Diffuse Proliferative Glomerulonephritis

Updated: Apr 28, 2015
  • Author: Moro O Salifu, MD, MPH, FACP; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Overview

Background

Diffuse proliferative glomerulonephritis (DPGN) is a term used to describe a distinct histologic form of glomerulonephritis common to various types of systemic inflammatory diseases, including autoimmune disorders (eg, systemic lupus erythematosus [SLE]), vasculitis syndromes (eg, Wegener granulomatosis), and infectious processes. In DPGN, more than 50% of the glomeruli (diffuse) show an increase in mesangial, epithelial, endothelial (proliferative), and inflammatory cells (ie, glomerulonephritis). (Increased cellularity is demonstrated in the image below.)

Light microscopy (trichrome stain) shows globally Light microscopy (trichrome stain) shows globally increased cellularity, numerous polymorphonuclear cells, cellular crescent (at left of photomicrograph) and fibrinoid necrosis (brick red staining at right of photomicrograph). These findings are characteristic of diffuse proliferative glomerulonephritis.

In contrast, when fewer than 50% of the glomeruli are involved, the condition is termed focal proliferative glomerulonephritis. However, this entity has the potential to progress to DPGN.

The diagnosis of DPGN is often suspected in a patient presenting with systemic inflammatory disease who manifests hematuria, proteinuria, and active urinary sediment or azotemia (ie, rise in serum urea nitrogen, creatinine). Histologic findings from kidney biopsy tissue are used to confirm the diagnosis.

Sporadic forms of renal diseases that can manifest histologically as focal, segmental, necrotizing, and crescentic glomerulonephritis or DPGN with undetermined incidence include microscopic polyangiitis; Churg-Strauss syndrome; essential mixed cryoglobulinemia, which also may manifest as membranoproliferative glomerulonephritis; Henoch-Schönlein purpura; and connective tissue diseases.

In severe forms of DPGN, epithelial proliferation obliterates the Bowman space (ie, crescents). The resulting acute kidney injury may manifest as an acute anuria or a steady decline in renal function. Spontaneous remission is rare, and treatment results are anecdotal.

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Pathophysiology

Most cases of DPGN result from the deposition of immune complexes in the mesangium, glomerular basement membrane (GBM), subendothelial or subepithelial locations. Antibodies may form immune complexes with circulating DNA before deposition (ie, immune complex deposition) or may bind directly to nonglomerular antigens already planted in the mesangium or GBM (ie, in situ immune complex formation). In anti-GBM disease, the antibodies act against the GBM. The pathogenesis of antineutrophil cytoplasmic antibody (ANCA)–associated glomerulonephritis is unknown, although microvasculitis is the predominant feature without immune complex formation.

Activation of the complement system through the classic pathway by immune complexes or direct cell-mediated injury in ANCA-associated glomerulonephritis results in the recruitment of inflammatory cellular infiltrates (eg, lymphocytes, macrophages, neutrophils), proliferation of the mesangial and endothelial cells, and necrosis. Cellular crescents and fibrin thrombi may be present in more severe cases. The net result is obliteration of the capillary loops and sclerosis, predisposing the patient to hypertension and renal failure.

The cellular and immunologic attack of the glomerulus renders the GBM permeable to protein, red blood cells, and white blood cells. Therefore, urinalysis during active inflammation (or glomerulonephritis) characteristically shows an active urinary sediment, ie, red blood cells or casts, white blood cells or casts, and variable degrees of proteinuria (ie, nephritic pattern).

Anti-GBM disease is an autoimmune disease in which autoantibodies are directed against type IV collagen in the GBM. Binding of these autoantibodies to the GBM induces rapidly progressive glomerulonephritis (RPGN) and crescentic glomerulonephritis. The clinical complex of anti-GBM nephritis and lung hemorrhage is Goodpasture syndrome. The typical morphologic pattern using light microscopy is DPGN, with focal necrotizing lesions and crescents in more than 50% of glomeruli (ie, crescentic glomerulonephritis). Acute nephrotic syndrome is rare, and a bimodal peak in incidence exists. Although any age group may be affected, the first peak in incidence occurs in the third to the sixth decades of life and the second occurs in the sixth to the seventh decades of life.

In patients with granulomatosis with polyangiitis (Wegener granulomatosis), renal biopsy findings typically reveal focal, segmental, necrotizing, pauci-immune glomerulonephritis with crescent formation.

In microscopic polyarteritis nodosa (PAN), the usual histopathologic lesion is a pauci-immune focal segmental necrotizing and crescentic glomerulonephritis. In Churg-Strauss syndrome, a minority of patients may develop focal segmental necrotizing glomerulonephritis; in mixed cryoglobulinemias, the characteristic morphologic lesions are diffuse mesangial proliferative or membranoproliferative glomerulonephritis. For Henoch-Schönlein purpura, light microscopic appearances can vary from mild mesangial proliferation and expansion to diffuse proliferation with glomerular crescents.

In rheumatoid arthritis (RA), lesions of mesangial proliferative glomerulonephritis and basement membrane thickening caused by subepithelial immune deposits may be observed. Occasional cases of focal mesangial proliferative glomerulonephritis with mesangial deposition of immunoglobulin G (IgG) and complement have been described in polymyositis and dermatomyositis. [1]

In addition to poststreptococcal glomerulonephritis, nephritic syndrome and RPGN can complicate acute immune-complex glomerulonephritis due to other viral, bacterial, fungal, and parasitic infections. Some of these warrant specific mention. Diffuse proliferative immune complex glomerulonephritis is a well-described complication of acute and subacute bacterial endocarditis and usually is associated with hypocomplementemia. The glomerular lesion typically resolves following eradication of the cardiac infection. Shunt nephritis is a syndrome characterized by immune complex glomerulonephritis secondary to infection of ventriculoatrial shunts inserted for treatment of childhood hydrocephalus.

The most common offending organism is coagulase-negative Staphylococcus. Renal impairment usually is mild and is associated with hypocomplementemia. Nephrotic syndrome complicates 30% of cases. Acute proliferative glomerulonephritis can also complicate chronic suppurative infections and visceral abscesses. Patients typically present with a fever of unknown origin and an active sediment. Although renal biopsy is used to detect immune deposits containing IgG and C3, serum complement levels usually are within the reference range.

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Epidemiology

Frequency

United States

The incidence of SLE in urban areas varies from 15-50 cases per 100,000 population per year. Renal involvement is evident clinically in 40-85% of patients with SLE. DPGN is the lesion observed in 35-40% of biopsies in lupus nephritis, and as many as 30% of these patients progress to terminal renal failure.

Anti-GBM disease is a rare disorder of unknown etiology with an annual incidence of 0.5 cases per million. About 50-70% of patients have lung hemorrhage; anti-GBM antibodies develop in the serum of more than 90% of patients with anti-GBM nephritis according to findings on specific radioimmunoassay.

Renal injury occurs in 80% of patients with Wegener granulomatosis. Renal biopsy tissue typically reveals focal, segmental, necrotizing, pauci-immune glomerulonephritis with crescent formation, which may progress to DPGN.

Cytoplasmic ANCAs are detected at presentation in 80% of patients with renal disease and in 10% more during follow-up. In contrast to the lung, granulomas rarely develop in the kidney.

Most cases of acute poststreptococcal glomerulonephritis are sporadic, although the disease can occur as an epidemic. The characteristic lesion visible using light microscopy is DPGN. Crescents may be present, and extraglomerular involvement usually is mild.

Nephritis is present in 80% of cases of Henoch-Schönlein purpura and manifests as a nephrotic urine sediment and moderate proteinuria. Macroscopic hematuria and nephrotic range proteinuria are uncommon.

International

The incidence of DPGN in renal biopsies varies from approximately 10-27% in Europe and 30% in the Middle East to 41% in Japan. Worldwide, the most common glomerulopathy is due to immunoglobulin A (IgA) nephropathy, accounting in most series for 10-40% of all glomerulonephritis. Up to 80% of patients with Henoch-Schönlein purpura (ie, anaphylactoid purpura), which is a distinct systemic vasculitis syndrome that is characterized by palpable purpura (most commonly distributed over the buttocks and lower extremities), arthralgias, and gastrointestinal signs and symptoms, have DPGN.

In 1987, after the introduction of assays for antineutrophil cytoplasmic antibodies (ANCA), the diagnosis of ANCA-positive vasculitis (ie, Wegener granulomatosis, microscopic polyarteritis) rose from 1.5 cases per million to about 6-7 cases per million.

Mortality/Morbidity

Advances in immunosuppressive therapy and renal replacement therapy have markedly reduced the mortality and morbidity rates of DPGN in the last 2 decades. A significant portion of morbidity and mortality rates in DPGN is due to complications of immunosuppressive therapy, including drug toxicity and infection.

  • In one short-term study consisting of 25 patients with severe lupus whose cases were followed for 9.4 months, the combined crude mortality (1 patient) plus end-stage renal disease ([ESRD] 1 patient) rate was 8%.
  • In one 10-year follow-up study of 86 patients treated aggressively (ie, with high-dose prednisone plus oral cyclophosphamide alone or with plasmapheresis) for severe lupus nephritis, patient survival at 5 and 10 years was 95% in the group that had remission. In the group without remission, patient survival was 69% at 5 years and 60% at 10 years. Renal survival rates were 94% at 5 and 10 years in the remission group but 46% at 5 years and 31% at 10 years in the group with no remission.
  • Mortality due to poststreptococcal glomerulonephritis is rare. Prior to the introduction of immunosuppressive therapy, more than 80% of patients with anti-GBM nephritis developed ESRD within 1 year, and many patients died from pulmonary hemorrhage or complications of uremia and infection. Renal failure is a poor prognostic marker for survival in patients with Wegener granulomatosis. In a series of 104 patients who presented to the Cleveland Clinic Foundation from 1982-1997, 11 of 23 patients who required dialysis died. In a Norwegian study of 108 patients with Wegener granulomatosis and renal involvement, 2- and 5-year renal survival rates were 86% and 75%, respectively. The 2- and 5-year patient survival rates were 88% and 74%, respectively. IgA nephropathy has an indolent course with a favorable outcome.
  • The actuarial renal survival rate in adults after 10 years is 80-85% in most of the European and Asian studies, is slightly less in studies from the United States, and is more than 90% in the few studies of children. [2, 3, 4] Renal death due to DPGN in IgA nephropathy is rare.

Race

Lupus nephritis has a 3-4 times greater incidence in black patients than in white patients. IgA nephropathy is more common in people of Asian origin than it is in whites of African American origin. Wegener granulomatosis is extremely rare in blacks compared to whites

Sex

See the list below:

  • Men tend to have more aggressive disease than women. However, for SLE, the female-to-male incidence ratio is 9:1 for women of childbearing age. By comparison, the female-to-male ratio is only 2:1 for disease developing during childhood or in people aged 65 or older. Males who develop SLE have the same incidence of renal disease as do females. [2]
  • Microscopic PAN is more common in males (ie, male-to-female ratio of 2:1). The distribution of Wegener granulomatosis among the sexes is roughly equal, with a slight male predominance. Males have a 2.7 times higher incidence of IgA nephropathy than females.

Age

See the list below:

  • Patients with Goodpasture syndrome typically are young males aged 5-40 years (the male-to-female ratio is 6:1). In contrast, patients presenting during the second peak in incidence, occurring in the sixth decade of life, rarely experience lung hemorrhage and have an almost equal sex distribution.
  • SLE occurs in all age groups, with the peak incidence occurring in women of childbearing age. Over 85% of patients are younger than 55 years.
  • Wegener granulomatosis develops in people of any age. Approximately 15% of patients are younger than 19 years, and only rarely does the disease occur before adolescence. The mean age of onset is approximately 40 years. The mean age of patients at onset in reports of PAN and microscopic polyangiitis is 48 years.
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