Purpose of review 1) Provide a Canadian perspective on the 2025 Kidney Disease Improving Global Outcomes (KDIGO) Autosomal Dominant Polycystic Kidney Disease (ADPKD) guidelines; 2) identify challenges and nuances in applying these guidelines in Canada; 3) highlight shifts in expert practice points for Canadian care providers; 4) outline opportunities for research, knowledge translation, and quality improvement in Canada. Sources of information The KDIGO 2025 Clinical Practice Guideline Update for the management of ADPKD, as well as a survey and discussion by Canadian experts in ADPKD. Methods The co-chairs invited stakeholders from the Canadian ADPKD community to ensure national representation, including adult and pediatric clinicians, trainees, a genetic counselor, and a patient partner with an Indigenous perspective. Members were surveyed to identify key practice points. Subgroups reviewed issues and drafted discussion topics. All members reviewed the final draft. Key Findings The committee commented on recommendations with nuance for Canadian practitioners, especially on multidisciplinary care, challenges with genetic testing, and the use of CKD therapies like sodium-glucose transport protein 2 (SGLT2) inhibitors in ADPKD. Limitations The committee relied on the evidence summaries produced by KDIGO and the experience and knowledge of committee members. The committee did not replicate or update the systematic reviews.

Background: Tolvaptan is the only approved treatment in Canada for slowing the progression of kidney enlargement and kidney function decline in people with autosomal dominant polycystic kidney disease (ADPKD). The Canadian Medical Assessment of Jinarc® Outcome Registry (C-MAJOR) registry evaluating long-term clinical outcomes of tolvaptan use was initiated in 2015, as per Health Canada requirements. Objective: To describe the study design and methodology of the C-MAJOR registry, and present baseline patient and disease characteristics, time to and reasons for treatment and study discontinuation, time to kidney replacement therapy (KRT), and the long-term safety with tolvaptan. Design: C-MAJOR is an ongoing, observational, non-interventional, multicenter registry study. Setting: Multicenter study at 24 polycystic kidney disease (PKD) clinics and centers across Canada. Participants: People with ADPKD treated with tolvaptan. Measurements: The primary study objective was to assess the impact of tolvaptan on health-related quality of life (HRQoL) using patient-reported outcome measures. Secondary study outcomes included time to KRT; mortality rate, and time to and cause of death; markers of kidney function; treatment adherence; time to and reasons for treatment/study discontinuation; and incidence of adverse events. This analysis focused on summarizing baseline demographic, clinical, treatment, and safety data collected between 2015 and December 2023. Methods: Outcomes were summarized descriptively or using the Kaplan-Meier method for time-to-event data. Results: Among 470 people with ADPKD enrolled and analyzed in C-MAJOR, the mean age at diagnosis and at tolvaptan initiation was 29.8 years and 44.4 years, respectively. Patients had a mean baseline total kidney volume of 2010.8 mL. Most patients (67%) had mild to moderate kidney dysfunction (chronic kidney disease [CKD] category G1-3a) and were at high risk of disease progression (Mayo class 1C-E) at baseline, with hypertension (85%) and hepatic cysts (72%) being common manifestations. Mean baseline patient-reported outcome scores were indicative of minimally impacted HRQoL, with mean ADPKD-Impact Scale scores of 1.6, 2.0, and 2.0 for the physical, fatigue, and emotional scales, respectively, and ADPKD Pain and Discomfort Scale scores of 1.8, 2.0, 1.4, and 2.1 for the Overall Pain and Discomfort, Dull Pain, Sharp Pain, and Discomfort severity scales, among others. Treatment and study discontinuation occurred in 29 and 27% of patients, respectively, with a mean time to discontinuation of 70.5 and 62.1 months. Adverse events were the primary reason for treatment (46%) and study (15%) discontinuations. During follow-up, 8% of patients progressed to KRT with a mean time to KRT of 82.5 months. Adverse events were reported in 93% of patients; most common adverse events (~25% each) were polyuria, nocturia and fatigue. Limitations: Recruitment from specialized PKD centers may limit generalizability, and patient-reported outcome analyses were limited to the subgroup enrolled prospectively (~40%) who completed assessments (<25%). Conclusions: This first report of 8-year follow-up data from the C-MAJOR registry confirms that most people with ADPKD treated with tolvaptan in Canada are in early CKD category of disease and at risk of rapid progression, with minimally impacted HRQoL at baseline. Registration number: NCT02925221.

Renal water reabsorption is classically regulated by vasopressin V2 receptor (V2R) signaling through cyclic AMP and protein kinase A, driving apical accumulation of aquaporin-2 (AQP2). However, collecting duct water handling is also modulated by vasopressin-independent mechanisms. Here, we examined intracellular soluble urate as a vasopressin-independent regulator of AQP2 trafficking. Intracellular urate accumulation in collecting duct cells was mediated by enhanced apical urate uptake via GLUT9b and reduced apical urate efflux through ABCG2, triggering phosphodiesterase-4 activation, reduced cAMP, and downstream AMP-activated protein kinase (AMPK) activation. The resulting AQP2 accumulation at the apical membrane was independent of V2R signaling, required ongoing endocytosis, and was associated with features of postendocytic apical trafficking of internalized AQP2. In vivo ABCG2 inhibition with probenecid increased apical AQP2 abundance and markedly attenuated tolvaptan-induced polyuria in both wild-type and Pkd1RC/RC autosomal dominant polycystic kidney disease (ADPKD) mice in a uricase-independent manner while preserving tolvaptan’s ADPKD-modifying efficacy. In a phase II trial with tolvaptan-treated patients with ADPKD, probenecid reduced urine volume and nocturia frequency. Together, these findings support a vasopressin-independent urate/AMPK/AQP2 pathway that regulates renal water handling and, in a preclinical ADPKD model, can uncouple cyst growth attenuation from the dose-limiting aquaretic effects of V2R antagonism.

Introduction:Autosomal dominant polycystic kidney disease (ADPKD) may impose physical and emotional burdens, partly through enlarged kidneys. The association of health-related quality-of-life (HRQOL) with total kidney volume (TKV) remains unclear, particularly in combination with kidney function and pain status. Methods:Participants diagnosed with ADPKD were recruited between 2017 and 2023. We examined the associations of TKV, estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration race-free creatinine equation (eGFR), and chronic kidney pain (Yes/No) with HRQOL (Short Form-36 [SF-36] scores) using multivariable linear regression. Factor analysis of mixed data (FAMD) was used to classify patients into clusters based on TKV, eGFR, and kidney pain; and their HRQOL was compared. Results:Of 456 participants, mean (SD) age was 47 (16) years, 216 (47%) were males, eGFR was 81 (27) ml/min per 1.73 m2, and median (interquartile range) TKV was 922 (532-1547) ml. Mean (95% confidence interval [CI]) SF-36) physical component summary (PCS) scores were 53 (52-55), 51 (50-53), and 51 (50-53) across increasing TKV tertiles (P = 0.02), respectively, even after adjusting for kidney pain and function. Mental component summary (MCS) scores were similar across tertiles. Lower eGFR and kidney pain were associated with worse HRQOL. We identified 4 clusters as follows: (i) low or moderate ADPKD severity, no pain; (ii) low or moderate ADPKD severity, kidney pain; (iii) high ADPKD severity, no pain; (iv) high ADPKD severity, kidney pain. Ranked from best to most impaired: PCS, 1 > 2 = 3 > 4; MCS, 1 = 3 > 2 = 4. Mediation analysis showed an indirect association between TKV and MCS through kidney pain. Conclusion:TKV is associated with physical health, independent of kidney pain and function, and with mental health (MH) indirectly through kidney pain. Alleviating kidney pain, preserving function, and limiting kidney enlargement in ADPKD may all help to improve HRQOL.

Fabry disease is a rare X-linked inborn error of metabolism that has a high prevalence of chronic kidney disease (CKD) and renal failure. It is due to the deficiency of the α-galactosidase A (α-Gal) lysosomal enzyme with subsequent accumulation of globotriaosylceramide (Gb3) in lysosomes. In the kidney, the podocyte is the main target of this disease, although all cell types are involved. The podocyte, being terminally differentiated, does not replicate and thus accumulates Gb3 throughout life. Podocytes are injured by Gb3, leading to their detachment from the glomerular basement membrane and subsequent loss in the urine. Albuminuria starts in childhood and progresses to overt proteinuria in the teens and 20 s. CKD ensues with adults starting dialysis at an average age of 42 years. Patients have a high prevalence of stroke and cardiomyopathy with hypertrophic change, heart failure, and dysrhythmias. Patient survival is limited in both genders. Diagnosis is based on the demonstration of a low α-Gal activity and a pathogenic GLA mutation. Clinical features are highly variable, which makes recognition of this condition difficult. Treatment with intravenous recombinant human enzyme replacement therapy (ERT) and oral pharmacologic chaperone are available. Control of proteinuria to 0.5 g/day or less is of critical importance to limit progression to end-stage renal disease. Early initiation of treatment gives the best results, but the optimal age to start is uncertain. Fabry nephropathy remains a challenge due to its multisystem nature, difficult diagnosis, and complicated management. It is important as a treatable cause of CKD.

Genetic variations in the genes encoding G protein-coupled receptors (GPCRs) can disrupt receptor structure and function, which can result in human genetic diseases. Disease-causing mutations have been reported in at least 55 GPCRs for more than 66 monogenic diseases in humans. The spectrum of pathogenic and likely pathogenic variants includes loss of function variants that decrease receptor signaling on one extreme and gain of function that may result in biased signaling or constitutive activity, originally modeled on prototypical rhodopsin GPCR variants identified in retinitis pigmentosa, on the other. GPCR variants disrupt ligand binding, G protein coupling, accessory protein function, receptor desensitization and receptor recycling. Next generation sequencing has made it possible to identify variants of uncertain significance (VUS). We discuss variants in receptors known to result in disease and in silico strategies for disambiguation of VUS such as sorting intolerant from tolerant and polymorphism phenotyping. Modeling of variants has contributed to drug development and precision medicine, including drugs that target the melanocortin receptor in obesity and interventions that reverse loss of gonadotropin-releasing hormone receptor from the cell surface in idiopathic hypogonadotropic hypogonadism. Activating and inactivating variants of the calcium sensing receptor (CaSR) gene that are pathogenic in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia have enabled the development of calcimimetics and calcilytics. Next generation sequencing has continued to identify variants in GPCR genes, including orphan receptors, that contribute to human phenotypes and may have therapeutic potential. Variants of the CaSR gene, some encoding an arginine-rich region that promotes receptor phosphorylation and intracellular retention, have been linked to an idiopathic epilepsy syndrome. Agnostic strategies have identified variants of the pyroglutamylated RF amide peptide receptor gene in intellectual disability and G protein-coupled receptor 39 identified in psoriatic arthropathy. Coding variants of the G protein-coupled receptor L1 (GPR37L1) orphan receptor gene have been identified in a rare familial progressive myoclonus epilepsy. The study of the role of GPCR variants in monogenic, Mendelian phenotypes has provided the basis of modeling the significance of more common variants of pharmacogenetic significance.

Congenital nephrogenic diabetes insipidus (NDI; also known as arginine vasopressin resistance) is a rare inherited disorder of water homeostasis, caused by insensitivity of the distal nephron to arginine vasopressin. Consequently, the kidney loses its ability to concentrate urine, which leads to polyuria, polydipsia and the risk of hypertonic dehydration. The diagnosis and management of NDI are very challenging and require an integrated, multidisciplinary approach. Here, we present 36 recommendations for diagnosis, treatment and follow-up in both children and adults, as well as emergency management, genetic counselling and family planning, for patients with NDI. These recommendations were formulated and graded by an international group of experts in NDI from paediatric and adult nephrology, urology and clinical genetics from the European Rare Kidney Disease Reference Network and the European Society of Paediatric Nephrology, as well as patient advocates, and were validated by a voting panel in a Delphi process. The goal of these recommendations is to provide guidance to health care professionals who care for patients with NDI and to patients and their families. In addition, we emphasize the need for further research on different aspects of this potentially life-threatening disorder to support the development of evidence-based guidelines in the future. Congenital nephrogenic diabetes insipidus is a rare but potentially life-threatening condition. This Consensus Statement provides clinical practice recommendations developed by the European Reference Network on Rare Kidney Diseases, the European Society for Paediatric Nephrology and patient advocates to support clinicians in the diagnosis, treatment and genetic counselling of children and adults with nephrogenic diabetes insipidus.

The synthesis of three fluorogenic chitobiosyl derivatives, modified at the non-reducing 4′-OH with, either a methyl, an isopropyl or a cyclohexylmethyl substituent, is described. The 4′-capped 4-methylumbelliferyl chitobiosides are hydrolysed by the human chitinase CHIT1 following Michaelis–Menten kinetics and in contrast to unmodified chitobiosyl-4-methylumbelliferone do not undergo transglycosylation. The compounds are also relatively poor hexosaminidase substrates and thus provide useful alternatives to 4′-deoxychitobiosyl-4-methylumbelliferone, previously reported by us as fluorogenic substrate to monitor CHIT1 activity as a marker for Gaucher disease state.

Fabry disease is a progressive, X‐linked lysosomal disorder caused by reduced or absent α‐galactosidase A activity due to GLA variants. The effects of migalastat were examined in a cohort of 125 Fabry patients with migalastat‐amenable GLA variants in the followME Pathfinders registry (EUPAS20599), an ongoing, prospective, patient‐focused registry evaluating outcomes for current Fabry disease treatments. We report annualised estimated glomerular filtration rate (eGFR) and Fabry‐associated clinical events (FACEs) in a cohort of patients who had received ≥3 years of migalastat treatment in a real‐world setting. As of August 2022, 125 patients (60% male) had a mean migalastat exposure of 3.9 years. At enrolment, median age was 58 years (males, 57; females, 60) with a mean eGFR of 83.7 mL/min/1.73 m2 (n = 122; males, 83.7; females, 83.8) and a median left ventricular mass index of 115.1 g/m2 (n = 61; males, 131.2; females, 98.0). Mean (95% confidence interval) eGFR annualised rate of change in the overall cohort (n = 116) was −0.9 (−10.8, 9.9) mL/min/1.73 m2/year with a similar rate of change observed across patients with varying levels of kidney function at enrolment. Despite population age and baseline morbidity, 80% of patients did not experience a FACE during the mean 3.9 years of migalastat exposure. The incidence of renal, cardiac, and cerebrovascular events was 2.0, 83.2, and 4.1 events per 1000 patient‐years, respectively. These data support a role of migalastat in preserving renal function and multisystem effectiveness during ≥3 years of migalastat treatment in this real‐world Fabry population.

"Buridan's ass" refers to a philosophical conundrum about free will. If a person is equally hungry and thirsty, which urge is satisfied first? A study of mouse models provides some answers and insights into clinical observations.

Background: A biomarker profile was evaluated longitudinally in patients with Fabry disease switched from enzyme-replacement therapy (ERT) to migalastat. Methods: 16 Gb3 isoforms and eight lyso-Gb3 analogues were analyzed in plasma and urine by LC-MS/MS at baseline and at three different time points in naive participants and participants switching from either agalsidase α or β to migalastat. Results: 29 adult participants were recruited internationally (seven centers). The Mainz Severity Score Index and mean biomarker levels remained stable (p ≥ 0.05) over a minimum of 12 months compared with baseline following the treatment switch. Conclusion: In this cohort of patients with Fabry disease with amenable mutations, in the short term, a switch from ERT to migalastat did not have a marked effect on the average biomarker profile.