IgA nephropathy most often affects children and young adults. More than half of those affected present with gross hematuria after an infection of the respiratory or, less commonly, gastrointestinal or urinary tract; 30% to 40% have only microscopic hematuria, with or without proteinuria, and 5% to 10% develop a typical acute nephritic syndrome. The hematuria typically lasts for several days and initially subsides, but then recurs periodically, usually in the setting of a viral infection. The course is highly variable. Many patients maintain normal renal function for decades. Slow progression to end-stage renal disease occurs in 25% to 50% of cases over a period of 20 years. Renal biopsy findings may help identify those with a poorer prognosis, as indicated by diffuse mesangial proliferation, segmental sclerosis, endocapillary proliferation, or tubulointerstitial fibrosis.
Hereditary nephritis refers to a group of glomerular diseases caused by mutations in genes encoding GBM proteins. The most common of these rare diseases are Alport syndrome and thin basement membrane disease. In Alport syndrome, nephritis is accompanied by sensorineural deafness and various eye disorders, including lens dislocation, posterior cataracts, and corneal dystrophy. Thin basement membrane disease is the most common cause of benign familial hematuria with no systemic manifestations.
The GBM is composed largely of type IV collagen, which is made up of heterotrimers of α3, α4, and α5 type IV collagen.
This form of type IV collagen is crucial for normal function of the lens, cochlea, and glomerulus. Mutation of any one of the α chains results in defective heterotrimer assembly and, consequently, the manifestations of Alport syndrome.
MORPHOLOGYOnhistologicexamination,glomeruliinhereditarynephritisappearunremarkableuntillateinthecourse.Withprogression,increasingglomerulosclerosis,vascularsclerosis,tubularatrophy,andinterstitialfibrosisaretypicalchanges.Undertheelectronmicroscope,theGBM is thin andattenuatedearlyinthecourse,butovertimedevelopsirregularfociofthickeningorattenuationwithpronouncedsplittingandlaminationofthelaminadensa,yieldinga“basketweave” appearance.IncontrasttoAlportsyndrome,diffuseanduniformthinningoftheglomerularbasementmembranesistheonlymorphologicfindinginthinbasementmembranedisease.
The majority of Alport syndrome patients have X-linked disease as a result of mutation of the gene on the X chromosome encoding the α5 chain of type IV collagen. Males therefore are affected more frequently and more severely than females and are more likely to develop end-stage renal disease and deafness. Rare autosomal recessive or dominant cases are linked to defects in the genes that encode α3 or α4 type IV collagen. Individuals with hereditary nephritis present at 5 to 20 years of age with gross or microscopic hematuria and proteinuria, and progress to overt renal failure by the ages of 20 to 50 years. Female carriers of X-linked Alport syndrome or carriers of either gender of the autosomal forms usually present with persistent asymptomatic hematuria and follow a benign nonprogressive clinical course. Heterozygous mutations in the genes encoding the α3 and α4 chains of type IV collagen are found in 40% of patients with thin basement membrane disease.
RPGN is characterized by the presence of crescents (crescentic GN) and in most cases appears to be immunologically mediated. It is a clinical syndrome and not a specific etiologic form of GN. RPGN is characterized by rapid loss of renal function, laboratory findings typical of the nephritic syndrome, and often severe oliguria. If untreated, it can rapidly lead to renal failure within a period of weeks to months.