Adult-Diagnosed Nonsyndromic Nephronophthisis in Australian Families Caused by Biallelic NPHP4 Variants.

There is increasing appreciation of nephronophthisis (NPHP) as an autosomal recessive cause of kidney failure and earlier stages of chronic kidney disease among adults. We identified 2 families with presumed adult-diagnosed nonsyndromic NPHP and negative diagnostic genetic testing results from our Renal Genetics Clinic. Both had 2 affected siblings without extrarenal phenotypes. After informed consent, research whole-genome sequencing was undertaken. Biallelic NPHP4 variants were identified in trans and clinically confirmed in all 4 affected individuals, confirming a genetic diagnosis. Participant 1 of the first family (F1P1) had kidney failure diagnosed at 19 years of age. An affected younger sibling (F1P2) reached kidney failure at age 15 years after kidney biopsy suggested NPHP. Pathogenic variants detected in NPHP4 in this family were NM_015102.4:c.3766C>T (p.Gln1256*) and a 31-kb deletion affecting exons 12 to 16. In the second family, F2P3 reached kidney failure at age 27 years having undergone kidney biopsy suggesting NPHP. An affected younger sibling (F2P4) has chronic kidney disease stage 4 at age 39 years. The NPHP4 variants detected were NM_015102.4:c.1998_1999del (p.Tyr667Phefs*23) and c.3646G>T (p.Asp1216Tyr). The latter variant was initially missed in diagnostic sequencing due to inadequate NPHP4 coverage (94.3% exonic coverage). With these reports, we identify NPHP4 as an appreciable genetic cause for adult-diagnosed nonsyndromic NPHP that should be considered by adult nephrologists.

Rationale and design of the HEALTHY-CATH trial: a randomised controlled trial of Heparin versus EthAnol Lock THerapY for the prevention of Catheter Associated infecTion in Haemodialysis patients.

BACKGROUND: Catheter-related bacteraemias (CRBs) contribute significantly to morbidity, mortality and health care costs in dialysis populations. Despite international guidelines recommending avoidance of catheters for haemodialysis access, hospital admissions for CRBs have doubled in the last decade. The primary aim of the study is to determine whether weekly instillation of 70% ethanol prevents CRBs compared with standard heparin saline. METHODS/DESIGN: The study will follow a prospective, open-label, randomized controlled design. Inclusion criteria are adult patients with incident or prevalent tunneled intravenous dialysis catheters on three times weekly haemodialysis, with no current evidence of catheter infection and no personal, cultural or religious objection to ethanol use, who are on adequate contraception and are able to give informed consent. Patients will be randomized 1:1 to receive 3 mL of intravenous-grade 70% ethanol into each lumen of the catheter once a week and standard heparin locks for other dialysis days, or to receive heparin locks only. The primary outcome measure will be time to the first episode of CRB, which will be defined using standard objective criteria. Secondary outcomes will include adverse reactions, incidence of CRB caused by different pathogens, time to infection-related catheter removal, time to exit site infections and costs. Prospective power calculations indicate that the study will have 80% statistical power to detect a clinically significant increase in median infection-free survival from 200 days to 400 days if 56 patients are recruited into each arm. DISCUSSION: This investigator-initiated study has been designed to provide evidence to help nephrologists reduce the incidence of CRBs in haemodialysis patients with tunnelled intravenous catheters. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Number: ACTRN12609000493246.

Streptococcal peritonitis in Australian peritoneal dialysis patients: predictors, treatment and outcomes in 287 cases.

BACKGROUND: There has not been a comprehensive, multi-centre study of streptococcal peritonitis in patients on peritoneal dialysis (PD) to date. METHODS: The predictors, treatment and clinical outcomes of streptococcal peritonitis were examined by binary logistic regression and multilevel, multivariate poisson regression in all Australian PD patients involving 66 centres between 2003 and 2006. RESULTS: Two hundred and eighty-seven episodes of streptococcal peritonitis (4.6% of all peritonitis episodes) occurred in 256 individuals. Its occurrence was independently predicted by Aboriginal or Torres Strait Islander racial origin. Compared with other organisms, streptococcal peritonitis was associated with significantly lower risks of relapse (3% vs 15%), catheter removal (10% vs 23%) and permanent haemodialysis transfer (9% vs 18%), as well as a shorter duration of hospitalisation (5 vs 6 days). Overall, 249 (87%) patients were successfully treated with antibiotics without experiencing relapse, catheter removal or death. The majority of streptococcal peritonitis episodes were treated with either intraperitoneal vancomycin (most common) or first-generation cephalosporins for a median period of 13 days (interquartile range 8-18 days). Initial empiric antibiotic choice did not influence outcomes. CONCLUSION: Streptococcal peritonitis is a not infrequent complication of PD, which is more common in indigenous patients. When treated with either first-generation cephalosporins or vancomycin for a period of 2 weeks, streptococcal peritonitis is associated with lower risks of relapse, catheter removal and permanent haemodialysis transfer than other forms of PD-associated peritonitis.

Review article: Addressing risk factors in chronic kidney disease mineral and bone disorder: can we influence patient-level outcomes?

Chronic kidney disease mineral and bone disorder (CKD-MBD), characterized by disturbances of calcium/phosphate/parathyroid hormone, bone abnormalities and vascular and soft tissue calcification, is highly prevalent in CKD and is a strong, independent predictor of bone fracture, cardiovascular disease and death. Clinical practice guidelines, such as the Kidney Disease Outcomes Quality Initiative (KDOQI) and Caring for Australasians with Renal Insufficiency (CARI), support the use of phosphate binders, vitamin D compounds and calcimimetics for treatment of CKD-MBD and recommend stringent targets for serum calcium, phosphate and parathyroid hormone. However, these recommendations are based primarily on the results of observational cohort studies and randomized controlled trials employing surrogate outcome measures. The aim of this paper is to review the available evidence addressing whether therapeutic strategies targeting CKD-MBD and its surrogate outcome measures appreciably influence patient-level outcomes ('hard' clinical end-points).

Aminoglycosides in hemodialysis patients: is the current practice of post dialysis dosing appropriate?

Aminoglycosides have been widely used in end-stage renal failure patients for the treatment of infections caused by gram-negative bacilli and Staphylococcus aureus. Traditionally, these agents are administered post dialysis to avoid premature dialytic clearance, although no studies have been performed to confirm that this dosing strategy represents the optimal treatment regimen. In recent years, a more complete understanding of the pharmacokinetics-pharmacodynamics of aminoglycosides has led to a global change in clinical practice from multiple to once-daily dosing in patients with normal renal function with the aim of providing intermittent pulses to maximize the peak concentration relative to overall drug exposure. These same considerations strongly support administration of aminoglycosides before, rather than after, hemodialysis. This study will review the key pharmacokinetic/pharmacodynamic considerations in aminoglycoside dosing, the relationship between serum aminoglycoside concentrations and efficacy/toxicity, the influence of renal function and hemodialysis on aminoglycoside pharmacokinetics/pharmacodynamics, and the mounting population pharmacokinetic and clinical study evidence supporting a paradigm shift in aminoglycoside dosing from post dialysis to predialysis.