(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
constitutional—fatigue, generalized weakness
neurologic—decreased memory and concentration, slow and slurred speech, myotonic jerks, seizures, altered smell and taste, peripheral neuropathy, sleep disturbances, restless leg syndrome
gastrointestinal—anorexia, nausea and vomiting, gastritisStay updated, free articles. Join our Telegram channel
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