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Glomerulonephritis is a primary or secondary autoimmune renal disease featuring inflammation of the glomeruli. It may be asymptomatic, or present with hematuria and/or proteinuria (blood resp. protein in the urine). There are many recognised types, divided in acute, subacute or chronic glomerulonephritis. Causes are infectious (bacterial, viral or parasitic pathogens), autoimmune or paraneoplastic. more...

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Acute glomerulonephritis

Acute diffuse proliferative GN

Histopathology: the majority of glomeruli present hypercellularity due to proliferation of endothelial and mesangial cells, inflammatory infiltrate with neutrophils and with monocytes. The Bowman space is reduced (compressed). Tubules are not affected.

Rapidly progressive GN (Crescentic GN)

Histopathology: The majority of glomeruli present "crescents". Formation of crescents is initiated by passage of fibrin into the Bowman space as a result of increased permeability of glomerular basement membrane. Fibrin stimulates the proliferation of parietal cells of Bowman capsule, and an influx of monocytes. Rapid growing and fibrosis of crescents compresses the capillary loops and decreases the Bowman space which leads to renal failure within weeks or months.

Mesangial proliferative GN

This type is due to deposition of polymerised IgA1 in the mesangium, with a localised proliferation of tissue. It is consistent with IgA nephritis (Berger's disease) and usually presents with macroscopic hematuria.

Minimal change GN

This form of GN usually (though not exclusively) presents in children with nephrotic syndrome and massive proteinuria. It is controlled with steroids. As the name indicates, there are no changes on light microscopy.

Chronic glomerulonephritis

Chronic glomerulonephritis represents the end-stage of all glomerulonephritis with unfavorable evolution.

Histopathology: few glomeruli may still present changes which permit to discern the etiology of CGN. The majority of the glomeruli are affected. Depending on the stage of the disease, they may present different degrees of hyalinization (hyalinosclerosis - total replacement of glomeruli and Bowman's space with hyaline). The hyaline is an amorphous material, pink, homogenous, resulted from combination of plasma proteins, increased mesangial matrix and collagen. Totally hyalines glomeruli are atrophic (smaller), lacking capillaries, hence non-functional. Obstruction of blood flow will produce secondary tubular atrophy, interstitial fibrosis and thickening of the arterial wall by hyaline deposits. Functional nephrons have dilated tubules, often with hyaline casts in the lumens. In the interstitium is present an abundant inflammatory infiltrate (mostly with lymphocytes).

This general (glomerular, vascular and interstitial) affection constitutes the so-called "end stage kidney". In most cases, it is associated with systemic hypertension.


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Membranoproliferative Glomerulonephritis Type II in a 10-year-old Girl
From Clinical Laboratory Science, 4/1/05 by Tibbs, Martha E

The clinical course of a 10-year-old female patient who presented with hematuria, proteinuria, and hypertension is described. Four months after being diagnosed with acute glomerulonephritis, the child was referred to a pediatric nephrologist due to persistent hematuria and unresolved proteinuria. A renal biopsy was performed due to the persistent urinary abnormalities and a family history of renal failure. The renal biopsy demonstrated pathological findings characteristic of membranoproliferative glomerulonephritis type II. The child was treated with an antihypertensive agent and steroids. Despite poor prognostic clinical and pathological features, she has minimal urinary abnormalities, normal renal function, and normal blood pressure on antihypertensive medication six years after the diagnosis of membranoproliferative glomerulonephritis type II.

ABBREVIATIONS: C3 = complement component 3; GBM = glomerular basement membranes; Ig = immunoglobulin; MPGN = membranoproliferative glomerulonephritis.

INDEX TERMS: C3 nephritic factor; complement; dense deposit disease; membranoproliferative glomerulonephritis; prednisone.

Clin Lab Sci 2005;18(2):84

The nephrotic and nephritic syndromes are clinical consequences of structural injury to the renal glomerulus, a vascular filter that clears the blood of waste products. Laboratory testing is required to distinguish the two syndromes. Proteinuria, the major clinical sign of nephrotic syndrome, results from altered permeability of the glomerular filtration barrier due to perturbations in visceral epithelial cells (podocytes). Nephrotic syndrome in children is the clinical manifestation of podocyte injury most commonly due to minimal change disease. Other causes include focal segmentai glomerulosclerosis, membranoproliferative glomerulonephritis, or membranous glomerulopathy. Children with nephritic syndrome usually present with gross hematuria that may be accompanied by hypertension and variable degrees of proteinuria. Inflammatory processes that target glomeruli, termed acute glomerulonephritis, alter capillary wall integrity, and allow red blood cells to leak into urine. For a more comprehensive analysis of acute glomerulonephritis, the reader is directed to the review by Vinen and Oliveira.1 Hematuria occurs in IgA nephropathy, hypocomplementemic glomerulonephritis, and hereditary renal disease (Table 1). Children who present with overlapping features of both nephrotic and nephritic syndromes should undergo thorough serological testing to narrow down the differential diagnosis. When hematuria and proteinuria are accompanied by hypocomplementemia (Table 1), a renal biopsy may be required to determine the underlying etiology and to guide therapeutic management. If the acute process is untreated, these patients risk progression to chronic glomerulonephritis and may require renal replacement therapy such as dialysis or transplantation (for an excellent review, see Coppo and Amora 2004).2

Membranoproliferative glomerulonephritis (MPGN), or mesangiocapillary glomerulonephritis, is caused by an abnormal immune response leading to antibody deposition in the kidneys. The membrane- portion refers to the histological observation of glomerular capillary wall thickening , due to glomerular basement membrane (GBM) alterations. Increased glomerular cellularity suggests there is a proliferative basis to the glomerulonephritis. Patients with MPGN typically experience a decline in renal function as a consequence of inflammation and structural alterations of the kidney.3,4 MPGN is subtyped into three categories based on the pathway of serum complement activation and altered renal morphology resulting from deposition of immunoglobulin and complement in glomeruli. All three subtypes of MPGN are characterized by a decreased serum C3 level in 80% to 90% of patients and the low serum complement level is an important clinical tool in the preliminary diagnosis of glomerulonephritis (Table 1). MPGN type I is characterized by the classical pathway of complement activation and immune deposits along the subendothelial aspect of the GBM. MPGN type II, or dense deposit disease, is characterized by 'dense' ribbon-like immune deposits within the GBM, alternative complement pathway activation, and circulating C3 nephritic factor. MPGN type III is characterized by subendothelial, subepithelial, and mesangial immune deposits with activation of the alternative complement pathway.5


In September 1997, a 10-year-old girl was seen by her family physician for a one week history of dysuria and brownish-colored urine. Upon physical examination, the patient was afebrile with a blood pressure of 124/92 mmHg. The urine dipstick was positive for protein. Urine microscopy showed numerous white and red blood cells. The child was diagnosed with acute glomerulonephritis and was prescribed a ten-day course of amoxicillin. In January 1998, the child returned to her physicians office with bronchitis. At that time she had a history of gross hematuria, her urine was brown in color, and the urine dipstick was positive for protein and blood. A ten-day treatment of clarithromycin was prescribed, blood tests were drawn, and the child was referred to a pediatric nephrologist.

At the pediatric nephrology clinic, the patient's only symptom was intermittent abdominal pain. Blood pressure was 130/90 mmHg and the physical exam was otherwise unremarkable. Urinalysis demonstrated persistent hematuria and proteinuria, the serum complement levels were normal, and the 24-hour total urine protein excretion was substantially elevated at 2,420 mg (normal is less than 150 to 250 mg/day). Additional laboratory results conducted on serum, summarized in Table 2, included decreased albumin, borderline low total protein, and elevated cholesterol and alkaline phosphatase. A renal ultrasound showed bilateral enlargement of the kidneys. Serology typical of postinfectious glomerulonephritis (Streptozyme®) or nephritis associated with systemic lupus erythematosus (anti-nuclear antibody) was negative. Her family history was remarkable for two maternal uncles with kidney disease each requiring a renal transplant while her mother's urinalysis was negative for blood. Her nephrologist suspected the child had a form of glomerulonephritis, likely IgA nephropathy, but was concerned about the possibility of hereditary nephritis. A kidney biopsy was performed to establish a definitive diagnosis.

The renal biopsy

The renal biopsy specimen contained over 60 glomeruli by light microscopy. Ten percent of the glomeruli were obsolescent or totally scarred. The remaining glomeruli showed lobular accentuation of the glomerular tufts secondary to diffusely increased cellularity, thickened capillary loops, and excess accumulation of mesangial matrix (Figure 1). The glomerular hypercellularity was due to increased mononuclear cells in the mesangium. Jones' silver stain showed thickened and focally duplicated GBM ('tram-tracks') with increased mesangial matrix (Figure 1, inset). Cellular crescents, or extracapillary proliferation in Bowman's space, were present in 10% of the glomeruli. Interstitial edema was apparent. The tubules and vessels were histologically unremarkable.

Direct immunofluorescence examination of the renal biopsy specimen revealed strong immunofluorescence staining for complement C3 along the glomerular capillary loops (3+ to 4+ intensity on a scale of 0 to 4+) accompanied by weaker staining in the mesangium (1+ to 2+) (Figure 2). Staining of capillary loops and mesangium with immunoglobulins IgG, IgA, and IgM was negative to weak (0 to 1+). Staining with complement C1q and fibrinogen was negative.

One glomerulus was examined by electron microscopy. Ultrastructural examination revealed numerous dense, elongated ribbon-like deposits along the lamina densa of GBM (Figure 3). Podocyte foot processes were effaced and the mesangial matrix was increased.

Clinical course

The renal biopsy results were consistent with MPGN type II or dense deposit disease. Based on the results of the renal biopsy, the child received six pulses of intravenous methylprednisolone on an every other day schedule. This was followed by oral prednisone, 60 mg every other day. For hypertension, the patient was prescribed an angiotensinconverting enzyme inhibitor, enalapril, 2.5 mg/day. Six months after the kidney biopsy and initiation of therapy, her serum albumin had increased to 3.8 mg/dL, her 24-hour total urine protein excretion had decreased to 760 mg and she had no further episodes of gross hematuria. She was treated with reducing doses of alternate day prednisone for the next three years. During this interval, her serum albumin and creatinine remained normal, her microscopic hematuria resolved and her 24-hour total urine protein excretion decreased to less than 500 mg per 24 hours. Six years after the diagnosis of MPGN type II and nearly three years after discontinuation of prednisone therapy, she continues to have normal renal function and normal blood pressure, no microscopic hematuria, and minimal proteinuria as demonstrated by a urine protein excretion of less than 500 mg per day.


Clinical findings

MPGN is a common childhood glomerulonephritis that usually progresses to chronic renal failure. Of the three subtypes of MPGN, type II is observed less frequently, accounting for about 20% to 30% of the cases of all MPGNs. Adults and children affected by MPGN type II are typically less than 20 years old with a median age of 11.5 years.4 Many children ultimately found to have MPGN originally receive medical attention due to asymptomatic hematuria and proteinuria. MPGN may present as either acute nephritic syndrome or nephrotic syndrome, with or without gross hematuria.3,4,6 Hypertension occurs in some patients due to water and sodium retention, increased production of renin by the kidney, and other complex mechanisms that regulate blood pressure. In some cases, a patient may present with findings typical of poststreptococcal acute glomerulonephritis; however, if resolution of the symptoms of postinfectious glomerulonephritis does not occur within six to eight weeks then other glomerulonephritides need to be considered (Table 1).4,5 Since the patient described in this report had persistent urinary abnormalities for a period of several months, it became likely that she did not have postinfectious glomerulonephritis and she underwent a kidney biopsy for the determination of a definitive diagnosis.

Laboratory findings

In a patient with MPGN, the major findings on the urinalysis are hematuria and proteinuria. Proteinuria may be pronounced and therefore lead to hypoalbuminemia, hyperlipidemia, and edema: all features characteristic of nephrotic syndrome. Edema may arise as a result of decreased oncotic pressure resulting in fluid leaking from the intravascular space (within the blood vessel) into the tissues when serum protein levels are decreased due to urinary losses.4,7 At presentation, the patient's blood urea nitrogen and creatinine levels are usually normal to slightly elevated, unless a rapidly progressive glomerulonephritis is evident. A normocytic, normochromic anemia may also be present.4

In all three subtypes of MPGN, a major laboratory finding is hypocomplementemia characterized by low levels of C3, which is important to help characterize and formulate a provisional diagnosis in a child with hematuria and proteinuria.3,4,7 Depressed serum C3 is related to increased catabolism and decreased synthesis of complement.5 The C3 nephritic factor, NF^sub a^, is present in 30% to 75% of cases.4 C3 nephritic factor is an IgG autoantibody that stabilizes the alternative pathway C3 convertase, C3bBb. The presence of C3 nephritic factor causes the formation of C3bBb that becomes resistant to inactivation by factor H and leads to very low C3 levels.7,8,9 Serum C4, C5, and properdin levels are usually normal in MPGN type II.5,9

Pathological findings

The kidneys show no gross abnormalities that reflect the pathologic process in MPGN type II, although some patients may have bilateral renal enlargement as is typical in most patients with any form of glomerulonephritis. To separate the types of MPGN, ultrastructural examination is required to demonstrate the glomerular alterations. In MPGN type II, transmission electron microscopy shows sausage-shaped or ribbon-like osmiophilic (electron dense) deposits within the lamina densa of the GBM.3-5,7 Tubular basement membranes may be widened by similar deposits. The deposits occupy short segments in the glomerulus that are distributed irregularly in less severe cases. The dense deposits may also occur in the mesangium.10

When examined by brightfield microscopy, the hematoxylineosin stain imparts a lobular accentuation to the glomerular architecture due to capillary wall thickening and variable mesangial hypercellularity.3,10 Occasionally crescents may involve a portion of the glomeruli.4,7,10 Mesangial sclerosis, or scarring, is more obvious with disease progression. The source of glomerular capillary wall thickening is revealed by periodic acid-Schiff (PAS) or Jones' silver stains that densely label duplicated basement membranes or 'tram-tracks' and impart weaker staining of the dense deposits.3,7 Thioflavin T stain gives a green coloration to the affected basement membranes when using fluorescence microscopy.5 Similar staining can be observed along Bowman's capsule and in the mesangia.10 PAS and Jones' stains highlight the mesangial sclerosis resulting from expansion of extracellular matrix.5,7 Tubular basement membranes may be thickened.3,5

Direct immunofluorescence microscopy shows extensive deposition of C3 within glomerular capillary loops and mesangia. Immunoglobulins are typically scarce; however, if they are present, the immunoglobulins are usually limited to a few glomerular segments.4,10


The pathogenesis of MPGN type II is unclear but the primary morphology is dense deposits in the GBM. By unknown mechanisms, glomerular inflammation occurs subsequently. The origin and nature of the dense deposits are unknown.3-5 C3 nephritic factor has been implicated in the pathogenesis of MPGN type II due to the hypocomplementemia. However, the disease progression does not appear to be affected by hypocomplementemia nor C3 nephritic factor.3-6


The indicators of poor prognosis in MPGN type II are hypertension, impaired renal function at time of diagnosis, nephrotic syndrome, and the presence of crescents.6,7 The higher the percentage of glomeruli with crescents, the more rapidly renal function deteriorates.3,10 Although most patients diagnosed with MPGN type II have no visual complaints, MPGN type II is associated with abnormal retinal function. Dense deposits are observed in the Bruch membrane and the basement membrane of the choriocapillaris. Drusen deposits and retinal pigment epithelial disturbances are characteristic of dense deposit disease retinopathy. These findings are more commonly seen in patients with longstanding MPGN type II.4,11-13 MPGN type II usually progresses slowly to chronic renal failure. Fifty percent of the children will develop chronic renal failure within ten years following diagnosis. Within 20 years of diagnosis, 80% to 90% have chronic renal failure.4


Several different therapies have been used, including anti-platelet therapy and immunosuppression.4,6,14 However, to date, there is no universally accepted form of therapy.4,14 Most pediatric nephrologists use alternate-day prednisone therapy.4 Prednisone appears to stabilize renal function and improves disease characteristics; however, it can produce side effects due to drug toxicity.14 These side effects include stunted growth in children, hypertension, weight gain, Cushinoid features, and mood swings/personality changes. Therapy with pulse intravenous methylprednisolone followed by alternate-day oral prednisone has an improved outcome.4,14-17 The alternate-day regimen either suppresses the immune process underlying glomerular inflammation or decreases inflammation itself to inactivate the disease.5

Treatment may vary according to clinical symptoms and laboratory evaluation. The goals of the treatment are to reduce symptoms, prevent complications, and slow progression of the disease. Some children may require dietary restrictions on sodium, fluids, and protein to control high blood pressure, swelling, and accumulation of waste products in the bloodstream. Antihypertensive and diuretic thetapy may be needed for treatment of edema and hypertension.4,7 Therapy with an angiotensin-converting enzyme inhibitor may be used to decrease urinary protein excretion and slow the progression of chronic renal failure. To manage chronic renal failure, dialysis or kidney transplantation may eventually be necessary.4 However, in 50% to 100% of kidney transplant recipients, recurrence of dense deposits in the transplanted kidney may develop.18-20 When MPGN type II reoccurs, it leads to graft loss in 10% to 20% of the patients.18,19


The patient described in this case study presented with hematuria, proteinuria, and elevated blood pressure. Contrary to most patients with MPGN type II, this 10-year-old female had a normal C3 complement level. Without the renal biopsy, this patient would not have been diagnosed with MPGN type II. Although the current therapy has done well in most cases to slow the progression of the disease, there is still a need for the development of a universally effective treatment that does not have significant adverse side effects.


This report is in compliance with Indiana University School of Medicine's institutional review board and the Health Insurance Portability and Accountability Act of 1996.


1. Vinen CS, Oliveira DB. Acute glomerulonephritis. Postgrad Med J 2003;79(930):206-13.

2. Coppo R, Amore A. New perspectives in treatment of glomerulonephritis. Pediatr Nephrol 2004;19(3):256-65.

3. Cameron JS, Turner DR, Heaton J, and others. Idiopathic mesangiocapillary glomerulonephritis: comparison of types I and II in children and adults and long-term prognosis. Am J Med 1983:74:175-92.

4. Andreoli SP. Chronic glomerulonephritis in childhood: membranoproliferative glomerulonephritis, Henoch-Schönlein purpura nephritis, and IgA nephropathy. Seminars in Nephrol 1995;42(6):1487-1503.

5. West CD. Idiopathic membranoproliferative glomerulonephritis in childhood. Pediatr Nephrol 1992;6:96-103.

6. Schwertz R, de Jong R, Gretz N, and others. Outcome of idiopathic membranoproliferative glomerulonephritis in children. Acta Paediatr 1996;85(3):308-12.

7. Kasinath BS. Sifting the causes of microscopic hematuria. Hosp Pract 1996;31(7):99-106, 109-10.

8. West CD, McAdams AJ. Paramesangial glomerular deposits in membranoproliferative glomerulonephritis type II correlate with hypocomplementemia. Am J of Kidney Dis 1995;25(6):853-61.

9. West CD, McAdams AJ. The alternative pathway C3 convertase and glomerular deposits. Pediatr Nephrol 1999:13:448-53.

10. Churg J. Renal disease classification and atlas of glomerular disease. Tokyo: IGAKU-SHOIN; 1982, p 83-109.

11. Kim RY, Faktorovich EG, Kuo CY, and others. Retinal function abnormalities in membranoproliferative glomerulonephritis type II. Am J of Ophthalmol 1997;123(5):619-28.

12. Leys A, Vanrenterghem Y, Van Damme B, and others. Sequential observation of fundus changes in patients with long standing membranoproliferative glomerulonephritis type II (MPGN type II). Eur J Ophthalmol 1991;1(1):17-22.

13. O'Brien C, Duvall-Young J, Brown M, and others. Electrophysiology of type II mesangiocapillary glomerulonephritis with associated fundus abnormalities. Br J Ophthalmol 1993;77(12):778-80.

14. Bergstein JM, Andreoli SP. Response of type I membranoproliferative glomerulonephritis to pulse methylprodnisolone and alternate-day prednisone therapy. Pediatr Nephrol 1995;9:268-71.

15. Tarshish P, Bernstein J, Tobin JN, and others. Treatment of mesangiocapillary glomerulonephritis with alternate-day prednisone-a report of the international study of kidney disease in children. Pediatr Nephrol 1992;6(2): 123-30.

16. McEnery PT, McAdams AJ, West CD. The effect of prednisone in a high-dose, alternate-day regimen on the natural history of idiopathic membranoproliferative glomerulonephritis. Med 1985;64(6):401-24.

17. Faedda R, Satta A, Tanda F, and others. Immunosuppressive treatment of membranoproliferative glomerulonephritis. Nephron 1994;67(1):59-65.

18. Shimizu T, Tanabe K, Oshima T, and others. Recurrence of membranoproliferative glomerulonephritis in renal allografts. Transplant Proc 1998;30:3910-13.

19. Andresdottir MB, Assmann KJM, Hoitsma AJ, and others. Renal transplantation in patients with dense deposit disease: morphological characteristics of recurrent disease and clinical outcome. Nephrol Dial Transplant 1999; 14:1723-31.

20. Turner DR, Cameron JS, Bewick M, and others. Transplantation in mesangiocapillary glomerulonephritis with intramembranous dense "deposits": recurrence of disease. Kidney Int 1976;9(5):439-48.

Martha E Tibbs MT(ASCP) is a Medical Technologist at Indiana University Hospital, Indianapolis IN.

Sharon P Andreoli is a pediatric nephrologist at Riley Children's Hospital, Indianapolis IN.

Carrie L Phillips MD is a Nephropathologist at Indiana University, Indianapolis IN.

Address for correspondence: Martha E Tibbs MT(ASCP), Indiana University Hospital, Pathology/Microbiology, UH3575, 550 N University Blvd, Indianapolis IN 46202. (317) 274-3896, (317) 278-0049 (fax).

The peer-reviewed Research and Reports Section seeks to publish reports of original research related to the clinical laboratory or one or more subspecialties, as well as information on important clinical laboratory-related topics such as technological, clinical, and experimented advances and innovations. Literature reviews are also included. Direct all inquiries to David G Fowler PhD CLS(NCA), Clin Lab Sci Research and Reports Editor, Dept of Clinical Laboratory Sciences, University of Mississippi Medical Center, 2500 North State St, Jackson MS 39216. (601) 984-6309, (601) 815-1717 (fax).

Copyright American Society for Clinical Laboratory Science Spring 2005
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