Julian Ba

Clinical Trial to Evaluate Omega-3 Fatty Acids and Alternate Day Prednisone in Patients with IgA Nephropathy: Report from the Southwest Pediatric Nephrology Study Group

This randomized, placebo-controlled, double-blind trial evaluated the role of prednisone and omega 3 fatty acids (O3FA) in patients with IgA nephropathy. Entry criteria were (1) biopsy-proven IgA nephropathy, (2) estimated GFR > or = 50 ml/min per 1.73 m2, and (3) moderate to severe proteinuria. Thirty-three patients were randomly assigned to receive prednisone 60 mg/m2 every other day for 3 mo, then 40 mg/m2 every other day for 9 mo, then 30 mg/m2 every other day for 12 mo (prednisone group); 32 were randomly assigned to receive O3FA 4 g/d for 2 yr (1.88 g eicosapentaenoic acid, 1.48 g docosahexaenoic acid; O3FA group); and 31 were randomly assigned to receive placebo (placebo group). Most (73%) patients completed 2 yr of treatment. Randomly assigned patients who were hypertensive were given enalapril 2.5 to 40 mg/d. The primary end point was time to failure, defined as estimated GFR <60% of baseline. An overall significance level of 0.10 was used. The three groups were comparable at baseline except that the O3FA group had higher urine protein to creatinine (UP/C) ratios than the placebo group (P = 0.003). Neither treatment group showed benefit over the placebo group with respect to time to failure, with 14 patient failures overall (two in the prednisone group, eight in the O3FA group, and four in the placebo group). The primary factor associated with time to failure was higher baseline UP/C ratios (P = 0.009). Superiority of prednisone or O3FA over placebo in slowing progression of renal disease was not demonstrated in this study. However, the relatively short follow-up period, inequality of baseline UP/C ratios, and small numbers of patients precludes definitive conclusions.

Aluminum-Related Bone Disease in Mild and Advanced Renal Failure: Evidence for High Prevalence and Morbidity and Studies on Etiology and Diagnosis

To study aluminum-related bone disease, bone biopsies and serum biochemical measurements were done in 97 patients on maintenance dialysis and in 100 patients with mild to moderate renal failure. Bone histology, histochemical staining for aluminum and determination of bone aluminum content were done. Stainable bone aluminum was found in 50% of dialyzed patients and in 5% of nondialyzed patients. The finding of stainable bone aluminum in dialyzed patients was associated with high morbidity and mortality; it was not only seen in most patients with low turnover osteomalacia, but also in 47% of patients with mixed uremic osteodystrophy and in 1 patient with predominant hyperparathyroid bone disease. Patients with stainable aluminum had lower bone mass and decreased activity of bone-forming and -resorbing cells. Cumulative doses of aluminum-containing phosphate binders were a major risk factor. Aluminum in drinking water represents an additional risk factor. Neither serum biochemical tests nor single infusion of deferoxamine could be employed as diagnostic tools. Bone biopsies were the only means for diagnosis.

Role of aberrant glycosylation of IgA1 molecules in the pathogenesis of IgA nephropathy.

Studies of the properties of immune complexes (IC) in the circulation, urine, and mesangium of IgA nephropathy (IgAN) patients have provided data relevant to the pathogenesis of this disease. IC contain predominantly polymeric IgA1 molecules which are deficient in galactose (Gal) residues on O-linked glycan chains in the hinge region (HR) of their heavy (H) chains. As a result of this aberrancy, a novel antigenic determinant(s) involving N-acetylgalactosamine (GalNAc) and perhaps sialic acid (SA) of O-linked glycans is generated and recognized by naturally occurring GalNAc-specific antibodies. Thus, IC in IgAN consist of Gal-deficient IgA1 molecules as an antigen, and GalNAc-specific IgG and/or IgA1 as an antibody. IgG antibodies to Gal-deficient IgA1 are probably induced by cross-reactive microbial antigens; they are present at variable levels not only in humans with or without IgAN but also in many phylogenetically diverse vertebrate species. Incubation of human mesangial cells with IC from sera of IgAN patients indicated that stimulation of cellular proliferative activity was restricted to the large (>800 kDa) complexes. These findings suggest that experimental approaches that prevent the formation of large Gal-deficient IgA1-IgG IC may be applied ultimately in an immunologically mediated therapy.

Partial H (β1H) deficiency and glomerulonephritis in two families

H (β1H) controls the C3b amplification loop by its ability to displace Bb from the alternative pathway convertase, C3b,Bb, and acts as a cofactor with I (C3b inactivator) to produce inactive C3b. Serum C3 levels are dependent to a large extent on the levels of H and I. Partial H deficiency was found in two families. The index case in Family 1 had vasculitis, thrombocytopenia, proteinuria, and depressed serum H and C3 levels. The index case in Family 2 had depressed serum H and B (Factor B) levels and IgA nephropathy which progressed to renal failure. His sister also had IgA nephropathy and depressed serum H and C3 levels. The depressed serum C3 level, B level, and H level could be responsible for the development of the immune diseases found in some members of these families.

Galactose-deficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability.

BACKGROUND AND OBJECTIVESnSerum levels of galactose-deficient IgA1 (Gd-IgA1) are elevated and heritable in Caucasian and Asian patients with IgA nephropathy (IgAN), but have not been characterized in African Americans (AA). Our objective was to determine whether serum Gd-IgA1 levels are increased in AA patients with IgAN and whether this is a heritable trait in this group.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnBlood and urine samples were obtained from 18 adult and 11 pediatric AA patients with biopsy-proven IgAN and from 34 of their first-degree relatives. Healthy controls included 150 Caucasian adults, 65 AA adults, 45 Caucasian children, and 49 AA children. Serum total IgA and Gd-IgA1 levels were measured in patients and controls. Significant differences between patient and control groups for serum total IgA, Gd-IgA1, and ratio of Gd-IgA1/total IgA were determined by the Mann-Whitney U test. Heritability was calculated using SOLAR.nnnRESULTSnAfter stratifying by age, 7 of 11 pediatric and 9 of 18 adult AA patients with IgAN had serum Gd-IgA1 levels above the 95th percentile for age-appropriate AA controls. For first-degree relatives, the serum Gd-IgA1 level was >95th percentile for 1 of 8 when the patients level was <95th percentile and 12 of 26 when the patients level was >95th percentile (P = 0.116, Fisher exact test). Heritability was 0.74 (P = 0.007).nnnCONCLUSIONSnSerum levels of Gd-IgA1 are often elevated in AA patients with IgAN and their first-degree relatives. Thus, aberrant IgA1 glycosylation is a heritable risk factor for IgAN in African Americans.

Familial IgA nephropathy in southeastern Kentucky.

BACKGROUNDnTwo decades ago, pedigrees of patients with IgA nephropathy (IgAN) from Pike County, KY, USA, provided evidence for a role of genetic factors in the pathogenesis of this disorder. Subsequently additional pedigrees were described for several communities from northern Italy. Recently, we found another cluster of patients in the Clay County, KY area, about 100 miles southwest of Pike County.nnnAIMnThe purpose of this study was to evaluate and expand the pedigrees of patients with IgAN from Clay County, KY to provide additional insight into the mechanisms of inheritance of IgAN and assess the possible influence of a founder effect on the prevalence of IgAN in the region.nnnMETHODnSince 1980, most patients with IgAN and their relatives in eastern KY have provided personal genealogic data. These data were used to construct pedigrees that included the patients born in Clay County. Nine of 11 patients with IgAN born in Clay County, KY, USA were members of 1 or more of 5 pedigrees, each with 3 - 11 patients with IgAN.nnnCONCLUSIONnOur findings suggest the possibility of a low-penetrance ancestral mutation in the IgAN kindreds from Clay County.