Contrast nephropathy in patients with impaired renal function: High versus low osmolar media

Contrast nephropathy in patients with impaired renal function: High versus low osmolar media. Prescription of low osmolar contrast to prevent nephrotoxicity in subjects with pre-existing renal impairment is costly and has not been clearly shown to be effective. We entered 249 subjects with a pre-contrast serum creatinine greater than 120 /xmol/liter (1.35 mg/dl) having cardiac catheterization or intravenous contrast into a randomized controlled trial comparing high and low osmolar contrast. The outcome assessed was a rise in serum creatinine repeated 48 to 72 hours after contrast. A further 117 patients entered the non-randomized prospective arm of the study. In the randomized study the serum creatinine rose by at least 25% after contrast in 8 of 117 (6.8%) given high and in 5 of 132 (3.8%) given low osmolar contrast (P > 0.05, one-tailed 95% confidence interval for the difference 3 to 7.8%). More severe renal failure (greater than 50% increase in serum creatinine) after contrast was uncommon (3.4% with high and 1.5% with low osmolar contrast). A rise in serum creatinine after contrast was significantly associated with the severity of the pre-contrast renal impairment and the presence of diabetes mellitus, but not with type of contrast. Diabetics with a serum creatinine greater than 200 µl/liter (2.25 mg/dl) pre-contrast had a highest risk of deterioration in renal function after contrast. We conclude that in patients with pre-existing renal impairment the incidence of contrast nephropathy was not significantly different comparing high osmolar and nonionic contrast. The potential benefit of nonionic contrast in moderate renal impairment is likely to be small, but trials in diabetics with severe renal impairment should be undertaken urgently

A Founder Effect in the Newfoundland Population Reduces the Bardet-Biedl Syndrome I (BBS1) Interval to 1 cM

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive disorder; major phenotypic findings include dysmorphic extremities, retinal dystrophy, obesity, male hypogenitalism, and renal anomalies. In the majority of northern European families with BBS, the syndrome is linked to a 26-cM region on chromosome 11q13. However, the finding, so far, of five distinct BBS loci (BBS1, 1q; BBS2, 16q; BBS3, 3p; BBS4, 15q; BBS5, 2q) has hampered the positional cloning of these genes. We use linkage disequilibrium (LD) mapping in an isolated founder population in Newfoundland to significantly reduce the BBS1 critical region. Extensive haplotyping in several unrelated BBS families of English descent revealed that the affected members were homozygous for overlapping portions of a rare, disease-associated ancestral haplotype on chromosome 11q13. The LD data suggest that the BBS1 gene lies in a 1-Mb, sequence-ready region on chromosome 11q13, which should enable its identification

Bilineal Disease and Trans-Heterozygotes in Autosomal Dominant Polycystic Kidney Disease

In searching for a putative third gene for autosomal dominant polycystic kidney disease (ADPKD), we studied the genetic inheritance of a large family (NFL10) previously excluded from linkage to both the PKD1 locus and the PKD2 locus. We screened 48 members of the NFL10 pedigree, by ultrasonography, and genotyped them, with informative markers, at both the PKD1 locus and the PKD2 locus. Twenty-eight of 48 individuals assessed were affected with ADPKD. Inspection of the haplotypes of these individuals suggested the possibility of bilineal disease from independently segregating PKD1 and PKD2 mutations. Using single-stranded conformational analysis, we screened for and found a PKD2 mutation (i.e., 2152delA; L736X) in 12 affected pedigree members. Additionally, when the disease status of these individuals was coded as “unknown” in linkage analysis, we also found, with markers at the PKD1 locus, significant LOD scores (i.e., >3.0). These findings strongly support the presence of a PKD1 mutation in 15 other affected pedigree members, who lack the PKD2 mutation. Two additional affected individuals had trans-heterozygous mutations involving both genes, and they had renal disease that was more severe than that in affected individuals who had either mutation alone. This is the first documentation of bilineal disease in ADPKD. In humans, trans-heterozygous mutations involving both PKD1 and PKD2 are not necessarily embryonically lethal. However, the disease associated with the presence of both mutations appears to be more severe than the disease associated with either mutation alone. The presence of bilineal disease as a confounder needs to be considered seriously in the search for the elusive PKD3 locus