirubin and bile stained casts

33. Management Bile cast nephropathy is treated by treating the liver injury (hydration, IV albumin, ERCP+stent etc.) Albumin dialysis has been used to remove bile acids and bilirubin in liver failure with mixed results

34. Prognosis The kidney injury is reversible if bilirubin levels are decreased early

35. Recovery of renal function may take several weeks depending on the extent of proximal tubulopathy and bile cast formation

36. AKI is a common complication of rhabdomyolysis Regular monitoring of renal function is necessary Once a diagnosis of rhabdo is made, patients should be managed aggressively  Aggressive fluid resuscitation for hypovolaemia; urine alkalinisation to protect the kidneys from myoglobin; mannitol to increase perfusion to the kidneys and decrease muscle oedema 

37. The general goals for preventive therapy in heme pigment-induced AKI are correcting volume depletion and preventing intratubular cast formation There are two modalities that have been used Volume repletion with NSS Alkaline- mannitol diuresis

38. Bile cast nephropathy is a rare entity caused by toxicity from bile acids, obstruction from bile casts, and systemic hypoperfusion Bile cast nephropathy may be under reported and should be considered in the differential diagnosis of AKI in liver disease Treatment is largely supportive directed to improving cholestasis