A novel COL4A1 frameshift mutation in familial kidney disease: the importance of the C-terminal NC1 domain of type IV collagen.

BACKGROUND: Hereditary microscopic haematuria often segregates with mutations of COL4A3, COL4A4 or COL4A5 but in half of families a gene is not identified. We investigated a Cypriot family with autosomal dominant microscopic haematuria with renal failure and kidney cysts. METHODS: We used genome-wide linkage analysis, whole exome sequencing and cosegregation analyses. RESULTS: We identified a novel frameshift mutation, c.4611_4612insG:p.T1537fs, in exon 49 of COL4A1. This mutation predicts truncation of the protein with disruption of the C-terminal part of the NC1 domain. We confirmed its presence in 20 family members, 17 with confirmed haematuria, 5 of whom also had stage 4 or 5 chronic kidney disease. Eleven family members exhibited kidney cysts (55% of those with the mutation), but muscle cramps or cerebral aneurysms were not observed and serum creatine kinase was normal in all individuals tested. CONCLUSIONS: Missense mutations of COL4A1 that encode the CB3 [IV] segment of the triple helical domain (exons 24 and 25) are associated with HANAC syndrome (hereditary angiopathy, nephropathy, aneurysms and cramps). Missense mutations of COL4A1 that disrupt the NC1 domain are associated with antenatal cerebral haemorrhage and porencephaly, but not kidney disease. Our findings extend the spectrum of COL4A1 mutations linked with renal disease and demonstrate that the highly conserved C-terminal part of the NC1 domain of the α1 chain of type IV collagen is important in the integrity of glomerular basement membrane in humans

Incidence of end-stage renal disease in the Turkish-Cypriot population of Northern Cyprus: a population based study.

BACKGROUND: This is the first report of the incidence and causes of end-stage renal disease (ESRD) of the Turkish-Cypriot population in Northern Cyprus. METHODS: Data were collected over eight consecutive years (2004-2011) from all those starting renal replacement therapy (RRT) in this population. Crude and age-standardised incidence at 90 days was calculated and comparisons made with other national registries. We collected DNA from the entire prevalent population. As an initial experiment we looked for two genetic causes of ESRD that have been reported in Greek Cypriots. RESULTS: Crude and age-standardised incidence at 90 days was 234 and 327 per million population (pmp) per year, respectively. The mean age was 63, and 62% were male. The age-adjusted prevalence of RRT in Turkish-Cypriots was 1543 pmp on 01/01/2011. The incidence of RRT is higher than other countries reporting to the European Renal Association - European Dialysis and Transplant Association, with the exception of Turkey. Diabetes is a major cause of ESRD in those under 65, accounting for 36% of incident cases followed by 30% with uncertain aetiology. 18% of the incident population had a family history of ESRD. We identified two families with thin basement membrane nephropathy caused by a mutation in COL4A3, but no new cases of CFHR5 nephropathy. CONCLUSIONS: This study provides the first estimate of RRT incidence in the Turkish-Cypriot population, describes the contribution of different underlying diagnoses to ESRD, and provides a basis for healthcare policy planning

Reporting renal biopsies from Cyprus: a systematic approach

Background: The etiology of renal disease varies in different parts of the world. In the Middle East, half of all patients reaching end-stage are categorised as either unknown etiology or hypertension-related nephropathy. Objectives: To report a renal biopsy series, in a reproducible format and manner, so that data can be compared directly among other series. Patients and Methods: Biopsies of native kidneys were performed in a 10-year period, at a tertiary referral hospital that provides the entire nephrology service for north Cyprus. Data are reported from 153 patients older than 17 years, who were either Turkish-Cypriot or from the Turkish mainland. Results: Mean biopsy rate was 48 per million population (pmp) per year. Mean age was 45.7 years (range 18-78). Overall, the sex distribution was similar (male 51%). The most common histopathological categories were primary glomerulonephritis (GN) (56%), secondary GN (27%), and tubulo-interstitial disease (14%). Of those with primary GN, 29% had secondary (2o) focal and segmental glomerulosclerosis (FSGS) (29%), followed by IgA nephropathy (24 %), membranous 18% and a further 11 patients with 1o FSGS (12%). The incidence of IgA nephropathy was 6.3 per pmp/year. When expressed as a percentage of the annual biopsy rate, 14% of all biopsies showed IgA nephropathy. Conclusions: To compare data among centres, they must be expressed in terms of the population (incidence pmp/year) and the biopsy rate. In our population, secondary FSGS is common and uncharacterised and we believe many will be caused by monogenic disease

Can we improve the diagnosis of renal failure? A revised coding system for the Middle East and North Africa

We reviewed the regional data on primary renal disease (PRD) causing end-stage renal failure (ESRF) during the decade 2000-2009. Reporting was generally inconsistent and diagnostic groups were poorly defined. We propose a system in which all diagnoses fall into one of eight broad groups: ESRF of uncertain etiology, congenital abnormalities of the kidney and urinary tract (CAKUT) and acquired uropathy, glomerular diseases, tubulo-interstitial disease (TID), other congenital and familial diseases, diabetes, renovascular disease and other specified diagnoses. Each group has sub-headings; for instance, primary glomerulonephritis, secondary glomerulonephritis, and hereditary glomerular disease. For each sub-heading, there is a list of specific diagnoses similar to that used by the European Dialysis and Transplant Association (EDTA) and United States Renal Data System (USRDS) coding systems. We also recommend that "etiology unknown" group should be reported in more detail as either "glomerular phenotype" or "tubular phenotype" and careful attention be paid to evidence for a family history of renal disease. To improve reporting, all patients who are diabetic, and all who have evidence of familial inheritance, should be recorded and a diagnostic category should be chosen. Thus, a diabetic patient is designated as "diabetic nephropathy" only if he/she fulfils the case definition for that diagnosis. We believe that the collection can be done much better as exemplified by the pediatric community, where data collection is very consistent, and there is a low rate of "unknown disease"

Fungal Peritonitis in Peritoneal Dialysis: Risk Factors and Prognosis

Although less common than bacterial peritonitis, fungal peritonitis is associated with much higher morbidity and mortality. In this study, we aimed to determine the risk factors for fungal peritonitis in peritoneal dialysis patients. The records of 109 peritoneal dialysis patients were analyzed. A total of 86 episodes of peritonitis attacks were recorded. Nine (10.5%) of these attacks were fungal peritonitis attacks. The fungal peritonitis attack rate of the population was 1 attack per 480.1 patient months. In order to determine predisposing factors for fungal peritonitis patients, patients with bacterial peritonitis and with no peritonitis admitted immediately before and after those with fungal peritonitis were used as controls. There was no statistically significant difference between the bacterial and fungal peritonitis groups with respect to symptoms and signs. Obligatory peritoneal dialysis treatment due to access or other medical problems (p = 0.04) and serum albumin levels (p = 0.01) were found to be significantly related with fungal peritonitis (p = 0.04). The mortality rate was 11.1%. When compared with the mortality rate of bacterial peritonitis (1.8%) during the same period, it was found to be significantly higher (p = 0.0001). The catheter removal was performed within 2-7 days (mean = 5.2 days) of the fungal peritonitis attacks. In conclusion, we decided that because fungal peritonitis attacks end up with high morbidity and mortality, prompt diagnosis and removal of the catheter is mandatory. Diagnosis highly depends on culture results, as signs and symptoms usually do not differ from that of bacterial peritonitis. Low serum albumin levels and obligatory peritoneal dialysis treatment are found to be the risk factors for fungal peritonitis

Provisional renal diagnosis in the Turkish-Cypriot renal replacement therapy (RRT) population at 90 days, by incidence per million population and percentage, in comparison with 2008 registry data for Greece, Turkey, and the UK.

*<p>Includes presumed glomerulonephritis not biopsy proven.</p

Incidence of renal replacement therapy (RRT) at 90 days by age and gender.

<p>Incidence of RRT at 90 days in Turkish Cypriots compared with 2008 registry data for Greece, Turkey, and English whites in males (A), and females (B). Error bars indicate 95% confidence intervals.</p