Polycystic Kidney Disease and the Vasopressin Pathway

Vasopressin, also known as arginine vasopressin or antidiuretic hormone, plays a pivotal role in maintaining body homeostasis. Increased vasopressin concentrations, measured by its surrogate copeptin, have been associated with disease severity as well as disease progression in polycystic kidney disease (PKD), and in experimental studies vasopressin has been shown to directly regulate cyst growth. Blocking vasopressin effects on the kidney via the vasopressin V2-receptor and lower circulating vasopressin concentration are potential treatment opportunities that have been the subject of study in PKD in recent years. Treatment with vasopressin V2-receptor antagonist tolvaptan has been shown to inhibit disease progression in experimental studies, as well as in a large randomized controlled trial involving 1,445 patients with autosomal dominant PKD, lowering total kidney volume growth from 5.5 to 2.8%, and the slope of the reciprocal of the serum creatinine level from -3.81 to -2.61 mg per mL(-1)/year. Alternatively, lowering circulating vasopressin could delay disease progression. Vasopressin is secreted in response to an increased plasma osmolality, which in turn is caused by a low fluid or high osmolar intake. Other lifestyle factors, like smoking, increase vasopressin concentration. Here, we provide a comprehensive review of the physiology as well as pathophysiology of vasopressin in PKD, the promising effects of tolvaptan treatment, and potential synergistic or additive treatments in combination with tolvaptan. In this study, we also review current evidence regarding the effect of influencing disease progression in PKD by lifestyle changes, especially by fluid intake. (C) 2017 The Author(s) Published by S. Karger AG, Base

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 m(2) 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

T1 vs. T2 weighted magnetic resonance imaging to assess total kidney volume in patients with autosomal dominant polycystic kidney disease

Purpose: In ADPKD patients total kidney volume (TKV) measurement using MRI is performed to predict rate of disease progression. Historically T1 weighted images (T1) were used, but the methodology of T2 weighted imaging (T2) has evolved. We compared the performance of both sequences. Methods: 40 ADPKD patients underwent an abdominal MRI at baseline and follow-up. TKV was measured by manual tracing with Analyze Direct 11.0 software. Three readers established intra- and interreader coefficients of variation (CV). T1 and T2 measured kidney volumes and growth rates were compared with ICC and Bland-Altman analyses. Results: Participants were 49.7 +/- 7.0 years of age, 55.0% female, with estimated GFR of 50.1 +/- 11.5 mL/min/1.73 m(2). CVs were low and comparable for T2 and T1 (intrareader: 0.83% [0.48-1.79] vs. 1.15% [0.34-1.77], P = 0.9, interreader: 2.18% [1.59-2.61] vs. 1.69% [1.07-3.87], P = 0.9). TKV was clinically similar, but statistically significantly different between T2 and T1: 1867 [1172-2721] vs. 1932 [1180-2551] mL, respectively (P = 0.006), with a bias of only 0.8% and high agreement (ICC 0.997). Percentage kidney growth during 2.2 +/- 0.3 years was similar for T2 and T1 (9.3 +/- 10.6% vs. 7.8 +/- 9.9%, P = 0.1, respectively), with a bias of 1.5% and high agreement (ICC 0.843). T2 was more often of sufficient quality for volume measurement (86.7% vs. 71.1%, P <0.001). Conclusions: In patients with ADPKD, measurement of kidney volume and growth rate performs similarly when using T2 compared to T1 weighted images, although T2 performs better on secondary outcome parameters; they are more often of sufficient quality for volume measurement and result in slightly lower intra- and interreader variability

Incident Gallstones During Somatostatin Analog Treatment are Associated with Acute Biliary Complications Especially After Discontinuation

INTRODUCTION: Gallstones are a known adverse effect of somatostatin analogs, but the exact incidence and clinical implications are unknown. OBJECTIVES: The aim of this study was to investigate the incidence of gallstones on imaging and related complications in unbiased trial data. METHODS: Data from the DIPAK 1 trial, in which 305 polycystic kidney disease patients were randomized to standard of care (SoC) or lanreotide for 120 weeks, were used. Magnetic resonance imaging (MRI) was performed at baseline and end of treatment and was assessed for the presence, number, and size of gallstones. For all patients who had gallstones at the end of the trial, we obtained follow-up after the trial. RESULTS: Of 249 patients with data available, 11 patients randomized to lanreotide and four randomized to SoC had gallstones at baseline. During the study, new gallstones were formed in 19/124 patients using lanreotide (15%) and 1/125 patients receiving SoC (1%). The odds ratio for gallstone formation with lanreotide use was 25.9 (95% confidence interval 3.37–198.8; p  20 stones in 69% of patients) and small (≤ 3 mm in 63% of patients). Of the 19 patients with incident gallstones during lanreotide treatment, 9 experienced gallstone-associated complications, 8 of whom experienced gallstone-associated complications after discontinuation of treatment (median time after discontinuation 2.5 years). In patients with gallstones at baseline and in patients receiving SoC, no complications occurred. CONCLUSIONS: Treatment with a somatostatin analog leads to the formation of multiple, small gallstones that are associated with severe complications, especially after discontinuation of therapy. CLINICAL TRIAL REGISTRY WEBSITE AND TRIAL NUMBER: ClinicalTrials.gov (https://clinicaltrials.gov); NCT01616927. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40268-021-00342-7

A rapid high-performance semi-automated tool to measure total kidney volume from MRI in autosomal dominant polycystic kidney disease.

OBJECTIVES: To develop a high-performance, rapid semi-automated method (Sheffield TKV Tool) for measuring total kidney volume (TKV) from magnetic resonance images (MRI) in patients with autosomal dominant polycystic kidney disease (ADPKD). METHODS: TKV was initially measured in 61 patients with ADPKD using the Sheffield TKV Tool and its performance compared to manual segmentation and other published methods (ellipsoidal, mid-slice, MIROS). It was then validated using an external dataset of MRI scans from 65 patients with ADPKD. RESULTS: Sixty-one patients (mean age 45 ± 14 years, baseline eGFR 76 ± 32 ml/min/1.73 m2) with ADPKD had a wide range of TKV (258-3680 ml) measured manually. The Sheffield TKV Tool was highly accurate (mean volume error 0.5 ± 5.3% for right kidney, - 0.7 ± 5.5% for left kidney), reproducible (intra-operator variability - 0.2 ± 1.3%; inter-operator variability 1.1 ± 2.9%) and outperformed published methods. It took less than 6 min to execute and performed consistently with high accuracy in an external MRI dataset of T2-weighted sequences with TKV acquired using three different scanners and measured using a different segmentation methodology (mean volume error was 3.45 ± 3.96%, n = 65). CONCLUSIONS: The Sheffield TKV Tool is operator friendly, requiring minimal user interaction to rapidly, accurately and reproducibly measure TKV in this, the largest reported unselected European patient cohort with ADPKD. It is more accurate than estimating equations and its accuracy is maintained at larger kidney volumes than previously reported with other semi-automated methods. It is free to use, can run as an independent executable and will accelerate the application of TKV as a prognostic biomarker for ADPKD into clinical practice. KEY POINTS: • This new semi-automated method (Sheffield TKV Tool) to measure total kidney volume (TKV) will facilitate the routine clinical assessment of patients with ADPKD. • Measuring TKV manually is time consuming and laborious. • TKV is a prognostic indicator in ADPKD and the only imaging biomarker approved by the FDA and EMA

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

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 m(2) 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