Higher beta-hydroxybutyrate ketone levels associated with a slower kidney function decline in ADPKD.

BACKGROUND AND HYPOTHESIS: Dysregulated energy metabolism is a recently discovered key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate concentrations are associated with reduced disease progression in patients with ADPKD. METHODS: We analyzed data from 670 patients with ADPKD participating in the DIPAK cohort, a multi-center prospective observational cohort study. Beta-hydroxybutyrate was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting, or had missing beta-hydroxybutyrate levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations. RESULTS: Of the participants, 61% were female, with an age of 47.3 ± 11.8 years, a height-adjusted total kidney volume (htTKV) of 834 (IQR 495-1327) ml/m, and an estimated glomerular filtration rate (eGFR) of 63.3 ± 28.9 mL/min/1.73m2. The median concentration of beta-hydroxybutyrate was 94 (IQR 68-147) µmol/L. Cross-sectionally, beta-hydroxybutyrate was neither associated with eGFR nor with htTKV. Longitudinally, beta-hydroxybutyrate was positively associated with eGFR slope (B = 0.35 ml/min/1.73m2 (95% CI 0.09 to 0.61), p = 0.007), but not with kidney growth. After adjustment for potential confounders, every doubling in beta-hydroxybutyrate concentration was associated with an improvement in the annual rate of eGFR by 0.33 ml/min/1.73m2 (95% CI 0.09 to 0.57, p = 0.008). CONCLUSION: These observational analyses support the hypothesis that interventions that raise beta-hydroxybutyrate concentration could reduce the rate of kidney function decline in patients with ADPKD.

Validation of a semi-automatic method to measure total liver volumes in polycystic liver disease on computed tomography - high speed and accuracy.

OBJECTIVES: Polycystic liver disease (PLD) is characterized by growth of hepatic cysts, causing hepatomegaly. Disease severity is determined using total liver volume (TLV), which can be measured from computed tomography (CT). The gold standard is manual segmentation which is time-consuming and requires expert knowledge of the anatomy. This study aims to validate the commercially available semi-automatic MMWP (Multimodality Workplace) Volume tool for CT scans of PLD patients. METHODS: We included adult patients with one (n = 60) or two (n = 46) abdominal CT scans. Semi-automatic contouring was compared with manual segmentation, using comparison of observed volumes (cross-sectional) and growth (longitudinal), correlation coefficients (CC), and Bland-Altman analyses with bias and precision, defined as the mean difference and SD from this difference. Inter- and intra-reader variability were assessed using coefficients of variation (CV) and we assessed the time to perform both procedures. RESULTS: Median TLV was 5292.2 mL (IQR 3141.4-7862.2 mL) at baseline. Cross-sectional analysis showed high correlation and low bias and precision between both methods (CC 0.998, bias 1.62%, precision 2.75%). Absolute volumes were slightly higher for semi-automatic segmentation (manual 5292.2 (3141.4-7862.2) versus semi-automatic 5432.8 (3071.9-7960.2) mL, difference 2.7%, p < 0.001). Longitudinal analysis demonstrated that semi-automatic segmentation accurately measures liver growth (CC 0.908, bias 0.23%, precision 4.04%). Inter- and intra-reader variability were small (2.19% and 0.66%) and comparable to manual segmentation (1.21% and 0.63%) (p = 0.26 and p = 0.37). Semi-automatic segmentation was faster than manual tracing (19 min versus 50 min, p = 0.009). CONCLUSIONS: Semi-automatic liver segmentation is a fast and accurate method to determine TLV and liver growth in PLD patients. KEY POINTS: • Semi-automatic liver segmentation using the commercially available MMWP volume tool accurately determines total liver volume as well as liver growth over time in polycystic liver disease patients. • This method is considerably faster than manual segmentation through the use of Hounsfield unit settings. • We used a real-life CT set for the validation and showed that the semi-automatic tool measures accurately regardless of contrast used for the CT scan or not, presence of polycystic kidneys, liver volume, and previous invasive treatment for polycystic liver disease.

Lanreotide Reduces Liver Growth In Patients With Autosomal Dominant Polycystic Liver and Kidney Disease.

BACKGROUND & AIMS: Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). There is need for robust long-term evidence for the volume-reducing effect of somatostatin analogues. We made use of data from an open-label, randomized trial to determine the effects of lanreotide on height-adjusted liver volume (hTLV) and combined height-adjusted liver and kidney volume (hTLKV) in patients with ADPKD. METHODS: We performed a 120-week study comparing the reno-protective effects of lanreotide vs standard care in 305 patients with ADPKD (the DIPAK-1 study). For this analysis, we studied the 175 patients with polycystic liver disease with hepatic cysts identified by magnetic resonance imaging and liver volume ≥2000 mL. Of these, 93 patients were assigned to a group that received lanreotide (120 mg subcutaneously every 4 weeks) and 82 to a group that received standard care (blood pressure control, a sodium-restricted diet, and antihypertensive agents). The primary endpoint was percent change in hTLV between baseline and end of treatment (week 120). A secondary endpoint was change in hTLKV. RESULTS: At 120 weeks, hTLV decreased by 1.99% in the lanreotide group (95% confidence interval [CI], -4.21 to 0.24) and increased by 3.92% in the control group (95% CI, 1.56-6.28). Compared with the control group, lanreotide reduced the growth of hTLV by 5.91% (95% CI, -9.18 to -2.63; P < .001). Growth of hTLV was still reduced by 3.87% at 4 months after the last injection of lanreotide compared with baseline (95% CI, -7.55 to -0.18; P = .04). Lanreotide reduced growth of hTLKV by 7.18% compared with the control group (95% CI, -10.25 to -4.12; P < .001). CONCLUSIONS: In this subanalysis of a randomized trial of patients with polycystic liver disease due to ADPKD, lanreotide for 120 weeks reduced the growth of liver and combined liver and kidney volume. This effect was still present 4 months after the last injection of lanreotide. ClinicalTrials.gov, Number: NCT01616927.

Automatic Measurement of Kidney and Liver Volumes from MR Images of Patients Affected by Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: The formation and growth of cysts in kidneys, and often liver, in autosomal dominant polycystic kidney disease (ADPKD) cause progressive increases in total kidney volume (TKV) and liver volume (TLV). Laborious and time-consuming manual tracing of kidneys and liver is the current gold standard. We developed a fully automated segmentation method for TKV and TLV measurement that uses a deep learning network optimized to perform semantic segmentation of kidneys and liver. METHODS: We used 80% of a set of 440 abdominal magnetic resonance images (T2-weighted HASTE coronal sequences) from patients with ADPKD to train the network and the remaining 20% for validation. Both kidneys and liver were also segmented manually. To evaluate the method's performance, we used an additional test set of images from 100 patients, 45 of whom were also involved in longitudinal analyses. RESULTS: TKV and TLV measured by the automated approach correlated highly with manually traced TKV and TLV (intraclass correlation coefficients, 0.998 and 0.996, respectively), with low bias and high precision (<0.1%±2.7% for TKV and -1.6%±3.1% for TLV); this was comparable with inter-reader variability of manual tracing (<0.1%±3.5% for TKV and -1.5%±4.8% for TLV). For longitudinal analysis, bias and precision were <0.1%±3.2% for TKV and 1.4%±2.9% for TLV growth. CONCLUSIONS: These findings demonstrate a fully automated segmentation method that measures TKV, TLV, and changes in these parameters as accurately as manual tracing. This technique may facilitate future studies in which automated and reproducible TKV and TLV measurements are needed to assess disease severity, disease progression, and treatment response.

Plasma copeptin levels predict disease progression and tolvaptan efficacy in autosomal dominant polycystic kidney disease.

In the TEMPO 3:4 Trial, treatment with tolvaptan, a vasopressin V2 receptor antagonist, slowed the increase in total kidney volume and decline in estimated glomerular filtration rate (eGFR) in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether plasma copeptin levels, a marker of plasma vasopressin, are associated with disease progression, and whether pre-treatment copeptin and treatment-induced change in copeptin are associated with tolvaptan treatment efficacy. This post hoc analysis included 1,280 TEMPO 3:4 participants (aged 18-50 years, estimated creatinine clearance ≥60 ml/min and total kidney volume ≥750 mL) who had plasma samples available at baseline for measurement of copeptin using an automated immunofluorescence assay. In placebo-treated subjects, baseline copeptin predicted kidney growth and eGFR decline over 3 years. These associations were independent of sex, age, and baseline eGFR, but were no longer statistically significant after additional adjustment for baseline total kidney volume. In tolvaptan-treated subjects, copeptin increased from baseline to week 3 (6.3 pmol/L versus 21.9 pmol/L, respectively). In tolvaptan-treated subjects with higher baseline copeptin levels, a larger treatment effect was noted with respect to kidney growth rate and eGFR decline. Tolvaptan-treated subjects with a larger percentage increase in copeptin from baseline to week 3 had a better disease outcome, with less kidney growth and eGFR decline after three years. Copeptin holds promise as a biomarker to predict outcome and tolvaptan treatment efficacy in ADPKD.

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.

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.

Effect of Lanreotide on Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease: The DIPAK 1 Randomized Clinical Trial.

Importance: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation in both kidneys and loss of renal function, eventually leading to a need for kidney replacement therapy. There are limited therapeutic management options. Objective: To examine the effect of the somatostatin analogue lanreotide on the rate of kidney function loss in patients with later-stage ADPKD. Design, Setting, and Participants: An open-label randomized clinical trial with blinded end point assessment that included 309 patients with ADPKD from July 2012 to March 2015 at 4 nephrology outpatient clinics in the Netherlands. Eligible patients were 18 to 60 years of age and had an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2. Follow-up of the 2.5-year trial ended in August 2017. Interventions: Patients were randomized to receive either lanreotide (120 mg subcutaneously once every 4 weeks) in addition to standard care (n = 153) or standard care only (target blood pressure <140/90 mm Hg; n = 152). Main Outcomes and Measures: Primary outcome was annual change in eGFR assessed as slope through eGFR values during the 2.5-year treatment phase. Secondary outcomes included change in eGFR before vs after treatment, incidence of worsening kidney function (start of dialysis or 30% decrease in eGFR), change in total kidney volume and change in quality of life (range: 1 [not bothered] to 5 [extremely bothered]). Results: Among the 309 patients who were randomized (mean [SD] age, 48.4 [7.3] years; 53.4% women), 261 (85.6%) completed the trial. Annual rate of eGFR decline for the lanreotide vs the control group was -3.53 vs -3.46 mL/min/1.73 m2 per year (difference, -0.08 [95% CI, -0.71 to 0.56]; P = .81). There were no significant differences for incidence of worsening kidney function (hazard ratio, 0.87 [95% CI, 0.49 to 1.52]; P = .87), change in eGFR (-3.58 vs -3.45; difference, -0.13 mL/min/1.73 m2 per year [95% CI, -1.76 to 1.50]; P = .88), and change in quality of life (0.05 vs 0.07; difference, -0.03 units per year [95% CI, -0.13 to 0.08]; P = .67). The rate of growth in total kidney volume was lower in the lanreotide group than the control group (4.15% vs 5.56%; difference, -1.33% per year [95% CI, -2.41% to -0.24%]; P = .02). Adverse events in the lanreotide vs control group included injection site discomfort (32% vs 0.7%), injection site papule (5.9% vs 0%), loose stools (91% vs 6.6%), abdominal discomfort (79% vs 20%), and hepatic cyst infections (5.2% vs 0%). Conclusions and Relevance: Among patients with later-stage autosomal dominant polycystic kidney disease, treatment with lanreotide compared with standard care did not slow the decline in kidney function over 2.5 years of follow-up. These findings do not support the use of lanreotide for treatment of later-stage autosomal dominant polycystic kidney disease. Trial Registration: ClinicalTrials.gov Identifier: NCT01616927.

Novel treatment protocol for ameliorating refractory, chronic pain in patients with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) patients can suffer from chronic pain that can be refractory to conventional treatment, resulting in a wish for nephrectomy. This study aimed to evaluate the effect of a multidisciplinary treatment protocol with sequential nerve blocks on pain relief in ADPKD patients with refractory chronic pain. As a first step a diagnostic, temporary celiac plexus block with local anesthetics was performed. If substantial pain relief was obtained, the assumption was that pain was relayed via the celiac plexus and major splanchnic nerves. When pain recurred, patients were then scheduled for a major splanchnic nerve block with radiofrequency ablation. In cases with no pain relief, it was assumed that pain was relayed via the aortico-renal plexus, and catheter-based renal denervation was performed. Sixty patients were referred, of which 44 were eligible. In 36 patients the diagnostic celiac plexus block resulted in substantial pain relief with a change in the median visual analogue scale (VAS) score pre-post intervention of 50/100. Of these patients, 23 received a major splanchnic nerve block because pain recurred, with a change in median VAS pre-post block of 53/100. In 8 patients without pain relief after the diagnostic block, renal denervation was performed in 5, with a borderline significant change in the median VAS pre-post intervention of 20/100. After a median follow-up of 12 months, 81.8% of the patients experienced a sustained improvement in pain intensity, indicating that our treatment protocol is effective in obtaining pain relief in ADPKD patients with refractory chronic pain.

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.

Modifiable factors associated with copeptin concentration: a general population cohort.

BACKGROUND: Vasopressin plays an important role in maintaining volume homeostasis. However, recent studies suggest that vasopressin also may play a detrimental role in the progression of chronic kidney disease. It therefore is of interest to identify factors that influence vasopressin concentration, particularly modifiable ones. STUDY DESIGN: Cross-sectional analyses. SETTING & PARTICIPANTS: Data used are from participants in a large general-population cohort study (Prevention of Renal and Vascular Endstage Disease [PREVEND]). Patients with a missing copeptin value (n=888), nonfasting blood sample (n=495), missing or assumed incorrect 24-hour urine collection (n=388), or heart failure (n=20) were excluded, leaving 6,801 participants for analysis. FACTOR: Identification of lifestyle- and diet-related factors that are associated with copeptin concentration. OUTCOMES: Copeptin concentration as surrogate for vasopressin. MEASUREMENTS: Copeptin was measured by an immunoluminometric assay as a surrogate for vasopressin. Associations were assessed in uni- and multivariable linear regression analyses. RESULTS: Median copeptin concentration was 4.7 (IQR, 2.9-7.6) pmol/L. When copeptin was studied as a dependent variable, the final stepwise backward model revealed associations with higher copeptin concentrations for lower 24-hour urine volume (P < 0.001), higher sodium excretion (P < 0.001), higher systolic blood pressure (P < 0.001), current smoking (P < 0.001), higher alcohol use (P < 0.001), higher urea excretion (P = 0.003), lower potassium excretion (P = 0.002), use of glucose-lowering drugs (P = 0.02), higher body mass index (P < 0.001), and higher plasma glucose level (P < 0.001). No associations with copeptin concentration were found for C-reactive protein or use of diuretics or nondiuretic antihypertensives. LIMITATIONS: The cross-sectional study design does not allow firm conclusions on cause-effect relationships. CONCLUSIONS: Important lifestyle- and diet-related factors associated with copeptin concentration are current smoking, alcohol use, protein and potassium intake, and particularly fluid and sodium intake. These data form a rationale to investigate whether intervening on these factors results in a lower vasopressin concentration with concomitant beneficial renal effects.

Estimation of total kidney volume in autosomal dominant polycystic kidney disease.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), obtaining measured total kidney volume (mTKV) by magnetic resonance (MR) imaging and manual tracing is time consuming. Two alternative MR imaging methods have recently been proposed to estimate TKV (eTKVellipsoid and eTKVPANK), which require less time. STUDY DESIGN: Cross-sectional and longitudinal diagnostic test study. SETTING & PARTICIPANTS: Patients with ADPKD with a wide range of kidney function and an approved T2-weighted MR image obtained at the University Medical Centers of Groningen, Leiden, Nijmegen, and Rotterdam, the Netherlands, in 2007 to 2014. Test set for assessing reproducibility, n=10; cohort for cross-sectional analyses, n=220; and cohort for longitudinal analyses, n=48. INDEX TESTS: Average times for eTKVellipsoid and eTKVPANK were 5 and 15 minutes, respectively. Bias is defined as (mTKV - eTKV)/mTKV × 100%; precision, as one standard deviation of bias. REFERENCE TESTS: mTKV using manual tracing to calculate the area within kidney boundaries times slice thickness. Average time for mTKV was 55 minutes. RESULTS: In the test set, intra- and intercoefficients of variation for mTKV, eTKVellipsoid, and eTKVPANK were 1.8% and 2.3%, 3.9% and 6.3%, and 3.0% and 3.4%, respectively. In cross-sectional analysis, baseline mTKV, eTKVellipsoid, and eTKVPANK were 1.96 (IQR, 1.28-2.82), 1.93 (IQR, 1.25-2.82), and 1.81 (IQR, 1.17-2.62) L, respectively. In cross-sectional analysis, bias was 0.02% ± 3.2%, 1.4% ± 9.2%, and 4.6% ± 7.6% for repeat mTKV, eTKVellipsoid, and eTKVPANK, respectively. In longitudinal analysis, no significant differences were observed between percentage change in mTKV (16.7% ± 17.1%) and percentage change in eTKVellipsoid (19.3% ± 16.1%) and eTKVPANK (17.8% ± 16.1%) over 3 years. LIMITATIONS: Results for follow-up data should be interpreted with caution because of the limited number of patients. CONCLUSIONS: Both methods for eTKV perform relatively well compared to mTKV and can detect change in TKV over time. Because eTKVellipsoid requires less time than eTKVPANK, we suggest that this method may be preferable in clinical care.

Validation of the Mayo Imaging Classification System for Predicting Kidney Outcomes in ADPKD.

BACKGROUND: The Mayo Imaging Classification was developed to predict the rate of disease progression in patients with autosomal dominant polycystic kidney disease. This study aimed to validate its ability to predict kidney outcomes in a large multicenter autosomal dominant polycystic kidney disease cohort. METHODS: Included were patients with ≥1 height-adjusted total kidney volume (HtTKV) measurement and ≥3 eGFR values during ≥1-year follow-up. Mayo HtTKV class stability, kidney growth rates, and eGFR decline rates were calculated. The observed eGFR decline was compared with predictions from the Mayo Clinic future eGFR equation. The future eGFR prediction equation was also tested for nonlinear eGFR decline. Kaplan-Meier survival analysis and Cox regression models were used to assess time to kidney failure using Mayo HtTKV class as a predictor variable. RESULTS: We analyzed 618 patients with a mean age of 47±11 years and mean eGFR of 64±25 ml/min per 1.73 m 2 at baseline. Most patients (82%) remained in their baseline Mayo HtTKV class. During a mean follow-up of 5.1±2.2 years, the mean total kidney volume growth rates and eGFR decline were 5.33%±3.90%/yr and -3.31±2.53 ml/min per 1.73 m 2 per year, respectively. Kidney growth and eGFR decline showed considerable overlap between the classes. The observed annual eGFR decline was not significantly different from the predicted values for classes 1A, 1B, 1C, and 1D but significantly slower for class 1E. This was also observed in patients aged younger than 40 years and older than 60 years and those with PKD2 mutations. A polynomial model allowing nonlinear eGFR decline provided more accurate slope predictions. Ninety-seven patients (16%) developed kidney failure during follow-up. The classification predicted the development of kidney failure, although the sensitivity and positive predictive values were limited. CONCLUSIONS: The Mayo Imaging Classification demonstrated acceptable stability and generally predicted kidney failure and eGFR decline rate. However, there was marked interindividual variability in the rate of disease progression within each class.

[Risk management with regard to QT-prolonging drugs]. / Risicomanagement rond QT-verlengende geneesmiddelen.

Drug-induced QT prolongation increases the risk of Torsade de Pointes (TdP). Drug-induced QT prolongation is a complex and unpredictable system due to many uncertainties. Risk factors such as electrolyte disturbances, heart failure and genetics play an important role in estimating the effect on QT prolongation. Moreover, the degree of QT prolongation is not always directly related to the risk of TdP and the assessment of the QT-interval is variable depending on the type and timing of QT measurement. Therefore, the variation in QT measurement may be larger than the effect of certain drugs on the QT interval. Because of the potentially lethal risk, several measures are undertaken to reduce the risk of QT prolongation and TdP, while their effect and proportionality are unclear. We suggest we should be less stringent in certain settings when risk of TdP is extremely low given the limited availability of our resources.

Automated Kidney and Liver Segmentation in MR Images in Patients with Autosomal Dominant Polycystic Kidney Disease: A Multicenter Study.

Background: Imaging-based total kidney volume (TKV) and total liver volume (TLV) are major prognostic factors in autosomal dominant polycystic kidney disease (ADPKD) and end points for clinical trials. However, volumetry is time consuming and reader dependent in clinical practice. Our aim was to develop a fully automated method for joint kidney and liver segmentation in magnetic resonance imaging (MRI) and to evaluate its performance in a multisequence, multicenter setting. Methods: The convolutional neural network was trained on a large multicenter dataset consisting of 992 MRI scans of 327 patients. Manual segmentation delivered ground-truth labels. The model's performance was evaluated in a separate test dataset of 93 patients (350 MRI scans) as well as a heterogeneous external dataset of 831 MRI scans from 323 patients. Results: The segmentation model yielded excellent performance, achieving a median per study Dice coefficient of 0.92-0.97 for the kidneys and 0.96 for the liver. Automatically computed TKV correlated highly with manual measurements (intraclass correlation coefficient [ICC]: 0.996-0.999) with low bias and high precision (-0.2%±4% for axial images and 0.5%±4% for coronal images). TLV estimation showed an ICC of 0.999 and bias/precision of -0.5%±3%. For the external dataset, the automated TKV demonstrated bias and precision of -1%±7%. Conclusions: Our deep learning model enabled accurate segmentation of kidneys and liver and objective assessment of TKV and TLV. Importantly, this approach was validated with axial and coronal MRI scans from 40 different scanners, making implementation in clinical routine care feasible.Clinical Trial registry name and registration number: The German ADPKD Tolvaptan Treatment Registry (AD[H]PKD), NCT02497521.

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.

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 < 0.001). Gallstones during lanreotide treatment were multiple (> 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.

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 m2. 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.