USMLE and COMLEX Review

Nephrology Supplement

Glomerulonephritis, and Acute Interstitial Nephritis

Northwestern Medical Review www.northwesternmedicalreview.com Lansing, Michigan 2014-2015

1. What is Tamm-Horsfall glycoprotein (THP)? Matching (4 – 15): Match the following urinary casts with the descriptions, conditions, or questions ______presented hereafter: ______A. Bacterial casts ______B. Crystal casts ______C. Epithelial casts D. Fatty casts ______E. Granular casts ______F. Hyaline casts G. Pigment casts

H. casts 2. What is a ? I. Waxy casts J. casts ______

______4. These types of casts are by far the most common ______urinary casts. They are composed of solidified Tamm-Horsfall mucoprotein and secreted from ______tubular cells under conditions of oliguria, ______concentrated , and acidic urine. ______

______5. These types of casts are pathognomonic of acute

tubular necrosis (ATN) and at times are 3. What are the major types of urinary casts? described as “muddy brown casts”. ______

6. A 6-year-old girl is admitted to the emergency department with fever, and puffy face, eyes, and trunk. Blood pressure taken on admission is

180/120. Her mother states that 10 days ago she had a sore throat, and she has voided very little urine within the past 24 hours. Serology of the

patient is significant for high antistreptolysin O titers and low Complement C3. Urinalysis of the child is most likely indicative of which type of

cast? ______

7. Presence of these types of urinary casts is often indicative of tubulointerstitial nephritis. ______8. Distinction of leukocytic casts from epithelial casts is sometimes difficult. What urinary test often helps to confirm presence of leukocytic casts? ______13. These types of urinary casts are often seen in 9. What urinary test is indicative of ? patients with and conjugated urobilinemia. ______14. What is the best description for the cast seen in ______the picture below? ______

______10. These casts are the second most common casts. The "muddy brown cast" seen in acute tubular necrosis is a type of this cast. 15. What do these two pictures depict and what is

wrong with them?

______

______11. These casts are indicative of very low urine flow and they are associated with severe, 16. What is the description of acute tubular necrosis longstanding disease and renal failure. (ATN)? They are notably larger than hyaline casts. ______

______

______17. What is the most common cause of acute renal injury (AKI)? 12. These caricature urinary casts are seen with ______polarized microscopy of the urine of a patient with . 18. What are the common causes of ATN? ______24. Distinguishing prerenal azotemia from acute tubular necrosis is important in clinical settings ______because fluid resuscitation often alleviates ______prerenal azotemia but is ineffective for treating ATN. What lab measurement would help to ______differentiate the two conditions from each other? ______19. What are the key findings in ATN? ______25. How do we measure FeNa+? ______20. What is the key pathognomonic cast seen in ______urinalysis of patients with ATN who present ______urinary tubular epithelial cells? ______21. What is the treatment for ATN? ______

22. Of the two types of ATN, ischemic and toxic, one 26. Which of the two improves rapidly in response to of the two causes “skip” lesions at various parts administration of large volume of IV fluids; ATN, of the , including proximal and distal or prerenal azotemia? tubules. Which type is it? ______

23. is defined as prerenal, renal, and 27. What is the difference between blood urea and postrenal. Which of the three types is similar to blood urea nitrogen? ATN? ______

______

28. What is the source of blood urea? BUN to Ratios and their Attributes ______Greater than 20:1 ______ Prerenal  BUN reabsorption is increased. ______ BUN is disproportionately elevated relative to creatinine in serum.  Dehydration is suspected. 29. What is the source of blood creatinine? ______Between 10:1 and 20:1  Normal or postrenal ______ Normal range. Can also be postrenal disease.  BUN reabsorption is within normal limits. 30. What is the physiologic significance of the BUN

to creatinine ratio? Less than 10:1 ______ Intrarenal ______ Renal damage causes reduced reabsorption ______of BUN, therefore lowering the BUN:Cr ratio.

______34. A 25-year-old African-American medical student ______plans on visiting Kenya as part of his international medical training program. He received a prescription for chloroquine and was 31. What is the normal BUN to creatinine ratio? advised to start the medication 10 days prior to ______his departure. Two days after taking the medication the patient is admitted to the hospital ______with the complaint of shortness of breath, pallor, jaundice, and low volume and dark urine. Serology of the patient is significant for 32. What major factors increase or decrease BUN to bilirubinemia and inclusions within the red cells. creatinine ratio? What is the LEAST LIKELY urinary finding in this ______patient? ______

A. 33. What is the most important clinical value of the B. Unconjugated BUN to creatinine ratio? C. Epithelial casts ______D. Muddy brown casts E. High levels of urinary sodium ______

35. Why does urinalysis show epithelial and muddy 39. In addition to FeNa of more than 2% in ATN and brown casts in ATN? less than 1% in prerenal azotemia, the two ______conditions are often characterized by their urinary sediments. How are they differentiated by their ______sediments? ______

36. Why, despite death of tubular cells, is the 40. What are the three common causes of intrinsic prognosis of ATN very good and kidney function acute renal injury? is resumed after removal of the etiological ______factors? ______

______41. Damage to what anatomical structures is the ______common cause of acute intrinsic renal failure? ______37. What is the postulated pathophysiology of ATN? ______42. What is the most common cause of acute renal injury? ______

43. ATN is more common in hospitalized patients. 38. Kidney failure is often described as prerenal, Name the common hospital-related predisposing renal, and postrenal. Which of the three factors: descriptions is more accurately applicable to ATN ______and which one is more applicable to ______glomerulonephritis? ______

44. Why are renal tubules primarily damaged in ______ATN? ______

Acute Tubular Necrosis Acute

 Both acutely affect and drop the GFR  Both cause a rapid rise in serum creatinine and BUN  Both are associated with change of urine color

Associated with hypertension Results from hypotension (remember the “H2O” mnemonic!)

Brown urine Red urine

Epithelial casts Red cell casts

Does not affect glomerulus (mainly tubules) Affects glomerulus

Lack of May have pre-nephrotic proteinuria

Neither has nephrosis or nephritis For the most part has a nephritic pattern

Does not cause glomerulonephritis May cause ATN

Etiology is ischemic or toxic Etiology is immune injury

FeNa is greater than 1% FeNa is less than 1%

Often rapidly progresses to end-stage failure Often slowly progresses to end-stage failure

Mostly reversible Mostly irreversible

45. A 75-year-old man is diagnosed with ______staphylococcal pneumonia. Serology shows ______bacteremia with non-methicillin resistant staph aureus. The patient is treated with nafcillin. On ______day 10 post-nafcillin therapy, the patient presents ______with fever, malaise, erythematous body rash, edema, dysuria, and lower back pain. Serology of ______the patient is significant for eosinophilia. What is ______the most likely diagnosis? ______

46. Summarize Major Causes of AIN. 48. AIN is often described as what type of hypersensitivity reaction? ______

______49. What is the tetrad of AIN? ______

47. What are the key cell types (casts) seen in acute glomerulonephritis (AG), acute tubular necrosis (ATN), and acute interstitial nephritis (AIN)

Acute Interstitial Nephritis (AIN) Acute Tubular Necrosis (ATN)

Both are rapidly developing conditions Both may be drug-induced (although drugs differ)

Less common More common

Spaces between tubules are affected Tubules are affected

Fever Often no fever

Hypertension (mostly) Hypotension (mostly)

WBC casts (and sterile pyuria) Epithelial casts and muddy brown casts

 Acute : Direct ascending bacterial  Ischemic or nephrotoxic, caused by: ischemia, invasion of renal medulla (Vesicoureteral Reflux) nephrotoxins, sepsis  Allergic AIN  Diagnosis of exclusion Drugs are mostly non-antibacterial (Exception: Drugs involved are mostly antibiotics Aminoglycoside)

Gallium-67 accumulation (uptake) Lack of Gallium-67 radionuclide accumulation

 Eosinophilia, , and interstitial edema  Anemia  , sterile pyuria, and hyperkalemia  Hyperkalemia  Slower renal function recovery after stopping the  Faster renal function recovery after stopping the offending medication (several weeks) offending medication (a few weeks)  Prednisone accelerates recovery  Prednisolone ineffective 50. Why, in contrast to acute tubular necrosis, is AIN 55. True/False: Hyperkalemia causes interstitial presented with Gallium-67 uptake? fibrosis ______56. What is the likely mechanism for hypokalemic

nephropathy? 51. True/False: Glomeruli and vessels are spared in ______AIN ______

52. True/False: AIN has an immune-mediated 57. True/False: Hypercalcemia causes interstitial mechanism fibrosis ______

53. True/False: AIN has a cell-mediated mechanism 58. What is the likely mechanism for hypercalcemic ______nephropathy? ______54. What are the top two causes of interstitial kidney injury? 59. Acute tubular necrosis (ATN) is not associated ______with proteinuria. Why? ______Answers: Glomerulonephritis ATN and AIN 1. Also known as uromodulin, it is Pathogenesis: Ischemia, , or a glycoprotein that is encoded by the uromodulin nephrotoxicity. They cause degeneration, (UMOD) gene and is the most abundant protein necrosis, and sloughing of tubular epithelial cells. excreted in ordinary urine. The presence of these casts indicates acute It is produced by the cells of the ascending loop tubular injury but does not indicate the extent or and it is the major protein constituent of urinary reversibility of the injury. casts. Leukocytes can also be incorporated into the Note: The other major protein that is seen in casts in cases of tubulo-interstitial urine under pathological conditions is albumin. (e.g. pyelonephritis). 2. Cylindrical structures produced by the kidney and It is often difficult to distinguish between epithelial present in the urine in certain disease states. casts and leukocytic casts; however, epithelial They form in the distal convoluted casts are usually larger than granulocytes (a key tubule and collecting ducts and then pass into the distinguishing factor). urine. “Muddy brown casts" of epithelial cells are They form via precipitation of Tamm- pathognomonic for ATN. Horsfall mucoprotein. Management of ATN: Aggressive treatment of In proteinuric conditions the casts, in addition to the precipitating factors (e.g. hydration and Tamm-Horsfall mucoprotein, include albumin and cessation of the offending drug). other proteins. Note: Tubular cells continually replace Cast formation is enhanced with dehydration, low themselves, and as such the urine flow and pH, and certain disease overall prognosis for ATN is quite good (recovery conditions. often happens within 7 to 21 days). 3. Urinary cast are two types: acellular and cellular 6. RBC Casts Acellular: Hyaline, granular, waxy, fatty, The child has post-streptococcal pigment, and crystal glomerulonephritis. Cellular: Red blood cell, white blood cell, History of sore throat, hematuria with red blood bacterial, and epithelial cell casts, hypertension, oliguria, and low serum C3 are cardinal findings in this condition. 4. Hyaline cast! These casts are indicative of glomerular damage They are seen in normal individuals after and are usually associated with nephritic intensive exercise and dehydration. syndromes. They are cylindrical and clear with a low They are seen in various causes of vasculitis refractive index and may be missed under bright- such as Goodpasture’s and Wegener’s field microscopy. granulomatosis, and certain types of systemic Due to ubiquitous presence of hyaline casts erythematosus. under pathological conditions, other inclusions They may also be associated with are formed via adherence to the hyaline cast. renal infarction and subacute bacterial 5. Epithelial casts endocarditis. Epithelial casts are formed by inclusion or 7. WBC casts adhesion of desquamated epithelial cells of the WBC casts are indicative tubular lining. of inflammation or , and their presence They are characterized by large, round nuclei strongly suggests pyelonephritis, and a lower amount of cytoplasm. tubulointerstitial nephritis, direct infection of the kidney, and sometimes glomerulonephritis. White blood cells can sometimes be difficult to They are relatively rigid, have a well-defined discern from epithelial cells and may require cylindrical shape, and possess a high refractive special staining. index. 8. Leukocytic esterase! The edges of the cylinders present with It is an enzyme present in the white blood cells, characteristic broken-off pieces and sharp and presence of it in the urine indicates the indentations. presence of white blood cells (leukocyturia). These casts are also known as “broad casts”, 9. Leukocytic esterase! and they are indicative of dilated ducts seen in chronic renal failure. It is an enzyme present in the white blood cells, and presence of it in the urine indicates the 13. Pigment casts are formed by the adhesion of presence of white blood cells (leukocyturia). metabolic breakdown products or drug pigments to hyaline matrix, and named due to their 10. Granular casts are due to breakdown of cellular discoloration. casts or the inclusion of aggregates of albumin or immunoglobulin light chains. The pigments are commonly derived from hemoglobin in hemolytic anemia, They are often described as fine or coarse; in rhabdomyolysis, in liver diseases, and however, this distinction does not have much drugs (rifampin, sulfas, deferoxamine, and diagnostic value. phenazopyridine). They are often cylinder-shaped and have a Hemoglobin casts are yellow-brown. higher refractive index than hyaline casts. Bilirubinemia produces yellow and golden-brown They are most often indicative of chronic renal color casts. disease, and like hyaline casts, they may be Note: In acute tubular necrosis, large numbers of seen for a short time after strenuous exercise. pigmented granular casts, a.k.a. “muddy brown The “muddy brown casts” seen in acute tubular casts”, can be considered a pigment cast as well. necrosis are a type of granular cast. 14. Epithelial casts are formed by inclusion or 11. Waxy casts suggest extremely low urine flow adhesion of desquamated epithelial cells of the and are associated with long-lasting and/or tubule lining. severe renal failure. The cells are distinguished by large, round nuclei Due to urine stasis and dilated kidney tubules, and a lower amount of cytoplasm. these casts are significantly larger than hyaline 15. These are crystals casts; however, there is casts. disagreement about whether they are casts or They are relatively rigid, have a well-defined merely crystals adhering to a cast or appearing in cylindrical shape, and possess a high refractive the urine. index. Another issue is that they do not appear in The edges of the cylinders present with cylindrical form. characteristic broken-off pieces and sharp The most important factors causing crystallization indentations. are increased acidity or alkalinity of the urine, These casts are also known as “broad casts”, and increased concentration of dissolved and they are indicative of dilated ducts seen in substances. chronic renal failure. Crystals are identified by their shape, color, and 12. Waxy casts suggest extremely low urine flow and by the urine pH, and they may be small, sand-like are associated with long-lasting and/or severe particles with no specific shape (amorphous) or renal failure. have specific shapes, such as needle-like (e.g. Due to urine stasis and dilated kidney tubules, urate crystals). these casts are significantly larger than hyaline Important crystals are uric acid, calcium oxalates, casts. amorphous phosphates, calcium carbonate, and cystine stones. 16. ATN is a kidney disorder that involves damage to fractional excretion of sodium (FENa+) to less and death of the epithelial tubular cells of the than 1%. kidneys, which can lead to acute kidney failure. In ATN the tubular epithelial cells that are 17. Acute tubular necrosis (ATN) involved in sodium reabsorption are damaged 18. Ischemic ATN: and the kidneys cannot retain sodium. As a result, FENa can rise to be more than 2%! Renal artery stenosis, hypovolemia, and severe hypotension longer than 30 minutes, septic Note: In severe cases of chronic hypoperfusion shock, DIC, and impaired renal auto-regulatory there may also be ischemic damage to the responses (COX inhibitors, ACE inhibitors, and tubular epithelium, which is a characteristic of angiotensin receptor blockers). ATN. + Toxic ATN: 25. FENa = [(UNa / PNa) / (PCr/PCr)] x 100 Endogenous toxins: Free hemoglobin and FENa is useful in the evaluation of acute kidney myoglobin, and crystal-induced nephropathy failure and low urine output. (urate), and multiple myeloma Low fractional excretion of sodium retention by Exogenous toxins: Drugs (aminoglycoside, the kidney suggests a pathophysiology extrinsic amphotericin B, cyclosporine, forscarnet, to the urinary system, such as volume depletion pentamidine and cisplatin) and toxic substances or decrease in effective circulating volume (e.g. (ethylene glycol, radiologic contrasts) low output heart failure). 19. ATN findings are: Higher values can suggest sodium wasting due to acute tubular necrosis or other causes of Elevated BUN and creatinine with or without intrinsic kidney failure. oliguria FE may be affected or invalidated Presence of predisposing conditions Na by diuretic use, since many diuretics may alter (hypotension, sepsis, drug therapy, and the kidney’s handling of sodium. rhabdomyolysis) 26. Prerenal azotemia! In ATN management may Urinalysis: Granular casts with or without tubular include restricting fluid intake to a volume equal epithelial cells to the volume of urine produced. 20. Muddy Brown Urine 27. BUN is the nitrogen component of urea 21. Treatment of the underlying cause (e.g. sepsis or Roughly one-half of blood urea hypotension) Both increase and decrease proportionately in 22. Ischemic ATN the blood Toxic ATN primarily affects the proximal tubules 23. Ischemic ATN is part of the spectrum of prerenal azotemia, and the two share the same causes and risk factors. 28. Urea is the primary nitrogen-containing metabolite of dietary protein and tissue protein turnover. 29. Creatinine is the product of muscle creatine catabolism 30. Creatinine is the product of muscle creatine catabolism 24. Fractional excretion of sodium (FENa+) 31. Usually between 10:1 and 20:1 In prerenal azotemia low renal perfusion drops * Values are expressed in mg/dL the GFR but the kidneys may still perform well 32. An increased ratio may be due to a condition that and they are able to retain sodium in response to causes a decrease in the flow of blood to the hypoperfusion. This causes a decrease in kidneys, such as congestive heart failure or dehydration. It may also be seen with Obstruction of tubules by tubular casts increased protein, from gastrointestinal bleeding Tubular Back-leak: Filtrate produced by the or increased protein in the diet. glomerulus is not restricted to injured tubules and The ratio may be decreased with liver leaks back into the interstitium and is then disease (due to decrease in the formation of reabsorbed into the blood vessels urea) and malnutrition. 38. Renal! 33. The ratio is predictive of prerenal injury when Diagnosis of ATN often requires exclusion of BUN:Cr exceeds 20 or when urea:Cr exceeds postrenal and prerenal causes of renal failure. 100 and urea is greater than 10. 39. ATN shows active centrifuged sediments that In prerenal injury, urea increases include muddy brown epithelial casts. Prerenal disproportionately to creatinine due to enhanced azotemia causes bland sediments (waxy or proximal tubular reabsorption that follows the granular) without significant cells. enhanced transport of sodium and water. Note: Significant cells are WBC, RBC, and 34. [B]. epithelial cells. The patient has an acute episode of hemolytic 40. ATN shows active centrifuged sediments that anemia due to G6PD that is induced by the use include muddy brown epithelial casts. Prerenal of the anti-malarial agent chloroquine. The red azotemia causes bland sediments (waxy or cell inclusions of the red cells (diagram) are granular) without significant cells. precipitated hemoglobin (Heinz bodies). Note: Significant cells are WBC, RBC, and Widespread hemolysis causes bilirubinemia, epithelial cells. hemoglobinemia, hemoglobinuria, and toxic ATN 41. Blood vessels (e.g. Wegener’s granulomatosis) due to hemoglobin damage to kidneys. Note that only conjugated bilirubin can be eliminated in Glomeruli (e.g. post-streptococcal the urine. glomerulonephritis) As a result of ATN, the patient presents with Tubules (Acute tubular necrosis) epithelial and muddy brown casts in addition to Interstitium (Acute interstitial nephritis) high levels of urinary sodium. Note that tubular 42. Acute tubular necrosis (ATN) cells are responsible for sodium reabsorption Accounts for 45% of cases of acute renal failure 35. Toxic and ischemic ATN both cause necrosis of 43. Blood transfusion reaction (i.e. iron overload) the epithelial lining of the tubular cells. Injury or trauma that damages the muscles (i.e. Hemoglobin and myoglobin are shown to have rhabdomyolysis) potent inhibitory effects on production of nitric oxide, and this may trigger widespread intrarenal Low blood pressure (hypotension) that lasts vasoconstriction and ischemia. The other reason longer than 30 minutes is direct tubular toxic effects. Recent major surgery The necrosed sloughed-off epithelial tubular cells Septic shock due to severe infection are passed into urine and they cause epithelial 44. Blood transfusion reaction (i.e. iron overload) casts, and assumption of bilirubin and Injury or trauma that damages the muscles (i.e. hemoglobin pigments by the casts leads to rhabdomyolysis) muddy brown casts Low blood pressure (hypotension) that lasts 36. Epithelial kidney cells have a very good longer than 30 minutes regenerative ability Recent major surgery ATN does not damage the tubular basement membrane Septic shock due to severe infection After managing the underlying causes (stopping 45. Acute interstitial nephritis, also known as acute offending medications or correcting ischemia) tubulointerstitial nephritis. kidney function is resumed within 1 to 2 weeks. 37. Renal vasoconstriction Acute interstitial nephritis (AIN) results from This relatively nonspecific binding allows for allergy to drugs (75%-85% of cases) and non- identification of sites with tumor growth, allergic causes (up to 25% of cases). inflammation, and both acute and chronic The non-drug allergy cases are mainly infection to be imaged by nuclear scanning. associated with (e.g. acute bacterial Therefore, AIN has high gallium uptake pyelonephritis), immune disorders (e.g. Sjögren's properties due to increased number of syndrome, systemic lupus erythematosus, and leukocytes, bacterial pyelonephritis, and Wegener’s granulomatosis) or neoplastic inflammation. disorders (e.g. lymphoproliferative disorders). 51. True Drugs that commonly cause AIN include 52. True penicillins (methicillin and nafcillin), 53. True (T-cells) cephalosporins, sulfonamides, NSAIDs, and proton pump inhibitors. 54. AIN and interstitial fibrosis! Acute allergic interstitial nephritis is by far more Notorious Drugs: Chinese herbs (aristolochic common in the elderly. acid), carmustine, cyclosporine, streptozotocin, and tacrolimus 46. Drugs: Penicillins, cephalosporins, NSAIDs, rifampin, sulfonamides, proton-pump inhibitors 55. False! Hypokalemia causes tubulointerstitial and allopurinol fibrosis Infections: Pyelonephritis 56. Hypokalemic nephropathy is associated with alterations in intrarenal vasoactive substances, Systemic Diseases: Sarcoidosis, Sjögren’s causing vasoconstriction, salt-sensitivity, and syndrome, lupus erythematosus, lymphoma, progression of interstitial fibrosis. leukemia Hypokalemia causes vasoconstriction, reduced 47. AG: RBC casts medullary blood flow, and intrarenal ischemia in AIN: WBC casts association with intrarenal angiotensin II and ATN: Epithelial (muddy brown casts) endothelin-1 generation. 48. AG: RBC casts It is also postulated that generalized renal anoxia AIN: WBC casts causes intrarenal complement activation, and stimulation of growth factors such as IGF-1 and ATN: Epithelial (muddy brown casts) TGF-β. These further contribute to the renal 49. hypertrophic response. Note: Angiotensin II and endothelin receptor antagonists are currently considered to be the first line management for fibrotic and sclerotic changes of the kidney. 57. True! Hypercalcemia causes tubulointerstitial fibrosis! 58. In hypercalcemic conditions calcium precipitates in the nephrons.

50. The body handles Ga3+ similar to ferric iron. This is also a compounding factor causing AIN in multiple myeloma and in hypercalcemic Gallium is bound (and concentrated) in areas of neoplastic conditions. inflammation as well as areas of rapid cell division. 59. It does not affect the glomeruli! It binds to transferrin, leukocytic transferrin-like proteins, bacterial siderospores (iron chelating sites), inflammatory proteins, and neutro-philic cell membranes.