Clinico-Pathologic Classification of Glomerular Diseases
(copyright)

See Table 1 for classification

Patients have low levels of complement in the serum and present with primary nephritic syndrome, or with a systemic disease associated with nephritic syndrome.

• Primary Nephritic Syndrome with Low Serum Complement

  Post Infectious GN, Proliferative GN, acute GN, post-streptococcal GN ***

  Clinical
  1. Nephrotic syndrome usually follows a 6-14 day latent period after a Group A beta-hemolytic streptococcal throat infection or a longer latent period after skin infection. Treatment of infections has decreased incidence of postinfectious G.N.
  2. Usually presents as: gross hematuria, edema, and hypertension.
  3. Reduced C3 and C4 during first 6-8 weeks.
  4. Identical clinical picture can be seen after many other bacterial infections
  5. Excellent prognosis with complete recovery of renal function particularly in children.
  6. Biopsy is performed only in cases with "atypical" presentation.
  
  Biopsy
  1. L.M. findings: hypercellular glomeruli are observed
  2. I.F. findings: deposition of IgG and of complement, with a granular pattern, along glomerular capillary loops.
  3. E.M. findings: confirms the presence of sub-epithelial electron dense deposits

  To review Bx see: HU Slide 4-A, HU Slide 4-B, HU Slide 4-C, HU Slide 4-D, and HU Slide 4-E. Harvard U.

  Pathogenesis In situ I.C. formation and complement activation. The Ag is possibly a "planted" cationic bacterial protein.

  Membranoproliferative GN Type I, mesangiocapillary GN *

  Clinical
  1. Can present as an acute nephritic syndrome with nephrotic syndrome.
  2. Frequently associated with Hepatitis C virus infection.
  3. More common in adolescents and children.
  4. Complement activation occurs in only 50% of cases in adults.
  5. Not a frequent disease.
  6. Diagnosis by renal biopsy
  
  Biopsy
  1. L.M. findings: Hypercellular lobulated glomeruli with "double" capillary basement membrane on special stains.
  2. I.F. findings: demonstrates IgG, IgM and complement at the periphery of the glomerular lobules
  3. E.M. findings: sub-endothelial electron dense deposits and new basement membrane deposition are observed

  To review Bx see: HU Slide 14-A, HU Slide 14-B, and HU Slide 14-C. Harvard U.

  Pathogenesis Deposition of circulating IC and complement activation
  

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• Systemic Diseases Causing Nephritic Syndrome with Low Serum Complement - Clinical and Pathologic Findings

  See Table 1 for classification

  Systemic Lupus Erythematosus, WHO Class III, and WHO Class IV ****

  Clinical
  1. Nephritic Syndrome and low serum complement in patient with lupus.
  2. The diagnosis of lupus erythematosus is made by clinical and serologic criteria.
  3. Lupus is frequent in African Americans.
  4. Renal biopsy is performed to confirm degree of glomerular proliferation and to decide on therapy.
  5. Proliferative lupus nephritis is treated with steroids and cytotoxic therapy (cyclophosphamide).
  
  Biopsy
  1. L.M. findings: In diffuse proliferative nephritis (WHO Class IV), all glomeruli are hypercellular and lobulated, with variable degrees of "double" capillary basement membrane. In focal Proliferative nephritis (WHO Class III), the above described changes are present in less than 50% of the glomeruli.
  2. I.F. findings: IgG, IgM, IgA, complement (full house) are demonstrated at the periphery of the glomerular lobules and in the mesangium.
  3. E.M. findings: Sub-endothelial and mesangial electron dense deposits are present. New basement membrane deposition is observed.

  

  To review Bx see: HU Slide 7-E, HU Slide 7-C, and HU Slide 7-F. Harvard U.

  GN in Infectious Endocarditis ***

  1. Nephritic syndrome and low serum complement in patient with endocarditis.
  2. Acute GN in the febrile patient should suggest endocarditis. Diagnosis confirmed by BX.
  3. GN usually resolves with appropriate antibiotic therapy.
  Biopsy as described in post-infectious GN

  HCV associated Mixed Cryoglobulinemia *

  1. Nephritic syndrome and low serum complement in patient with hepatitis C.
  2. Frequently: purpuric skin lesions, and arthritis
  3. Lab:
     HCV - positive
     cryoglobulins - positive
     C4 - very low
     rheumatoid factor - very high.
  4. Due to production of mixed IgG-IgM cryoglobulins.
  Biopsy as described in membranoproliferative GN

Patients with normal serum complement levels can present with a primary nephritic syndrome, or nephritic syndrome and a systemic disease.

• Primary Nephritic Syndrome with Normal Serum Complement

  IgA Nephropathy or Berger’s Disease **

  Clinical
  1. Hematuria, either recurrent gross hematuria immediately following a viral illness or as persistent microscopic hematuria. Serum creatinine is normal. Occasionally presents with acute renal failure..
  2. Prognosis good when patients have only hematuria.
  3. Patients with significant proteinuria more likely to have progressive renal insufficiency.
  4. Frequent world-wide. In North America, frequent among Native Americans.
  5. Diagnosis made by renal biopsy.
  6. Some patients, more frequently children, can have a systemic disease with disseminated vasculitis: Henoch Schoenlein Purpura
  
  Biopsy
  1. L.M. findings: Glomeruli show increased mesangial matrix and cellularity.
  2. I.F. findings: Intense granular IgA deposition, with a mesangial pattern, is observed.
  3. E.M. findings: confirms electron dense deposits in the mesangium

  

  To review Bx see: HU Slide 12-A, HU Slide 12-B, and HU Slide 12-C. Harvard U.

  Pathogenesis Deposition of circulating IC (unknown antigen). IC are found in the glomeruli and in many vessels

  Hereditary Nephritis or Alport' s Syndrome *

  Clinical
  1. Very rare familial renal disease frequently associated with nerve deafness.
  2. More common and severe in males who develop renal failure and ESRD in early adulthood.
  3. Prognosis is variable in females.
  4. Microscopic or gross hematuria is the most common presentation. Serum creatinine is normal.
  5. Ocular disorders may occur.
  6. At present, can only be diagnosed by renal bx.
  
  Biopsy
  1. L.M. findings: Glomeruli do not show diagnostic changes. Interstitial foam cells are frequent.
  2. I.F. findings: shows absence of Ig deposition.
  3. E.M. findings: Diagnosis is made by E.M.: thickening, splitting, splintering of glomerular capillary basement membrane.
  Pathogenesis Genetic defect resulting in disturbance in composition of the basement membrane. Certain components of collagen IV are absent: alpha 5 isoform in X-linked Alport syndrome, alpha 3 or alpha 4 isoforms in patients with autosomal inheritance.

  ANCA-Associated Pauci - immune complex Rapidly Progressive GN **

  Clinical
  1. Insidious onset of nephritic syndrome progressing to renal failure: in weeks designated rapidly progressive renal failure
  2. Can present as acute renal failure.
  3. Progression to uremia and ESRD is frequently rapid unless diagnosed and treated early.
  4. Serologic marker is ANCA (anti-neutrophil cytoplasmic antigen).
  5. Many consider this disorder to be a form of "microscopic polyarteritis" with renal involvement being the only clinical sign.
  6. Not a frequent disease.
  7. Therapy is initiated after diagnosis is confirmed by biopsy.
  
  Biopsy
  1. L.M. findings: Glomeruli are surrounded by crescents, the hallmark of RPGN. Vasculitis is rarely seen on the biopsy.
  2. I.F. findings: demonstrates fibrin in the crescents. Ig are absent.
  3. E.M. findings: Electron dense deposits are not seen.
  4. Differential diagnosis: must be differentiated from other 2 forms of crescentic RPGN - anti-basement membrane disease and immune complex mediated RPGN.

  To review Bx see: HU Slide 10-B, and HU Slide 10-D. Harvard U.

  Pathogenesis Probably all cases represent vasculitis and T cell mediated glomerular injury.
  

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• Systemic Diseases Causing Nephritic Syndrome with Normal Serum Complement - Clinical and Pathologic Findings

  See Table 1 for classification

  Systemic Lupus Erythematosus, WHO Class II ***

  Clinical
  1. Nephritic syndrome and normal serum complement in patient with lupus.
  2. The diagnosis of lupus erythematosus is made by clinical and serologic criteria.
  3. Lupus is frequent among African Americans.
  4. This type of SLE presents with fewer urinary abnormalities and less reduction in renal function than WHO III and WHO IV.
  5. Good prognosis in the majority of cases.
  6. Renal biopsy is performed to differentiate from other forms of lupus nephritis and to decide on therapy.
  
  Biopsy
  1. L.M. findings: In mesangial lupus nephritis (WHO class II), glomeruli show increased mesangial matrix and cellularity.
  2. I.F. findings: Intense granular IgA, IgG, IgM and complement deposition, with a mesangial pattern, is observed.
  3. E.M. findings: confirms electron dense deposits in the mesangium.

  To review Bx see: HU Slide 13-A, HU Slide 13-B, and HU Slide 13-C. Harvard U.

  Goodpasture Syndrome, Anti-Basement Membrane Disease *

  Clinical
  1. Very rare disease.
  2. Pulmonary hemorrhage, nephritic syndrome.
  3. Hemoptysis and hematuria are the usual presenting symptoms; can present as acute renal failure.
  4. Diagnosis depends on demonstrating anti-GBM Ab in serum or tissue.
  5. Requires aggressive treatment with high dose steroids and plasmapheresis to prevent evolution to ESRD.
  6. Renal Bx confirms the diagnosis.
  
  Biopsy
  1. L.M. findings: shows a crescentic GN.
  2. I.F. findings: linear pattern of IgG deposition is seen along glomerular capillary loops. Fibrin is present in crescents.
  3. E.M. findings: not contributory to the diagnosis.
  4. Differential diagnosis: must be differentiated from other 2 forms of crescentic RPGN - pauci-immune ANCA associated RPGN and immune complex mediated RPGN.

  To review Bx see: HU Slide 9-C, HU Slide 9-D, and HU Slide 9-E. Harvard U.

  Pathogenesis In situ production of I.C. The Ag is the "Goodpasture Ag", i.e., non collagenous domain of the alpha 3 chain of collagen IV in lamina densa of basement membrane.
  Note: The well defined pathogenesis makes this disease a favorite on Boards.

  Systemic Vasculitis **

  Clinical
  1. Patients with vascultis can present with nephritic syndrome or acute renal failure and normal serum complement.
  2. ANCA is a useful tool for diagnosis:
     • Polyarteritis nodosa is associated with P-ANCA
     • Wegener's Granulomatosis is associated with C-ANCA
     • Henoch-Schonlein purpura (HSP) is not associated with ANCA.
  
  Biopsy In polyarteritis nodosa and in Wegener's granulomatosis, the glomeruli are surrounded by crescents. The crescentic GN is called "pauci-immune complex RPGN" because the glomeruli do not show immunoglobulin deposition . Convsersely, HSP has mesangial deposition of IgA in the glomeruli. HSP is the systemic variant of IgA Nephropathy. All forms of vasculitis are focal and therefore, despite the patient's signs and symptoms, not likely to be represented in the renal biopsy or in the biopsy of other tissues.
  Pathogenesis: Although the exact pathogenesis of the various vasculitis is unknown, research studies point to T-cell mediated injury. HSP is possibly immune complex mediated: blood vessels show deposition of IgA. It is considered the systemic variant of IgA nephropathy.

  To review Bx see: HU Slide 8-C. Harvard U.

  Thrombotic Thrombocytopenic Purpura (TTP) *

  Clinical
  1. Nephritic syndrome or acute renal failure; normal complement.
  2. Hemorrhages and purpura, neurologic symptoms, hemolytic anemia, hematuria.
  3. Renal biopsy confirms the diagnosis of this rare disease.
  4. Treatment: plasma pheresis
  
  Biopsy L.M. findings: Platelet-fibrin thrombi in arterioles and small arteries Pathogenesis It is a thrombotic microangiopathy, where endothelial damage leads to aggregation of platelets, followed by thrombocytopenia and a microangiopathic form of hemolysis.

  Thrombotic microangiopathy is the underlying pathology of other clinical syndromes:
  

  • hemolytic uremic syndrome
  • eclampsia
  • para-neoplastic syndrome
  • malignant hypertension
  • therapy induced (cyclosporine)

  Hemolytic Uremic Syndrome *

  Clinical
  1. Nephritic syndrome or acute renal failure; normal complement.
  2. Particularly in children, preceeded by gastrointestinal infection with specific strains of E. Coli, followed by acute nephritic syndrome and hemolytic anemia. Not a frequent disease.
  3. Good prognosis in children, variable in adults.
  4. Renal involvement i.e. renal failure much worse than in TTP.

  Thrombotic microangiopathy is the underlying pathology of other clinical syndromes:
  

  • TTP
  • eclampsia
  • para-neoplastic syndrome
  • malignant hypertension
  • therapy induced (cyclosporine)

  
  Biopsy & Pathogenesis

  thrombotic microangiopathy as in TTP

• Pre-Renal Etiology ***

  Pre-renal azotemia is caused by conditions that reduce either true renal perfusion or "effective" renal perfusion. True renal perfusion may be reduced by volume contraction, gastrointestinal bleeding, diuretics, or shock. Effective renal perfusion is reduced by congestive heart failure, cirrhosis, and nephrotic syndrome. Drugs that affect intrarenal hemodynamics such as NSAID’s (which reduce prostaglandins) and ACE-I’s (which reduce AII), can also cause pre-renal azotemia. Correction of the underlying disease will usually correct the renal failure. Renal biopsies are only performed in acute renal failure when the diagnosis cannot be established clinically, and renal failure does not reverse. The major laboratory clues to the diagnosis of pre-renal azotemia are a "benign" urinalysis, and avid sodium retention, i.e. low urine sodium or a fractional excretion of sodium < 1%.

• Renal Etiology

  1. Glomerular diseases - Rapidly progressive GN (RPGN)
     a - Pauci-immune complex RPGN, ANCA associated; can present as primary nephritic syndrome with normal serum complement or as systemic disease - vasculitis. Biopsy shows crescents and immune complex deposition is not present - described under primary nephritic syndrome with normal complement and systemic disease with normal complement and nephritic syndrome.
     b - Anti-basement membrane disease (Goodpasture): described among systemic diseases with nephritic syndrome and normal serum complement. Biopsy shows crescents and linear pattern by immunohistochemistry.
     c - Immune complex mediated RPGN. Several immune complex mediated GN can present as RPGN, including lupus, IgA nephropathy, Henoch Schoeinlein Purpura, endocarditis. Biopsy shows crescents and immune complex deposition corresponding to the disease.
     

  2. Tubulointerstitial Diseases

     Acute Interstitial (AIN) Nephritis **

     Click to enlarge	Clinical Characterized by various combinations of fever, skin rash, arthralgias or arthritis, and eosinophilia. Eosinophils in the urine are helpful in making the diagnosis. The most common cause is drug induced. Drug induced AIN presents as acute renal failure after a mean of 2 weeks on the offending agent (range: 1 dose - many months). Renal biopsy confirms the diagnosis. Prognosis generally good after removal of offending agent.
     	Etiology Most frequently it is secondary to nonsteroidal anti-inflammatory drugs or antibiotics. Can be idiopathic.
     	Biopsy Tubulointerstitial mononuclear infiltrate with eosinophils and/or granulomas.

     Acute Tubular Necrosis (ATN) **

     Clinical
     1. Acute fall in the GFR as manifested by a rapid rise in the serum creatinine in the setting of either ischemia (shock), or nephrotoxins.
     2. The most common nephrotoxins include antibiotics-aminoglycosides, radiocontrast dye, and myoglobin (rhabdomyolysis).
     3. Patients may either be oliguric (urine output < 400 ml/day) or non-oliguric.
     4. In the setting of ischemia or nephrotoxins, the diagnosis of ATN is usually established by a urinalysis with many granular or "dirty brown" casts.
     5. The urine sodium will be high with a fractional excretion of sodium > 2%.
     6. The diagnosis is almost always established on clinical grounds, but renal biopsy may be necessary to rule out rapidly progressive GN or interstitial nephritis if features are atypical.
     7. There is no specific therapy, and supportive care is effective.
     8. Recovery of renal function is expected in 1-3 weeks.
     
     Biopsy In cases of ATN, the most important contribution of the Bx is to rule out GN and interstitial nephritis. Tubules can appear normal or show mild changes, such as dilatation. Also observed are desquamated necrotic epithelial cells and granular material in the tubules. If present, pigmented casts are diagnostic.
     Pathogenesis Ischemia or toxin
  
  
  

• Post-Renal or Obstructive Etiology

  Clinical Presentation Urinary tract obstruction, an important reversible problem, must be excluded in all patients who present with acute renal failure. Particularly consider obstruction as a cause of ARF in: very young children (congenital disorders), older men (prostate disease), and patients with a history of pelvic or abdominal malignancy. Note that the patient can have significant obstruction in the absence of urinary symptoms or change in urine output or flow.
  Clinical Evaluation The urinalysis is generally benign. The most important diagnostic test is an ultrasound of the kidneys to exclude hydronephrosis. If bladder outlet obstruction is suspected, an indwelling urinary catheter is placed. Once obstruction is identified, a urologic evaluation is performed to determine the etiology. Renal biopsy is generally not indicated in these patients.
  
  

  • Chronic renal failure

    Renal biopsy shows non-specific findings: sclerosed glomeruli, thickened vessels, atrophic tubules and interstitial fibrosis. Most often the diagnostic criteria that defined the various glomerular diseases in their earlier stages are no longer present. The accepted pathology diagnosis in theses cases is "end-stage kidney"; this term has replaced the obsolete term "chronic GN".
  
  
  This learning module is copyright material owned by S Meleg-Smith, MD and NK Krane, MD at Tulane University Medical School. It may be reproduced for teaching/learning purpose with proper attribution.
  

  The authors are grateful to Erich J. Meihoff, who made this Web page possible in 1998, and to Brendan Doyle for assistance in continuous updating.

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  Last modified on February 6, 2001 at 12:25 pm