55 research outputs found
Natural history of small asymptomatic kidney and residual stones over a long-term follow-up: systematic review over 25 years
No full textObjective: to systematically review the natural history of small asymptomatic kidney and residual stones, as the incidental identification of small, asymptomatic renal calculi has risen with increasing use of high-resolution imaging. Materials and methods: we reviewed the natural history of small asymptomatic kidney and residual stones using the Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. We searched MEDLINE, Scopus, EMBASE, EBSCO, Cochrane library and Clinicaltrials.gov using themes of ‘asymptomatic’, ‘nephrolithiasis’, ‘observation’, ‘symptoms’, ‘admission’, ‘intervention’ and similar allied terms for all English language articles from 1996 to 2020 (25 years). Inclusion criteria were studies with ≥50 patients, stones ≤10 mm, and a mean follow-up of ≥24 months. Primary outcomes were occurrence of symptoms, emergency admission, and interventions. Results: our literature search returned 2247 results of which 10 papers were included in the final review. Risk of symptomatic episodes ranged from 0% to 59.4%. Meta-analysis did not identify any significant difference in the likelihood of developing symptoms when comparing stones <5 mm to those >5 mm, nor those <10 mm to those >10 mm. Risk of admission varied from 14% to 19% and the risk of intervention from 12% to 35%. Meta-analysis showed a significantly decreased likelihood of intervention for stones <5 vs >5 mm and <10 vs >10 mm. Studies had variable risk of bias due to heterogeneous reporting of outcome measures with significant likelihood that observed differences in results were compatible with chance alone (Symptoms: I2=0%, Cochran’s Q = 3.09, P = 0.69; Intervention: I2=0%, Cochran’s Q = 1.76, P = 0.88). Conclusions: the present systematic review indicates that stone size is not a reliable predictor of symptoms; however, risk of intervention is greater for stones >5mm vs <5 mm and >10 vs <10 mm. This review will inform urologists as they discuss management strategies with patients who have asymptomatic renal stones and offer insight to committees during the development of evidence-based guidelines.</p
Exome sequencing identifies a disease variant of the mitochondrial ATP-Mg/Pi carrier SLC25A25 in two families with kidney stones
No full textBackground:Calcium kidney stones are common and recurrences are often not preventable by available empiric remedies. Their etiology is multifactorial and polygenic, and an increasing number of genes are implicated. Their identification will enable improved management.Methods: DNA from three stone-formers in a Southampton family (UK) and two from an Italian family were analyzed independently by whole exome sequencing and selected variants were genotyped across all available members of both pedigrees. A disease variant of SLC25A25 (OMIM 608745), encoding the mitochondrial ATP-Mg/Pi carrier 3 (APC3) was identified, and analyzed structurally and functionally with respect to its calcium-regulated transport activity.Results:All five patients had a heterozygous dominant SLC25A25 variant (rs140777921; GRCh37.p13: chr 9 130868670 G>C; p.Gln349His; Reference Sequence NM_001006641.3). Non-stone formers also carried the variant indicating incomplete penetrance. Modeling suggests that the variant lacks a conserved polar interaction, which may cause structural instability. Calcium-regulated ATP transport was reduced to ~20% of the wild type, showing a large reduction in function.Conclusion:The transporter is important in regulating mitochondrial ATP production. This rare variant may increase urine lithogenicity through impaired provision of ATP for solute transport processes in the kidney, and/or for purinergic signaling. Variants found in other genes may compound this abnormality
The genetic and metabolic basis of kidney stone disease
No full textKidney stone disease (KSD) is a common, heritable, frequently recurrent condition affecting approximately 10–20% of people. Patients may be asymptomatic or experience severe pain, haematuria, urinary tract infections, and, in extreme cases, multi-organ failure. KSD and its treatments reduce health-related quality of life and its rising prevalence will cost the National Health Service over £300 million annually in England by 2030. Despite their relevance, the mechanisms underlying stone formation remain poorly understood, limiting effective preventive strategies. In this thesis, I investigate the genetic architecture of KSD to uncover molecular mechanisms and therapeutic targets for the disease.
I conduct the largest genetic association studies of KSD to date, integrating combined-sex, and sex-specific analyses, European- and trans-ancestry data, and common and rare genetic variants. These studies identify novel genetic associations with KSD and highlight genes linked to mineral metabolism and renal structural disorders.
Using Mendelian randomisation (MR) and colocalisation analyses, I reveal a shared genetic architecture between adiposity and KSD, implicating a causal GIPR missense variant which I propose alters renal tubular osteopontin secretion, affecting risk of stone formation. Drug-target MR analyses suggest that modulating gastric inhibitory polypeptide receptor pathways may reduce KSD risk.
To investigate the mechanisms linking mineral metabolism and renal cysts to KSD, I integrate multiomic and chromatin interaction data with MR and colocalisation analyses. I identify three biological pathways contributing to approximately 12–17% of KSD cases: impaired DGKδ-mediated calcium-sensing receptor signalling; increased NaPi-IIa-mediated renal phosphate excretion; and defective 24-α-hydroxylase-mediated 1,25-dihydroxyvitamin D inactivation. I further establish a causal, bidirectional relationship between non-polycystic renal cysts and KSD, implicating TBX2-mediated effects.
These findings support a “lithogenic triad” of urine supersaturation, stasis, and tubular epithelial injury in KSD pathogenesis. By integrating multiple analytical approaches with distinct and orthogonal sources of bias , I provide insights into causal mechanisms and therapeutic targets for KSD, laying the foundation for future translational research
The role of the G-protein subunit, G-alpha-11, and the adaptor protein 2 sigma subunit, ap2-sigma-2, in the regulation of calcium homeostasis
No full textThe calcium sensing receptor (CaSR) is a G-protein coupled receptor (GPCR) that plays a central role in calcium homeostasis. Loss-of-function mutations of the CaSR cause familial hypocalciuric hypercalcaemia type 1 (FHH1), whilst gain-of-function mutations are associated with autosomal dominant hypocalcaemia (ADH). However, 35% of cases of FHH and 60% of cases of ADH are not due to CaSR mutations. This thesis demonstrates that FHH type 2 (FHH2) and the new clinical disorder, ADH type 2 (ADH2), are due to loss- and gain-of-function mutations in the G-protein subunit, Gα11, respectively. The CaSR signals through Gα11 and FHH2-associated mutations are shown to exert their effects through haploinsufficiency. Three-dimensional modelling of ADH2-associated Gα11 mutations predicts impaired GTPase activity and increases in the rate of GDP/GTP exchange. Furthermore, mouse models of FHH2 and ADH2 have been identified and re-derived to enable in vivo studies of the role of Gα11 in calcium homeostasis. I also demonstrate that FHH3 is due to loss-of-function mutations in the adaptor protein 2 sigma subunit, AP2σ2, which exert dominant-negative effects. AP2σ2 is a component of the adaptor protein 2 (AP2), which is a crucial component of clathrin-coated vesicles (CCV) and facilitates clathrin-mediated endocytosis of plasma membrane components such as GPCRs. All of the identified FHH3-associated mutations affect the Arg15 residue of AP2σ2, which forms key polar contacts with CCV cargo proteins. This thesis proposes that FHH3-associated AP2σ2 mutations impair CaSR internalisation and thus negatively impact on CaSR signalling. In addition, these studies show that these signalling defects can be rectified by the use of the CaSR allosteric modulator cinacalcet, which may represent a useful therapeutic modality for FHH3 patients. In summary, FHH2 is due to loss-of-function mutations in Gα11 causing haploinsufficiency, whilst FHH3 is due to loss-of-function mutations in AP2σ2, which exert dominant-negative effects. In contrast, ADH2 is due to gain-of-function mutations in Gα11
Monitoring Calcium-Sensing Receptor (CaSR)-Induced Intracellular Calcium Flux Using an Indo-1 Flow Cytometry Assay
No full textThe calcium-sensing receptor (CaSR) has a critical role in maintaining serum calcium concentrations within the normal physiological range, and mutations in the receptor, or components of its signaling and trafficking pathway, cause disorders of calcium homeostasis. Inactivating mutations cause neonatal severe hyperparathyroidism or familial hypocalciuric hypercalcemia (FHH), while gain-of-function mutations cause autosomal dominant hypocalcemia (ADH). Characterizing the functional impact of mutations of the CaSR, and components of the CaSR-signaling pathway, is clinically important to enable correct diagnoses of FHH and ADH, optimize management, and prevent inappropriate parathyroidectomy or vitamin D supplementation. CaSR signals predominantly by activating the G-alpha subunit-11 to mobilize calcium release from intracellular stores. Thus, measurement of CaSR-induced intracellular calcium (Ca2+i) signaling is the gold standard method to investigate the pathogenicity of CaSR genetic variants. This protocol describes a method to assess CaSR-induced Ca2+I signaling using the Indo-1 calcium indicator dye and flow cytometry. This method has been used to assess multiple genetic variants in CaSR and components of its signaling and trafficking pathway in HEK293 cells.</p
Genetics of kidney stone disease
No full textKidney stone disease (nephrolithiasis) is a common problem that can be associated with alterations in urinary solute composition including hypercalciuria. Studies suggest that the prevalence of monogenic kidney stone disorders, including renal tubular acidosis with deafness, Bartter syndrome, primary hyperoxaluria and cystinuria, in patients attending kidney stone clinics is ∼15%. However, for the majority of individuals, nephrolithiasis has a multifactorial aetiology involving genetic and environmental factors. Nonetheless, the genetic influence on stone formation in these idiopathic stone formers remains considerable and twin studies estimate a heritability of >45% for nephrolithiasis and >50% for hypercalciuria. The contribution of polygenic influences from multiple loci have been investigated by genome-wide association and candidate gene studies, which indicate that a number of genes and molecular pathways contribute to the risk of stone formation. Genetic approaches, studying both monogenic and polygenic factors in nephrolithiasis, have revealed that the following have important roles in the aetiology of kidney stones: transporters and channels; ions, protons and amino acids; the calcium-sensing receptor (a G protein-coupled receptor) signalling pathway; and the metabolic pathways for vitamin D, oxalate, cysteine, purines and uric acid. These advances, which have increased our understanding of the pathogenesis of nephrolithiasis, will hopefully facilitate the future development of targeted therapies for precision medicine approaches in patients with nephrolithiasis
Suprapubic catheterisation: a study of 1000 elective procedures
No full textObjectives
To investigate the risks and long-term outcomes of suprapubic catheter (SPC) insertion in a population predominantly with spinal cord injury.
Materials and Methods
We used the theatre database at the National Spinal Injuries Centre in Stoke Mandeville Hospital to identify 1000 consecutive SPC insertions from 1998 to 2015. We retrospectively analysed all records for these patients.
Results
Follow-up ranged from 4 weeks to 16.45 years (median 3.3 years). Either cystoscopy-guided suprapubic puncture (Lawrence Add-a-Cath trochar) or a direct incision onto a urethral sound (Lowsley retractor) followed by cystoscopy was used for 98% of insertions. Complications graded as Clavien–Dindo IIIb or higher occurred in 0.6% of patients. Return to theatre was necessary in 0.4%, including three laparotomies due to bleeding or misplacement of the catheter, but no bowel injuries occurred. One death occurred within 30 days due to pulmonary embolism. There were no significant differences in outcomes between insertion methods. Tolerance of long-term suprapubic catheterisation was high, despite 59% of cases experiencing mostly minor complications. Tract losses during routine community change and variability in antibiotic prescribing highlighted areas for educational development which could improve patient outcomes.
Conclusions
This study supports the view that the risk of major complications from SPC insertion is lower than previously reported. Minor complications related to the catheter are common in the long term but are generally well tolerated
Role of Genetic Testing in Kidney Stone Disease: A Narrative Review
No full textPurpose of Review: Kidney stone disease (KSD) is a common and potentially life-threatening condition, and half of patients experience a repeat kidney stone episode within 5–10 years. Despite the ~50% estimate heritability of KSD, international guidelines have not kept up with the pace of discovery of genetic causes of KSD. The European Association of Urology guidelines lists 7 genetic causes of KSD as ‘high risk’. Recent Findings: There are currently 46 known monogenic (single gene) causes of kidney stone disease, with evidence of association in a further 23 genes. There is also evidence for polygenic risk of developing KSD. Evidence is lacking for recurrent disease, and only one genome wide association study has investigated this phenomenon, identifying two associated genes (SLC34A1 and TRPV5). However, in the absence of other evidence, patients with genetic predisposition to KSD should be treated as ‘high risk’. Further studies are needed to characterize both monogenic and polygenic associations with recurrent disease, to allow for appropriate risk stratification. Durability of test result must be balanced against cost. This would enable retrospective analysis if no genetic cause was found initially. Summary: We recommend genetic testing using a gene panel for all children, adults < 25 years, and older patients who have factors associated with high risk disease within the context of a wider metabolic evaluation. Those with a genetic predisposition should be managed via a multi-disciplinary team approach including urologists, radiologists, nephrologists, clinical geneticists and chemical pathologists. This will enable appropriate follow-up, counselling and potentially prophylaxis
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