Effects of salt and protein intake on polyuria in V2RA-treated ADPKD patients.

BACKGROUND: The only treatment proven to be renoprotective in autosomal dominant polycystic kidney disease (ADPKD) is a vasopressin V2-receptor antagonist (V2RA). However, aquaresis-associated side effects limit tolerability. We investigated whether salt and/or protein intake influences urine volume and related endpoints in V2RA-treated ADPKD patients. METHODS: In this randomized, controlled, double-blind, crossover trial, ADPKD patients treated with maximally tolerated dose of a V2RA were included. While on a low salt and low protein diet, patients were given additional salt and protein to mimic regular intake, which was subsequently replaced by placebo in random order during four 2-week periods. Primary endpoint was change in 24-h urine volume. Secondary endpoints were change in quality of life, measured glomerular filtration rate (mGFR), blood pressure and copeptin level. RESULTS: Twelve patients (49 ± 8 years, 25.0% male) were included. Baseline salt and protein intake were 10.8 ± 1.3 g/24-h and 1.2 ± 0.2 g/kg/24-h, respectively. During the low salt and low protein treatment periods, intake decreased to 5.8 ± 1.6 g/24-h and 0.8 ± 0.1 g/kg/24-h, respectively. Baseline 24-h urine volume (5.9 ± 1.2 L) decreased to 5.2 ± 1.1 L (-11%, P = .004) on low salt and low protein, and to 5.4 ± 0.9 L (-8%, P = .04) on low salt. Reduction in 24-h urine volume was two times greater in patients with lower urine osmolality (-16% vs -7%). Polyuria quality of life scores improved in concordance with changes in urine volume. mGFR decreased during the low salt and low protein, while mean arterial pressure did not change during study periods. Plasma copeptin decreased significantly during low salt and low protein periods. CONCLUSION: Lowering dietary salt and protein intake has a minor effect on urine volume in V2RA-treated ADPKD patients. Reduced intake of osmoles decreased copeptin concentrations and might thus increase the renoprotective effect of a V2RA in ADPKD patients.

Thiazide diuretics and the rate of disease progression in autosomal dominant polycystic kidney disease: an observational study.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), hypertension is prevalent and cardiovascular events are the main cause of death. Thiazide diuretics are often prescribed as second-line antihypertensives, on top of renin-angiotensin-aldosterone system (RAAS) blockade. There is a concern, however, that diuretics may increase vasopressin concentration and RAAS activity, thereby worsening disease progression in ADPKD. We aimed to investigate the validity of these suggestions. METHODS: We analysed an observational cohort of 533 ADPKD patients. Plasma copeptin (surrogate for vasopressin), aldosterone and renin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Linear mixed models were used to assess the association of thiazide use with estimated glomerular filtration rate (eGFR) decline and Cox proportional hazards models for the association with the composite kidney endpoint of incident end-stage kidney disease, 40% eGFR decline or death. RESULTS: A total of 23% of participants (n = 125) used thiazide diuretics at baseline. Compared with non-users, thiazide users were older, a larger proportion was male, they had lower eGFRs and similar blood pressure under more antihypertensives. Plasma copeptin was higher, but this difference disappeared after adjustment for age and sex. Both renin and aldosterone were higher in thiazide users. There was no difference between thiazide users and non-users in the rate of eGFR decline {difference -0.35 mL/min/1.73 m2 per year [95% confidence interval (CI) -0.83 to -0.14], P = 0.2} during 3.9 years of follow-up (interquartile range 2.5-4.9). This did not change after adjustment for potential confounders [difference final model: 0.08 mL/min/1.73 m2 per year [95% CI -0.46 to -0.62], P = 0.8). In the crude model, thiazide use was associated with a higher incidence of the composite kidney endpoint [hazard ratio (HR) 1.53 (95% CI 1.05-2.23), P = 0.03]. However, this association lost significance after adjustment for age and sex and remained unassociated after adjustment for additional confounders [final model: HR 0.80 (95% CI 0.50-1.29), P = 0.4]. CONCLUSIONS: These data do not show that thiazide diuretics have a detrimental effect on the rate of disease progression in ADPKD and suggest that these drugs can be prescribed as second-line antihypertensives.

Salt, but not protein intake, is associated with accelerated disease progression in autosomal dominant polycystic kidney disease.

In autosomal dominant polycystic kidney disease (ADPKD), there are only scarce data on the effect of salt and protein intake on disease progression. Here we studied association of these dietary factors with the rate of disease progression in ADPKD and what the mediating factors are by analyzing an observational cohort of 589 patients with ADPKD. Salt and protein intake were estimated from 24-hour urine samples and the plasma copeptin concentration measured as a surrogate for vasopressin. The association of dietary intake with annual change in the estimated glomerular filtration rate (eGFR) and height adjusted total kidney volume (htTKV) growth was analyzed with mixed models. In case of significant associations, mediation analyses were performed to elucidate potential mechanisms. These patients (59% female) had a mean baseline age of 47, eGFR 64 mL/min/1.73m2 and the median htTKV was 880 mL. The mean estimated salt intake was 9.1 g/day and protein intake 84 g/day. During a median follow-up of 4.0 years, eGFR was assessed a median of six times and 24-hour urine was collected a median of five times. Salt intake was significantly associated with annual change in eGFR of -0.11 (95% confidence interval 0.20 - -0.02] mL/min/1.73m2) per gram of salt, whereas protein intake was not (-0.00001 [-0.01 - 0.01] mL/min/1.73m2) per gram of protein). The effect of salt intake on eGFR slope was significantly mediated by plasma copeptin (crude analysis: 77% mediation, and, adjusted analysis: 45% mediation), but not by systolic blood pressure. Thus, higher salt, but not higher protein intake may be detrimental in ADPKD. The substantial mediation by plasma copeptin suggests that this effect is primarily a consequence of a salt-induced rise in vasopressin.

Determinants of Urine Volume in ADPKD Patients Using the Vasopressin V2 Receptor Antagonist Tolvaptan.

RATIONALE & OBJECTIVE: The vasopressin V2 receptor antagonist (V2RA) tolvaptan is the first drug that has been shown to slow the rate of kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD). However, V2RAs also cause polyuria, with urine output that averages 6L/d. We assessed determinants of urine volume in patients with ADPKD using V2RAs because such information may help develop strategies to improve V2RA tolerability. STUDY DESIGN: Clinical trial of patients with ADPKD studied at baseline, after 3 weeks of V2RA treatment (tolvaptan, 90/30mg, in the last week), and after a 3-week washout period. SETTING & PARTICIPANTS: The trial included patients with ADPKD with a wide range of kidney function (measured glomerular filtration rates [mGFRs]; range, 18-148mL/min/1.73m2). INTERVENTION: Tolvaptan treatment for 3 weeks. OUTCOMES: 24-hour urine volume. ANALYTICAL APPROACH: Multivariable regression analysis with stepwise backward elimination was performed both during and without V2RA treatment to evaluate the influence of 24-hour osmolar excretion, mGFR, and total kidney volume on associations between tolvaptan and urine volume. RESULTS: Included were 27 patients (48% men, aged 46±9.8 years with mGFRs of 61±35mL/min/1.73m2). V2RA treatment caused a median increase in urine volume of 128% (interquartile range, 75%-202%), to 5,930±1,790mL. 24-hour osmolar excretion was strongly associated with 24-hour urine volume (standardized ß = 0.73; P < 0.001). During V2RA use, no independent associations were detected between 24-hour urine volume and mGFR, total kidney volume, or V2RA concentration. LIMITATIONS: Limited sample size, no standardized diets. CONCLUSIONS: Osmolar excretion is the major determinant of urine volume in patients taking V2RAs as a consequence of the inability to concentrate urine. Restriction of osmolar intake may therefore limit V2RA-induced polyuria, giving patients more control over the aquaretic side effects and improving the tolerability of these drugs.

Case report: a thiazide diuretic to treat polyuria induced by tolvaptan.

BACKGROUND: Currently, the vasopressin V2 receptor antagonist tolvaptan is the only available treatment for autosomal dominant polycystic kidney disease (ADPKD), but there are tolerability issues due to aquaretic side-effects such as polyuria. A possible strategy to ameliorate these side-effects may be addition of a thiazide diuretic, this is an established treatment in nephrogenic diabetes insipidus, a condition where vasopressin V2 receptor function is absent. CASE PRESENTATION: We describe a 46-year-old male ADPKD-patient, who was prescribed tolvaptan, which caused polyuria of around 5 l per day. Hydrochlorothiazide was added to treat hypertension, which resulted in a marked decrease in urine production. While using tolvaptan, rate of eGFR decline was - 1.35 mL/min/1.73m2 per year, whereas after hydrochlorothiazide was initiated this was - 3.97 mL/minute/1.73m2 per year. CONCLUSIONS: This case report indicates that while addition of hydrochlorothiazide may improve tolerability of vasopressin V2 receptor antagonists, co-prescription should only be used with great scrutiny as it may decrease tolvaptan effect on rate of ADPKD disease progression.

HYDROchlorothiazide versus placebo to PROTECT polycystic kidney disease patients and improve their quality of life: study protocol and rationale for the HYDRO-PROTECT randomized controlled trial.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD. METHODS: The HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m2, and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care. OUTCOMES: The primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m2 per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume. CONCLUSION: The HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD.

Prostaglandin E2, Osmoregulation, and Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Prostaglandin E2 (PGE2) plays a physiological role in osmoregulation, a process that is affected early in autosomal dominant polycystic kidney disease (ADPKD). PGE2 has also been implicated in the pathogenesis of ADPKD in preclinical models, but human data are limited. Here, we hypothesized that urinary PGE2 excretion is associated with impaired osmoregulation, disease severity, and disease progression in human ADPKD. METHODS: Urinary excretions of PGE2 and its metabolite (PGEM) were measured in a prospective cohort of patients with ADPKD. The associations between urinary PGE2 and PGEM excretions, markers of osmoregulation, eGFR and height-adjusted total kidney volume were assessed using linear regression models. Cox regression and linear mixed models were used for the longitudinal analysis of the associations between urinary PGE2 and PGEM excretions and disease progression defined as 40% eGFR loss or kidney failure, and change in eGFR over time. In two intervention studies, we quantified the effect of starting tolvaptan and adding hydrochlorothiazide to tolvaptan on urinary PGE2 and PGEM excretions. RESULTS: In 562 patients with ADPKD (61% female, eGFR 63±28 ml/min per 1.73 m 2 ), higher urinary PGE2 or PGEM excretions were independently associated with higher plasma copeptin, lower urine osmolality, lower eGFR, and greater total kidney volume. Participants with higher baseline urinary PGE2 and PGEM excretions had a higher risk of 40% eGFR loss or kidney failure (hazard ratio, 1.28; 95% confidence interval [CI], 1.13 to 1.46 and hazard ratio, 1.50; 95% CI, 1.26 to 1.80 per two-fold higher urinary PGE2 or PGEM excretions) and a faster change in eGFR over time (-0.39 [95% CI, -0.59 to -0.20] and -0.53 [95% CI, -0.75 to -0.31] ml/min per 1.73 m 2 per year). In the intervention studies, urinary PGEM excretion was higher after starting tolvaptan, while urinary PGE2 excretion was higher after adding hydrochlorothiazide to tolvaptan. CONCLUSIONS: Higher urinary PGE2 and PGEM excretions in patients with ADPKD are associated with impaired osmoregulation, disease severity, and progression.

Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial.

BACKGROUND AND OBJECTIVES: The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ameliorate this side effect. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a clinical study and an animal study. In a randomized, controlled, double-blind, crossover trial, we included 13 tolvaptan-treated patients with ADPKD. Patients were treated for three 2-week periods with hydrochlorothiazide, metformin, or placebo in random order. Primary outcome was change in 24-hour urine volume. We also measured GFR and a range of metabolic and kidney injury markers. RESULTS: Patients (age 45±8 years, 54% women, measured GFR of 55±11 ml/min per 1.73 m2) had a baseline urine volume on tolvaptan of 6.9±1.4 L/24 h. Urine volume decreased to 5.1 L/24 h (P<0.001) with hydrochlorothiazide and to 5.4 L/24 h (P<0.001) on metformin. During hydrochlorothiazide treatment, plasma copeptin (surrogate for vasopressin) decreased, quality of life improved, and several markers of kidney damage and glucose metabolism improved. Metformin did not induce changes in these markers or in quality of life. Given these results, the effect of adding hydrochlorothiazide to tolvaptan was investigated on long-term kidney outcome in an animal experiment. Water intake in tolvaptan-hydrochlorothiazide cotreated mice was 35% lower than in mice treated with tolvaptan only. Combination treatment was superior to "no treatment" on markers of disease progression (kidney weight, P=0.003 and cystic index, P=0.04) and superior or equal to tolvaptan alone. CONCLUSIONS: Both metformin and hydrochlorothiazide reduced tolvaptan-caused polyuria in a short-term study. Hydrochlorothiazide also reduced polyuria in a long-term animal model without negatively affecting nephroprotection. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_21_CJN11260821.mp3.

The association of glucagon with disease severity and progression in patients with autosomal dominant polycystic kidney disease: an observational cohort study.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors and ketogenesis have been shown to ameliorate disease progression in experimental autosomal dominant polycystic kidney disease (ADPKD). Glucagon is known to lower mTOR activity and stimulate ketogenesis. We hypothesized that in ADPKD patients, higher endogenous glucagon is associated with less disease severity and progression. METHODS: Data were analysed from 664 Dutch ADPKD patients participating in the Developing Intervention Strategies to Halt Progression of ADPKD observational cohort, including patients >18 years of age with an estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2 and excluding patients with concomitant diseases or medication use that may impact the natural course of ADPKD. The association between glucagon and disease severity and progression was tested using multivariate linear regression and mixed modelling, respectively. RESULTS: The median glucagon concentration was 5.0 pmol/L [interquartile range (IQR) 3.4-7.2) and differed significantly between females and males [4.3 pmol/L (IQR 2.9-6.0) and 6.6 (4.5-9.5), P < 0.001, respectively]. Intrasubject stability of glucagon in 30 patients showed a strong correlation (Pearson's correlation coefficient 0.893; P < 0.001). Moreover, glucagon showed significant associations with known determinants (sex, body mass index and copeptin; all P < 0.01) and known downstream effects (glucose, haemoglobin A1c and cholesterol; all P < 0.05), suggesting that glucagon was measured reliably. Cross-sectionally, glucagon was associated with eGFR and height-adjusted total kidney volume, but in the opposite direction of our hypothesis, and these lost significance after adjustment for confounders. Glucagon was not associated with an annual decline in kidney function or growth in kidney volume. CONCLUSIONS: These data do not provide evidence for a role of endogenous glucagon as a protective hormone in ADPKD. Intervention studies are needed to determine the relation between glucagon and ADPKD.

Effects of Dapagliflozin on Volume Status When Added to Renin-Angiotensin System Inhibitors.

Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart and kidney failure in patients with type 2 diabetes, possibly due to diuretic effects. Previous non-placebo-controlled studies with SGLT2 inhibitors observed changes in volume markers in healthy individuals and in patients with type 2 diabetes with preserved kidney function. It is unclear whether patients with type 2 diabetes and signs of kidney damage show similar changes. Therefore, a post hoc analysis was performed on two randomized controlled trials (n = 69), assessing effects of dapagliflozin 10 mg/day when added to renin-angiotensin system inhibition in patients with type 2 diabetes and urinary albumin-to-creatinine ratio ≥30 mg/g. Blood and 24-h urine was collected at the start and the end of treatment periods lasting six and 12 weeks. Effects of dapagliflozin compared to placebo on various markers of volume status were determined. Fractional lithium excretion, a marker of proximal tubular sodium reabsorption, was assessed in 33 patients. Dapagliflozin increased urinary glucose excretion by 217.2 mmol/24 h (95% confidence interval (CI): from 155.7 to 278.7, p < 0.01) and urinary osmolality by 60.4 mOsmol/kg (from 30.0 to 90.9, p < 0.01), compared to placebo. Fractional lithium excretion increased by 19.6% (from 6.7 to 34.2; p < 0.01), suggesting inhibition of sodium reabsorption in the proximal tubule. Renin and copeptin increased by 46.9% (from 21.6 to 77.4, p < 0.01) and 33.0% (from 23.9 to 42.7, p < 0.01), respectively. Free water clearance (FWC) decreased by -885.3 mL/24 h (from -1156.2 to -614.3, p < 0.01). These changes in markers of volume status suggest that dapagliflozin exerts both osmotic and natriuretic diuretic effects in patients with type 2 diabetes and kidney damage, as reflected by increased urinary osmolality and fractional lithium excretion. As a result, compensating mechanisms are activated to retain sodium and water.

Effects of Treating Primary Aldosteronism on Renal Function.

Longstanding primary aldosteronism (PA) has deleterious effects on renal function, often masked until treatment (adrenalectomy or spironolactone) is initiated. It has been suggested that PA causes relative glomerular hyperfiltration, explaining the decline in estimated glomerular filtration rate (eGFR) after treatment. In this retrospective study, the authors retrieved the clinical characteristics and eGFR of 134 PA patients before and 6 months after treatment. Using multiple regression analysis, the predictors for eGFR decline and the predictors of ultimately attained renal function in 113 patients was assessed. eGFR declined by 15.3±14.2 (range 19-63) mL/min, independent predictors were pretreatment plasma aldosterone, eGFR, plasma renin, and plasma potassium. Independent predictors of ultimately attained eGFR after treatment were pretreatment plasma aldosterone, age, eGFR, and plasma potassium. Our findings lend support to the hypothesis that higher aldosterone levels cause relative glomerular hyperfiltration. The severity of pretreatment aldosterone excess is the most important risk factor for renal function decline.