Nephrology




(1)
Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, AB, Canada

 




Acute Renal Failure: Pre-renal


NEJM 2007 357:8


Differential Diagnosis



TRUE INTRAVASCULAR FLUID LOSS





  • hemorrhage


  • gi loss—diarrhea, vomiting


  • renal loss—diuretic, osmotic


  • skin loss—increased insensible losses, sweating, burns


DECREASED EFFECTIVE CIRCULATING FLUID





  • heart failure


  • hypoalbuminemia—protein-losing enteropathy, nephrotic, cirrhosis, malnutrition


  • third spacing


  • sepsis


ALTERED RENAL HEMODYNAMICS





  • afferent—renal artery stenosis (RAS), fibromuscular dysplasia, ASA, NSAIDs, cyclosporin, tacrolimus, cocaine, hypercalcemia (vasospasm)


  • efferent—ACE inhibitors, ARB, renal vein thrombosis


Pathophysiology



RISK FACTORS

—patients with advanced age, hypertension, chronic kidney disease, renal artery stenosis, or on medications (NSAIDs, ACE inhibitors, ARBs) are particularly susceptible to ischemic insults due to impaired auto-regulation


Related topic

Renal Artery Stenosis (p. 65)


Investigations



BASIC





  • labs—CBCD, lytes, urea, Cr, Ca, urinalysis, urine lytes, urine Cr


  • microbiology—blood C&S, urine C&S


SPECIAL





  • renal artery stenosis workup—renal Doppler, captopril renogram, CT/MR renal angiogram (use with caution in renal failure)


Diagnostic Issues



COCKCROFT–GAULT FORMULA





  • creatinine clearance (SI units)—CrCl = (140–age) × (weight in kg)/(Cr in μmol/L), multiply by 1.2 if male


  • creatinine clearance (US units )—CrCl = (140–age) × (weight in lbs × 0.37)/(Cr in mg/dL × 88.4), multiply by 1.2 if male


  • note—creatinine is used to estimate GFR, but 5% of creatinine is secreted and thus overestimates GFR. At low GFR, proportion of creatinine secreted becomes higher, so overestimates even more


FEATURES SUGGESTING PRE-RENAL CAUSES





  • urea:Cr ratio—(urea in mmol/L × 10) > Cr in μmol/L [or in US units: (urea in mg/dL/20) > Cr in mg/dL]. Urea reabsorption increases during pre-renal failure, resulting in a disproportionally high serum urea level


  • 10–20–30 rule—urine Na+ <10 mmol/L or Cl− <20 mmol/L and K+ >30 mmol/L


  • F e N a—(UNa/PNa)/(UCr/PCr) × 100%, <1%


  • urinalysis—bland, high specific gravity


DISTINGUISHING FEATURES BETWEEN PRE-RENAL FAILURE AND ATN









































 
Pre-renal
ATN

Urea:Cr ratio (SI)
(Urea × 10) > Cr
(Urea × 20) < Cr

Urea:Cr ratio (US)
Urea > (Cr × 20)
Urea < (Cr × 10)

Increase in Cr
Variable
<44 μmol/L/day [<0.5 mg/dL/day]

Urinalysis
Normal
Heme granular casts

Urine Na
<20 mmol/L
>30 mmol/L

FENa

<1%
>2%

Urine osmo
>500 mOsm/kg
<350 mOsm/kg


Management



TREAT UNDERLYING CAUSE

—fluid resuscitation (NS 0.5–1 L IV bolus over 2–4 h), then 100–200 mL/h with frequent volume reassessments


RENAL REPLACEMENT

—dialysis (peritoneal, hemodialysis). If needed, usually temporary


Treatment Issues



CRITERIA FOR DIALYSIS IN ACUTE RENAL FAILURE

★AEIOU★



  • A cidosis—persistent despite medical treatment


  • E lectrolytes—persistent severe hyperkalemia despite medical treatment


  • I ntoxication—ASA, Li, methanol


  • O verload—persistent fluid overload despite medical treatment


  • U remia—pericarditis, encephalopathy


Acute Renal Failure: Renal



Differential Diagnosis



VASCULAR





  • emboli—atherothrombotic, cholesterol


  • microangiopathic hemolytic anemia—TTP, HUS, scleroderma, malignant hypertension


  • vasculitis—PAN, Takayasu’s


  • hypertension—chronic


TUBULAR





  • acute tubular necrosis (ATN)—ischemia, sepsis, contrast dye, aminoglycosides, amphotericin, acyclovir, myoglobin, hemoglobin, uric acid


  • intra-tubular obstruction—uric acid, indinavir, calcium oxalate, acyclovir, methotrexate, light chains (myeloma)


INTERSTITIAL (ACUTE INTERSTITIAL NEPHRITIS, AIN)





  • iatrogenic—proton pump inhibitors, penicillins, cephalosporins, sulfonamides, rifampin, NSAIDs, diuretics


  • infections—pyelonephritis


  • infiltrate—Sjogren’s, sarcoidosis


  • idiopathic


GLOMERULAR





  • nephrotic—MCD, MGN, FSGS, MPGN-I rarely if ever cause acute renal failure on their own


  • nephritic—IgA, MPGN-II, mesangial proliferative GN, RPGN



    • anti – GBM antibody—Goodpasture’s, anti-GBM antibody nephritis


    • immune complex—SLE, HBV, HCV, endocarditis, post-strep/infectious GN, IgA, cryoglobulinemia, shunt nephritis


    • pauci-immune—granulomatosis with polyangiitis (GPA), Churg–Strauss, microscopic polyarteritis (MPA)


Clinical Features



HISTORY

—duration (previous Cr), N&V, diarrhea, blood loss, obstructive urinary symptoms (frequency, urgency, hesitancy, slow stream, incontinence), hemoptysis, hematuria, edema, contrast dye, nephrotoxins, past medical history (recent infections, HBV, HCV, HF, diabetes, hypertension, malignancy, connective tissue disease), medications (ACE inhibitors, ARB, NSAIDs, ASA, cyclosporine, penicillins, cephalosporins, acyclovir, amphotericin, chemotherapy)


PHYSICAL

—orthostatic vitals especially heart rate and blood pressure, respiratory and cardiac examination (JVP, heart failure), abdominal examination (masses, renal bruit), ankle edema, cholesterol emboli


Related Topic

Glomerulonephritis (p. 80)


Investigations



BASIC





  • labs—CBCD, lytes, urea, Cr, urinalysis, urine lytes, urine Cr


  • etiology workup—ANA, anti-dsDNA, ENA, p-anca, c-anca, anti-GBM antibody, C3, C4, CK, uric acid, ASO-titer, HBV/HCV serology, RF, cryoglobulin, quantitative Ig, serum protein electrophoresis, urinary protein electrophoresis, urine eosinophils


  • microbiology—blood C&S, urine C&S if suspect infection


  • imaging—US renal


SPECIAL





  • imaging—CXR, echocardiogram


  • special—renal biopsy


Investigation Issues



DISTINGUISHING FEATURES BETWEEN VARIOUS RENAL ETIOLOGIES

































































 
Urinalysis
Other tests

Vascular
Bland
Peripheral smear (TTP)
 
Urinary eosinophils (cholesterol emboli)
p-anca

ANA (lupus), ENA

Tubular
Muddy brown casts (ATN)
CK (rhabdomyolysis)

Uric acid (gout)

Interstitial
WBC casts, urinary eosinophils
Systemic eosinophilia

Glomerular
RBC casts
c-anca (GPA)
 
Acanthocyte (dysmorphic RBC)
p-anca
 
Oval fat body
Eosinophilia (Churg-Strauss)
 
Fatty cast
Anti-GBM (Goodpasture’s syndrome)
   
ANA, anti-dsDNA (SLE)
   
ASO titer (PSGN)
   
Blood C&S, echo (infectious endocarditis)
   
HBV/HCV serology, SPE, UPE (multiple myeloma)
   
Cryoglobulins, rheumatoid factor (cryoglobulinemia)


Management



PREVENTION

—avoid contrast dye, nephrotoxins if possible


TREAT UNDERLYING CAUSE

—nephrotic syndrome (low-salt diet and furosemide for volume regulation if needed; statin if needed to correct hyperlipidemia)


RENAL REPLACEMENT

—dialysis (peritoneal, hemodialysis)


Specific Entities



PSEUDO-RENAL FAILURE

—cimetidine and trimethoprim may reduce tubular secretion of creatinine causing a small but significant increase in serum creatinine in the absence of ↓ GFR


MULTIPLE MYELOMA AND RENAL FAILURE





  • pre-renal—N&V, renal vein thrombosis, calcium-induced vasospasm, nephrogenic diabetes insipidus (hypercalcemia)


  • renal—secondary amyloidosis (λ), light chain deposition disease (κ), myeloma kidney (tubulointerstitial damage due to increased light chain absorption through proximal tubule), Bence Jones/cast nephropathy, plasma cell infiltration, cryoglobulinemia, pyelonephritis, sepsis


  • post-renal—renal stones (hypercalcemia), neurogenic bladder


NSAID-INDUCED RENAL FAILURE





  • pre-renal—inhibition of prostaglandin synthesis leading to afferent vasoconstriction, hypertensive nephropathy


  • renal—acute interstitial nephritis, nephrotic syndrome (minimal change disease, membranous)


ACUTE TUBULAR NECROSIS (ATN)





  • pathophysiology—tubular damage → decreased reabsorption of Na → vasoconstriction → decreased GFR. Also may be related to tubular blockage from damaged epithelial cells. Risk factors include elderly (GFR ↓ by 1 mL/min/year after age 40), pre-existing renal dysfunction, decreased cardiac function, diabetes, dehydration, and multiple nephrotoxins


  • treatments—after the insults are stopped, may start to recover in 3–5 days. Generally takes 7–21 days (some up to 8 weeks) for full recovery


CONTRAST NEPHROPATHY





  • pathophysiology—contrast-induced vasospasm, hyperosmolar load and oxygen free radical generation → acute tubular injury → ↑ Cr or ↓ GFR by 25%. Usually develops immediately after exposure to contrast, peaks in 48–72 h. Risk factors and recovery time course same as ATN. Key differential diagnosis is renal atheroemboli after arterial catheterization (usually delayed onset of renal failure and may see other signs of arterial ischemia)


  • risk factors—patient risk factors (pre-existent renal failure, multiple myeloma, diabetes mellitus, hypertension, volume contraction, HF, exposure to nephrotoxins such as NSAIDs or aminoglycosides, recent acute coronary syndrome), procedural risk factors (increased dye load, increased osmolar dye load)


  • prevention—avoid contrast dye, nephrotoxins, and volume depletion if possible. If contrast absolutely required, use low (iohexol) or iso-osmolal (iodixanol) non-ionic agents. Hydration options include (1) IV 1/2 NS at 1 mL/kg/h starting 12 h before until 12 h after contrast exposure; (2) IV NS or NaHCO 3 154 mmol/L at 3 mL/kg/h starting 1 h before until 6 h after contrast exposure; (3) IV N-acetylcysteine 150 mg/kg in 500 mL 0.9% NS given 30 min before contrast exposure, followed by 50 mg/kg in 500 mL 0.9% NS IV given over 4 h after (alternatively, N-acetylcysteine 600 mg PO BID on day of and day after contrast exposure)


Acute Renal Failure: Post-renal



Differential Diagnosis



URETHRA

—stricture, stenosis


PROSTATE

—BPH, prostatitis, cancer


BLADDER

—cancer, stones, clots, neurogenic


URETERS

(bilateral involvement)



  • intraluminal—cancer, stones, clots, papillary necrosis


  • extraluminal—cancer, retroperitoneal fibrosis, pregnancy


Investigations



BASIC





  • labs—CBCD, lytes, Cr/urea, urinalysis


  • imaging—US abd/pelvis


SPECIAL





  • post-residual volume—>200 mL suggests obstruction


  • CT abd /KUB/IVP—if suspect stones or tumors


  • diuresis renography or urography


Diagnostic Issues



RENAL US

—hydronephrosis suggests post-renal causes. However, retroperitoneal fibrosis and acute post-renal obstruction may not show hydronephrosis


Management



TREAT UNDERLYING CAUSE

—Foley catheter. For BPH (tamsulosin 0.4 mg PO daily or TURP)


RENAL REPLACEMENT

—dialysis (peritoneal, hemodialysis)


Glomerulopathies



Pathophysiology of Glomerulopathies



AUTOIMMUNE PHENOMENON

—antibodies binding to structural components of glomeruli (more glomerular basement membrane and podocytes involvement in nephrotic syndrome, more mesangium and endothelium involvement in nephritic syndrome), circulating antigen–antibody complexes, and/or cell-mediated immunity → further immune activation and damage to glomeruli


PATHOLOGY TERMS

—focal = <50% of glomeruli, diffuse= > 50% of glomeruli, segmental = segment of glomerulus, global = entire glomerulus


Clinical Features



CLINICAL MANIFESTATIONS OF GLOMERULAR DISEASES




































Clinical manifestation
Examples

Asymptomatic proteinuria
FSGS, mesangial proliferative GN, diabetic nephropathy

Nephrotic syndrome
MCD, FSGS, MGN, MPGN, amyloidosis, light chain deposition disease, diabetic nephropathy

Asymptomatic hematuria
Thin basement membrane disease, IgA nephropathy, Alport’s syndrome

Recurrent gross hematuria
Thin basement membrane disease, IgA nephropathy, Alport’s syndrome

Acute nephritis
Post-infectious GN, IgA nephropathy, lupus nephritis, MPGN

Rapidly progressive glomerular nephritis (RPGN)
See text

Pulmonary-renal syndrome
Antiglomerular basement membrane antibody disease, immune complex vasculitis, pauci-immune (ANCA) vasculitis

Chronic renal failure
Sclerosed glomerular disease


DISTINGUISHING FEATURES BETWEEN NEPHROTIC AND NEPHRITIC SYNDROMES





















































 
Nephrotic
Nephritic

Onset
Slower
Faster

Edema
++++
++

Blood pressure
N/↓
↑

Volume/JVP
N/↓
↑

Proteinuria
>3 g/day
May be <3 g/day

Hematuria
May occur
+++

Urine sediment
Hyaline casts, lipid droplets (oval fat body)
Dysmorphic RBC, WBC, RBC casts, granular casts

Albumin
↓↓↓
N/mild ↓

Creatinine
N/↑
Usually ↑

Serum Na
May be ↓↓
N/mild ↓

NOTE: nephrotic syndrome ≠ nephrotic range proteinuria (proteinuria >3 g/day without other symptoms and signs)


Nephrotic Syndrome



DIFFERENTIAL DIAGNOSIS

—minimal change disease, membranous GN, focal segmental glomerulosclerosis, MPGN (type 1), diabetes, amyloidosis, IgA nephropathy, HIV, drug-associated (NSAIDs, gold, pamidronate)


CLINICAL FEATURES

—proteinuria (>3 g/day), edema, hypoalbuminemia, hyperlipidemia, lipiduria, hypercoagulability


INVESTIGATIONS

—CBCD, lytes, urea, Cr, 24-h urine for protein and Cr, spot urine protein/Cr ratio, renal biopsy (simplification/effacement of visceral podocyte foot processes, classically non-inflammatory), lipid profile


POOR PROGNOSTIC FACTORS

—male, age >50, ↑ creatinine, proteinuria >10 g/day, proteinuria >6 months, hypertension


TREATMENTS

—Na restriction, blood pressure control, ACE inhibitor/ARB, treatment of dyslipidemia, steroid, cyclophosphamide, cyclosporine, anticoagulate if high risk


COMPLICATIONS

—ARF/hypovolemia, malnutrition, hyperlipidemia, infections (especially encapsulated bacteria), arterial/venous thrombosis (30–40%), renal vein thrombosis, edema


Nephritic Syndrome



DIFFERENTIAL DIAGNOSIS

—MPGN (type 2), rapidly progressive/crescentic GN (anti-GBM, immune, pauci-immune), IgA nephropathy


CLINICAL FEATURES

—hematuria, proteinuria, hypertension, azotemia


INVESTIGATIONS

—CBCD, lytes, urea, Cr, ANA, anti-dsDNA, ENA, p-anca, c-anca, anti-GBM, C3, C4 (complements low except for IgA nephropathy), CK, uric acid, ASO titer, HBV serology, HCV serology, cryoglobulin, quantitative Ig, serum protein electrophoresis, renal biopsy


TREATMENTS

—steroid, cyclophosphamide, mycophenolate mofetil, rituximab


Specific Entities



MINIMAL CHANGE DISEASE (MCD)





  • pathophysiology—T-cell abnormality → ↑ glomerular permeability


  • causes—primary, secondary (NSAIDs, Li, interferon, NHL, Hodgkin’s, leukemia, HIV, mononucleosis)


  • clinical features—pure nephrotic (minimal hematuria, no RBC casts, creatinine not elevated)


  • pathology—light microscopy (normal), immunofluorescence (no immune complexes), electron microscopy (effacement of podocyte foot processes)


  • treatments—steroid, cyclophosphamide, cyclosporine


  • prognosis—90% steroid responsive, 10% steroid resistant, end-stage renal disease rare


MEMBRANOUS GN (MGN)





  • causes—primary, secondary (gold, penicillamine, captopril, solid tumors (breast, colon, and lung), Hodgkin’s, SLE, rheumatoid arthritis, autoimmune thyroiditis, syphilis, HBV, HCV, chronic transplant rejection)


  • clinical features—pure nephrotic (minimal hematuria, no RBC casts)


  • pathology—light microscopy (basement membrane thickening, spikes), immunofluorescence (immune complexes IgG, and complements in subepithelial space), electron microscopy (same as immunofluorescence)


  • treatments—steroid, cyclophosphamide, cyclosporine or tacrolimus


  • prognosis—40% remission, 30% stable, 30% end-stage renal disease over 10–20 years


FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

(more severe form of MCD)



  • causes—primary, secondary (Li, heroin, lymphomas, HIV. May also be associated with sickle cell disease, hypertension, and obesity)


  • clinical features—pure nephrotic (minimal hematuria, no RBC casts)


  • pathology—light microscopy (segmental areas of sclerosis), immunofluorescence (no immune complexes), electron microscopy (effacement of podocyte foot processes)


  • treatments—steroid, cyclophosphamide, cyclosporine or tacrolimus


  • prognosis—large percentage with end-stage renal disease over 15–20 years


MEMBRANOPROLIFERATIVE GN (MPGN)





  • pathophysiology—type 1 = immune complex deposition disease. Type 2 = activation of complement system via C3 nephritic factor (IgG against C3 convertase), with decreased C3 and normal C4


  • causes—primary, secondary type 1 (HCV, HBV, endocarditis, abscess, infected shunts, CLL, lymphomas, SLE, cryoglobulinemia), secondary type 2 (partial lipodystrophy, sickle cell, complement deficiency)


  • clinical features—50% nephrotic (usually type 1), 20% asymptomatic proteinuria/hematuria, 30% acute nephritic (usually type 2)


  • pathology—light microscopy (basement membrane thickening, mesangial cell hypercellularity), immunofluorescence (complements along capillary walls), electron microscopy (type 1 shows discrete deposits in mesangium, type 2 shows deposits as continuous ribbon in glomerular basement membrane)


  • treatments—steroid, cyclophosphamide, cyclosporine


  • prognosis—40–75% end-stage renal disease over 10–15 years


RAPIDLY PROGRESSIVE GN (RPGN)—ANTI-GLOMERULAR BASEMENT MEMBRANE ANTIBODY DISEASE





  • pathophysiology—antibody against α3 chain of type IV collagen


  • causes—Goodpasture’s syndrome, anti-GBM antibody nephritis


  • clinical features—nephritic (hematuria, proteinuria, ARF). Goodpasture syndrome also has lung involvement whereas anti-GBM antibody nephritis affects kidney alone


  • pathology—immunofluorescence (linear staining)


  • treatments—plasmapheresis with IV pulse steroids followed by PO steroids with PO cyclophosphamide for 1 year


RAPIDLY PROGRESSIVE GN (RPGN)—IMMUNE COMPLEX





  • pathophysiology—deposition of circulating immune complex in glomeruli, usually in subendothelial location


  • causes—SLE, HBV, HCV, endocarditis, post-strep GN, post-infectious GN, IgA nephropathy, cryoglobulinemia, shunt nephritis


  • clinical features—nephritic (hematuria, proteinuria, ARF)


  • pathology—immunofluorescence (granular staining)


  • treatments—IV pulse steroids followed by PO steroids with IV monthly cyclophosphamide for 1 year, rituximab. If infection related, treat underlying infection


RAPIDLY PROGRESSIVE GN (RPGN)—PAUCI-IMMUNE COMPLEX





  • causes—granulomatosis with polyangiitis (c-anca), microscopic polyangiitis (p-anca), Churg–Strauss


  • clinical features—nephritic (hematuria, proteinuria, ARF). May have lung involvement


  • pathology—immunofluorescence (no staining)


  • treatments—IV pulse steroids followed by PO steroids with PO cyclophosphamide for 1 year, rituximab


IGA NEPHROPATHY





  • pathophysiology—abnormal regulation of production or structure of IgA in response to environmental antigens → illness triggers production of IgA and/or IgA immune complex → deposit in mesangium


  • causes—primary, secondary (HSP, celiac disease, dermatitis herpetiformis, cirrhosis, HIV, malignancies, seronegative spondyloarthropathies)


  • clinical features—50% recurrent macroscopic hematuria with URTI, 30–40% persistent microhematuria and proteinuria, 10% rapidly progressive renal failure, <10% nephrotic syndrome


  • pathology—light microscopy (focal or diffuse mesangial hypercellularity and matrix expansion), immunofluorescence (extensive IgA deposition in mesangium and capillary walls), electron microscopy (mesangial deposits). Patients presenting with nephrotic syndrome may also have nephrotic histologic picture. Note most of the time IgA nephropathy is a clinical diagnosis. No biopsy unless ARF or severe symptoms


  • treatments—ACE inhibitor may slow progression. Steroids, cytotoxic agents


  • prognosis—20–40% end-stage renal disease over 20 years


Related Topics

Acute Renal Failure (p. 78)

Chronic Kidney Disease (p. 83)


Chronic Kidney Disease


NEJM 2007 357:13


Differential Diagnosis



CAUSES OF ACUTE RENAL FAILURE

—pre-renal, renal, post-renal (see ACUTE RENAL FAILURE p. 78)


CHRONIC KIDNEY DISEASES





  • renovascular disease—atherosclerosis, hypertensive nephropathy, glomerulosclerosis (with age)


  • diabetes—proteinuria


  • glomerulonephritis


  • polycystic kidney disease


  • multiple myeloma


  • nephrotoxins—NSAIDs


Pathophysiology



DEFINITION OF CHRONIC KIDNEY DISEASE

—>3 months of abnormal renal function, suggests irreversible component


CLASSIFICATION OF CHRONIC KIDNEY DISEASE





  • stage I (GFR ≥90 mL/min/1.73 m2, proteinuria)—observe, consider ACE inhibitor


  • stage II (GFR 60–89 mL/min/1.73 m2)—consider ACE inhibitor, nephrology referral


  • stage IIIa (GFR 45–59 mL/min/1.73 m2)—nephrology referral


  • stage IIIb (GFR 30–44 mL/min/1.73 m2)—nephrology referral


  • stage IV (GFR 15–29 mL/min/1.73 m2)—consider renal replacement therapy (dialysis or transplantation)


  • stage V (GFR <15 mL/min/1.73 m2)—dialysis, transplantation, or palliation


RISK FACTORS FOR CHRONIC KIDNEY DISEASE DEVELOPMENT AND PROGRESSION

—old age, hypertension, proteinuria (not just a surrogate marker), high-protein diet, dyslipidemia


Clinical Features



SIGNS AND SYMPTOMS OF CHRONIC KIDNEY DISEASE





  • volume overload


  • electrolyte/acid–base balance—hyperkalemia


  • metabolic acidosis


  • normocytic anemia


  • calcium/phosphate balance—↓ 1,25(OH)2 vitamin D3 synthesis in kidney, ↑ PO4 due to decreased filtration → ↓ Ca → ↑ PTH → renal osteodystrophy (osteitis fibrosa with increased bone resorption from secondary hyperparathyroidism; osteomalacia with decreased bone resorption and unmineralized bone due to aluminum binder use (now uncommon); adynamic bone disease with decreased bone resorption due to oversuppression of PTH)


  • uremic symptoms

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Mar 26, 2017 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Nephrology

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