Search

Background and objectives Autosomal Dominant Polycystic Kidney Disease (ADPKD) presents with variable disease severity and progression. Advanced imaging biomarkers may provide insights into cystic and non-cystic processes leading to kidney failure in different age groups. Methods This pilot study included 39 ADPKD patients with kidney failure, stratified into three age groups (56 years old). Advanced imaging biomarkers were assessed using an automated instance cyst segmentation tool. The biomarkers were compared with an age- and sex-matched ADPKD cohort in early chronic kidney disease (CKD). Results Ht-total parenchymal volume correlated negatively with age at kidney failure. The median Ht-total parenchymal volume was significantly lower in patients older than 56 years. Cystic burden was significantly higher at time of kidney failure and especially in patients who reached it before age 46. The cyst index at kidney failure was comparable across age groups and Mayo Imaging Classes. Advanced imaging biomarkers showed higher correlation with Ht-total kidney volume in early CKD than at kidney failure. Cyst index and parenchymal index were relatively stable over five years prior to kidney failure, whereas Ht-total cyst volume and cyst parenchymal surface area increased significantly. Conclusion Age-related differences in advanced imaging biomarkers suggest variable pathophysiological mechanisms in ADPKD patients with kidney failure. Further studies are needed to validate the utility of these biomarkers in predicting disease progression and guiding treatment strategies.

This study assessed the safety profile of high-volume (10 mL) 3% sodium tetradecyl sulfate (STS) sclerotherapy for the treatment of renal cysts in patients with autosomal dominant polycystic kidney disease. A total of 211 sclerotherapy treatments were performed in 169 patients over a 5-year period, with a comparison of 2 patient cohorts based on the STS volumes used. The first cohort (n = 112) received a high volume (greater than 10 mL) of STS, and the second cohort (n = 57) received a low volume (less than 10 mL). The minor adverse event rate for the cohorts was 14.5% and 9.6%, respectively (P = .310), with postprocedure pain being the most common event. One major adverse event occurred, for which the patient required hospitalization for infection after low-volume STS treatment. Doses of STS higher than those currently recommended by the Food and Drug Administration for intravascular use allow large renal cysts to be treated safely in the setting of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of renal cysts, leading to the loss of functional nephrons. Recommendations for individuals with ADPKD to maintain a healthy diet and lifestyle are largely similar to those for the general population. However, recent evidence from preclinical models suggests that more tightly specified dietary regimens, including caloric restriction, intermittent fasting, and ketogenic diets, hold promise to slow disease progression, and the results of ongoing human clinical trials are eagerly awaited. These dietary interventions directly influence nutrient signaling and substrate availability in the cystic kidney, while also conferring systemic metabolic benefits. The present review focuses on the importance of local and systemic metabolism in ADPKD and summarizes current evidence for dietary interventions to slow disease progression and improve quality of life.

Background and objectives Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable. On average, protein-truncating PKD1 mutations are associated with the most severe kidney disease among all mutation classes. Here, we report that patients with protein-truncating PKD1 mutations may also have mild kidney disease, a finding not previously well recognized. Design, setting, participants, & measurements From the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease, 487 patients had PKD1 and PKD2 sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification on the basis of age- and height-adjusted total kidney volume was used to assess their cystic disease severity; classes 1A or 1B were used as a proxy to define mild disease. Multivariable linear regression was performed to test the effects of age, sex, and mutation classes on log-transformed height-adjusted total kidney volume and eGFR. Results Among 174 study patients with typical imaging patterns and protein-truncating PKD1 mutations, 32 (18%) were found to have mild disease on the basis of imaging results (i.e., Mayo Clinic Imaging class 1A–1B), with their mutations spanning the entire gene. By multivariable analyses of age, sex, and mutation class, they displayed mild disease similar to patients with PKD2 mutations and Mayo Clinic Imaging class 1A–1B. Most of these mildly affected patients with protein-truncating PKD1 mutations reported a positive family history of ADPKD in preceding generations and displayed significant intrafamilial disease variability. Conclusions Despite having the most severe mutation class, 18% of patients with protein-truncating PKD1 mutations had mild disease on the basis of clinical and imaging assessment. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_18_CJN11100720_final.mp3

Using age- and height-adjusted total kidney volume, the Mayo Clinic Imaging Classification provides a validated approach to assess the risk of chronic kidney disease (CKD) progression in autosomal dominant polycystic kidney disease (ADPKD), but requires excluding patients with atypical imaging patterns, whose clinical characteristics have been poorly defined. We report an analysis of the prevalence, clinical and genetic characteristics of patients with atypical polycystic kidney disease by imaging. Patients from the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease recruited between 2016 and 2018 completed a standardized clinical questionnaire, kidney function assessment, genetic testing, and kidney imaging by magnetic resonance or computed tomography. We compared the prevalence, clinical features, genetics, and renal prognosis of atypical versus typical polycystic kidney disease by imaging. Forty-six of the 523 (8.8%) patients displayed atypical polycystic kidney disease by imaging; they were older (55 vs. 43 years; P PKD1 or PKD2 mutation (9.2% vs. 80.4%; P

Rationale & Objective Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder. Progressive increase in cyst number and size leads to kidney failure in a majority of patients. Large kidney cysts, although few, can be especially deleterious by impeding kidney blood flow and obstructing urine flow over a large region. Foam sclerotherapy is a minimally invasive procedure that may be used to ablate large cysts. We examined the effectiveness and safety of foam sclerotherapy for kidney volume reduction in patients with ADPKD. Study Design Prospective cohort study. Setting & Participants Adults with ADPKD at a tertiary referral center in Toronto. Predictor Foam sclerotherapy. Outcomes Volume of treated kidneys and adverse events. Analytical Approach Treated and nontreated kidney volume, kidney function, tolerability, and symptoms were analyzed within each patient. Results We performed 77 foam sclerotherapy treatment sessions in 66 patients. Foam sclerotherapy was associated with a 21.8% volume reduction of the treated kidneys (n = 95; median, 1,138 [IQR, 801-1,582] mL before vs 891 [IQR, 548-1,450] mL after; P, Graphical abstract

Introduction Discordance in kidney disease severity between affected relatives is a recognized feature of autosomal dominant polycystic kidney disease (ADPKD). Here, we report a systematic study of a large cohort of families to define the prevalence and clinical features of intrafamilial discordance in ADPKD. Methods The extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease (eTGESP) cohort includes 1390 patients from 612 unrelated families with ADPKD ascertained in a regional polycystic kidney disease center. All probands underwent comprehensive PKD1 and PKD2 mutation screening. Total kidney volume by magnetic resonance imaging (MRI) was available in 500 study patients. Results Based on (i) rate of estimated glomerular filtration rate (eGFR) decline, (ii) age at onset of end-stage renal disease (ESRD), and (iii) Mayo Clinic Imaging Classification (MCIC), 20% of patients were classified as having mild disease, and 33% as having severe disease. Intrafamilial ADPKD discordance with at least 1 mild and 1 severe case was observed in 43 of 371 (12%) families, at a similar frequency regardless of the responsible gene (PKD1/PKD2/no mutation detected) or mutation type (protein-truncating versus nontruncating). Intrafamilial discordance was more common in larger families and was present in 30% of families with more than 5 affected members. The heritability of age at onset of ESRD was similar between different mutation types. Conclusion Extreme kidney disease discordance is present in at least 12% of families with ADPKD, regardless of the underlying mutated gene or mutation class. Delineating genetic and environmental modifiers underlying the observed intrafamilial ADPKD variability will provide novel insights into the mechanisms of progression in ADPKD., Graphical abstract

BACKGROUND AND OBJECTIVES: Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable. On average, protein-truncating PKD1 mutations are associated with the most severe kidney disease among all mutation classes. Here, we report that patients with protein-truncating PKD1 mutations may also have mild kidney disease, a finding not previously well recognized. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease, 487 patients had PKD1 and PKD2 sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification on the basis of age- and height-adjusted total kidney volume was used to assess their cystic disease severity; classes 1A or 1B were used as a proxy to define mild disease. Multivariable linear regression was performed to test the effects of age, sex, and mutation classes on log-transformed height-adjusted total kidney volume and eGFR. RESULTS: Among 174 study patients with typical imaging patterns and protein-truncating PKD1 mutations, 32 (18%) were found to have mild disease on the basis of imaging results (i.e., Mayo Clinic Imaging class 1A–1B), with their mutations spanning the entire gene. By multivariable analyses of age, sex, and mutation class, they displayed mild disease similar to patients with PKD2 mutations and Mayo Clinic Imaging class 1A–1B. Most of these mildly affected patients with protein-truncating PKD1 mutations reported a positive family history of ADPKD in preceding generations and displayed significant intrafamilial disease variability. CONCLUSIONS: Despite having the most severe mutation class, 18% of patients with protein-truncating PKD1 mutations had mild disease on the basis of clinical and imaging assessment. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_18_CJN11100720_final.mp3

The duration of hemodialysis (HD) sessions for the treatment of acute ethylene glycol poisoning is dependent on concentration, the operational parameters used during HD, and the presence and severity of metabolic acidosis. Ethylene glycol assays are not readily available, potentially leading to undue extension or premature termination of HD. We report a prediction model for the duration of high-efficiency HD sessions based retrospectively on a cohort study of 26 cases of acute ethylene glycol poisoning in 24 individuals treated by alcohol dehydrogenase competitive inhibitors, cofactors and HD. Two patients required HD for more than 14 days, and two died. In 19 cases, the mean ethylene glycol elimination half-life during high-efficiency HD was 165 minutes (95% confidence interval of 151-180 minutes). In a training set of 12 patients with acute ethylene glycol poisoning, using the 90th percentile half-life (195 minutes) and a target ethylene glycol concentration of 2 mmol/l (12.4 mg/dl) allowed all cases to reach a safe ethylene glycol under 3 mmol/l (18.6 mg/dl). The prediction model was then validated in a set of seven acute ethylene glycol poisonings. Thus, the HD session time in hours can be estimated using 4.7 x (Ln [the initial ethylene glycol concentration (mmol/l)/2]), provided that metabolic acidosis is corrected.

The absence of a positive family history (PFH) in 10%–25% of patients poses a diagnostic challenge for autosomal dominant polycystic kidney disease (ADPKD). In the Toronto Genetic Epidemiology Study of Polycystic Kidney Disease, 210 affected probands underwent renal function testing, abdominal imaging, and comprehensive PKD1 and PKD2 mutation screening. From this cohort, we reviewed all patients with and without an apparent family history, examined their parental medical records, and performed renal imaging in all available parents of unknown disease status. Subsequent reclassification of 209 analyzed patients revealed 72.2% (151 of 209) with a PFH, 15.3% (32 of 209) with de novo disease, 10.5% (22 of 209) with an indeterminate family history, and 1.9% (four of 209) with PFH in retrospect. Among the patients with de novo cases, we found two families with germline mosaicism and one family with somatic mosaicism. Additionally, analysis of renal imaging revealed that 16.3% (34 of 209) of patients displayed atypical PKD, most of which followed one of three patterns: asymmetric or focal PKD with PFH and an identified PKD1 or PKD2 mutation (15 of 34), asymmetric and de novo PKD with proven or suspected somatic mosaicism (seven of 34), or focal PKD without any identifiable PKD1 or PKD2 mutation (eight of 34). In conclusion, PKD without an apparent family history may be due to de novo disease, missing parental medical records, germline or somatic mosaicism, or mild disease from hypomorphic PKD1 and PKD2 mutations. Furthermore, mutations of a newly identified gene for ADPKD, GANAB, and somatic mosaicism need to be considered in the mutation-negative patients with focal disease.

Total kidney volume (TKV) is a validated prognostic biomarker for risk assessment in autosomal dominant polycystic kidney disease (ADPKD). TKV by manual segmentation (MS) is the “gold standard” but is time-consuming and requires expertise. The purpose of this study was to compare TKV-based prognostic performance by ellipsoid (EL) vs. MS in a large cohort of patients. Cross-sectional study of 308 patients seen at a tertiary referral center; all had a standardized MRI with typical imaging of ADPKD. An experienced radiologist blinded to patient clinical results performed all TKV measurements by EL and MS. We assessed the agreement of TKV measurements by intraclass correlation(ICC) and Bland-Altman plot and also how the disagreement of the two methods impact the prognostic performance of the Mayo Clinic Imaging Classification (MCIC). We found a high ICC of TKV measurements (0.991, p 20%. We also found a high degree of agreement of the individual MCIC risk classes (i.e. 1A to 1E) with a Cohen’s weighted-kappa of 0.89; but 42 cases (13.6%) were misclassified by EL with no misclassification spanning more than one risk class. The sensitivity and specificity of EL in distinguishing low-risk (1A-B) from high-risk (1C-E) MCIC prognostic grouping were 96.6% and 96.1%, respectively. Overall, we found an excellent agreement of TKV-based risk assessment between EL and MS. However, caution is warranted for patients with MCIC 1B and 1C, as misclassification can have therapeutic consequence.

Infections are a major contributor to morbidity and mortality in end-stage renal disease (ESRD) patients. A better understanding of the interplay between infectious processes and ESRD may eventually lead to the development of targeted treatment strategies aimed at lowering overall disease morbidity and mortality. Monogenic causes are a major contributor to the development of adult chronic kidney disease (CKD). Recent studies identified a genetic cause in 10% to 20% of adults with CKD. With the introduction of whole-exome sequencing (WES) into clinical mainstay, this proportion is expected to increase in the future. Once patients develop CKD/ESRD due to a genetic cause, secondary changes, such as a compromised immune status, affect overall disease progression and clinical outcomes. Stratification according to genotype may enable us to study its effects on secondary disease outcomes, such as infectious risk. Moreover, this knowledge will enable us to better understand the molecular interplay between primary disease and secondary disease outcomes.We conducted a literature review using search engines such as PubMed, PubMed central, and Medline, as well as cumulative knowledge from our respective areas of expertise.This is a transdisciplinary perspective on infectious complications in ESRD due to monogenic causes, such as autosomal dominant polycystic kidney disease (ADPKD), combining expertise in genomics and immunology.In ADPKD, infection is a frequent complication manifesting primarily as lower urinary tract infection and less frequently as renal infection. Infectious episodes may be a direct consequence of a specific underlying structural abnormality, for example the characteristic cysts, among others. However, evidence suggests that infectious disease risk is also increased in ESRD due to secondary not-well-understood disease mechanisms. These disease mechanisms may vary depending on the underlying nature of the primary disease. While the infectious disease risk is well documented in ADPKD, there are currently insufficient data on the risk in other monogenic causes of ESRD. WES in combination with novel technologies, such as RNA sequencing and single-cell RNA sequencing, can provide insight into the molecular mechanisms of disease progression in different monogenic causes of CKD/ESRD and may lead to the development of novel risk-stratification profiles in the future.This is not a systematic review of the literature and the proposed perspective is tainted by the authors' point of view on the topic.WES in combination with novel technologies such as RNA sequencing may enable us to fully unravel underlying disease mechanisms and secondary disease outcomes in monogenic causes of CKD and better characterize individual risk profiles. This understanding will hopefully facilitate the development of novel targeted therapies.Les infections contribuent largement à la morbidité et à la mortalité observées chez les patients atteints d’insuffisance rénale terminale (IRT). Une meilleure compréhension des interactions entre le processus infectieux et l’IRT pourrait éventuellement mener au développement de traitements ciblés visant la réduction de la morbidité et de la mortalité liées à la maladie. Les causes monogéniques sont en bonne partie responsables du développement de l’insuffisance rénale chronique (IRC) chez l’adulte. Des études récentes pointent vers une cause génétique dans 10 à 20 % des cas d’IRC, une proportion qui devrait s’accroître avec l’introduction du séquençage de l’exome entier (WES) comme soutien clinique principal. Lorsque les patients évoluent vers l’IRC/IRT de cause génétique, des changements secondaires, notamment un état immunologique fragilisé, affectent la progression globale de la maladie et les résultats cliniques. La stratification selon le génotype pourrait permettre d’étudier ses effets sur l’issue de pathologies secondaires comme le risque infectieux. En outre, cette information nous permettrait de mieux comprendre l’interaction moléculaire entre les résultats des pathologies primaires et secondaires.Nous avons procédé à une revue de la littérature à l’aide des moteurs de recherche PubMed, PubMed central et Medline, de même qu’avec nos connaissances cumulatives dans nos domaines d’expertise respectifs.Il s’agit d’une perspective interdisciplinaire sur les complications infectieuses en contexte d’IRT dues à des causes monogéniques, notamment une la polykystose rénale autosomique dominante (ADPKD), qui combine l’expertise en génomique et en immunologie.Les infections constituent une complication fréquente en contexte d’ADPKD et se manifestent principalement sous la forme d’une infection urinaire basse et moins souvent comme une infection rénale. Les épisodes infectieux pourraient être une conséquence directe d’une anomalie structurelle sous-jacente, notamment des kystes caractéristiques, entre autres. Toutefois, des données indiquent que le risque de maladie infectieuse en contexte d’IRT augmente aussi en raison de mécanismes secondaires mal connus; ceux-ci peuvent varier selon la nature sous-jacente de la pathologie primaire. Bien que le risque de maladie infectieuse soit bien documenté en contexte d’ADPKD, on dispose actuellement de données insuffisantes sur ce risque pour les autres causes monogéniques de l’IRT. Le WES, combiné aux nouvelles technologies telles que le séquençage d’ARN et le séquençage d’ARN unicellulaire, peut éclairer sur les mécanismes moléculaires régissant la progression de la maladie pour les différentes causes monogéniques de l’IRC/IRT et pourrait jouer un rôle dans l’élaboration de nouveaux profils de stratification des risques dans le futur.L’étude ne constitue pas une revue systématique de la littérature. De plus, la perspective proposée est teintée du point de vue des auteurs sur le sujet.Le WES, combiné aux nouvelles technologies telles que le séquençage d’ARN, pourrait nous permettre d’abord de mieux comprendre les mécanismes sous-jacents de la maladie et l’issue des pathologies secondaires des causes monogéniques de l’IRT, puis de mieux caractériser les profils de risque individuels. Ces informations, nous l’espérons, contribueront à faciliter le développement de nouveaux traitements ciblés.

The field of therapeutics in autosomal dominant polycystic kidney disease (ADPKD) has seen a significant expansion recently, as major clinical trials have provided promising evidence in favor of new disease-modifying drugs. Though these trials are encouraging, limitations are noticeable in the form of methodological issues that restrict the interpretation of results. In this review, we discuss the methodological pitfalls of high-profile clinical interventional trials for ADPKD which have been published since 2009. Issues in study design, patient selection and follow-up, analyses and reporting of results are presented. From this review, we highlight a number of suggestions for future improvement including designs to enrich a more homogeneous patient population (i.e. based on their age-adjusted total kidney volume and/or underlying mutation class) at high-risk for disease progression, appropriate study duration and patient sample size that are matched to the disease severity of the study patients, and the use of baseline characteristics (i.e. renal function, TKV, and the proportion of PKD1 and PKD2 patients) of the analyzed patients as a quality control measure to assess any potential imbalance in randomization. Furthermore, the recognition that TKV change is not a linear trait is important in both the study design and interpretation. Implementing these lessons learned from the published trials will greatly enhance the robustness and validity of future clinical trials in ADPKD.

Background Estimating the prevalence of autosomal dominant polycystic kidney disease (ADPKD) is challenging because of age-dependent penetrance and incomplete clinical ascertainment. Early studies estimated the lifetime risk of ADPKD to be about one per 1000 in the general population, whereas recent epidemiologic studies report a point prevalence of three to five cases per 10,000 in the general population. Methods To measure the frequency of high-confidence mutations presumed to be causative in ADPKD and autosomal dominant polycystic liver disease (ADPLD) and estimate lifetime ADPKD prevalence, we used two large, population sequencing databases, gnomAD (15,496 whole-genome sequences; 123,136 exome sequences) and BRAVO (62,784 whole-genome sequences). We used stringent criteria for defining rare variants in genes involved in ADPKD ( PKD1 , PKD2 ), ADPLD ( PRKCSH , SEC63 , GANAB , ALG8 , SEC61B , LRP5 ), and potential cystic disease modifiers; evaluated variants for quality and annotation; compared variants with data from an ADPKD mutation database; and used bioinformatic tools to predict pathogenicity. Results Identification of high-confidence pathogenic mutations in whole-genome sequencing provided a lower boundary for lifetime ADPKD prevalence of 9.3 cases per 10,000 sequenced. Estimates from whole-genome and exome data were similar. Truncating mutations in ADPLD genes and genes of potential relevance as cyst modifiers were found in 20.2 cases and 103.9 cases per 10,000 sequenced, respectively. Conclusions Population whole-genome sequencing suggests a higher than expected prevalence of ADPKD-associated mutations. Loss-of-function mutations in ADPLD genes are also more common than expected, suggesting the possibility of unrecognized cases and incomplete penetrance. Substantial rare variation exists in genes with potential for phenotype modification in ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is caused primarily by mutations of two genes, PKD1 and PKD2. In the presence of a positive family history of ADPKD, genetic testing is currently seldom indicated as the diagnosis is mostly based on imaging studies using well-established criteria. Moreover, PKD1 mutation screening is technically challenging due to its large size, complexity (i.e. presence of six pseudogenes with high levels of DNA sequence similarity) and extensive allelic heterogeneity. Despite these limitations, recent studies have delineated a strong genotype–phenotype correlation in ADPKD and begun to unravel the role of genetics underlying cases with atypical phenotypes. Furthermore, adaptation of next-generation sequencing (NGS) to clinical PKD genetic testing will provide a high-throughput, accurate and comprehensive screen of multiple cystic disease and modifier genes at a reduced cost. In this review, we discuss the evolving indications of genetic testing in ADPKD and how NGS-based screening promises to yield clinically important prognostic information for both typical as well as unusual genetic (e.g. allelic or genic interactions, somatic mosaicism, cystic kidney disease modifiers) cases to advance personalized medicine in the era of novel therapeutics for ADPKD.

A 48-year-old Caucasian male patient with newly diagnosed neuroendocrine tumor of the pancreas with multiple liver metastases developed severe and refractory hypercalcemia. Complementary investigations were compatible with humoral hypercalcemia with high parathyroid hormone-related peptide (PTHrP) levels. Hypercalcemia was refractory to medical treatments for more than 2 years. Serum calcium returned to normal values only after 4 cycles of peptide receptor radionuclide therapy with Lu-octreotate, with concomitant reduction of PTHrP level and tumor regression. The use of radionuclide therapy could be an option for the management of severe humoral hypercalcemia in patients with inoperable metastatic pancreatic neuroendocrine tumor.