Cryoglobulinaemia and rapidly deteriorating renal function in chronic lymphocytic leukaemia.

Cryoglobulinaemia is a rare condition characterized by serum immunoglobulins or immunocomplexes which precipitate at temperatures below 37 °C and redissolve on warming. Cryoglobulinaemic vasculitis develops in ~ 15% of patients positive for cryoglobulin serology and is often associated with an underlying infectious, autoimmune or lymphoproliferative disease. We describe a case of cryoglobulinaemic vasculitis, which manifested as purpura and rapidly deteriorating renal function in a patient with chronic lymphocytic leukaemia and coexistent parvovirus infection. This case illustrates the complex pathophysiology of cryoglobulinaemic renal injury, and suggests that infection may serve as a trigger in the presence of other pathophysiological factors.

Genetic variation of DKK3 may modify renal disease severity in ADPKD.

Significant variation in the course of autosomal dominant polycystic kidney disease ( ADPKD) within families suggests the presence of effect modifiers. Recent studies of the variation within families harboring PKD1 mutations indicate that genetic background may account for 32 to 42% of the variance in estimated GFR (eGFR) before ESRD and 43 to 78% of the variance in age at ESRD onset, but the genetic modifiers are unknown. Here, we conducted a high-throughput single-nucleotide polymorphism (SNP) genotyping association study of 173 biological candidate genes in 794 white patients from 227 families with PKD1. We analyzed two primary outcomes: (1) eGFR and (2) time to ESRD (renal survival). For both outcomes, we used multidimensional scaling to correct for population structure and generalized estimating equations to account for the relatedness among individuals within the same family. We found suggestive associations between each of 12 SNPs and at least one of the renal outcomes. We genotyped these SNPs in a second set of 472 white patients from 229 families with PKD1 and performed a joint analysis on both cohorts. Three SNPs continued to show suggestive/significant association with eGFR at the Dickkopf 3 (DKK3) gene locus; no SNPs significantly associated with renal survival. DKK3 antagonizes Wnt/beta-catenin signaling, which may modulate renal cyst growth. Pending replication, our study suggests that genetic variation of DKK3 may modify severity of ADPKD resulting from PKD1 mutations.

Genetics and phenotypic characteristics of autosomal dominant polycystic kidney disease in Finns.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, leading to renal insufficiency and renal transplantation. Mutation screening in the major gene for ADPKD, the polycystic kidney disease type 1 (PKD1) gene, has often been incomplete because of multiple homologous copies of this gene elsewhere on chromosome 16. Furthermore, there are only a few studies investigating genotype-phenotype correlations in patients with ADPKD. In this study, we screened the entire coding region of the PKD1 and PKD2 genes in 17 Finnish families with ADPKD via long-range polymerase chain reaction, single-strand conformation polymorphism analysis, and direct sequencing. We were able to identify mutations co-segregating with ADPKD in all 16 families linked to PKD1 by haplotype analysis. Of these mutations, six were insertions/deletions, five nonsense mutations, and five missense mutations. In the only PKD2-linked family, we found a missense mutation, R322Q. With the exception of one mutation (L845S in PKD1), all mutations were novel. Mutations and their location did not have a strong correlation with the phenotype with the exception of subarachnoidal hemorrhage or brain aneurysm, where mutations were located more often at the 5' end of the PKD1 gene than at the 3' end of the PKD1 gene.

Progression of kidney disease varies between families with defects in the polycystic kidney disease type 1 gene in eastern Finland.

OBJECTIVE: To characterize, for the first time, the phenotype and clinical course of autosomal dominant polycystic kidney disease (ADPKD) in Finnish patients. MATERIAL AND METHODS: All patients underwent an abdominal sonographic examination and most of those with ADPKD underwent magnetic resonance angiography of the head. Haplotype analysis was used to classify 20 ADPKD families into those with defects in either the polycystic kidney disease type 1 (PKD1) or polycystic kidney disease type 2 (PKD2) genes. Evaluation of the rate of progression of kidney disease in patients with ADPKD was based on creatinine values. RESULTS: Haplotype analysis showed that 16 families had defects in the PKD1 gene and one had defects in the PKD2 gene. Three families were excluded because of uninformative haplotypes. The final study population consisted of 79 unaffected family members, 109 patients with defects in the PKD1 gene and 10 with defects in the PKD2 gene. Higher prevalences of hepatic cysts (3% in healthy relatives, 60% in PKD1 patients and 90% in PKD2 patients; p < 0.001), subarachnoid hemorrhage or cerebral aneurysms (1%, 12% and 0%, respectively; p < 0.001), proteinuria (1%, 23% and 0%, respectively; p < 0.001) and hematuria (5%, 30% and 0%, respectively; p < 0.001) were found in PKD1 patients compared to the healthy relatives. PKD1 patients had a faster progression of kidney disease than PKD2 patients (p < 0.001). The progression of kidney disease varied substantially among the PKD1 families. CONCLUSION: The relative proportions of PKD1 and PKD2 patients and the phenotype of ADPKD were similar in our Finnish patients compared to previous studies in other populations. However, the progression of kidney disease differed substantially among PKD1 families, indicating a heterogeneic genetic background of PKD1 in Finnish patients.

Insulin resistance is related to left ventricular hypertrophy in patients with polycystic kidney disease type 1.

BACKGROUND: Left ventricular hypertrophy (LVH) is common in patients with autosomal dominant polycystic kidney disease (ADPKD). Although insulin resistance contributes to cardiac hypertrophy, the relationship between insulin resistance and LVH in patients with ADPKD has not been previously studied. METHODS: We performed M-mode and color Doppler echocardiography on 176 family members (106 patients and 70 healthy relatives) from 16 families with polycystic kidney disease type 1 (PKD1). Left ventricular mass index (LVMI) was calculated using the Penn equation and corrected for body surface area. Fasting insulin and glucose concentrations were measured and insulin resistance was evaluated by means of the homeostasis model assessment. RESULTS: In multivariate regression analysis, insulin resistance was significantly associated with LVMI in healthy relatives (P < 0.01) and patients with PKD1 (P < 0.05) independent of age, weight, systolic blood pressure, and albuminuria. CONCLUSION: Insulin resistance is associated with LVMI in patients with PKD1 independently of other factors known to increase LVMI.