Commentary: Tolvaptan for Autosomal Dominant Polycystic Kidney Disease (ADPKD) - an update

Autosomal Dominant Polycystic Kidney Disease (ADPKD) affects up to 70 000 people in the UK and the most common inherited cause of end-stage kidney disease (ESKD). It is generally a late-onset multisystem disorder characterised by bilateral kidney cysts, liver cysts and an increased risk of intracranial aneurysms. Approximately 50% of people with ADPKD reach ESKD by age 60. Disease-associated pain, discomfort, fatigue, emotional distress and, impaired mobility can impact health-related quality of life. The approval of tolvaptan, a vasopressin V2 receptor antagonist, has greatly advanced the care for people with ADPKD, shifting the focus from general chronic kidney disease management to targeted therapeutic approaches. While guidance from NICE and SMC provides a foundational framework, this is not clear or comprehensive enough to offer practical guidance for healthcare professionals in real-world settings. This commentary expands on the previous United Kingdom Kidney Association (UKKA) commentary in 2016 with an updated evidence base, the incorporation of real-world data and expert opinion to provide practical guidance to healthcare professionals. Through co-development with people affected by ADPKD, it now incorporates valuable patient perspectives and offers practical recommendations for the UK kidney community seeking to harmonise the quality of care of all people with ADPKD

Constraining the Nature of Dark Energy using the SKA

We investigate the potential of the Square Kilometer Array Telescope (SKA) to constrain the sound speed of dark energy. The Integrated Sachs Wolfe (ISW) effect results in a significant power spectrum signal when CMB temperature anisotropies are cross-correlated with galaxies detectable with the SKA in HI. We consider using this measurement, the autocorrelation of HI galaxies and the CMB temperature power spectrum to derive constraints on the sound speed. We study the contributions to the cross-correlation signal made by galaxies at different redshifts and use redshift tomography to improve the signal-to-noise. We use a chi-square analysis to estimate the significance of detecting a sound speed different from that expected in quintessence models, finding that there is potential to distinguish very low sound speeds from the quintessence value.Comment: 8 pages, 8 figures; updated references for publication MNRA

Rare disease gene association discovery in the 100,000 Genomes Project

\ua9 The Author(s) 2025. Up to 80% of rare disease patients remain undiagnosed after genomic sequencing1, with many probably involving pathogenic variants in yet to be discovered disease–gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project2. A total of 141 new associations were identified, including five for which independent disease–gene evidence was recently published. Following in silico triaging and clinical expert review, 69 associations were prioritized, of which 30 could be linked to existing experimental evidence. The five associations with strongest overall genetic and experimental evidence were monogenic diabetes with the known β cell regulator3,4UNC13A, schizophrenia with GPR17, epilepsy with RBFOX3, Charcot–Marie–Tooth disease with ARPC3 and anterior segment ocular abnormalities with POMK. Further confirmation of these and other associations could lead to numerous diagnoses, highlighting the clinical impact of large-scale statistical approaches to rare disease–gene association discovery

Rare disease gene association discovery in the 100,000 Genomes Project

Up to 80% of rare disease patients remain undiagnosed after genomic sequencing1, with many probably involving pathogenic variants in yet to be discovered disease–gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project2. A total of 141 new associations were identified, including five for which independent disease–gene evidence was recently published. Following in silico triaging and clinical expert review, 69 associations were prioritized, of which 30 could be linked to existing experimental evidence. The five associations with strongest overall genetic and experimental evidence were monogenic diabetes with the known β cell regulator3,4 UNC13A, schizophrenia with GPR17, epilepsy with RBFOX3, Charcot–Marie–Tooth disease with ARPC3 and anterior segment ocular abnormalities with POMK. Further confirmation of these and other associations could lead to numerous diagnoses, highlighting the clinical impact of large-scale statistical approaches to rare disease–gene association discovery

An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct

Quantifying association of early proteinuria and estimated glomerular filtration rate changes with long-term kidney failure in C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis using the United Kingdom RaDaR Registry

\ua9 2025 International Society of Nephrology. Introduction: C3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN) are rare disorders that frequently result in kidney failure over the long-term. Presently, there are no disease-specific treatments approved for these disorders, although there is much interest in the therapeutic potential of complement inhibition. However, the limited duration and necessarily small size of controlled trials means there is a need to quantify how well short-term changes in estimated glomerular filtration rate (eGFR) and proteinuria predict the clinically important outcome of kidney failure. Methods: We address this using longitudinal data from the UK Registry of Rare Kidney Diseases (RaDaR) involving retrospective and prospective data collection with linkage to hospital laboratories via automated feeds of 371 patients. Analyses of kidney survival were conducted using Kaplan–Meier and Cox regression with eGFR slope estimated using linear mixed models. Results: In a median of 11.0 (inter quartile range 7.4-15.1) years follow-up, 148 patients (40%) reached kidney failure. There was no significant difference in progression to kidney failure between C3G and IC-MPGN groups. Baseline urine protein-creatinine ratio (UPCR), although high, was not associated with kidney failure in either group. Two-year eGFR slope had a modest association with kidney failure. In contrast, both 20%‒50% and 50 mg/mmol reductions in UPCR between 0-12 months were associated with lower kidney failure risk in both groups. Notably, those with a UPCR under 100 mg/mmol at 12 months had a substantially lower risk of kidney failure (hazard ratio 0.10 (95% confidence interval 0.03-0.30). Conclusions: Overall, proteinuria a short time after diagnosis is strongly associated with long-term outcomes and a UPCR under 100 mg/mmol at one year is associated with a substantially lower kidney failure risk

How simple are \u27simple renal cysts\u27?

The increasing use of medical imaging as an investigative tool is leading to the incidental and frequent finding of renal cysts in the general population. The presence of a solitary or multiple renal cysts has been generally considered benign in the absence of a family history of renal cystic disease or evidence of chronic kidney disease. Nonetheless, a number of recent studies have questioned this consensus by reported associations with the development of hypertension or malignant change. For these reasons, some clinicians consider the presence of renal cysts to be a contraindication to kidney donation. The situation is complicated by the different usage of the term \u27simple\u27 by some radiologists (to indicate non-complex lesions) or nephrologists (to indicate age-related non-hereditary lesions). We propose that the term \u27simple\u27 be replaced with the morphological description, Stage I renal cyst (Bosniak Classification). The presence of a Stage I renal cyst should not preclude kidney donation. However, occult renal disease should be excluded and appropriate donor assessment performed

Verifying Higher-Order Functional Programs with Pattern-Matching Algebraic Data Types

Type-based model checking algorithms for higher-order recursion schemes have recently emerged as a promising approach to the verification of functional programs.We introduce pattern-matching recursion schemes (PMRS) as an accurate model of computation for functional programs that manipulate algebraic data-types. PMRS are a natural extension of higher-order recursion schemes that incorporate pattern-matching in the defining rules. This paper is concerned with the following (undecidable) verification problem: given a correctness property φ, a functional program P (qua PMRS) and a regular input set I, does every term that is reachable from I under rewriting by P satisfy φ? To solve the PMRS verification problem, we present a sound semi-algorithm which is based on model-checking and counterexample guided abstraction finement. Given a no-instance of the verification problem, the method is guaranteed to terminate. From an order-n PMRS and an input set generated by a regular tree grammar, our method constructs an order-n weak PMRS which over-approximates only the first-order pattern-matching behaviour, whilst remaining completely faithful to the higher-order control flow. Using a variation of Kobayashi's type-based approach, we show that the (trivial automaton) model-checking problem for weak PMRS is decidable. When a violation of the property is detected in the abstraction which does not correspond to a violation in the model, the abstraction is automatically refined by 'unfolding' the pattern-matching rules in the program to give successively more and more accurate weak PMRS models. Copyright © 2011 ACM