Inflammatory diseases of the kidney present to us in a wide variety of ways. They can present as a nephrotic syndrome or with more active sediment in the urine and rapid loss of renal function known as the nephritic syndrome or they may present as gradual loss of renal function usually with some degree of proteinuria or the patient may already be in end stage renal disease with the need to go on dialysis and have a renal transplant. What is the way to distinguish between these entities? The gold standard is the renal biopsy though that too may be confusing as the proliferative component of many of the GNs may offer different diagnoses. I am going to be discussing membranoproliferative GN (MPGN) mostly.
Membranoproliferative glomerulonephritis (MPGN), also termed mesangiocapillary glomerulonephritis, is diagnosed on the basis of a glomerular-injury pattern that is common to a heterogeneous group of diseases. MPGN accounts for approximately 7 to 10% of all cases of biopsy-confirmed glomerulonephritis and ranks as the third or fourth leading cause of end-stage renal disease among the primary glomerulonephritides. Although some diseases associated with MPGN are well known, recent advances have identified additional MPGN-associated conditions.
MPGN usually presents in childhood but can present at any age. Its course varies from a benign slowly progressive disease to a rapid progression to dialysis dependent disease. The varied clinical presentation is caused by differences in the pathogenesis of the disorder and in the timing of the diagnostic biopsy relative to the clinical course. The degree of kidney impairment also varies, and hypertension may or may not be present. Patients who present early in the disease process, when the kidney biopsy shows proliferative lesions, are more likely to have a nephritic phenotype, and those with crescentic MPGN may present with a rapidly progressive glomerulonephritis. In contrast, patients with biopsies showing advanced changes that include both repair and sclerosis are more likely to have a nephrotic phenotype. Patients with classic MPGN often have features of both the acute nephritic syndrome and the nephrotic syndrome — termed the nephritic–nephrotic phenotype.
The typical features of MPGN on light microscopy include mesangial hypercellularity, endocapillary proliferation, and capillary-wall remodeling (with the formation of double contours) — all of which result in lobular accentuation of the glomerular tufts. At one time nephrologists tended to call the disease with evidence of capillary wall remodelling i.e. double contours, mesangioproliferative GN.
These changes result from the deposition of immunoglobulins, complement factors, or both in the glomerular mesangium and along the glomerular capillary walls. On the basis of the electron-microscopical findings, MPGN is traditionally classified as:
- primary (idiopathic) MPGN type I (MPGN I),
- type II (MPGN II),
- type III (MPGN III) or secondary MPGN.
MPGN I, the most common form, is characterized by subendothelial deposits.
MPGN II is characterized by dense deposits in the glomerular basement membrane (“dense-deposit disease”).
Secondary MPGN, described by Rennke, is most often due to hepatitis C and other infections.
MPGN III has both subepithelial and subendothelial deposits.
As currently classified, MPGN I and MPGN III are likely to include cases of both immune-complex–mediated and complement-mediated MPGN. It is best to view each case as either immune-complex-mediated or complement mediated. Thus, immune-complex–mediated MPGN may occur when there are increased levels of circulating immune complexes, and complement-mediated MPGN may occur because of disorders associated with dysregulation of the alternative pathway of complement.
Here is a diagram taken from the NEJM review article
Because of persistent antigenemia, antigen-antibody immune complexes form as a result of chronic infections, elevated levels of circulating immune complexes may also be due to autoimmune diseases, or paraproteinemias caused by monoclonal gammopathies. The immune complexes trigger the activation of the classical pathway of complement and the deposition of complement factors of the classical pathway and terminal complement pathway in the mesangium and along the capillary walls. A kidney-biopsy specimen typically shows immunoglobulin and complement on immunofluorescence microscopy.
What infections can cause MPGN?
Chronic viral infections such as hepatitis C and hepatitis B, with or without circulating cryoglobulins, are an important cause of MPGN. Hepatitis C, which was recognized as a common cause of immune-complex–mediated MPGN in the 1990s, is now considered to be the main viral infection causing MPGN.
In addition to viral infections, chronic bacterial infections (e.g., endocarditis, shunt nephritis, and abscesses), fungal infections, and parasitic infections are associated with MPGN, particularly in the developing world. Bacteria associated with MPGN include staphylococcus, Mycobacterium tuberculosis, streptococci, Propionibacterium acnes, Mycoplasma pneumoniae, brucella, Coxiella burnetii, nocardia, and meningococcus.
Which of the autoimmune diseases cause MPGN?
MPGN occurs in a number of autoimmune diseases. These include systemic lupus erythematosus and, occasionally, Sjögren’s syndrome, rheumatoid arthritis, and mixed connective-tissue disorders.
Recent studies indicate that glomerular deposition of monoclonal immunoglobulin as a result of monoclonal gammopathy (also called dysproteinemia or plasma-cell dyscrasia), with or without cryoglobulins, is associated with MPGN.
A schematic model of MPGN associated with dysregulation of the alternative pathway is shown. The injury phase develops because of the deposition of complement factors of the alternative pathway and terminal complement complex due to mutations and antibodies to complement-regulating proteins.
The complement cascade plays an important role in innate immunity. Complement factors can induce a potent inflammatory response that results in phagocyte chemotaxis, with opsonization and lysis of cells, including microorganisms. Complement activation occurs through the classical, lectin, or alternative pathways, all of which converge to form C3 convertase, which cleaves C3 into C3a and C3b. C3b, in the presence of factor B and factor D, associates with C3 convertase, generating even more C3 convertase and resulting in a potent amplification loop.
Dysregulation of the alternative pathway can occur because of mutations in or autoantibodies to complement-regulating proteins . For example, mutations in proteins that regulate the assembly and activity of C3 convertase and degradation of C3b, such as factors H, I, and B and factor H–related protein 5, result in dysregulation of the alternative pathway.
Acquired and Genetic Abnormalities Associated with Complement-Mediated MPGN.
Whatever the mechanism may be, dysregulation of the alternative pathway results in activated complement products, including C3b and terminal complement factors, which are delivered indiscriminately to endothelial surfaces, including glomeruli. The deposition of these complement products and debris in the mesangium and subendothelial region triggers glomerular inflammation and leads to MPGN. Immunoglobulins are not directly involved; thus, complement-mediated MPGN is typically immunoglobulin-negative but complement-positive on immunofluorescence studies.
Despite multiple genetic risk factors, MPGN due to complement abnormalities often develops relatively late in life, suggesting that additional insults or environmental factors are required.
The deposition of immunoglobulin, complement, or both in the mesangium and subendothelial region of the capillary wall triggers an acute injury, which is often followed by an inflammatory (cellular or proliferative) phase, with an influx of inflammatory cells. A subsequent reparative phase occurs, during which new mesangial matrix results in mesangial expansion, along with the generation of new glomerular basement membrane, which looks like a duplicated basement membrane (so-called tram tracks or double contours).
How to evaluate MPGN.
When a kidney-biopsy specimen from a patient with MPGN shows immunoglobulins, evaluate for infections, autoimmune diseases, and monoclonal gammopathies.
Relevant tests for the detection of infections include:
- blood cultures
- serologic tests for viral, bacterial, and fungal infections.
- Look for cryoglobulins.
- Do tests for the detection of monoclonal gammopathy which include serum and urine electrophoresis, immunofixation studies, and free light-chain assays
- If the results are positive results do bone marrow studies for a more precise diagnosis.
- Positive screening tests for an autoimmune disease should be followed by specific tests for the autoimmune disease.
If the biopsy specimen from a patient with MPGN shows bright C3 immunostaining (with minimal or no immunoglobulin staining), an evaluation to detect abnormalities of the alternative pathway is indicated regardless of whether an electron microscopic examination shows dense-deposit disease or C3GN.
The initial evaluation of the alternative pathway should include:
- measurement of serum complement levels
- serum levels of the membrane-attack complex
- an alternative pathway functional assay
- hemolytic complement assays
- followed by genetic analysis for mutations and allele variants of complement factors
- assays for the presence of autoantibodies to complement-regulating proteins, including tests for the detection of C3 nephritic factor.
How to treat MPGN?
- Early studies (predating ACE-i and ARBs) used alternate day steroids. Retrospective studies showed no clear benefit from glucocorticoid therapy, but treatment was not as prolonged in adults as it was in children.
- Heparin and warfarin, frequently combined with glucocorticoids and cytotoxic agents, have not been confirmed in a prospective study.
- An early randomized, controlled trial showed that the combination of aspirin and dipyridamole slowed the decline in the glomerular filtration rate in adults with idiopathic MPGN, but there was no long-term benefit, suggesting that prolonged antiplatelet therapy is required for a sustained benefit.
- Limited uncontrolled data suggest that calcineurin inhibitors may reduce proteinuria in some patients with MPGN.
- In patients with a rapidly progressive course and crescents on renal biopsy, a few small, uncontrolled studies have suggested a benefit with high-dose “pulse” glucocorticoids, either as monotherapy or in combination with azathioprine, cyclophosphamide, or mycophenolate mofetil.
- The lack of randomized, controlled trials and the current understanding that multiple pathogenic processes lead to MPGN make it impossible to give strong treatment recommendations in this patient population.
- Patients with normal kidney function, no active urinary sediment, and non–nephrotic-range proteinuria can be treated conservatively with angiotensin II blockade to control blood pressure and reduce proteinuria, since the long-term outcome is relatively benign in this context. Follow-up is required to detect early deterioration in kidney function.
- Eculizumab, an anti-C5 monoclonal antibody that inhibits C5 activation, has been used successfully in patients with atypical hemolytic–uremic syndrome due to complement abnormalities in the alternative pathway. The role of such anticomplement agents in MPGN is not delineated but offers exciting possibilities for the future.
- MPGN often recurs in kidney-transplant recipients. Recurrence rates range from 27 to 65%, depending on the study.
Two major pathophysiological factors — the deposition of immunoglobulin and the deposition of complement in the glomerular mesangium and capillary walls — may lead to MPGN. The presence of immune-complex–mediated MPGN necessitates evaluation for infections, autoimmune diseases, and monoclonal gammopathy. Complement-mediated MPGN is further subdivided into dense-deposit disease and C3GN, depending on the electron-microscopical findings; the presence of complement-mediated MPGN necessitates evaluation of the alternative pathway. Evaluation of MPGN according to the underlying pathophysiological processes may facilitate proper treatment.