Post-streptococcal glomerulonephritis (PSGN)

Post-streptococcal glomerulonephritis (PSGN): It follows an episode of streptococcal sore throat or impetigo (skin infection). PSGN is most common in children between the ages of 3-7 years and is more common in boys. It is considered a type III hypersensitivity reaction. It presents with edema, periorbital puffiness, hematuria (cola colored urine), hypertension, fever, malaise and oliguria 1-4 weeks after a streptococcal infection. BUN and creatinine levels will rise. Microscopically, glomeruli are diffusely enlarged and hypercellular from neutrophil and macrophage infiltrate and mesangial proliferation. Immunofluorescence shows lumpy-bumpy, granular deposits of IgG, IgM and C3 in the glomeruli. EM shows subepithelial humps composed of immune complex deposits, obliteration of foot processes and in some cases, subendothelial, mesangial and intramembranous deposits. Antistreptococcal antibodies will be positive, C3 is low for 2-4 weeks then becomes normal, C4 is normal. RBC casts are seen in urine. Most cases are transient with full recovery of renal function while some may progress to ESRD. Adults with PSGN have a worse prognosis. Treatment is supportive, antibiotics may be needed if infection is active, some cases may need steroids and dialysis.

Alport syndrome or hereditary nephritis: It is an inherited disorder transmitted in most cases in an X-linked manner and in others by AR or AD manner. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes which code for type IV collagen. The glomerular basement membrane contains type IV collagen. It presents with progressive loss of renal function, microscopic or gross hematuria, proteinuria, hypertension, edema, fatigue, bilateral sensorineural hearing loss, anterior lenticonus, vision loss, corneal and retinal changes and aortic aneurysms.

Thin basement membrane disease is a milder form of Alport syndrome without the extra-renal manifestations.

Diagnosis is by skin or renal biopsy and molecular genetic testing. Immunostaining with antibodies to alpha-5 chains in type IV collagen is negative in skin biopsies while alpha-5, 3 and 4 chains are present in renal biopsies in Alport syndrome. Electron microscopy shows thinning of the glomerular basement membrane in earlier stages and GBM thickening with alpha 3, 4 and 5 deposits in later stages. Audiometry and eye exam should be done. Prenatal diagnosis can be done by chorionic villus sampling and amniocentesis. Treatment is with ACE inhibitors or ARBs to delay the progression of renal disease, dialysis and renal transplant.

IgA nephropathy or Berger’s disease: It is the most common cause of primary glomerulonephritis, caused by the deposition of IgA in the glomerulus. It is more common in men. It presents with gross hematuria, flank pain, edema, ankle swelling, hypertension typically following an URTI or gastrointestinal infection. Some cases may proceed to end stage renal disease. Excess amounts of abnormal IgA or poorly galactosylated IgA1 triggers the generation of glycan specific autoantibodies. IgA immune complexes are deposited in mesangium and activate alternative complement pathway and possibly the lectin pathway, with resultant podocyte damage. Biopsy shows mesangial proliferation and mesangial deposits. Immunofluorescence shows IgA deposits in glomerular mesangium, dermis, lung, liver and intestines. Mild cases do not need treatment. When proteinuria exceeds 1 gram/day, ACE inhibitors and ARBs are used. Corticosteroids and cyclophosphamide can be used for severe cases.

Immunofluorescence microscopy showing mesangial deposits of IgA

Lupus nephritis: It is more common in women and is seen as a complication of SLE. Most cases of lupus are idiopathic, with a possible viral trigger. Drug induced lupus is seen due to quinidine, methyldopa, chlorpromazine, hydralazine, isoniazid, procainamide and methyldopa. The renal pathology in SLE is immune-complex mediated. It is considered a type III hypersensitivity reaction. Immune complexes deposit in the mesangium, subendothelial and subepithelial spaces. There is a lack of immune tolerance to nuclear self-antigens. Nucleic acids released from neutrophils activate intrarenal inflammation and cytokines such as alpha and beta interferons are released along with complement activation causing renal damage.

WHO classification of lupus nephritis

It presents with proteinuria, microscopic hematuria, glomerulonephritis, renal failure, nephritic and nephrotic syndrome. Tubulointerstitial disease and vasculitis is seen. Treatment is with a combination of prednisone and cyclophosphamide. Mycophenolate mofetil can be used instead of cyclophosphamide.

Goodpasture syndrome or anti-glomerular basement membrane disease: It is an autoimmune disorder characterized by the development of antibodies to collagen (apha 3 chain of type IV collagen), in the basement membrane of the alveoli and renal glomeruli. It is more common in men and is triggered by cigarette smoking, inhaled hydrocarbons and viruses. It has been associated with HLA-DR15 (DR2). Individuals with HLA-DR7 and DR1 have less risk of Goodpasture syndrome. HLA-B8 and DR2 are associated with bad prognosis. It causes a rapidly progressive glomerulonephritis. It presents with hemoptysis, edema, hematuria, proteinuria, hypertension, cough, dyspnea, anemia and hepatomegaly. Crackles or rhonchi can be auscultated over the lungs. Renal biopsy shows focal proliferative to crescentic glomerulonephritis, linear deposits of IgG and complement along the glomerular capillaries. Lung biopsy shows focal necrosis of the alveolar wall, hemosiderin laden macrophages and linear deposits of IgG along the alveolar basement membrane. Treatment is with plasmapheresis to remove the antibodies from plasma, steroids and cyclophosphamide.

Membranoproliferative glomerulonephritis or MPGN: It is a glomerular disorder seen in children and young adults and characterized by hypocomplementemia. It may present as a nephritic or nephrotic syndrome. Gross hematuria and hypertension are common and symptoms are commonly preceded by a respiratory tract infection. It tends to progress slowly to end-stage renal disease and often recurs after renal transplantation. It may result from cryoglobulinemia, HepB, HepC infections, HIV, bacterial infections like abscess, malaria, leprosy, schistosomiasis, infective endocarditis, SLE, scleroderma, Sjogren’s syndrome, complement deficiency, leukemias,lymphomas, cirrhosis, cystic fibrosis, sarcoidosis and HUS etc.

Histologically, MPGN is characterized by diffuse mesangial cell proliferation and the thickening of capillary walls due to subendothelial extension of the mesangium. Complement activation plays a central role in all forms of MPGN. There are three types of MPGN as follows:

Treatment is with corticosteroids, cyclophosphamide, cyclosporine, plasma exchange, aspirin, dipyridamole and rituximab.

Rapidly progressive glomerulonephritis or RPGN or crescentic glomerulonephritis: It is characterized by rapid decline in renal function presenting as a nephritic or nephrotic syndrome which progresses to ESRD. It is seen in Goodpasture syndrome, lupus nephritis, Henoch Schonlein purpura, post-streptococcal glomerulonephritis, ANCA-associated pauci-immune glomerulonephritis (Granulomatosis with polyangiitis (GPA), Churg Strauss syndrome), cryoglobulinemia and IgA nephropathy. Underlying pathology is severe glomerular injury with the rupture of glomerular capillary loops. Biopsy shows characteristic glomerular crescents , seen in >50% of the glomeruli. Crescents result from proliferation of the parietal epithelium of Bowman’s capsule with macrophages, neutrophils, lymphocytes, fibrin and collagen. Glomerular capillary collapse is seen along with atrophic tubules. Treatment is with steroids, cyclophosphamide, rituximab, mycophenolate mofetil, plasma exchange, infliximab, etanercept, adalimumab, complement inhibitors, dialysis and renal transplant, if needed.

Circumferential cellular crescent is present, associated with collapse of the underlying glomerular capillaries (methenamine silver, x400).