Successful restoration of arteriovenous dialysis access patency after late intervention.

BACKGROUND: Arteriovenous dialysis access may be lost due to stenosis and thrombosis. Patency may be restored by thrombectomy or thrombolysis, but this is often not undertaken when the presentation is delayed. The success rate of delayed intervention is largely unknown. METHODS: In this single-centre study, we identified all instances of arteriovenous vascular access (VA) failure treated with angioplasty, thrombectomy or thrombolysis between August 2010 and July 2013. Patency rates immediately after intervention, and after 3 months, were assessed using multilevel mixed effects logistic regression. RESULTS: Sixty failures occurred in 41 accesses (38 patients). The access age at failure was 495 (316-888) days. Intervention was carried out after >48 h in 19 failures (32%). Immediate patency was achieved in 46 failures, of which 32 remained patent after 3 months. Delaying intervention increased the likelihood of achieving immediate patency (OR 0.55, 95% CI 0.31-1.0, P = 0.05). Having lost arteriovenous accesses previously increased the risk of immediate failure (OR 4.0, 95% CI 1.07-14.95, P = 0.04). There was no association between failure-to-intervention-time and 3-month patency rates (P = 0.23). Effect estimates did not differ between arteriovenous fistulae and synthetic arteriovenous grafts. CONCLUSION: Delayed intervention for failed arteriovenous VA may result in superior early patency rates and yields equivalent 3-month patency rates.This is the author's accepted version and will be under embargo until 12 months from the date of publication. The final version is available from OUP at http://ckj.oxfordjournals.org/content/8/1/8

Patient Survey of current water Intake practices in autosomal dominant Polycystic kidney disease: the SIPs survey

Background: Autosomal dominant polycystic kidney disease (ADPKD) affects 12.5 million worldwide. Vasopressin drives cysts growth and in animal models can be suppressed through high water intake. A randomized controlled trial of ‘high’ versus ‘standard’ water intake in ADPKD is essential to determine if this intervention is beneficial. We conducted an ADPKD patient survey to gain an understanding of current fluid intake practices and the design challenges of a randomized water intake trial. Methods: In collaboration with the PKD Charity, we developed and distributed an online survey to ADPKD patients over age 16 years and not on renal replacement therapy. Results: Of the 2377 invited, 89 ADPKD patients completed the Survey of current water Intake practices in autosomal dominant Polycystic kidney disease (SIPs) online questionnaire. Most were female (65, 73%) and white (84, 94%), with a median age group of 45–49 years. The risk of contamination between treatment arms was highlighted by the survey as the majority (70, 79%) routinely discussed ADPKD management with family despite only 17% sharing the same household. More participants reported drinking beyond thirst (65, 73%) than those actually indicating a daily fluid intake of >2 L (54, 61%). This discrepancy emphasizes inaccuracies of fluid intake estimates and the requirement for objective methods of measuring water intake. Overall, only 51% believed high water intake was beneficial, while 91% were willing to participate in research evaluating this. Conclusion: ADPKD poses unique design challenges to a randomized water intake trial. However, the trial is likely to be supported by the ADPKD community and could impact significantly on PKD management and associated healthcare costs.We thank the PKD Charity for their help with the survey. R.E.-D. is supported by the PKD Charity and the Addenbrooke’s Charitable Trust. T.F.H. and F.E.K.F. are supported by the National Institute for Health Research (NIHR) and the Cambridge Biomedical Research Centre. This work was also supported by the British Renal Society and the British Kidney Patient Association

Vitamin K antagonists predispose to calciphylaxis in patients with end-stage renal disease.

BACKGROUND/AIMS: Calciphylaxis is associated with a poor prognosis in dialysis patients, and its pathogenesis remains incompletely understood. Although the use of vitamin K antagonists (VKA) has been implicated, previous reports are conflicting. We aimed to determine if vitamin K antagonists conferred an increased risk of calciphylaxis in patients on dialysis. METHODS: We performed a single-centre, retrospective cohort study of 2,234 patients receiving dialysis, and compared the characteristics of those with and without calciphylaxis. RESULTS: We identified 5 cases of calciphylaxis (all female) between January 2009 and December 2013. Overall, 142 patients (6.4%) were treated with VKA during the study period. Calciphylaxis was more common in the VKA group (4 of 142 patients, OR = 61, 95% CI 6.7-546, p = 0.0001). VKA was withdrawn in all cases and treatment instituted with sodium thiosulphate, cinacalcet and supportive measures. All patients recovered, although there was one sudden cerebrovascular death during follow-up. CONCLUSION: Treatment with VKA predisposes to the development of calciphylaxis.TFH is funded by the Cambridge BRC and NIHR.This is the accepted manuscript for a paper published in Nephron Clinical Practice, Vol. 129, No. 3, 2015, DOI:10.1159/00037144

High water vs. ad libitum water intake for autosomal dominant polycystic kidney disease: a randomized controlled feasibility trial.

BACKGROUND: Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) and is a key therapeutic target. Evaluation of high water intake as an alternative to pharmacological vasopressin blockade is supported by patients. However feasibility, safety and adherence-promoting strategies required to deliver this remain unknown. AIMS: Assess the feasibility of a definitive randomized high water intake trial in ADPKD. METHODS: In this prospective open-label randomized trial, adult ADPKD patients with eGFR ≥ 20 ml/min/1.73 m2 were randomized to prescribed high water (HW) intake targeting urine osmolality (UOsm) ≤270 mOsm/kg, or ad libitum (AW) intake (UOsm >300 mOsm/kg). Self-management strategies including home-monitoring of urine-specific gravity (USG) were employed to promote adherence. RESULTS: We enrolled 42 participants, baseline median eGFR (HW 68.4 [interquartile range (IQR) 35.9-107.2] vs. AW 75.8 [IQR 59.0-111.0 ml/min/1.73 m2, P = 0.22) and UOsm (HW 353 [IQR 190-438] vs. AW 350 [IQR 240-452] mOsm/kg, P = 0.71) were similar between groups. After 8 weeks, 67% in the HW vs. 24% in AW group achieved UOsm ≤270 mOsm/kg, P = 0.001. HW group achieved lower UOsm (194 [IQR 190-438] vs. 379 [IQR 235-503] mOsm/kg, P = 0.01) and higher urine volumes (3155 [IQR 2270-4295] vs. 1920 [IQR 1670-2960] ml/day, P = 0.02). Two cases of hyponatraemia occurred in HW group. No acute GFR effects were detected. In total 79% (519/672) of USG were submitted and 90% (468/519) were within target. Overall, 17% withdrew during the study. CONCLUSION: DRINK demonstrated successful recruitment and adherence leading to separation between treatment arms in primary outcomes. These findings suggest a definitive trial assessing the impact of high water on kidney disease progression in ADPKD is feasible

Per-treatment post-hoc analysis of clinical trial outcomes with Tolvaptan in autosomal dominant polycystic kidney disease

Introduction: In pivotal trials of patients with autosomal dominant polycystic kidney disease at risk of rapid progression, tolvaptan slowed estimated glomerular filtration rate (eGFR) decline in early-to-moderate (TEMPO 3:4 [NCT00428948]) and moderate-to-late stage (REPRISE [NCT02160145]) chronic kidney disease (CKD). Discontinuation was less frequent in REPRISE (15.0%) than TEMPO 3:4 (23.0%), given that in REPRISE, only subjects who tolerated tolvaptan 60/30 mg daily initiated the double-blind phase. We evaluated whether the greater treatment effect in REPRISE was attributable to different completion rates. Methods: We conducted post hoc analyses of TEMPO 3:4 and REPRISE completers, defined as subjects who took trial drug to the end of the treatment period in TEMPO 3:4 (3 years) or REPRISE (1 year). Efficacy (rate of change in eGFR for tolvaptan versus placebo) was analyzed as in each trial. Subjects from TEMPO 3:4 and REPRISE were also matched by propensity score for age, gender, and baseline eGFR to explore potential additional determinants of treatment effect. Results: The annualized tolvaptan treatment effect in TEMPO 3:4 completers (difference versus placebo of 0.98 mL/min/1.73 m2/year) and REPRISE completers (difference of 1.23) was similar to that of the respective total trial populations (TEMPO 3:4: 0.94; REPRISE: 1.27). The treatment effect of tolvaptan was also similar between matched subjects. Conclusion: Greater treatment completion rate did not drive greater treatment effect in REPRISE. The more advanced CKD of REPRISE subjects may be more relevant. More rapid decline in kidney function in later-stage CKD enabled the effects of tolvaptan to be more easily discerned

Developing a patient-centred tool for pain measurement and evaluation in autosomal dominant polycystic kidney disease.

BACKGROUND: Pain affects 60% of the autosomal dominant polycystic kidney disease (ADPKD) population. Despite being an early and debilitating symptom, it is poorly characterized and management is suboptimal. This study aimed to develop an ADPKD-specific pain assessment tool (APAT) to facilitate pain research. METHODS: Following a systematic review of PATs used in ADPKD studies and against international recommendations for pain trials, our multi-disciplinary team of clinical experts and patients constructed an ADPKD-pain conceptual framework of key pain evaluation themes. We compiled a new APAT covering domains prioritized within our framework using components of questionnaires validated in other chronic pain disorders. The APAT was administered longitudinally within a randomized high-water intake trial (NCT02933268) to ascertain feasibility and provide pilot data on ADPKD pain. RESULTS: Thirty-nine ADPKD participants with chronic kidney disease Stages 1-4 provided 129 APAT responses. Each participant completed a median of 3 (range 1-10) assessments. Respondents' mean ± standard deviation age was 47 ± 13 years; 59% (23) were female; and 69% (27) had enlarged kidneys with median time from diagnosis 14.2 (interquartile range 7.0-25.9) years. Pain (52%) and associated analgesic use (29%) were common. Pain severity was associated with increasing age [odds ratio (OR) = 1.07, P = 0.009], female gender (OR = 4.34, P = 0.018), estimated glomerular filtration rate <60 mL/min/1.73 m2 (OR = 5.45, P = 0.021) and hypertension (OR = 12.11, P = 0.007), but not with kidney size (P = 0.23). The APAT achieved good internal consistency (Cronbach's alpha coefficient = 0.91) and test-retest reliability (domain intra-class correlation coefficients ranging from 0.62 to 0.90). CONCLUSIONS: The APAT demonstrated good acceptability and reliability, and following further validation in a larger cohort could represent an invaluable tool for future ADPKD pain studies.Addenbrookes Charitable Trust Kidney Care UK British Renal Society Kidney Research U

Randomised controlled trial of high versus ad libitum water intake in patients with autosomal dominant polycystic kidney disease: rationale and design of the DRINK feasibility trial.

Introduction Vasopressin stimulates cyst growth in Autosomal Dominant Polycystic Kidney Disease (ADPKD) leading to enlarged kidneys, hypertension and renal failure. Vasopressin receptor blockade slows disease progression. Physiological suppression of vasopressin secretion through high water intake could achieve a similar effect, necessitating a definitive large-scale trial of high water intake in ADPKD. The objective of the DRINK trial is to answer the key design and feasibility questions required to deliver a successful definitive water intake trial. Methods and Analysis We describe the design of a single-centre, open label, prospective, randomised controlled trial. DRINK aims to enroll 50 ADPKD patients, over the age 16years with an eGFR≥20ml/min/1.73m2. Participants will be randomised 1:1 to high water (HW) intake based on an individualised water intake prescription, or to ad libitum(AW) water intake. The HW group will aim for a dilute urine (urine osmolality≤270mOsmo/kg) as a surrogate marker of vasopressin suppression, and those in the AW group will target more concentrated urine. Participants will have an 8week treatment period, and will be seen at week 0, 2,4 and 8, undergoing assessments of fluid status, renal function and serum and urine osmolalities. They will receive dietary advice, and self-monitor urine specific gravity and fluid intake. The trial employs smartphone technology to permit home monitoring and remote direct data capture. The primary feasibility endpoints are recruitment rate and separation between arms in measured urinary osmolality. Key secondary assessments include acceptability, adherence, health-related quality of life, acute effects of high water intake on measured (51Cr-EDTA) and estimated glomerular filtration rate, and ADPKD-related pain. Ethics and Dissemination Ethical approval was awarded by the East of England Essex Research Ethics Committee (16/EE/0026). The results of DRINK will be submitted to peer reviewed journals, and presented to patients via the PKD Charity. Trial Registration Details: NCT02933268 and ISCRTN1679495

Randomised controlled trial of high versus ad libitum water intake in patients with autosomal dominant polycystic kidney disease: rationale and design of the DRINK feasibility trial.

INTRODUCTION: Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) leading to enlarged kidneys, hypertension and renal failure. Vasopressin receptor blockade slows disease progression. Physiological suppression of vasopressin secretion through high water (HW) intake could achieve a similar effect, necessitating a definitive large-scale trial of HW intake in ADPKD. The objective of the DRINK trial is to answer the key design and feasibility questions required to deliver a successful definitive water intake trial. METHODS AND ANALYSIS: We describe the design of a single-centre, open-label, prospective, randomised controlled trial. The "Determining feasibility of R andomisation to high vs. ad libitum water In take in Polycystic K idney Disease" (DRINK) trial aims to enrol 50 patients with ADPKD, over the age of 16 years with an estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2. Participants will be randomised 1:1 to HW intake based on an individualised water intake prescription, or to ad libitum (AW) water intake. The HW group will aim for a dilute urine (urine osmolality ≤270 mOsm/kg) as a surrogate marker of vasopressin suppression, and those in the AW group will target more concentrated urine. Participants will have an 8-week treatment period, and will be seen at weeks 0, 2, 4 and 8, undergoing assessments of fluid status, renal function and serum and urine osmolalities. They will receive dietary advice, and self-monitor urine specific gravity and fluid intake. The trial employs smartphone technology to permit home monitoring and remote direct data capture. The primary feasibility end points are recruitment rate and separation between arms in measured urinary osmolality. Key secondary assessments include acceptability, adherence, health-related quality of life, acute effects of HW intake on measured (51Cr-EDTA) and eGFR and ADPKD-related pain. ETHICS AND DISSEMINATION: Ethical approval was awarded by the East of England Essex Research Ethics Committee (16/EE/0026). The results of DRINK will be submitted to peer-reviewed journals, and presented to patients via the PKD Charity. TRIAL REGISTRATION NUMBER: NCT02933268 and ISCRTN16794957

Establishing a core outcome set for autosomal dominant polycystic kidney disease : report of the Standardized Outcomes in Nephrology–Polycystic Kidney Disease (SONG-PKD) consensus workshop

The omission of outcomes that are of relevance to patients, clinicians and regulators across trials in autosomal dominant polycystic kidney disease (ADPKD) limits shared decision-making. The Standardized Outcomes in Nephrology – Polycystic Kidney Disease (SONG-PKD) Initiative convened an international consensus workshop on 25th October 2018, to discuss the identification and implementation of a potential core outcome set for all ADPKD trials. This article summarizes the discussion from the workshops and the SONG-PKD core outcome set. Key stakeholders including 11 patients/caregivers and 47 health professionals (nephrologists, policymakers, industry and researchers) attended the workshop. Four themes emerged: Relevance of trajectory and impact of kidney function included concerns about a patient’s prognosis and uncertainty of when they may need to commence kidney replacement therapy, and the lack of an early prognostic marker to inform long-term decisions; Discerning and defining pain specific to ADPKD highlighted the challenges in determining the origin of pain, adapting to the chronicity and repeated episodes of pain, the need to place emphasis on pain management and to have a validated measure for pain; Highlighting ADPKD consequences encompassed cyst-related complications and reflected patient’s knowledge because of family history and the hereditary nature of ADPKD; Risk of life-threatening but rare consequences such as cerebral aneurysm meant considering both frequency and severity of the outcome. Kidney function, mortality, cardiovascular disease and pain were established as the core outcomes for ADPKD