What are the diagnostic and treatment approaches for Membranoproliferative Glomerulonephritis (MPGN), Nephrotic Syndrome, Nephritic Syndrome, Tubulointerstitial Disease, Urinary Tract Infections, and Acute Renal Failure?

Board-Relevant Information on Key Renal Conditions

Membranoproliferative Glomerulonephritis (MPGN)

Modern Classification Framework

MPGN is no longer considered a single disease entity but rather a pattern of glomerular injury with multiple distinct etiologies that must be differentiated by immunofluorescence patterns. 1

The classification is based on three immunofluorescence patterns:

• Immune complex-mediated (Ig-positive ± complement): Suggests classical complement pathway activation requiring workup for infections (HCV, HBV, HIV, endocarditis), autoimmune diseases (SLE, Sjögren's), and monoclonal gammopathies (multiple myeloma, MGUS) 1
• Complement-dominant (Ig-negative, C3-positive): Termed "C3 glomerulopathy," indicates alternative complement pathway dysregulation 1
• Immunofluorescence-negative (Ig-negative, C3-negative): Raises suspicion for chronic thrombotic microangiopathy, TTP/HUS, scleroderma, transplant glomerulopathy, antiphospholipid syndrome, or malignant hypertension 1

Diagnostic Workup

For C3 glomerulopathy specifically:

• In children: Genetic screening for mutations in C3, complement factors H/I/B, CD46, and CFHR 1-5 1
• In adults: Test for acquired autoantibodies including C3 nephritic factor (C3Nef) and anti-factor H antibody 1
• Specialized laboratories at University of Iowa and National Jewish Health offer these tests 1

Treatment Approach

For idiopathic MPGN with nephrotic syndrome AND progressive renal decline, use oral cyclophosphamide or MMF plus low-dose alternate-day or daily corticosteroids for less than 6 months. 1

Treatment indications can be broadened to include:

• Nephrotic syndrome with or without progressive decline 1
• Active nephritic syndrome 1
• Rapidly progressive disease with or without crescents 1

Do NOT treat patients with advanced CKD, severe tubulointerstitial fibrosis, small kidneys, or chronic inactive disease with immunosuppression. 1

Patients with normal eGFR and non-nephrotic proteinuria have good long-term outcomes and can be managed conservatively with close monitoring of renal function, proteinuria, and urine microscopy 1

Critical Pitfall

All MPGN biopsies should be evaluated by experienced nephropathologists due to the rarity and importance of proper classification. 1

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Nephrotic Syndrome

Clinical Definition

Characterized by:

• Proteinuria >3.5 g/day 2
• Hypoalbuminemia 2
• Edema 2
• Hyperlipidemia 2

Major Complications

Patients with nephrotic syndrome face significant morbidity and mortality from thromboembolic and cardiovascular complications, independent of the underlying glomerular disease. 2

The greater the proteinuria, the greater the long-term risk for renal failure 2

Membranous Nephropathy (Most Common Primary Cause)

Idiopathic membranous nephropathy remains the most common glomerular disease causing nephrotic syndrome in adults. 2

Treatment approach:

• Supportive care first: Diuretics plus ACE inhibitors combined with ARBs, though these have limited effect 2
• Immunosuppressive options (controversial with significant adverse effects): Corticosteroids, alkylating agents, cyclosporin A, tacrolimus, mycophenolate mofetil 2
• Up to 40% eventually reach ESRD despite treatment 2

Monoclonal Immunoglobulin-Associated Disease

When nephrotic syndrome occurs with detectable serum/urine monoclonal immunoglobulin:

• Specify the MIg type (kappa vs lambda) in the diagnosis 1
• Document extent of involvement (glomeruli, tubular basement membranes, interstitium, vessels) 1
• Correlate with known hematologic conditions (multiple myeloma, MGRS, MGUS) 1
• If no hematologic disease is known, recommend appropriate workup 1

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Nephritic Syndrome

Clinical Definition

Nephritic syndrome is characterized by hematuria, proteinuria, hypertension, and in some cases acute kidney injury and fluid retention, all characteristic of acute glomerulonephritis. 3

Classic presentation includes:

• Tea-colored urine 4
• Red blood cell casts on urinalysis 4, 5
• Hypertension 3
• Edema 3
• Acute renal dysfunction 4

Emergency Recognition

Rapidly progressive glomerulonephritis (RPGN) with rapid decline in kidney function over days to weeks constitutes a medical emergency and must not be missed, as it can lead to irreversible kidney damage within weeks if untreated. 4, 5

RPGN is characterized by:

• Extensive crescent formation (usually >50% of glomeruli) on biopsy 5
• Rapid creatinine rise over days to weeks 4, 5

Major Etiologies

Most common causes encountered in primary care:

• Infection-related glomerulonephritis: Now predominantly caused by staphylococci and gram-negative organisms (not streptococci as historically) 6, 3
• IgA nephropathy 3
• Lupus nephritis 3
• MPGN (see above section) 3
• ANCA-associated vasculitis: Most common cause of rapidly progressive kidney failure 5, 3

Infection-Related Glomerulonephritis

The epidemiology has dramatically changed: staphylococci and gram-negative strains now predominate over streptococci. 6

High-risk populations:

• Alcoholics (even without cirrhosis) 6
• Diabetics 6
• IV drug users 6

Common infection sites: oropharynx, skin, lung, endocarditis 6

Ongoing or new nosocomial infection is almost invariably associated with developing glomerular proliferative changes, even on repeat biopsy. 6

Poor prognostic factors:

• Age >50 years 6
• Purpura 6
• Endocarditis 6
• Glomerular extracapillary proliferation (crescents) 6

Prognosis is poor with 50% developing chronic disease and 11% mortality 6

Diagnostic Workup for RPGN

Essential serologies: ANCA, ANA, anti-GBM antibodies, complement levels 5

Kidney biopsy is crucial to confirm diagnosis and assess disease activity versus chronicity 5

Treatment of RPGN

Early diagnosis and prompt initiation of immunosuppressive therapy are critical for favorable outcomes. 5

For ANCA-associated vasculitis:

• Induction with cyclophosphamide or rituximab plus glucocorticoids 5
• Exclude infection before starting significant immunosuppression 5

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Tubulointerstitial Disease

Prognostic Significance in MPGN

Only the degree of tubulointerstitial damage on initial biopsy is determinative for prognosis of childhood MPGN. 7

Reporting Standards

When reporting renal biopsies, additional findings must include:

• Extent of tubular atrophy and interstitial fibrosis (quantified as percentage) 1
• Presence of interstitial nephritis 1
• Acute tubular injury 1
• Calculation of chronicity score is endorsed 1

Light-Chain Proximal Tubulopathy

When differential diagnosis includes light-chain proximal tubulopathy:

• Paraffin immunofluorescence is recommended 1
• Immunohistochemical stains for light chains may detect intracellular MIg when routine and pronase studies are negative 1

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Urinary Tract Infection (Acute Pyelonephritis)

High-Risk Populations

Diabetic patients are particularly vulnerable to complications including renal abscesses and emphysematous pyelonephritis. 1

Additional high-risk groups:

• Anatomic urinary tract abnormalities 1
• Vesicoureteral reflux 1
• Renal obstruction 1
• Pregnancy 1
• Nosocomial infection 1
• Treatment-resistant pathogens 1
• Transplant recipients 1
• Immunosuppressed patients 1

Diagnostic Challenge in Diabetes

Up to 50% of diabetic patients with pyelonephritis will not have typical flank tenderness, making clinical diagnosis more difficult. 1

Imaging Indications

Imaging is NOT indicated for initial evaluation of uncomplicated acute pyelonephritis. 1

Imaging should be obtained when:

• No clinical response after 72 hours of appropriate antibiotics (95% of uncomplicated cases become afebrile within 48 hours, nearly 100% within 72 hours) 1
• Suspected complications (abscess, pyonephrosis, emphysematous pyelonephritis) 1
• High-risk patient populations 1

Complications

• Renal abscess: Microabscesses coalesce during acute phase 1
• Perirenal abscess: Occurs when renal abscess ruptures into perinephric space 1
• Pyonephrosis: Infection confined to obstructed collecting system requiring prompt decompression 1

HCV-Associated Cryoglobulinemic Nephritis

When UTI workup reveals glomerulonephritis in HCV-positive patients:

Three main glomerular patterns from cryoglobulin deposition: diffuse membranoproliferative glomerulonephritis (80% of cases), mesangial proliferative pattern, and membranous pattern 1

Clinical presentations:

• Isolated proteinuria <3 g/24h with microscopic hematuria (30%) 1
• Nephrotic syndrome (20%) 1
• Acute nephritic syndrome (15%) 1
• Chronic renal insufficiency (10%) 1
• Acute renal failure (10%) 1

Renal biopsy is mandatory in any HCV patient with urinary abnormalities and/or unexplained renal impairment. 1

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Acute Renal Failure

Triage Decision-Making

Creatinine >3 mg/dL severely limits drug efficacy and enhances toxicity, requiring urgent intervention. 4

Creatinine >5 mg/dL may require hemofiltration or dialysis. 4

When to Send to Emergency Department

Immediate ER referral for:

• RPGN with rapid decline over days to weeks 4, 5
• Full-blown acute nephritic syndrome (tea-colored urine, significant proteinuria, RBC casts, hypertension, edema, acute renal dysfunction) 4
• Creatinine rising over days to weeks 4

Outpatient Management Appropriate For

• Isolated microscopic hematuria without proteinuria, normal BP, stable renal function 4
• Mild proteinuria with microscopic hematuria, normal renal function, no systemic symptoms (expedited nephrology referral) 4
• Post-infectious GN with clear antecedent infection, mild symptoms, stable renal function 4

Pre-Transfer Workup

Essential tests before transfer:

• Urinalysis with microscopy to confirm glomerular hematuria and quantify proteinuria 4, 5
• Basic metabolic panel (BUN, creatinine, electrolytes) 4
• Complete blood count for anemia or thrombocytopenia 4

Differential Diagnosis in Nephrotic Syndrome with ARF

When nephrotic syndrome presents with acute renal failure, consider:

• Acute tubular necrosis 8
• Renal vein thrombosis 8
• Acute tubulointerstitial nephritis 8
• Superimposed crescentic glomerulonephritis on primary glomerular disease 8

Treatment of Superimposed Crescentic GN

For membranous nephropathy with superimposed crescentic GN causing ARF: steroids plus cyclophosphamide can stabilize renal function. 8

Prognosis in Infectious GN

Destructive glomerular proliferation persists until infection is eradicated, despite rescue treatment with corticosteroids and/or cytostatic drugs. 6

Outcomes in infectious GN:

• 11% mortality 6
• 26% recover renal function 6
• 50% follow chronic course 6
• Infection represents a frequent and often overlooked cause of ESRD 6