Increased water intake reduces long-term renal and cardiovascular disease progression in experimental polycystic kidney disease.

Polycystic kidney disease (PKD) is the most common inherited cause of kidney failure and currently has limited treatment options. Increasing water intake reduces renal cyst growth in the pck rat (a genetic ortholog of autosomal recessive PKD) but it is not clear if this beneficial effect is present in other models of PKD. In this study, we tested the hypothesis that high water intake (HWI) reduces the progression of cystic renal disease in Lewis polycystic kidney (LPK) rats (a genetic ortholog of human nephronophthisis-9). Groups of female and male LPK (n = 8-10 per group) and Lewis (n = 4 per group) rats received water ad libitum supplemented with or without 5% glucose [to simulate HWI or normal water intake (NWI) respectively] from postnatal weeks 3 to 16. Water intake increased ~1.3-fold in the LPK+HWI group compared to LPK+NWI rats between weeks 3 to 10 but the differences were not significant at later timepoints. In LPK rats, HWI reduced the increases in the kidney to body weight ratio by 54% at week 10 and by 42% at week 16 compared to NWI (both p<0.01). The reduction in kidney enlargement was accompanied by decreases in the percentage renal cyst area, percentage renal interstitial collagen and proteinuria (all p<0.05). At week 16, HWI reduced systolic blood pressure and the heart to body to weight ratio by 16% and 21% respectively in males LPK rats (both p<0.01). In conclusion, a modest increase in water intake during the early phase of disease was sufficient to attenuate renal cystic disease in LPK rats, with secondary benefits on hypertension and cardiovascular disease. These data provide further preclinical evidence that increased water intake is a potential intervention in cystic renal diseases.

Is serum copeptin a modifiable biomarker in autosomal dominant polycystic kidney disease?

The availability of disease-modifying drugs for the management of autosomal dominant polycystic kidney disease (ADPKD) has accelerated the need to accurately predict renal prognosis and/or treatment response in this condition. Arginine vasopressin (AVP) is a critical determinant of postnatal kidney cyst growth in ADPKD. Copeptin (the C-terminal glycoprotein of the precursor AVP peptide) is an accurate surrogate marker of AVP release that is stable and easily measured by immunoassay. Cohort studies show that serum copeptin is correlated with disease severity in ADPKD, and predicts future renal events [decline in renal function and increase in total kidney volume (TKV)]. However, serum copeptin is strongly correlated with creatinine, and its additional value as a prognostic biomarker over estimated glomerular filtration rate and TKV is not certain. It has also been suggested that copeptin could be a predictive biomarker to select ADPKD patients who are most likely to benefit from AVP-modifying therapies, but prospective data to validate this assumption are required. In this regard, long-term randomised clinical trials evaluating the effect of prescribed water intake on renal cyst growth may contribute to addressing this hypothesis. In conclusion, although serum copeptin is aligned with the basic pathogenesis of ADPKD, further rigorous studies are needed to define if it will contribute to enabling the delivery of personalised care in ADPKD.

Relative Validity of a Beverage Frequency Questionnaire Used to Assess Fluid Intake in the Autosomal Dominant Polycystic Kidney Disease Population.

Maintaining hydration sufficient to reduce levels of arginine vasopressin has been hypothesised to slow kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). The semi-quantitative beverage frequency questionnaire (BFQ) was designed to measure usual fluid intake over the past month. The aim of this study was to assess the validity and reliability of the BFQ compared with the 24-h urine biomarkers. Participants with ADPKD (18⁻67 years; estimated glomerular filtration rate (eGFR) ≥ 30 mL/min1.73 m²) completed the BFQ. Serum creatinine, eGFR, 24-h urine volume, and osmolality were measured. Pearson correlation coefficients, paired t test, and Bland⁻Altman plots were used to evaluate agreement between the methods. A subset repeated the BFQ to assess reliability. A total of 121 participants (54% male, 43 ± 11 years; mean ± SD) completed the BFQ and at least one 24-h urine collection. The correlation between the BFQ and the 24-h urine volume was moderate (r = 0.580) and weaker with the 24-h urine osmolality (r = -0.276). The Bland⁻Altman plots revealed good agreement between the BFQ and the 24-h urine volume with no obvious bias; however, the limits of agreement were wide (-1517⁻1943 mL). The BFQ1 and BFQ2 were strongly correlated (r = 0.799, p < 0.001) and were not significantly different (p = 0.598). The BFQ is a valid and reliable tool to assess the usual fluid intake of the ADPKD population.

Effect of dimethyl fumarate on renal disease progression in a genetic ortholog of nephronophthisis.

Dimethyl fumarate is an FDA-approved oral immunomodulatory drug with anti-inflammatory properties that induces the upregulation of the anti-oxidant transcription factor, nuclear factor erythroid-derived factor 2. The aim of this study was to determine the efficacy of dimethyl fumarate on interstitial inflammation and renal cyst growth in a preclinical model of nephronophthisis. Four-week-old female Lewis polycystic kidney disease (a genetic ortholog of human nephronophthisis-9) rats received vehicle (V), 10 mg/kg (D10) or 30 mg/kg (D30) ( n = 8-9 each) dimethyl fumarate in drinking water for eight weeks. Age-matched Lewis control rats were also studied ( n = 4 each). Nuclear factor erythroid-derived factor 2 was quantified by whole-slide image analysis of kidney sections. Renal nuclear factor erythroid-derived factor 2 activation was partially reduced in vehicle-treated Lewis polycystic kidney disease rats compared to Lewis control (21.4 ± 1.7 vs. 27.0 ± 1.6%, mean ± SD; P < 0.01). Dimethyl fumarate upregulated nuclear factor erythroid-derived factor 2 in both Lewis Polycystic Kidney Disease (D10: 35.9 ± 3.8; D30: 33.6 ± 3.4%) and Lewis rats (D30: 34.4 ± 1.3%) compared to vehicle-treated rats ( P < 0.05). Dimethyl fumarate significantly reduced CD68+ cell accumulation in Lewis polycystic kidney disease rats (V: 31.7 ± 2.4; D10: 23.0 ± 1.1; D30: 21.5 ± 1.9; P < 0.05). In Lewis polycystic kidney disease rats, dimethyl fumarate did not alter the progression of kidney enlargement (V: 6.4 ± 1.6; D10: 6.9 ± 1.2; D30: 7.3 ± 1.3%) and the percentage cystic index (V: 59.1 ± 2.7; D10: 55.7 ± 3.5; D30: 58.4 ± 2.9%). Renal dysfunction, as determined by the serum creatinine (Lewis + V: 26 ± 4 vs. LPK + V: 60 ± 25 P < 0.01; LPK + D10: 47 ± 7; LPK + D30: 47 ± 9 µmol/L), and proteinuria were also unaffected by dimethyl fumarate treatment. In conclusion, the upregulation of nuclear factor erythroid-derived factor 2 by dimethyl fumarate reduced renal macrophage infiltration in nephronophthisis without adverse effects, suggesting that it could potentially be used in combination with other therapies that reduce the rate of renal cyst growth. Impact statement This is the first study to investigate the effects of dimethyl fumarate in a model of cystic kidney disease. The study assessed the therapeutic efficacy of dimethyl fumarate in upregulating renal nuclear factor erythroid-derived factor 2 expression, reducing macrophage accumulation and cyst progression in a Lewis polycystic kidney disease rat model. This study demonstrates that dimethyl fumarate significantly upregulated renal nuclear factor erythroid-derived factor 2 expression and attenuates renal macrophage infiltration, but had no effect on renal cyst progression, cardiac enlargement, and improving renal function.

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.