Resident Conference 2004

1. Resident Conference 2004 Katy Moran MD July 13, 2004

2. Case Presentationadapted from Singh AK, Colvin RB. Case 36-2003: A 68 year old woman with impaired renal function. N Engl J Med 2003; 349;2055-63. • HPI: 68 yo WF c/o dyspnea, subj fever one month agonebulizers given  sx improved • 14 d ago malaise, diffuse myalgias tx with ibuprofen  sx minimally improve • 10 d agodeveloped pruritis, temp 100.0prescribed cetirizine (Zyrtec) • 6 d ago  UA ++ protein, WBC 50, mod tubular cells, BUN 20 mg/dL, Cr 1.5 mg/dL (baseline 0.8)d/c ibuprofen • Admission  emesis, malaise, fatigue, oliguria but no dyspnea, fever, chills, CP, abd pain, diarrhea, dysuria, arthralgia, rash

3. Meds: HCTZ, Estrogen, Asprin, MVI, ibuprofen • NKDA • PMH • HTN • Endometrial carcinoma s/p TAH • Appy • SH: remote tobacco use, 1 glass wine/day, married with several children • FH: NC

4. T 99.0, BP 110/75, P 66 • Physical exam remarkable only for trace peripheral edema, otherwise normal • Labs • UA: +++ protein, tr ketones, 0-2 RBCs and WBCs, 0-2 hyaline casts, 3-5 granular casts, 0-2 waxy casts, SG 1.030 • CBC: WBC 14,700 - N66L11Band4M4E14, plts 208,000, Hg 12.1, Hct 37.2 • Coags nl

5. Serum chemistries • T Prot 7.4, Alb 2.0, Globulin 5.4, BUN 40, Cr 3.7, Ca 7.1, Phos 6.3, Mg nl, AST nl, ALT nl • Na 125, K 3.0, Cl 95, CO2 24, Anion gap 6 • Studies: CT abd/pelvis-overall unremarkable, specifically no hydronephrosis

6. Hospital course • Plan: d/c HCTZ and NSAIDs, observe • Day 2 - pruritis and nausea resolve, oliguria persists, results of 24 hour urine 3.4 g protein • Day 3 - steroids initiated • Days 4-5 - oliguria persists, BUN and Cr continue to rise, 98 mg/dL and 7.6 mg/dL respectively • Day 5 – Diagnostic procedure: renal biopsy • What results would you predict?

7. Objectives • Examine the differential diagnosis of intrinsic renal failure in the context of a clinical case • Review the pathophysiology of interstitial nephritis • Briefly review the role of NSAIDs in renal failure • Examine the role of the nephrotic syndrome with AIN and ARF

8. Clinical problem: Acute renal failure • Acute renal failure • Prerenal - reduction of blood flow to kidneys • No history of hypotension, heart failure, sepsis or other factors that make cause renal hypoperfusion • Intrinsic – process within the kidneys • Most likely given lack of evidence of other etiology • Post Renal – obstruction of urine flow • No evidence of hydronephrosis on imaging

9. Intrinsic Renal Failure • Differential Diagnosis • Acute Glomerulonephritis • Acute Interstitial Nephritis • Tubular disease • Vascular disease

10. Acute Glomerulonephritis • Presentation • HTN • Edema • Renal failure • Hematuria • RBC casts • May have mild proteinuria

11. Quick review: so what are these RBC casts, anyway? • When a glomerular lesion is present, RBCs are extravasated through the glomerulus into the tubular lumen • Proteins secreted from tubules (Tamm Horsfall glycoproteins) remain in the lumen for an extended period of time • These proteins take the shape of the lumen, forming a “cast” and trap the nearby RBCs in their matrix • Glomerular disease usually means urinary stasis, i.e. more time for proteins to become trapped in the lumen

12. RBC casts

13. Acute Glomerulonephritis • Case analysis • Urine prior to admission lacking rbcs or rbc casts • Urine on admission with few red cell casts, few WBC casts but + granular casts • History of HTN in the past medical history but this was well controlled, BP on admission normotensive

14. Interstitial Nephritis • Presentation • May be asymptomatic or have nonspecific nausea, vomiting, malaise • Allergic symptoms can be a clue – rash, fever, eosinophilia or eosinophiluria • Urine sediment: WBCs, RBCs, white cell casts • Usually nl or minimal protein in urine

15. Pathology of acute interstitial nephritis • The hallmark is the infiltration of inflammatory cells into the interstitial compartment with sparing of glomeruli and interstitial edema • Infiltrating cell population is comprised mainly of T cells (often CD4+) and monocytes. Plasma cells, neutrophils, and eosinophils may be seen • In nearly all cases, the tubular epithelium involved in the inflammatory process will aberrantly express MHC class II antigens and adhesion molecules like ICAM, important for the engagement of T cells • Together with interstitial edema, this infiltrate causes the tubules to be pushed away from one another, rather than lying closely together • Most forms of acute interstitial nephritis do not have immune deposits present

16. Picture of AIN and Normal • Normal glomerulus, normal interstitium • Interstitial inflammation and unremarkable glomerulus

17. Types of Interstitial Nephritis Singh, A. K. et al. N Engl J Med 2003;349:2055-2063

18. Interstitial Nephritis • Case analysis • Symptoms of low grade fever, pruritis on admission • Urinary sediment prior to admission +WBCs • Eosiniphilia • Possible etiologies • NSAIDs  ibuprofen • HCTZ • However, urine on admit few WBCs and heavy proteinuria

19. Tubular Disease • Definition • Acute tubular necrosis • Ischemia, progression of prerenal cause • Toxin • Drugs (AG, amphotericin, cisplatin) • Contrast • Pigments (myoglobin, Hb), crystals (uric acid) or protein (Ig light chains) • UA: muddy brown, pigmented granular and epithelial cell casts and free epithelial cells • Ischemic or toxic injury to the tubular epithelial cells  cell sloughing into the tubular lumen

20. Case analysis • UA on admit with granular casts, not diagnostic of ATN but would be consistent with ATN • SG on high end of nl so concentrating ability preserved, less consistent with ATN • Predisposing factors? • No ischemia, toxin, contrast, crystal • Protein - Globulin high at 5.4, SPEP/UPEP non revealing

21. Vascular Causes of ARF • Differential Diagnosis • Renal artery stenosis • Especially bilateral stenosis plus an ACE-inhibitor • HTN crisis • Scleroderma renal crisis • Cholesterol emboli • HUS/TTP • Case analysis • Not consistent with clinical picture

22. Renal Biopsy • Why biopsy? • Uncertainty about diagnosis • Degree and severity of renal failure • Lack of recovery after discontinuation of likely offending agent • Performed on Day 5

23. Renal-Biopsy Specimen Showing Interstitial Nephritis (Hematoxylin and Eosin) Singh, A. K. et al. N Engl J Med 2003;349:2055-2063

24. NSAIDs and Acute interstitial nephritis • Compared with “classic” AIN, disease due to NSAIDs is: • Less likely to present with hematuria, eosinophilia, or fever • More likely to cause renal dysfunction, requiring dialysis in 33% of cases • More likely to coincide with nephrotic syndrome

25. AIN and Nephrotic syndome • Nephrotic syndrome • Clinical features • Heavy proteinuria (>3.5 g/d), hypoalbuminemia, edema, hyperlipidemia, lipiduria • Case analysis: Proteinuria, low albumin compatible, however lipids were normal • Frequently accompanies NSAID induced AIN, especially pts >50 yo • Mechanism • Unknown • Hypothesis: NSAID metabolite may induce inflammation and recruit and activate T cells

26. The Role of NSAIDS • NSAID and electrolytes • Renal prostaglandins also play a role in water balance • Antagonize the role of ADH  causing water retention disproportionate to sodium retention • Inhibit active chloride transport by thick ascending limb of loop of Henle • Regulate medullary blood flow • Case analysis – hyponatriemia on admission may be related to NSAID effect

27. Biopsy Results • With standard staining glomeruli were normal • No thickening of capillary wall, scarring, immunoglobulin deposition, complement, fibrinogen • Electron microscopy • Effacement of foot processes and villous hypertrophy of podocytes

28. Renal-Biopsy Specimen Showing Minimal-Change Glomerular Disease Singh, A. K. et al. N Engl J Med 2003;349:2055-2063

29. Summary of case • Clinical picture compatible with acute interstitial nephritis with nephrotic syndrome • Biopsy with AIN with tubular injury and minimal change disease • Case follow-up: • Pt required 3 dialysis treatments during hospitalization and was treated with steroids • Kidney function gradually improved with Cr 1.2 mg/dL fifteen days after admission

30. Board Review Questions • A 73 yo WF with rheumatic heart disease is being treated with ampicillin and gentamicin for endocarditis. One week into the course she develops a morbilliform rash and fever. Her creatinine and BUN have doubled from baseline, and the UA is positive for blood, protein, WBCs. Ultrasound shows bilaterally enlarged kidneys. Most likely cause: • A) Tubular necrosis caused by AG • B) Membranous nephropathy resulting from endocarditis • C) Enterococcal pyelonephritis • D) Cystitis • E) Hypersensitivity reaction to ampicillin

31. The answer is (E) hypersensitivity rxn to ampicillin • Learning point: Acute interstitial nephritis may be caused by a number of drugs. Classic features include: • Hematuria • Fever • Skin rash • UA protein, WBCs, maybe eosinophils • Ultrasound: enlarged kidneys

32. A 50 yo man is hospitalized for treatment of enterococcal endocarditis. He has been receiving ampicillin and gentamicin for the past 2 weeks but is persistently febrile. Labs: Na 145, K 5.0, Cl 110, HCO3 20, BUN 14, Cr 3.5, Urine Na 20, Urine Cr 3000. Most likely cause of ARF? • (A) Tubular necrosis • (B) Insensible skin losses • (C) Renal artery embolism • (D) Cardiac failure • (E) Nausea and vomiting

33. The answer is (A) tubular necrosis • Learning point: Calculation of FENa • U Na x P Cr / P Na x U Cr x100 • In this case FENa 1.4  impaired Na reabsorption, more likely intrinsic renal failure • Prerenal azotemia = avid Na reabsorption • Intrinsic renal dysfunction = impaired Na reabsorption

34. Which of the following patients is most likely to develop destruction of renal papillae with tubulointerstitial damage? • (A) A middle aged man who has consumed “moonshine alcohol” distilled in an automobile radiator • (B) An older man with early stage prostate CA • (C) A young adult woman with B-thalassemia • (D) An older woman who uses analgesics for chronic headaches • (E) Middle aged woman with her first UTI that is responding to antibiotics

35. The answer is (D) an older woman on chronic analgesics • Learning point: Renal papillary necrosis is classically associated with long term analgesic abuse. Other causes include sickle cell anemia, diabetic nephropathy, acute obstructive nephropathy. • NOT associated with prostate CA, a single UTI. • Lead can cause tubular atrophy and fibrosis of small renal arteries.

36. Objectives revisited: • Differential diagnosis of intrinisic renal failure • Pathology of acute interstitial nephritis • NSAIDs and renal failure • Nephrotic syndrome and interstitial nephritis

37. Questions?

38. Resources • Singh AK, Ucci A, Madias NE. Predominant tubulointerstitial lupus nephritis. Am J Kidney Dis 1996;27:273-278 • Singh AK, Colvin RB. Case 36-2003: A 68 year old woman with impaired renal function. N Engl J Med 2003; 349;2055-63. • Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Engl J Med 1984;310:563-572. • Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Engl J Med 1984;310:563-572. • Tam VK, Green J, Schwieger J, Cohen AH. Nephrotic syndrome and renal insufficiency associated with lithium therapy. Am J Kidney Dis 1996;27:715-720. • Chen CY, Pang VF, Chen CS. Pathological and biochemical modifications of renal function in ibuprofen-induced interstitial nephritis. Ren Fail 1996;18:31-40. • Michel, DM, Kelly, CJ. Acute interstitial nephritis. J Am Soc Nephrol 1998; 9:506. • Rennke HG, Roos PC, Wall SG. Drug-induced interstitial nephritis with heavy glomerular proteinuria. N Engl J Med 1980;302:691-692. • Rossert, J. Drug-induced acute interstitial nephritis. Kidney Int 2001; 60:804. • Up to date • Hricik, Sedor, Ganz. Nephrology Clinical Secrets. • Sabatine, Mark. Pocket Medicine. • Stone, Richard. Harrison’s Principles of Internal Medicine Self Assessment and Board Review. • MD Consult