Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Arginine vasopressin promotes kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Increased water intake reduces arginine vasopressin and urine osmolality and may slow kidney cyst growth. METHODS: In this randomized controlled 3-year clinical trial, we randomly assigned adults with ADPKD who had a height-corrected total kidney volume in Mayo imaging subclass categories 1B to 1E and an estimated glomerular filtration rate of 30 ml/min/1.73 m2 or greater to (1) water intake prescribed to reduce 24-hour urine osmolality to 270 mOsmol/kg or less or (2) ad libitum water intake irrespective of 24-hour urine osmolality. The primary end point was the percentage annualized rate of change in height-corrected total kidney volume. RESULTS: A total of 184 patients participated in either the ad libitum water intake group (n=92) or the prescribed water intake group (n=92). Over 3 years, there was no difference in the annualized rate of change in height-corrected total kidney volume between the ad libitum (7.8% per year; 95% confidence interval [CI], 6.6 to 9.0) and prescribed (6.8% per year; 95% CI, 5.8 to 7.7) water intake groups (mean difference, −0.97% per year; 95% CI, −2.37 to 0.44; P=0.18). The difference in mean 24-hour urine osmolality between the ad libitum and prescribed water intake groups was −91 mOsmol/kg (95% CI, −127 to −54 mOsmol/kg), with 52.3% of patients achieving adherence to the target 24-hour urine osmolality and no reduction in serum copeptin over 3 years. The frequency of adverse events was similar between groups. CONCLUSIONS: For patients with ADPKD, prescribed water intake was not associated with excess adverse events and achieved the target 24-hour urine osmolality for half of the patients but did not reduce copeptin or slow the growth of total kidney volume over 3 years compared with ad libitum water intake. (Funded by the National Health and Medical Research Council of Australia [grant GNT1138533], Danone Research, PKD Australia, the University of Sydney, and the Westmead Medical Research Foundation; Australian New Zealand Clinical Trials Registry number, ACTRN12614001216606).

Randomised controlled trial to determine the efficacy and safety of prescribed water intake to prevent kidney failure due to autosomal dominant polycystic kidney disease (PREVENT-ADPKD).

INTRODUCTION: Maintaining fluid intake sufficient to reduce arginine vasopressin (AVP) secretion has been hypothesised to slow kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, evidence to support this as a clinical practice recommendation is of poor quality. The aim of the present study is to determine the long-term efficacy and safety of prescribed water intake to prevent the progression of height-adjusted total kidney volume (ht-TKV) in patients with chronic kidney disease (stages 1-3) due to ADPKD. METHODS AND ANALYSIS: A multicentre, prospective, parallel-group, open-label, randomised controlled trial will be conducted. Patients with ADPKD (n=180; age ≤65 years, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2) will be randomised (1:1) to either the control (standard treatment+usual fluid intake) or intervention (standard treatment+prescribed fluid intake) group. Participants in the intervention arm will be prescribed an individualised daily fluid intake to reduce urine osmolality to ≤270 mOsmol/kg, and supported with structured clinic and telephonic dietetic review, self-monitoring of urine-specific gravity, short message service text reminders and internet-based tools. All participants will have 6-monthly follow-up visits, and ht-TKV will be measured by MRI at 0, 18 and 36 months. The primary end point is the annual rate of change in ht-TKV as determined by serial renal MRI in control vs intervention groups, from baseline to 3 years. The secondary end points are differences between the two groups in systemic AVP activity, renal disease (eGFR, blood pressure, renal pain), patient adherence, acceptability and safety. ETHICS AND DISSEMINATION: The trial was approved by the Human Research Ethics Committee, Western Sydney Local Health District. The results will inform clinicians, patients and policy-makers regarding the long-term safety, efficacy and feasibility of prescribed fluid intake as an approach to reduce kidney cyst growth in patients with ADPKD. TRIAL REGISTRATION NUMBER: ANZCTR12614001216606.

Rituximab to treat gemcitabine-induced hemolytic-uremic syndrome (HUS) in pancreatic adenocarcinoma: a case series and literature review.

PURPOSE: Hemolytic-uremic syndrome (HUS) is a rare side effect of gemcitabine, which is reported as having a high morbidity and mortality despite interventions with standard HUS therapies including plasmapheresis. The purpose of this report was to describe the successful treatment of gemcitabine-induced HUS (G-HUS) with rituximab. It also aims to summarize the literature regarding the morbidity and mortality of G-HUS in pancreatic adenocarcinoma depending on the treatment given, ultimately providing some guidance for beneficial therapies. METHODS: This is a retrospective report of three patients with pancreatic adenocarcinoma who developed G-HUS and were treated with a combination of therapies including rituximab. RESULTS: All three patients received a combination of therapies to treat their HUS. One patient appeared to have some benefit with plasmapheresis. Resolution occurred following one course of rituximab for all three patients. This resolution has been long lasting with a minimum of eighteen month's follow-up. Similarly, in our literature review a variety of therapies were utilized, but immune therapies appear to reverse HUS if other therapies are failing. CONCLUSION: Rituximab can be an effective therapy for reversal of hemolysis and stabilization of renal function in G-HUS when other therapies fail.

Unlocking the code: mining the urinary proteome after renal transplantation.

Diagnosis of transplant dysfunction usually requires kidney biopsy. Sidgel et al. compared urinary proteomics with matched kidney biopsies to develop a biomarker panel to differentiate acute rejection, BK viral nephropathy, and chronic allograft nephropathy. The results suggest that monitoring a panel of urinary peptides may ultimately facilitate noninvasive diagnosis and management of common transplant complications.

Fab fragments of ovine antibody to colchicine enhance its clearance in the rat.

CONTEXT: Colchicine is an anti-inflammatory alkaloid used for the treatment of acute gout, but has a narrow therapeutic index. Colchicine overdoses are relatively rare, but have high mortality requiring rapid treatment. OBJECTIVE: To evaluate the ability of a newly available ovine fragment antigen-binding (Fab) antibody to colchicine (ColchiFab(™)) to protect rats against renal and other injury 24 h after colchicine ingestion. MATERIALS AND METHODS: Rats were gavaged with colchicine (5 mg/kg), then 2 h later injected intraperitoneally with 5 ml of sterile saline, or Fab anti-colchicine, a newly available ovine antibody to colchicine. Samples of blood were taken at 1, 2, 5 and 24 h after gavage, and urine was collected from 5 to 24 h after gavage. Concentrations of colchicine in tissue, blood and urine were measured by liquid chromatography/mass spectrometry, concentrations of Fab anti-colchicine, urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 or KIM-1 by enzyme-linked immunosorbent assay or ELISA, while concentrations of creatine kinase and creatinine (Cr) were measured enzymatically. RESULTS: Colchicine equilibrated rapidly throughout the body and increased serum creatine kinase. Fab anti-colchicine also rapidly redistributed to the blood and remained at high concentrations over 24 h. Fab anti-colchicine caused a rapid 7.1-fold increase in serum colchicine level, followed by excretion of both colchicine and Fab anti-colchicine through the urine. This was associated with the accumulation of colchicine in the kidney, a reversal of colchicine-induced diarrhoea, and increasing urinary NGAL level; from 168 ± 48 to 477 ± 255 ng/mmol Cr [mean ± standard deviation or SD]. DISCUSSION: Fab anti-colchicine greatly increased the clearance of colchicine, although increasing NGAL level suggested the presence of mild kidney damage. CONCLUSION: These data suggest clinical utility for Fab anti-colchicine in the treatment of colchicine overdose.

A comparison of the ability of levels of urinary biomarker proteins and exosomal mRNA to predict outcomes after renal transplantation.

BACKGROUND: mRNA for biomarkers of kidney injury extracted from urinary exosomes may reflect or predict levels of the corresponding protein after transplantation and clinical outcomes. METHODS: Urinary exosomes were isolated from patients following renal transplantation, from healthy controls, and patients with CKD. Expression of exosomal mRNA for the injury biomarkers neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and cystatin C was compared with the concentrations of corresponding urinary proteins, 18S RNA and serum creatinine. RESULTS: All biomarker protein concentrations increased after transplantation, and urinary NGAL and IL-18 at 24 and 168 h correlated with the day 7 creatinine reduction ratio (CRR). Exosomal18S RNA increased after transplantation, but exosomal mRNA for NGAL, IL-18 and cystatin C did not correlate with the day 7 CRR, or urinary biomarker concentrations at any time after transplantation. Exosomal NGAL mRNA was lower 4 h after transplantation than in control exosomes. In contrast, exosomal mRNA for cystatin C was unchanged after transplantation and in CKD, although urinary cystatin C temporarily increased following transplantation. Urinary KIM-1 increased after transplantation, but exosomal mRNA for KIM-1 remained undetectable. In CKD 18S RNA was raised, and exosomal mRNA for NGAL, IL-18 and cystatin C was detected in all patients. While urinary NGAL was greater in CKD than control subjects, exosomal NGAL mRNA was unchanged. Exosomal IL-18 mRNA was increased in CKD, but not IL-18 protein. CONCLUSIONS: After renal transplantation, urinary NGAL and IL-18 levels reflect the day 7 CRR. However, while mRNA for these biomarkers is present in exosomes, their levels do not reflect or predict urinary biomarker levels or the CRR. This likely reflects the fact that packaging of mRNA in exosomes is selective, and is not necessarily representative of mRNA in the parent cells responsible for biomarker production.

Outcomes of cardiac surgery in chronic kidney disease.

OBJECTIVE: To identify predictors of early and late outcomes of cardiac surgery in patients with chronic kidney disease. METHODS: Patients (n=545) with serum creatinine≥200 µmol/L or renal dialysis were identified from databases maintained by the largest Sydney cardiothoracic surgical units with data consistent with the Australian and New Zealand Society of Cardiothoracic Surgeons data definitions. The patient data were matched against the National Dialysis Database and the New South Wales Register of Births, Deaths, and Marriages. Statistical analysis was used to identify predictors of early and late outcomes. RESULTS: The Kaplan-Meier estimate of 1-, 5-, and 10-year survival for all patients was 78%, 56%, and 36%, respectively. The outcomes were similar after coronary bypass surgery and valve replacement and were also similar for dialysis and nondialysis patients. The odds ratios for the significant independent predictors of outcomes were, for perioperative death, age (1.4 per decade), emergency surgery (7.0), redo surgery (3.8), left ventricular impairment (moderate, 2.7; severe, 4.4); for new early postoperative dialysis, estimated glomerular filtration rate<20 mL/min (3.8), emergency surgery (2.7), tricuspid valve surgery (4.4); for new permanent dialysis within 6 months of surgery, serum estimated glomerular filtration rate<20 mL/min (odds ratio, 4.6). The hazard ratio for the independent predictors of late death in those alive 6 months after surgery was 1.4 per decade for age and 1.4 for moderate or severe left ventricular impairment. CONCLUSIONS: Left ventricular impairment is a risk factor for perioperative and late death in patients with kidney disease. After cardiac surgery, preoperative dialysis-dependent and dialysis-free patients had similar long-term outcomes.