Resident Conference 2004

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Resident Conference 2004

• Katy Moran MD
• July 13, 2004

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Case Presentationadapted from Singh AK, Colvin
RB. Case 36-2003 A 68 year old woman with
impaired renal function. N Engl J Med 2003
3492055-63.

• 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

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• 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

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• 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

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• 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

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• 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?

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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

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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

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Intrinsic Renal Failure

• Differential Diagnosis
• Acute Glomerulonephritis
• Acute Interstitial Nephritis
• Tubular disease
• Vascular disease

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Acute Glomerulonephritis

• Presentation
• HTN
• Edema
• Renal failure
• Hematuria
• RBC casts
• May have mild proteinuria

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• 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

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RBC casts
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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

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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

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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

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Picture of AIN and Normal

• Normal glomerulus, normal interstitium

• Interstitial inflammation and unremarkable
  glomerulus

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Types of Interstitial Nephritis
Singh, A. K. et al. N Engl J Med
20033492055-2063
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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

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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

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• 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

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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

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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

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Renal-Biopsy Specimen Showing Interstitial
Nephritis (Hematoxylin and Eosin)
Singh, A. K. et al. N Engl J Med
20033492055-2063
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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

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AIN and Nephrotic syndome

• Nephrotic syndrome
• Clinical features
• Heavy proteinuria (gt3.5 g/d), hypoalbuminemia,
  edema, hyperlipidemia, lipiduria
• Case analysis Proteinuria, low albumin
  compatible, however lipids were normal
• Frequently accompanies NSAID induced AIN,
  especially pts gt50 yo
• Mechanism
• Unknown
• Hypothesis NSAID metabolite may induce
  inflammation and recruit and activate T cells

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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

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• 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

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Renal-Biopsy Specimen Showing Minimal-Change
Glomerular Disease
Singh, A. K. et al. N Engl J Med
20033492055-2063
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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

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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

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• 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

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• 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

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• 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

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• 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

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• 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.

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

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Questions?
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Resources

• Singh AK, Ucci A, Madias NE. Predominant
  tubulointerstitial lupus nephritis. Am J Kidney
  Dis 199627273-278
• Singh AK, Colvin RB. Case 36-2003 A 68 year old
  woman with impaired renal function. N Engl J Med
  2003 3492055-63.
• Clive DM, Stoff JS. Renal syndromes associated
  with nonsteroidal anti-inflammatory drugs. N Engl
  J Med 1984310563-572.
• Clive DM, Stoff JS. Renal syndromes associated
  with nonsteroidal anti-inflammatory drugs. N Engl
  J Med 1984310563-572.
• Tam VK, Green J, Schwieger J, Cohen AH. Nephrotic
  syndrome and renal insufficiency associated with
  lithium therapy. Am J Kidney Dis 199627715-720.
  
• Chen CY, Pang VF, Chen CS. Pathological and
  biochemical modifications of renal function in
  ibuprofen-induced interstitial nephritis. Ren
  Fail 19961831-40.
• Michel, DM, Kelly, CJ. Acute interstitial
  nephritis. J Am Soc Nephrol 1998 9506.
• Rennke HG, Roos PC, Wall SG. Drug-induced
  interstitial nephritis with heavy glomerular
  proteinuria. N Engl J Med 1980302691-692.
• Rossert, J. Drug-induced acute interstitial
  nephritis. Kidney Int 2001 60804.
• Up to date
• Hricik, Sedor, Ganz. Nephrology Clinical Secrets.
  
• Sabatine, Mark. Pocket Medicine.
• Stone, Richard. Harrisons Principles of
  Internal Medicine Self Assessment and Board
  Review.
• MD Consult