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

Combinatorial Conflicting Homozygosity (CCH) analysis enables the rapid identification of shared genomic regions in the presence of multiple phenocopies.

The ability to identify regions of the genome inherited with a dominant trait in one or more families has become increasingly valuable with the wide availability of high throughput sequencing technology. While a number of methods exist for mapping of homozygous variants segregating with recessive traits in consanguineous families, dominant conditions are conventionally analysed by linkage analysis, which requires computationally demanding haplotype reconstruction from marker genotypes and, even using advanced parallel approximation implementations, can take substantial time, particularly for large pedigrees. In addition, linkage analysis lacks sensitivity in the presence of phenocopies (individuals sharing the trait but not the genetic variant responsible). Combinatorial Conflicting Homozygosity (CCH) analysis uses high density biallelic single nucleotide polymorphism (SNP) marker genotypes to identify genetic loci within which consecutive markers are not homozygous for different alleles. This allows inference of identical by descent (IBD) inheritance of a haplotype among a set or subsets of related or unrelated individuals

Seeking Clarity within Cloudy Effluents: Differentiating Fungal from Bacterial Peritonitis in Peritoneal Dialysis Patients

Fungal peritonitis is a serious complication of peritoneal dialysis (PD) therapy with the majority of patients ceasing PD permanently. The aims of this study were to identify risk factors and clinical associations that may discriminate between fungal from bacterial peritonitis.We retrospectively identified episodes of fungal peritonitis from 2001-2010 in PD patients at Liverpool and Westmead Hospitals (Australia). Fungal peritonitis cases were matched in a 1:2 ratio with patients with bacterial peritonitis from each institution's dialysis registry, occurring closest in time to the fungal episode. Patient demographic, clinical and outcome data were obtained from the medical records.Thirty-nine episodes of fungal peritonitis (rate of 0.02 episodes per patient-year of dialysis) were matched with 78 episodes of bacterial peritonitis. Candida species were the commonest pathogens (35/39; 90% episodes) with Candida albicans (37%), Candida parapsilosis (32%) and Candida glabrata (13%) the most frequently isolated species. Compared to bacterial peritonitis, fungal peritonitis patients had received PD for significantly longer (1133 vs. 775 catheter-days; p = 0.016), were more likely to have had previous episodes of bacterial peritonitis (51% vs. 10%; p = 0.01), and to have received prior antibacterial therapy (51% vs. 10%; p = 0.01). Patients with fungal peritonitis were less likely to have fever and abdominal pain on presentation, but had higher rates of PD catheter removal (79% vs. 22%; p<0.005), and permanent transfer to haemodialysis (87% vs. 24%; p<0.005). Hospital length of stay was significantly longer in patients with fungal peritonitis (26.1 days vs. 12.6 days; p = 0.017), but the all-cause 30-day mortality rate was similar in both groups. Fluconazole was a suitable empiric antifungal agent; with no Candida resistance detected.Prompt recognition of clinical risk factors, initiation of antifungal therapy and removal of PD catheters are key considerations in optimising outcomes

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

Diseases Working Group

Background The largest data on the epidemiology of primary glomerular diseases (PGDs) are obtained from the databases of countries or centers. Here, we present the extended results of the Primary Glomerular Diseases Study of the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) Working Group. Methods Data of patients who underwent renal biopsy and received the diagnosis of PGD were recorded in the database prepared for the study. A total of 4399 patients from 47 centers were evaluated between May 2009 and May 2019. The data obtained at the time of kidney biopsy were analyzed. After the exclusion of patients without light microscopy and immunofluorescence microscopy findings, a total of 3875 patients were included in the study. Results The mean age was 41.5 +/- 14.9 years. 1690 patients were female (43.6%) and 2185 (56.3%) were male. Nephrotic syndrome was the most common biopsy indication (51.7%). This was followed by asymptomatic urinary abnormalities (18.3%) and nephritic syndrome (17.8%). The most common PGD was IgA nephropathy (25.7%) followed by membranous nephropathy (25.6%) and focal segmental glomerulosclerosis (21.9%). The mean total number of glomeruli per biopsy was 17 +/- 10. The mean baseline systolic blood pressure was 130 +/- 20 mmHg and diastolic blood pressure was 81 +/- 12 mmHg. The median proteinuria, serum creatinine, estimated GFR, and mean albumin values were 3300 (IQR: 1467-6307) mg/day, 1.0 (IQR: 0.7-1.6) mg/dL, 82.9 (IQR: 47.0-113.0) mL/min and 3.2 +/- 0.9 g/dL, respectively. Conclusions The distribution of PGDs in Turkey has become similar to that in other European countries. IgA nephropathy diagnosed via renal biopsy has become more prevalent compared to membranous nephropathy.C1 [Turkmen, Aydin; Yazici, Halil] Istanbul Univ, Istanbul Med Fac, Nephrol, Istanbul, Turkey.[Sumnu, Abdullah] Istanbul Medipol Univ, Med Fac, Nephrol, Istanbul, Turkey.[Cebeci, Egemen; Ozturk, Savas] Haseki Training & Res Hosp, Nephrol, Istanbul, Turkey.[Eren, Necmi] Kocaeli Univ, Med Fac, Nephrol, Kocaeli, Turkey.[Seyahi, Nurhan] Istanbul Univ, Cerrahpasa Med Fac, Nephrol, Istanbul, Turkey.[Dilek, Kamil] Uludag Univ, Med Fac, Nephrol, Bursa, Turkey.[Dede, Fatih] Ankara Numune Training & Res Hosp, Nephrol, Ankara, Turkey.[Derici, Ulver] Gazi Univ, Med Fac, Nephrol, Ankara, Turkey.[Unsal, Abdulkadir] Hamidiye Sisli Etfal Training & Res Hosp, Nephrol, Istanbul, Turkey.[Sahin, Garip] Eskisehir Osmangazi Univ, Med Fac, Nephrol, Eskisehir, Turkey.[Sipahioglu, Murat] Erciyes Univ, Med Fac, Nephrol, Kayseri, Turkey.[Gok, Mahmut; Sahin, Gulizar Manga] Sultan Abdulhamit Han Training & Res Hosp, Nephrol, Istanbul, Turkey.[Tatar, Erhan] Izmir Bozyaka Training & Res Hosp, Nephrol, Izmir, Turkey.[Dursun, Belda] Pamukkale Univ, Med Fac, Nephrol, Denizli, Turkey.[Sipahi, Savas] Sakarya Univ, Med Fac, Nephrol, Adapazari, Sakarya, Turkey.[Yilmaz, Murvet] Bakirkoy Sadi Konuk Training & Res Hosp, Nephrol, Istanbul, Turkey.[Suleymanlar, Gultekin] Akdeniz Univ, Med Fac, Nephrol, Antalya, Turkey.[Ulu, Sena] Afyon Kocatepe Univ, Med Fac, Nephrol, Afyon, Turkey.[Gungor, Ozkan] Sutcu Imam Univ, Med Fac, Nephrol, Kahramanmaras, Turkey.[Kutlay, Sim] Ankara Univ, Ibni Sina Hosp, Med Fac, Nephrol, Ankara, Turkey.[Bahcebasi, Zerrin Bicik] Dr Lutfi Kirdar Kartal Training & Res Hosp, Nephrol, Istanbul, Turkey.[Sahin, Idris] Inonu Univ, Med Fac, Nephrol, Malatya, Turkey.[Kurultak, Ilhan] Trakya Univ, Med Fac, Nephrol, Edirne, Turkey.[Turkmen, Kultigin] Necmettin Erbakan Univ, Meram Med Fac, Nephrol, Konya, Turkey.[Yilmaz, Zulfikar] Dicle Univ, Med Fac, Nephrol, Diyarbakir, Turkey.[Kazancioglu, Rumeyza Turan] Bezmialem Vakif Univ, Med Fac, Nephrol, Istanbul, Turkey.[Cavdar, Caner] Dokuz Eylul Univ, Med Fac, Nephrol, Izmir, Turkey.[Candan, Ferhan] Cumhuriyet Univ, Med Fac, Nephrol, Sivas, Turkey.[Aydin, Zeki] Darica Farabi Training & Res Hosp, Nephrol, Kocaeli, Turkey.[Oygar, Duriye Deren] Doktor Burhan Nalbantoglu State Hosp, Nicosia, Cyprus.[Gul, Cuma Bulent] Bursa Yuksek Ihtisas Training & Res Hosp, Nephrol, Bursa, Turkey.[Arici, Mustafa] Hacettepe Univ, Med Fac, Nephrol, Ankara, Turkey.[Paydas, Saime] Cukurova Univ, Med Fac, Nephrol, Adana, Turkey.[Taymez, Dilek Guven] Kocaeli State Hosp, Nephrol, Kocaeli, Turkey.[Kucuk, Mehmet] Okmeydani Training & Res Hosp, Nephrol, Istanbul, Turkey.[Trablus, Sinan] Istanbul Training & Res Hosp, Nephrol, Istanbul, Turkey.[Turgutalp, Kenan] Mersin Univ, Med Fac, Nephrol, Mersin, Turkey.[Koc, Leyla] Taksim Training & Res Hosp, Nephrol, Istanbul, Turkey.[Sezer, Siren] Baskent Univ, Med Fac, Nephrol, Ankara, Turkey.[Duranay, Murat] Ankara Numune Training & Res Hosp, Nephrol, Ankara, Turkey.[Bardak, Simge] Batman State Hosp, Nephrol, Batman, Turkey.[Altintepe, Lutfullah] Selcuk Univ, Selcuk Med Fac, Nephrol, Konya, Turkey.[Arikan, Izzet Hakki] Marmara Univ, Med Fac, Nephrol, Istanbul, Turkey.[Azak, Alper] Balikesir Training & Res Hosp, Nephrol, Balikesir, Turkey.[Odabas, Ali Riza] Goztepe Training & Res Hosp, Nephrol, Istanbul, Turkey