End-stage renal disease (ESRD) is a major public health problem, affecting 1 in 1,000 individuals and with an annual death rate of 20% despite dialysis treatment. IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of ESRD worldwide; it affects up to 1.3% of the population and its pathogenesis is unknown. Kidneys of people with IgAN show deposits of IgA-containing immune complexes with proliferation of the glomerular mesangium (Fig. 1). Typical clinical features include onset before age 40 with haematuria and proteinuria (blood and protein in the urine), and episodes of gross haematuria following mucosal infections are common; 30% of patients develop progressive renal failure. Although not generally considered a hereditary disease, striking ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested a heretofore undefined genetic component. By genome-wide analysis of linkage in 30 multiplex IgAN kindreds, we demonstrate linkage of IgAN to 6q22-23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked. These findings for the first time indicate the existence of a locus with large effect on development of IgAN and identify the chromosomal location of this disease gene.

Fabry disease is a rare X-linked disorder, characterized by deficient activity of the lysosomal enzyme alpha-galactosidase A. This leads to systemic accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in all body tissues and organs, including the kidney. Renal manifestations are less evident in female heterozygotes than in male hemizygotes, according to the Lyon hypothesis. Accumulation of Gb3 occurs mainly in the epithelial cells of Henle's loop and distal tubule, inducing early impairment in renal concentrating ability; involvement of the proximal tubule induces Fanconi syndrome. All types of glomerular cells are involved, especially podocytes, and glomerular proteinuria may occur at a young age. The evolution of renal Fabry disease is characterized by progressive deterioration of renal function to end-stage renal failure (ESRF). Ultrastructural study of kidney biopsies reveals typical bodies in the cytoplasm of all types of renal cells, characterized by concentric lamellation of clear and dark layers with a periodicity of 35-50 A. Management of progressive renal disease requires dietetic and therapeutic strategies, usually indicated in developing chronic renal failure, with dialysis and renal transplantation required for patients with ESRF. The recent development of enzyme replacement therapy, however, should make it possible to prevent or reverse the progressive renal dysfunction associated with Fabry disease.

Fabry disease is a rare lysosomal storage disorder which results from deficient activity of the enzyme α‐galactosidase A. The resultant deposition and progressive accumulation of glycosphingolipids in all types of body tissue leads to severe clinical manifestations involving the heart, CNS and kidney. Renal manifestations are observed relatively early in the course of the disease, and progression to end‐stage renal failure is common in hemizygous males in the third to fifth decades of life. Renal biopsy specimens reveal evidence of diffuse intracytoplasmic glycosphingolipid accumulation, mainly affecting podocytes and epithelial cells of distal tubules, which are strikingly enlarged and vacuolated. On electron microscopy the deposits appear as typical osmiophilic inclusion bodies in the cytoplasm of all kinds of renal cells, and show a characteristic ‘onion skin’ or ‘zebra’ appearance. These pathological features are also evident in heterozygous females. Deposits occur before the development of renal impairment. As patients age, the disease progresses in cells throughout the kidney, and is associated with increasing glycosphingolipid accumulation. Conclusion: The age‐related evolution of renal pathology in Fabry disease is closely correlated with progressive intracellular deposition of glycosphingolipid and ultimately leads to end‐stage renal failure.

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