Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease.

Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease The effect of increased water intake on kidney cyst growth in patients with polycystic kidney disease was compared for two groups randomly assigned to either prescribed or ad libitum water intake. Over 3 years, there was no difference in height-corrected total kidney volume between the groups.

Clinical characteristics and outcomes of hyponatraemia associated with oral water intake in adults: a systematic review.

INTRODUCTION: Excessive water intake is rarely associated with life-threatening hyponatraemia. The aim of this study was to determine the clinical characteristics and outcomes of hyponatraemia associated with excess water intake. METHODS: This review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All studies (case reports, observational or interventional studies) reporting excess water intake and hyponatraemia in adults (1946-2019) were included. RESULTS: A total of 2970 articles were identified and 177 were included (88.7% case reports), consisting of 590 patients. The mean age was 46±16 years (95% CI 44 to 48 years), 47% female, 52% had a chronic psychiatric disorder and 31% had no underlying condition. The median volume of water consumed and serum sodium at presentation was 8 L/day (95% CI 8.9 to 12.2 L/day) and 118 mmol/L (95% CI 116 to 118 mmol/L), respectively. The motivator for increased water consumption was psychogenic polydipsia (55%); iatrogenic (13%); exercise (12%); habitual/dipsogenic polydipsia (7%) and other reasons (13%). The clinical features on presentation were severe in 53% (seizures, coma); moderate in 35% (confusion, vomiting, agitation) and mild in 5% (dizziness, lethargy, cognitive deficit) and not reported in 5% of studies. Treatment was supportive in 41% of studies (fluid restriction, treatment of the underlying cause, emergency care), and isotonic and hypertonic saline was used in 18% and 28% of cases, respectively. Treatment-related complications included osmotic demyelination (3%) and rhabdomyolysis (7%), and death occurred in 13% of cases. CONCLUSION: Water intoxication is associated with significant morbidity and mortality and requires daily intake to substantially exceed population-based recommendations. The limitations of this analysis are the low quality and high risk of bias of the included studies. PROSPERO REGISTRATION NUMBER: A pre-existing protocol in the international prospective register of systematic reviews was updated to incorporate any new amendments and reregistered at http://www.crd.york.ac.uk/PROSPERO (registration no. CRD42019129809).

Long-term dietary nitrate supplementation does not reduce renal cyst growth in experimental autosomal dominant polycystic kidney disease.

Augmentation of endogenous nitric oxide (NO) synthesis, either by the classical L-arginine-NO synthase pathway, or the recently discovered entero-salivary nitrate-nitrite-NO system, may slow the progression of autosomal dominant polycystic kidney disease (ADPKD). To test this hypothesis, the expression of NO in human ADPKD cell lines (WT 9-7, WT 9-12), and the effect of L-arginine on an in vitro model of three-dimensional cyst growth using MDCK cells, was examined. In addition, groups of homozygous Pkd1RC/RC mice (a hypomorphic genetic ortholog of ADPKD) received either low, moderate or high dose sodium nitrate (0.1, 1 or 10 mmol/kg/day), or sodium chloride (vehicle; 10 mmol/kg/day), supplemented drinking water from postnatal month 1 to 9 (n = 12 per group). In vitro, intracellular NO, as assessed by DAF-2/DA fluorescence, was reduced by >70% in human ADPKD cell lines, and L-arginine and the NO donor, sodium nitroprusside, both attenuated in vitro cyst growth by up to 18%. In contrast, in Pkd1RC/RC mice, sodium nitrate supplementation increased serum nitrate/nitrite levels by ~25-fold in the high dose group (P<0.001), but kidney enlargement and percentage cyst area was not altered, regardless of dose. In conclusion, L-arginine has mild direct efficacy on reducing renal cyst growth in vitro, whereas long-term sodium nitrate supplementation was ineffective in vivo. These data suggest that the bioconversion of dietary nitrate to NO by the entero-salivary pathway may not be sufficient to influence the progression of renal cyst growth in ADPKD.

Effect of Reducing Ataxia-Telangiectasia Mutated (ATM) in Experimental Autosomal Dominant Polycystic Kidney Disease.

The DNA damage response (DDR) pathway is upregulated in autosomal dominant polycystic kidney disease (ADPKD) but its functional role is not known. The ataxia-telangiectasia mutated (ATM) and AT and Rad3-related (ATR) protein kinases are key proximal transducers of the DDR. This study hypothesized that reducing either ATM or ATR attenuates kidney cyst formation and growth in experimental ADPKD. In vitro, pharmacological ATM inhibition by AZD0156 reduced three-dimensional cyst growth in MDCK and human ADPKD cells by up to 4.4- and 4.1-fold, respectively. In contrast, the ATR inhibitor, VE-821, reduced in vitro MDCK cyst growth but caused dysplastic changes. In vivo, treatment with AZD0156 by oral gavage for 10 days reduced renal cell proliferation and increased p53 expression in Pkd1RC/RC mice (a murine genetic ortholog of ADPKD). However, the progression of cystic kidney disease in Pkd1RC/RC mice was not altered by genetic ablation of ATM from birth, in either heterozygous (Pkd1RC/RC/Atm+/-) or homozygous (Pkd1RC/RC/Atm-/-) mutant mice at 3 months. In conclusion, despite short-term effects on reducing renal cell proliferation, chronic progression was not altered by reducing ATM in vivo, suggesting that this DDR kinase is dispensable for kidney cyst formation in ADPKD.

Up-Regulation of DNA Damage Response Signaling in Autosomal Dominant Polycystic Kidney Disease.

DNA damage and alterations in DNA damage response (DDR) signaling could be one of the molecular mechanisms mediating focal kidney cyst formation in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that markers of DNA damage and DDR signaling are increased in human and experimental ADPKD. In the human ADPKD transcriptome, the number of up-regulated DDR-related genes was increased by 16.6-fold compared with that in normal kidney, and by 2.5-fold in cystic compared with that in minimally cystic tissue (P < 0.0001). In end-stage human ADPKD tissue, γ-H2A histone family member X (H2AX), phosphorylated ataxia telangiectasia and radiation-sensitive mutant 3 (Rad3)-related (pATR), and phosphorylated ataxia telangiectasia mutated (pATM) localized to cystic kidney epithelial cells. In vitro, pATR and pATM were also constitutively increased in human ADPKD tubular cells (WT 9-7 and 9-12) compared with control (HK-2). In addition, extrinsic oxidative DNA damage by hydrogen peroxide augmented γ-H2AX and cell survival in human ADPKD cells, and exacerbated cyst growth in the three-dimensional Madin-Darby canine kidney cyst model. In contrast, DDR-related gene expression was only transiently increased on postnatal day 0 in Pkd1RC/RC mice, and not altered at later time points up to 12 months of age. In conclusion, DDR signaling is dysregulated in human ADPKD and during the early phases of murine ADPKD. The constitutive expression of the DDR pathway in ADPKD may promote survival of PKD1-mutated cells and contribute to kidney cyst growth.

Assessment of Dietary Sodium Intake Using the Scored Salt Questionnaire in Autosomal Dominant Polycystic Kidney Disease.

The excess intake of dietary sodium is a key modifiable factor for reducing disease progression in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that the scored salt questionnaire (SSQ; a frequency questionnaire of nine sodium-rich food types) is a valid instrument to identify high dietary salt intake in ADPKD. The performance of the SSQ was evaluated in adults with ADPKD with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 during the screening visit of the PREVENT-ADPKD trial. High dietary sodium intake (HSI) was defined by a mean 24-h urinary sodium excretion ≥ 100 mmol/day from two collections. The median 24-h urine sodium excretion was 132 mmol/day (IQR: 112-172 mmol/d) (n = 75; mean age: 44.6 ± 11.5 years old; 53% female), and HSI (86.7% of total) was associated with male gender and higher BMI and systolic blood pressure (p < 0.05). The SSQ score (73 ± 23; mean ± SD) was weakly correlated with log10 24-h urine sodium excretion (r = 0.29, p = 0.01). Receiving operating characteristic analysis showed that the optimal cut-off point in predicting HSI was an SSQ score of 74 (area under the curve 0.79; sensitivity 61.5%; specificity 90.0%; p < 0.01). The evaluation of the SSQ in participants with a BMI ≥ 25 (n = 46) improved the sensitivity (100%) and the specificity (100%). Consumers with an SSQ score ≥ 74 (n = 41) had higher relative percentage intake of processed meats/seafood and flavourings added to cooking (p < 0.05). In conclusion, the SSQ is a valid tool for identifying high dietary salt intake in ADPKD but its value proposition (over 24-h urinary sodium measurement) is that it may provide consumers and their healthcare providers with insight into the potential origin of sodium-rich food sources.

Regression of Peritubular Capillaries Coincides with Angiogenesis and Renal Cyst Growth in Experimental Polycystic Kidney Disease.

BACKGROUND/AIM: The natural history of the renal microvasculature changes in PKD is not known. The aim of this study was to test the hypothesis that angiogenesis is coupled with kidney cyst expansion, and the loss of peritubular capillary networks precedes the onset of interstitial fibrosis. METHODS: The renal microvasculature (RECA-1 and CD34) was evaluated in groups of Lewis polycystic kidney (LPK) rats and juvenile cystic kidney (jck) mice during the early, mid and late stage of disease. In addition, LPK rats and jck mice received sirolimus to determine if the reduction in renal cyst growth is in part mediated by the suppression of angiogenesis. RESULTS: In LPK rats, the loss of peritubular capillaries occurred in early-stage disease and paralleled cyst formation whereas in jck mice it was delayed to the mid stage. In both models, vasa recta were displaced by growing cysts and regressed in LPK rats with disease progression but lengthened in jck mice. Cortical and medullary capillary neoangiogenesis occurred during the early stage in both models and persisted with progression. Treatment with sirolimus reduced cyst enlargement but did not alter the progression of renal microvasculature changes in either model. CONCLUSION: Regression of peritubular capillaries and disruption of vasa recta occur in parallel with angiogenesis and the progressive enlargement of kidney cysts. These data suggest that the regrowth of peritubular capillaries together with inhibition of angiogenesis are potential strategies to be considered in the treatment of PKD.

The role of DNA damage as a therapeutic target in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is caused by heterozygous germ-line mutations in either PKD1 (85%) or PKD2 (15%). It is characterised by the formation of numerous fluid-filled renal cysts and leads to adult-onset kidney failure in ~50% of patients by 60 years. Kidney cysts in ADPKD are focal and sporadic, arising from the clonal proliferation of collecting-duct principal cells, but in only 1-2% of nephrons for reasons that are not clear. Previous studies have demonstrated that further postnatal reductions in PKD1 (or PKD2) dose are required for kidney cyst formation, but the exact triggering factors are not clear. A growing body of evidence suggests that DNA damage, and activation of the DNA damage response pathway, are altered in ciliopathies. The aims of this review are to: (i) analyse the evidence linking DNA damage and renal cyst formation in ADPKD; (ii) evaluate the advantages and disadvantages of biomarkers to assess DNA damage in ADPKD and finally, (iii) evaluate the potential effects of current clinical treatments on modifying DNA damage in ADPKD. These studies will address the significance of DNA damage and may lead to a new therapeutic approach in ADPKD.

The regulation of miRNAs by reconstituted high-density lipoproteins in diabetes-impaired angiogenesis.

Diabetic vascular complications are associated with impaired ischaemia-driven angiogenesis. We recently found that reconstituted high-density lipoproteins (rHDL) rescue diabetes-impaired angiogenesis. microRNAs (miRNAs) regulate angiogenesis and are transported within HDL to sites of injury/repair. The role of miRNAs in the rescue of diabetes-impaired angiogenesis by rHDL is unknown. Using a miRNA array, we found that rHDL inhibits hsa-miR-181c-5p expression in vitro and using a hsa-miR-181c-5p mimic and antimiR identify a novel anti-angiogenic role for miR-181c-5p. miRNA expression was tracked over time post-hindlimb ischaemic induction in diabetic mice. Early post-ischaemia when angiogenesis is important, rHDL suppressed hindlimb mmu-miR-181c-5p. mmu-miR-181c-5p was not detected in the plasma or within HDL, suggesting rHDL specifically targets mmu-miR-181c-5p at the ischaemic site. Three known angiogenic miRNAs (mmu-miR-223-3p, mmu-miR-27b-3p, mmu-miR-92a-3p) were elevated in the HDL fraction of diabetic rHDL-infused mice early post-ischaemia. This was accompanied by a decrease in plasma levels. Only mmu-miR-223-3p levels were elevated in the hindlimb 3 days post-ischaemia, indicating that rHDL regulates mmu-miR-223-3p in a time-dependent and site-specific manner. The early regulation of miRNAs, particularly miR-181c-5p, may underpin the rescue of diabetes-impaired angiogenesis by rHDL and has implications for the treatment of diabetes-related vascular complications.