Disease Progression In Autosomal Dominant Polycystic Kidney Disease Research Articles

Global analysis of urinary extracellular vesicle small RNAs in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic renal disease progressing to end-stage renal disease. There is a pressing need for the identification of early ADPKD biomarkers to enable timely intervention and the development of effective therapeutic approaches. Here, we profiled human urinary extracellular vesicles small RNAs by small RNA sequencing in patients with ADPKD and compared their differential expression considering healthy control individuals to identify dysregulated small RNAs and analyze downstream interaction to gain insight about molecular pathophysiology. This is a cross-sectional study where urine samples were collected from a total of 23 PKD1-ADPKD patients and 28 healthy individuals. Urinary extracellular vesicles were purified, and small RNA was isolated and sequenced. Differentially expressed Small RNA were identified and functional enrichment analysis of the critical miRNAs was performed to identify driver genes and affected pathways. miR-320b, miR-320c, miR-146a-5p, miR-199b-3p, miR-671-5p, miR-1246, miR-8485, miR-3656, has_piR_020497, has_piR_020496 and has_piR_016271 were significantly upregulated in ADPKD patient urine extracellular vesicles and miRNA-29c was significantly downregulated. Five 'driver' target genes (FBRS, EDC3, FMNL3, CTNNBIP1 and KMT2A) were identified. The findings of the present study make significant contributions to the understanding of ADPKD pathogenesis and to the identification of novel biomarkers and potential drug targets aimed at slowing disease progression in ADPKD.

Dapagliflozin administration for 1year promoted kidney enlargement in patient with ADPKD.

To date, there is insufficient evidence regarding use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for patients with autosomal-dominant polycystic kidney disease (ADPKD), as such cases have been excluded from previous clinical trials exploring the kidney protection effects of such medications. Here, findings of an ADPKD patient who received dapagliflozin, a selective SGLT2 inhibitor, for 1year are presented. A 38-year-old woman with a family history of ADPKD wished for treatment with dapagliflozin. After starting administration at 10mg/day, total kidney volume (TKV) continued to increase, from 1641 to 1764mL after 84days and then to 2297mL after 340days. The estimated glomerular filtration rate (eGFR) was also decreased from 67.3 to 56.2mL/min/1.73m2, and then to 51.4mL/min/1.73m2 at those times. Immediately after discontinuation of dapagliflozin, TKV and eGFR were slightly improved to 2263mL and 55.1mL/min/1.73m2, respectively. Following a review of basic research studies, we consider that increased intratubular urinary osmotic pressure, compensatory glucose reabsorption by sodium-glucose cotransporter-1 in the late proximal tubule, and hypertrophy shown in collected cells caused by increased vasopressin may be associated with ADPKD disease progression. Caution may be needed when administering dapagliflozin to patients with ADPKD.

Matrix Metalloproteinase-7 in Urinary Extracellular Vesicles Identifies Rapid Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

There is an unmet need for biomarkers of disease progression in autosomal dominant polycystic kidney disease (ADPKD). This study investigated urinary extracellular vesicles (uEVs) as a source of such biomarkers. Proteomic analysis of uEVs identified matrix metalloproteinase 7 (MMP-7) as a biomarker predictive of rapid disease progression. In validation studies, MMP-7 was predictive in uEVs but not in whole urine, possibly because uEVs are primarily secreted by tubular epithelial cells. Indeed, single-nucleus RNA sequencing showed that MMP-7 was especially increased in proximal tubule and thick ascending limb cells, which were further characterized by a profibrotic phenotype. Together, these data suggest that MMP-7 is a biologically plausible and promising uEV biomarker for rapid disease progression in ADPKD. In ADPKD, there is an unmet need for early markers of rapid disease progression to facilitate counseling and selection for kidney-protective therapy. Our aim was to identify markers for rapid disease progression in uEVs. Six paired case-control groups ( n =10-59/group) of cases with rapid disease progression and controls with stable disease were formed from two independent ADPKD cohorts, with matching by age, sex, total kidney volume, and genetic variant. Candidate uEV biomarkers were identified by mass spectrometry and further analyzed using immunoblotting and an ELISA. Single-nucleus RNA sequencing of healthy and ADPKD tissue was used to identify the cellular origin of the uEV biomarker. In the discovery proteomics experiments, the protein abundance of MMP-7 was significantly higher in uEVs of patients with rapid disease progression compared with stable disease. In the validation groups, a significant >2-fold increase in uEV-MMP-7 in patients with rapid disease progression was confirmed using immunoblotting. By contrast, no significant difference in MMP-7 was found in whole urine using ELISA. Compared with healthy kidney tissue, ADPKD tissue had significantly higher MMP-7 expression in proximal tubule and thick ascending limb cells with a profibrotic phenotype. Among patients with ADPKD, rapid disease progressors have higher uEV-associated MMP-7. Our findings also suggest that MMP-7 is a biologically plausible biomarker for more rapid disease progression.

Predicting autosomal dominant polycystic kidney disease progression: review of promising Serum and urine biomarkers.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the leading causes of end-stage renal disease. In spite of the recent tremendous progress in the understanding of ADPKD pathogenesis, the molecular mechanisms of the disease remain incompletely understood. Considering emerging new targeted therapies for ADPKD, it has become crucial to disclose easily measurable and widely available biomarkers for identifying patients with future rapid disease progression. This review encompasses all the research with a shared goal of identifying promising serum or urine biomarkers for predicting ADPKD progression or response to therapy. The rate of the ADPKD progress varies significantly between patients. The phenotypic variability is only partly explained by the underlying genetic lesion diversity. Considering significant decline in kidney function in ADPKD is not usually evident until at least 50% of the parenchyma has been destroyed, conventional kidney function measures, such as glomerular filtration rate (GFR), are not suitable for monitoring disease progression in ADPKD, particularly in its early stages. Since polycystic kidney enlargement usually precedes the decline in GFR, height-adjusted total kidney volume (ht-TKV) has been accepted as an early biomarker for assessing disease severity in ADPKD patients. However, since measuring ht-TKV is time-consuming and observer-dependent, the identification of a sensitive and quickly measurable biomarker is of a great interest for everyday clinical practice. Throughout the last decade, due to development of proteomic and metabolomic techniques and the enlightenment of multiple molecular pathways involved in the ADPKD pathogenesis, a number of urine and serum protein biomarkers have been investigated in ADPKD patients, some of which seem worth of further exploring. These include copeptin, angiotensinogen, monocyte chemoattractant protein 1, kidney injury molecule-1 and urine-to-plasma urea ratio among many others. The aim of the current review is to provide an overview of all of the published evidence on potentially clinically valuable serum and urine biomarkers that could be used for predicting disease progression or response to therapy in patients with ADPKD. Hopefully, this review will encourage future longitudinal prospective clinical studies evaluating proposed biomarkers as prognostic tools to improve management and outcome of ADPKD patients in everyday clinical practice.

Otomozal dominant polikistik böbrek hastalığında tolvaptan kullanımı: Tek merkez deneyimi

Aim: Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease that progresses to end-stage renal disease (ESRD). Tolvaptan is a disease-modifying agent that slows cyst growth and kidney disease progression in ADPKD. In this study, we examined the effects and side effects of tolvaptan in high-risk ADPKD patients using tolvaptan. We share our experience of this study.
 
 Methods: Twenty-seven ADPKD patients who were at high risk according to the Mayo Clinical Classification and accepted treatment were included in the study. Tolvaptan 60 mg/day orally was started in patients to slow the ADPKD. The daily dose was increased to 120 mg depending on the patients’ response to tolvaptan treatment and their tolerance to side effects. The patients were followed up during tolvaptan treatment to observe the effects and side effects of the medication.
 
 Results: The mean age of the patients was 40.3±8.2. Hypertension was present in 81.5% of the patients, and they mostly used renin angiotensin aldosterone system inhibitors. As aquaretic side effects of tolvaptan treatment, there was thirst in 14 patients (51.9%), polydipsia in 10 patients (37%), dry mouth in 5 patients (18.5%), and nocturia in 4 patients (14.8%). In addition, although liver enzyme elevation, hypernatremia, and acute kidney injury were observed in one patient each, these side effects did not lead to permanent discontinuation of the drug. Polyuria was observed in all patients, but the patients tolerated the polyuria well and continued to use tolvaptan treatment. 
 
 Conclusion: Although the patients experienced side effects related to tolvaptan treatment, none of the patients discontinued the drug permanently. We observed that patients generally tolerated tolvaptan treatment well.

#3521 ASSOCIATION BETWEEN NEPROLITHIASIS AND KIDNEY DISEASE PROGRESSION IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE PATIENTS: A PROSPECTIVE COHORT STUDY

Abstract Background and Aims Nephrolithiasis is a common complication in Autosomal dominant polycystic kidney disease (ADPKD) patients and is known to occur in up to 8% to 36% of the patients. A few in vitro and in vivo studies showed that kidney and ureter stone formation could accelerate renal disease progression in ADPKD. However, its association between nephrolithiasis and renal function deterioration remains unknown in ADPKD patients. Methods This is a study from single center prospective cohort called HOPE-PKD. A total of 410 study subjects with abdominal computed tomography (CT) scan within 1 year before the enrollment were analyzed. Study subjects were divided into two groups according to the CT results as follows: Patients with papillary calcification, calyceal stone, ureter stone, or renal stone were classified as a stone group (n = 80, 19.5%), and patients only with renal cyst calcification or without any stones in the kidney and ureter were classified as a no-stone group (n = 330, 80.5%). The primary outcome was defined as the initiation of renal replacement therapy due to end-stage renal disease. The secondary outcome was a composite outcome of a 50% decline in estimated glomerular filtration rate (eGFR), doubling serum creatinine from baseline, or the initiation of renal replacement therapy. The hazard ratios (HRs) and 95% confidence interval (95% CI) for the outcome were analyzed using multivariate Cox regression analysis. Results There was no difference in the baseline characteristics between the stone group and the no-stone group. During a median 5.18 [interquartile range 3.41 - 8.03] year of follow-up, the primary and secondary outcomes occurred in 51 (12.4%) and 96 (23.4%) patients, respectively. In the unadjusted Cox regression analysis, there was no significant difference in the survival analysis between the two groups. However, after adjusting possible confounding factors (age, sex, body mass index, eGFR, comorbidity of hypertension and diabetes, serum uric acid, phosphorous and calcium level, results of PKD1 and PKD2 gene analysis, and Mayo classification), the stone group showed an increased risk of the primary and secondary outcome of HR 2.84 (95% CI 1.26 - 6.38; p-value 0.012) and HR 1.83 (95% CI 1.03 - 3.27; p-value 0.041), respectively compared to the no-stone group (Figure 1). Conclusion This is the first prospective cohort study showing that nephrolithiasis is associated with poor renal outcomes in patients with APDKD. Further clinical studies of nephrolithiasis in ADPKD patients are warranted to improve renal outcomes.

A Low-Cost Sequencing Platform for Rapid Genotyping in ADPKD and its Impact on Clinical Care

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure. Because of the heterogeneity in disease progression in ADPKD, parameters predicting future outcome are important. The disease-causing genetic variant is one of these parameters. A multiplex polymerase chain reaction (PCR)-based panel (MPP) was established for analysis of 6 polycystic kidney disease (PKD) genes (PKD1, PKD2, HNF1B, GANAB, DZIP1L, and PKHD1) in 441 patients with ADPKD. Selected patients were additionally sequenced using Sanger sequencing or a custom enrichment-based gene panel. Results were combined with clinical characteristics to assess the impact of genetic data on clinical decision-making. Variants of unclear significance (VUS) were considered diagnostic based on a classic ADPKD clinical phenotype. Using the MPP, disease-causing variants were detected in 65.3% of patients. Sanger sequencing and the custom gene panel in 32 patients who were MPP-negative revealed 20 variants missed by MPP, (estimated overall false negative rate 24.6%, false-positive rate 9.4%). Combining clinical and genetic data revealed that knowledge of the genotype could have impacted the treatment decision in 8.2% of patients with a molecular genetic diagnosis. Sequencing only the PKD1 pseudogene homologous region in MPP-negative patients resulted in an acceptable false-negative rate of 3.28%. The MPP yields rapid genotype information at lower costs and allows for simple extension of the panel for new disease genes. Additional sequencing of the PKD1 pseudogene homologous region is required in negative cases. Access to genotype information even in settings with limited resources is important to allow for optimal patient counseling in ADPKD.

Cardiac Manifestations in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD): A Single-Center Study.

Key Points Cardiovascular disease—a key driver of morbidity in CKD—is common in patients with autosomal dominant polycystic kidney disease (ADPKD).Pathologic echocardiography findings, including valvular defects, aortic root dilation, and hypertrophy, are found in most patients with ADPKD.These findings correlate with parameters indicating disease progression in ADPKD. Echocardiography should be offered to all patients with ADPKD. Background ADPKD is the most common monogenetic kidney disease and results in kidney failure in >75% of affected individuals. As a systemic disorder, ADPKD is associated with a variety of extrarenal manifestations, including cardiac manifestations, that affect the majority of patients. We characterized the cardiac involvement in patients with ADPKD from the German AD(H)PKD registry and compared them with kidney donor candidates as controls. Methods In this single-center cohort study, we evaluated 141 patients with ADPKD (44.17±11.23 years) from the German AD(H)PKD registry and 60 kidney donor candidates (55.08±10.21 years). All patients underwent clinical examination, abdominal MRI, and transthoracic echocardiography. Results Of the patients with ADPKD, 65% showed hypertrophy of the left ventricle (as defined by an end-diastolic interventricular septal wall thickness [IVSd] >10 mm) compared with 55% in control patients. Mitral regurgitation was the most common finding among 54% of patients with ADPKD who exhibited valvular dysfunction, albeit mild in most patients. Interestingly, left ventricular ejection fraction (LV-EF) differed significantly between both groups, with higher values in patients with ADPKD (64%±6% versus 60%±6%), whereas other parameters, including IVSd, left ventricular end-diastolic diameter (LVEDD), tricuspid annular plane systolic excursion (TAPSE), and pressure gradients across the aortic and tricuspid valve were similar between groups. Correlations of echocardiographic parameters with markers of disease progression revealed statistically significant associations for aortic root diameter (P=0.01), the pressure gradient across the aortic valve (AV dPmax; P=0.0003), and IVSd (P=0.0001), indicating rapid kidney disease progression may also be associated with cardiac findings. Conclusion Cardiovascular abnormalities are prevalent in patients with ADPKD. Considering the importance of cardiovascular disease for outcomes in CKD, early management and possibly prevention are important goals of any treatment scheme. Consequently, echocardiography should be offered to all patients with ADPKD in routine management.

Nuclear Condensation of CDYL Links Histone Crotonylation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease.

Emerging evidence indicates that epigenetic modulation of gene expression plays a key role in the progression of autosomal dominant polycystic kidney disease (ADPKD). However, the molecular basis for how the altered epigenome modulates transcriptional responses, and thereby disease progression in ADPKD, remains largely unknown. Kidneys from control and ADPKD mice were examined for the expression of CDYL and histone acylations. CDYL expression and its correlation with disease severity were analyzed in a cohort of patients with ADPKD. Cdyl transgenic mice were crossed with Pkd1 knockout mice to explore CDYL's role in ADPKD progression. Integrated cistromic and transcriptomic analyses were performed to identify direct CDYL target genes. High-sensitivity mass spectrometry analyses were undertaken to characterize CDYL-regulated histone lysine crotonylations (Kcr). Biochemical analysis and zebrafish models were used for investigating CDYL phase separation. CDYL was downregulated in ADPKD kidneys, accompanied by an increase of histone Kcr. Genetic overexpression of Cdyl reduced histone Kcr and slowed cyst growth. We identified CDYL-regulated cyst-associated genes, whose downregulation depended on CDYL-mediated suppression of histone Kcr. CDYL assembled nuclear condensates through liquid-liquid phase separation in cultured kidney epithelial cells and in normal kidney tissues. The phase-separating capacity of CDYL was required for efficient suppression of locus-specific histone Kcr, of expression of its target genes, and of cyst growth. These results elucidate a mechanism by which CDYL nuclear condensation links histone Kcr to transcriptional responses and cystogenesis in ADPKD.

Assessing Risk of Rapid Progression in Autosomal Dominant Polycystic Kidney Disease and Special Considerations for Disease-Modifying Therapy

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure, accounting for 5%-10% of cases. Predicting which patients with ADPKD will progress rapidly to kidney failure is critical to assess the risk-benefit ratio of any intervention and to consider early initiation of long-term kidney protective measures that will maximize the cumulative benefit of slowing disease progression. Surrogate prognostic biomarkers are required to predict future decline in kidney function. Clinical, genetic, environmental, epigenetic, and radiologic factors have been studied as predictors of progression to kidney failure in ADPKD. A complex interaction of these prognostic factors determines the number of kidney cysts and their growth rates, which affect total kidney volume (TKV). Age-adjusted TKV, represented by the Mayo imaging classification, estimates each patient's unique rate of kidney growth and provides the most individualized approach available clinically so far. Tolvaptan has been approved to slow disease progression in patients at risk of rapidly progressive disease. Several other disease-modifying treatments are being studied in clinical trials. Selection criteria for patients at risk of rapid progression vary widely among countries and are based on a combination of age, baseline glomerular filtration rate (GFR), GFR slope, baseline TKV, and TKV rate of growth. This review details the approach in assessing the risk of disease progression in ADPKD and identifying patients who would benefit from long-term therapy with disease-modifying agents.

Use of the Urine-to-Plasma Urea Ratio to Predict ADPKD Progression.

Predicting disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) poses a challenge, especially in early-stage disease when kidney function is not yet affected. Ongoing growth of cysts causes maximal urine-concentrating capacity to decrease from early on. We therefore hypothesized that the urine-to-plasma urea ratio, as a reflection of the urine-concentrating capacity, can be used as a marker to predict ADPKD progression. The urine-to-plasma urea ratio was calculated by dividing concentrations of early morning fasting spot urine urea by plasma urea. First, this ratio was validated as surrogate marker in 30 patients with ADPKD who underwent a prolonged water deprivation test. Thereafter, association with kidney outcome was evaluated in 583 patients with ADPKD with a broad range of kidney function. Multivariable mixed-model regression was used to assess association with eGFR slope, and logarithmic regression to identify patients with rapidly progressive disease, using a cutoff of -3.0 ml/min per 1.73 m2 per year. The urine-to-plasma urea ratio was compared with established predictors, namely, sex, age, baseline eGFR, Mayo Clinic height-adjusted total kidney volume class, and PKD gene mutation. The maximal urine-concentrating capacity and urine-to-plasma urea ratio correlated strongly (R=0.90; P<0.001). Next, the urine-to-plasma urea ratio was significantly associated with rate of eGFR decline during a median follow-up of 4.0 (interquartile range, 2.6-5.0) years, both crude and after correction for established predictors (β=0.58; P=0.02). The odds ratio of rapidly progressive disease was 1.35 (95% confidence interval, 1.19 to 1.52; P<0.001) for every 10 units decrease in urine-to-plasma urea ratio, with adjustment for predictors. A combined risk score of the urine-to-plasma urea ratio, Mayo Clinic height-adjusted total kidney volume class, and PKD mutation predicted rapidly progressive disease better than each of the predictors separately. The urine-to-plasma urea ratio, which is calculated from routine laboratory measurements, predicts disease progression in ADPKD in addition to other risk markers. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_01_27_CJN10470620_final.mp3.

Predictors of progression in autosomal dominant and autosomal recessive polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are characterized by bilateral cystic kidney disease leading to progressive kidney function decline. These diseases also have distinct liver manifestations. The range of clinical presentation and severity of both ADPKD and ARPKD is much wider than was once recognized. Pediatric and adult nephrologists are likely to care for individuals with both diseases in their lifetimes. This article will review genetic, clinical, and imaging predictors of kidney and liver disease progression in ADPKD and ARPKD and will briefly summarize pharmacologic therapies to prevent progression.

The Controversial Role of Fibrosis in Autosomal Dominant Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the progressive growth of cysts but it is also accompanied by diffuse tissue scarring or fibrosis. A number of recent studies have been published in this area, yet the role of fibrosis in ADPKD remains controversial. Here, we will discuss the stages of fibrosis progression in ADPKD, and how these compare with other common kidney diseases. We will also provide a detailed overview of some key mechanistic pathways to fibrosis in the polycystic kidney. Specifically, the role of the ‘chronic hypoxia hypothesis’, persistent inflammation, Transforming Growth Factor beta (TGFβ), Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and microRNAs will be examined. Evidence for and against a pathogenic role of extracellular matrix during ADPKD disease progression will be provided.

Serum Uric Acid and Progression of Autosomal Dominant Polycystic Kidney Disease: Results from the HALT PKD Trials.

Epidemiological studies have suggested that elevated serum uric acid may contribute to the progression of chronic kidney disease. However, no large prospective study has examined whether hyperuricemia is an independent risk factor for the progression of autosomal dominant polycystic kidney disease (ADPKD). We measured uric acid in stored serum samples from the 2-year study visit of 671 participants from the HALT PKD multicenter trials. Participants were categorized according to uric acid tertiles. For Study A (participants aged 15-49 years with preserved kidney function, n=350), we used linear mixed effects models to examine the association between uric acid and repeated measures of height-adjusted total kidney volume (htTKV), the primary outcome for Study A. For Study B (participants aged 18-64 with decreased kidney function, n=321), we used Cox proportional hazards models to assess the hazard for the combined endpoint of 50% loss in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), or death, the primary outcome for Study B. To assess the association of uric acid with the slope of eGFR decline (secondary outcome of HALT A and B), we used linear mixed effects models for the combined population of Study A and B. In the unadjusted model, the annual change in htTKV was 2.7% higher in the highest uric acid tertile compared to the lowest (p<0.001), but this difference became insignificant after adjustment for gender. Men had faster TKV growth than women (p<0.001). There was no difference in eGFR decline between the 3 uric acid tertiles. Hazard ratios for the clinical endpoint were 2.9 (95% confidence interval, 1.9-4.4) and 1.8 (1.1-2.8) respectively in the high and medium uric acid groups in unadjusted and partially adjusted models (p<0.001), but the significance was lost after adjustment for baseline eGFR. Results were similar when uric acid was examined as a continuous variable. Elevated serum uric acid is not an independent risk factor for disease progression in ADPKD.

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.

KIM-1 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease: HALT-PKD Results

Background: Cyst compression of renal tubules plays a role in the progression of autosomal dominant polycystic kidney disease (ADPKD) and may induce expression of kidney injury molecule-1 (KIM-1). Whether urinary KIM-1 indexed for creatinine (uKIM-1/Cr) is a prognostic marker of disease progression in ADPKD is unknown.In this secondary analysis of a prospective cohort study, we sought to determine whether patients with high as opposed to low uKIM-1/CR at baseline had greater rates of eGFR loss and height-adjusted total kidney volume (HtTKV) increase. Methods: Baseline uKIM-1/Cr values were obtained from 754 participants in Halt Progression of Polycystic Kidney Disease (HALT-PKD) studies A (early ADPKD) and B (late ADPKD). The predictor was uKIM-1/Cr, which was dichotomized by a median value of 0.2417 pg/g, and the primary outcomes were measured longitudinally over time. Mixed-effects linear models were used in the analysis to calculate the annual slope of change in eGFR and HtTKV. Results: Patients with high uKIM-1/Cr (above the median) had an annual decline in eGFR that was 0.47 mL/min greater than that in those with low uKIM-1/Cr (p = 0.0015) after adjustment for all considered covariates. This association was seen in study B patients alone (0.45 mL/min; p = 0.009), but not in study A patients alone (0.42 mL/min; p = 0.06). High baseline uKIM-1/Cr was associated with higher HtTKV in the baseline cross-sectional analysis compared to low uKIM-1/Cr (p = 0.02), but there was no difference between the groups in the mixed-effects model annual slopes. Conclusion: Elevated baseline uKIM-1/Cr is associated with a greater decline in eGFR over time. Further research is needed to determine whether uKIM-1/Cr improves risk stratification in patients with ADPKD.

SO091URINE-TO-PLASMA UREA RATIO, AS SURROGATE MARKER FOR URINE CONCENTRATING CAPACITY, IS ASSOCIATED WITH DISEASE PROGRESSION IN ADPKD

Abstract Introduction Predicting disease progression in autosomal dominant polycystic kidney disease (ADPKD) patients poses a challenge, especially in early stage disease when renal function is not yet affected. The ongoing formation and growth of cysts causes the urine concentrating capacity to decrease from early on in the disease. We therefore hypothesized that the easy and inexpensive to measure urine-to-plasma urea ratio (UPU ratio), which is assumed to be surrogate for maximal urine concentrating capacity, can be used as marker to predict disease progression in ADPKD. Methods The UPU ratio was calculated by dividing urea concentration in a fasting morning spot urine sample by plasma urea concentration adjusted for plasma creatinine concentration. First, we validated the UPU ratio in 30 ADPKD patients who underwent a prolonged water deprivation test to measure the maximal urine concentrating capacity. Thereafter, the association of the UPU ratio with renal outcome was evaluated in 583 ADPKD patients participating in the DIPAK observational cohort (inclusion criteria: age&amp;gt;18 years, eGFR &amp;gt;15 mL/min/1.73m2, no concomitant diseases affecting eGFR, without V2 receptor antagonist prescription). Kidney function was assessed as eGFR by the creatinine based CKD-EPI formula, height adjusted total kidney volume (htTKV) by MRI and copeptin (surrogate for vasopressin) by ELISA. Results In the water deprivation test participants (n=30), the UPU ratio was strongly correlated with maximal urine concentrating capacity (R = 0.67, p&amp;lt;0.001). This association remained significant after correcting for sex, age, htTKV and eGFR (st. β = 0.53, p = 0.007). In these subjects maximal urine concentrating capacity as well as UPU ratio were associated with the rate of eGFR decline during a median follow-up of 6.3 yr (12 eGFR assessments per patient) assessed using linear mixed modeling, also when corrected for sex, baseline age and eGFR (β = 0.009, p = 0.04, and β = 5.56, p&amp;lt;0.001, resp.). We subsequently corroborated in the larger DIPAK observational cohort (n=583, 58% female, mean age 47 yr median eGFR 60 mL/min/1.73m2 and htTKV 898 ml/m), that the UPU ratio was significantly associated with rate of eGFR decline during a median follow-up of 4.0 yr (6 eGFR assessments per patient): β = 0.23, p = 0.005. This association remained significant when corrected for sex, baseline age and eGFR (β = 0.32, p&amp;lt;0.001) and even when additionally corrected for Mayo class, PDK mutation and copeptin (β = 0.40, p &amp;lt;0.001). Stepwise backward multivariate regression analysis resulted in a final model including the UPU ratio, PKD mutation, Mayo Class and copeptin. Cox survival analysis showed that a lower baseline UPU ratio (indicating less urine concentrating capacity) was significantly associated with a higher risk to develop the combined renal endpoint of incidence of start of kidney replacement therapy, eGFR &amp;lt;15 mL/min/1.73m2 or eGFR decrease &amp;gt;40% during follow-up (adjusted Hazard Ratio per SD = 1.39, p = 0.007). Limiting the aforementioned analyses to the subgroup of patients with relative early stage disease (n=122, age &amp;lt;40 yr and eGFR &amp;gt;60 mL/min/1.73m2) rendered essentially similar results, with an adjusted β for UPU ratio in the final model of 0.33 (p = 0.04). In this subgroup with a limited number of events (n=10), Cox survival analysis did not reach formal significance (adjusted HR per SD: 2.67, p = 0.055). Conclusion The UPU ratio, which is calculated from routine laboratory measurements, predicts renal prognosis in ADPKD in addition to other, more laborious to measure and expensive risk markers. Notably, this marker of urine concentrating capacity also shows promise in early-stage disease.

Coexistence of autosomal dominant polycystic kidney disease type 1 and hereditary renal hypouricemia type 2: A model of early-onset and fast cyst progression.

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous inherited disease characterized by renal and extrarenal manifestations with progressive fluid-filled cyst development leading to end-stage renal disease. The rate of disease progression in ADPKD exhibits high inter- and intrafamilial variability suggesting involvement of modifier genes and/or environmental factors. Renal hypouricemia (RHUC) is an inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and chronic kidney disease (CKD). However, the two disorders have distinct and well-delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and RHUC (type 1) in a single individual have been reported. We report a family with two members: an ADPKD 24-year-old female which presented bilateral renal cysts in utero and hypouricemia since age 5, and her mother with isolated hypouricemia. Next-generation sequencing identified two mutations in two genes PKD1 and SLC2A9 in this patient and one isolated SLC2A9 mutation in her mother, showing RHUC type 2, associated to CKD. The coexistence of these two disorders provides evidence of SLC2A9 variant could act as a modifier change, with synergistic actions, that could promote cystogenesis and rapid ADPKD progression. This is the first case of coexistence of PKD1 and SLC2A9 mutations treated with tolvaptan.

High water vs. ad libitum water intake for autosomal dominant polycystic kidney disease: a randomized controlled feasibility trial.

Background Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) and is a key therapeutic target. Evaluation of high water intake as an alternative to pharmacological vasopressin blockade is supported by patients. However feasibility, safety and adherence-promoting strategies required to deliver this remain unknown. Aims Assess the feasibility of a definitive randomized high water intake trial in ADPKD. Methods In this prospective open-label randomized trial, adult ADPKD patients with eGFR ≥ 20 ml/min/1.73 m2 were randomized to prescribed high water (HW) intake targeting urine osmolality (UOsm) ≤270 mOsm/kg, or ad libitum (AW) intake (UOsm >300 mOsm/kg). Self-management strategies including home-monitoring of urine-specific gravity (USG) were employed to promote adherence. Results We enrolled 42 participants, baseline median eGFR (HW 68.4 [interquartile range (IQR) 35.9-107.2] vs. AW 75.8 [IQR 59.0-111.0 ml/min/1.73 m2, P = 0.22) and UOsm (HW 353 [IQR 190-438] vs. AW 350 [IQR 240-452] mOsm/kg, P = 0.71) were similar between groups. After 8 weeks, 67% in the HW vs. 24% in AW group achieved UOsm ≤270 mOsm/kg, P = 0.001. HW group achieved lower UOsm (194 [IQR 190-438] vs. 379 [IQR 235-503] mOsm/kg, P = 0.01) and higher urine volumes (3155 [IQR 2270-4295] vs. 1920 [IQR 1670-2960] ml/day, P = 0.02). Two cases of hyponatraemia occurred in HW group. No acute GFR effects were detected. In total 79% (519/672) of USG were submitted and 90% (468/519) were within target. Overall, 17% withdrew during the study. Conclusion DRINK demonstrated successful recruitment and adherence leading to separation between treatment arms in primary outcomes. These findings suggest a definitive trial assessing the impact of high water on kidney disease progression in ADPKD is feasible.

High water vs. ad libitum water intake for autosomal dominant polycystic kidney disease: a randomized controlled feasibility trial.

BackgroundVasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) and is a key therapeutic target. Evaluation of high water intake as an alternative to pharmacological vasopressin blockade is supported by patients. However feasibility, safety and adherence-promoting strategies required to deliver this remain unknown.AimsAssess the feasibility of a definitive randomized high water intake trial in ADPKD.MethodsIn this prospective open-label randomized trial, adult ADPKD patients with eGFR ≥ 20 ml/min/1.73 m2 were randomized to prescribed high water (HW) intake targeting urine osmolality (UOsm) ≤270 mOsm/kg, or ad libitum (AW) intake (UOsm >300 mOsm/kg). Self-management strategies including home-monitoring of urine-specific gravity (USG) were employed to promote adherence.ResultsWe enrolled 42 participants, baseline median eGFR (HW 68.4 [interquartile range (IQR) 35.9–107.2] vs. AW 75.8 [IQR 59.0–111.0 ml/min/1.73 m2, P = 0.22) and UOsm (HW 353 [IQR 190–438] vs. AW 350 [IQR 240–452] mOsm/kg, P = 0.71) were similar between groups. After 8 weeks, 67% in the HW vs. 24% in AW group achieved UOsm ≤270 mOsm/kg, P = 0.001. HW group achieved lower UOsm (194 [IQR 190–438] vs. 379 [IQR 235–503] mOsm/kg, P = 0.01) and higher urine volumes (3155 [IQR 2270–4295] vs. 1920 [IQR 1670–2960] ml/day, P = 0.02). Two cases of hyponatraemia occurred in HW group. No acute GFR effects were detected. In total 79% (519/672) of USG were submitted and 90% (468/519) were within target. Overall, 17% withdrew during the study.ConclusionDRINK demonstrated successful recruitment and adherence leading to separation between treatment arms in primary outcomes. These findings suggest a definitive trial assessing the impact of high water on kidney disease progression in ADPKD is feasible.