IgA nephropathy (IgAN) is a complex trait determined by genetic and environmental factors. Most IgAN patients exhibit a characteristic undergalactosylation of the O-glycans of the IgA1 hinge region, which promotes formation and glomerular deposition of immune complexes. It is not known whether this aberrant glycosylation is the result of an acquired or inherited defect, or whether the presence of aberrant IgA1 glycoforms alone can produce IgAN. A newly validated lectin enzyme-linked immunosorbent assay (ELISA) was used to determine the serum level of galactose-deficient IgA1 (Gd-IgA1) in a cohort of 89 IgAN patients and 266 of their relatives. High Gd-IgA1 levels (Ն95th percentile for controls) were observed in all 5 available patients with familial IgAN, in 21 of 45 (47%) of their at-risk relatives (assuming autosomal dominant inheritance), and in only 1 of 19 (5%) of unrelated individuals who married into the family. This provides evidence that abnormal IgA1 glycosylation is an inherited rather than acquired trait. Similarly, Gd-IgA1 levels were high in 65 of 84 (78%) patients with sporadic IgAN and in 50 of 202 (25%) blood relatives. Heritability of Gd-IgA1 was estimated at 0.54 (P ϭ 0.0001), and segregation analysis suggested the presence of a major dominant gene on a polygenic background. Because most relatives with abnormal IgA1 glycoforms were asymptomatic, additional cofactors must be required for IgAN to develop. The fact that abnormal IgA1 glycosylation clusters in most but not all families suggests that measuring Gd-IgA1 may help distinguish patients with different pathogenic mechanisms of disease.

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The evaluation of familial glomerulonephritis in patients with IgA nephropathy who were from central and eastern Kentucky resulted in the discovery of potentially related pedigrees containing 14 patients. An additional 17 members of the pedigrees had clinical glomerulonephritis, and 6 had "chronic nephritis" noted on their death certificates. Six patients with IgA nephropathy had a common ancestor. In addition, both parents of six patients with the disease came from families with other cases of IgA nephropathy. No single HLA haplotype or antigen was found in all the patients with IgA nephropathy. Our data on these pedigrees strongly support an inherited mechanism in the pathogenesis of IgA nephropathy in some patients.

IntroductionAlthough end-stage renal disease (ESRD) and surrogate markers for renal dysfunction are frequently used as outcome markers for IgA nephropathy, the clinical course after reaching ESRD is not well documented. This study examined outcomes of progression to ESRD and age at death in a cohort of adults with IgA nephropathy with a long duration of follow-up.MethodsPatient and kidney survival of 251 adult patients with IgA nephropathy from the southeastern United States diagnosed between January 1, 1976 and December 31, 2005 were analyzed.ResultsMedian age at diagnosis was 36.9 years. Most patients were men (69%) and Caucasian (95%). Only 46% had an estimated glomerular filtration rate >60 ml/min per 1.73 m2 at diagnosis. Mean follow-up time from time of diagnostic biopsy to death or end of study was 19.3 years. Of 251 patients, 132 (53%) progressed to ESRD and 97 (39%) died. Life expectancy was reduced by 10.1 years, with a median observed age of death at 65.7 years and a median expected age at death of 75.8 years. Eighty-three percent of the deaths occurred after progression to ESRD.ConclusionLife expectancy is substantially reduced for patients diagnosed with IgA nephropathy in the southeastern United States.

While numerous groups have reported high prevalences of plasma lipid abnormalities in their renal transplant recipients, we have been unable to confirm this finding. We have suggested that the routine use of alternate-day steroids (ADS) in our patients may be responsible. To test that hypothesis, a prospective controlled trial of equal total dose ADS versus daily steroids (DS) was conducted. Four months after transplant and before entering the trial, transplant study patients had significantly higher serum cholesterol (243 +/- 9 mg/dl) than either normal controls (cholesterol 200 +/- 7 mg/dl, alpha = 0.01) or hemodialysis patients (cholesterol 211 +/- 9 mg/dl, alpha = 0.01). They also had higher serum triglyceride than controls (129 +/- 7 mg/dl vs. 98 +/- 8 mg/dl, alpha = 0.01). After randomization to DS or ADS and 1 year of further followup study, the ADS group had a significant decrease in both serum triglyceride (139 +/- 9 to 100 +/- 7 mg/dl, P less than 0.01) and cholesterol (251 +/- 16 to 220 +/- 9 mg/dl, P less than 0.05) while the DS group's serum triglyceride and cholesterol values remained unchanged. Serum triglyceride and cholesterol in the ADS group had decreased to values that were not significantly different from 41 normal healthy controls. Dose spacing per se, and not the use of a lower total dose of prednisone, appears to result in a lower prevalence of abnormal plasma lipids after successful renal transplantation.