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Nephrology, Dialysis, Transplantation :... Mar 2024Molecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies showed high a heritability of nephrolithiasis, but data on prevalence...
BACKGROUND
Molecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies showed high a heritability of nephrolithiasis, but data on prevalence and characteristics of genetic disease in unselected adults with nephrolithiasis are lacking. This study was conducted to fill this important knowledge gap.
METHODS
We performed whole exome sequencing in 787 participants of the Bern Kidney Stone Registry, an unselected cohort of adults with ≥ 1 past kidney stone episode (KSF), and 114 non-stone-forming individuals (NKSF). An exome-based panel of 34 established nephrolithiasis genes was analyzed and variants assessed according to ACMG criteria. Pathogenic (P) or likely pathogenic (LP) variants were considered diagnostic.
RESULTS
Mean age of KSF was 47±15 years, and 18% were first time KSF. A Mendelian kidney stone disease was present in 2.9% (23 of 787) of KSF. The most common genetic diagnoses were cystinuria (SLC3A1, SLC7A9; n=13), Vitamin D-24 hydroxylase deficiency (CYP24A1; n=5) and primary hyperoxaluria (AGXT, GRHPR, HOGA1; n=3). 8.1% (64 of 787) of KSF were monoallelic for LP/P variants predisposing to nephrolithiasis, most frequently in SLC34A1/A3 or SLC9A3R1 (n=37), CLDN16 (n=8) and CYP24A1 (n=8). KSF with Mendelian disease had a lower age at the first stone event (30±14 years vs. 36±14 years, p=0.003), were more likely to have cystine stones (23.4% vs. 1.4%) and less likely to have calcium oxalate monohydrates stones (31.9% vs. 52.5%) compared to KSF without genetic diagnosis. The phenotype of KSF with variants predisposing to nephrolithiasis was subtle and showed significant overlap with KSF without diagnostic variants. In NKSF, no Mendelian disease was detected, and LP/P variants were significantly less prevalent compared to KSF (1.8% vs. 8.1%).
CONCLUSION
Mendelian disease is uncommon in unselected adult KSF, yet variants predisposing to nephrolithiasis are significantly enriched in adult KSF.
PubMed: 38544324
DOI: 10.1093/ndt/gfae074 -
Journal of Pediatric Urology Feb 2024Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of metabolism that causes oxalate deposition, leading to recurrent calcium oxalate kidney...
BACKGROUND
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of metabolism that causes oxalate deposition, leading to recurrent calcium oxalate kidney stones, chronic kidney disease and systemic oxalosis, which produces a broad range of serious life-threatening complications. Patients with PH1 have delayed diagnosis due to the rarity of the disease and the overlap with early-onset kidney stone disease not due to primary hyperoxaluria.
OBJECTIVE
The objective of this study was to determine the clinical features of individuals <21 years of age with PH1 that precede its diagnosis. We hypothesized that a parsimonious set of features could be identified that differentiate patients with PH1 from patients with non-primary hyperoxaluria-associated causes of early-onset kidney stone disease.
STUDY DESIGN
We determined the association between clinical characteristics and PH1 diagnosis in a case-control study conducted between 2009 and 2021 in PEDSnet, a clinical research network of eight US pediatric health systems. Each patient with genetically confirmed PH1 was matched by sex and PEDSnet institution to up to 4 control patients with kidney stones without PH of any type. We obtained patient characteristics and diagnostic test results occurring before to less than 6 months after study entrance from a centralized database query and from manual chart review. Differences were examined using standardized differences and multivariable regression.
RESULTS
The study sample included 37 patients with PH1 and 147 controls. Patients with PH1 were younger at diagnosis (median age of 3 vs 13.5 years); 75 % of children with PH1 were less than 8 years-old. Patients with PH1 were more likely to have combinations of nephrocalcinosis on ultrasound or CT (43 % vs 3 %), lower eGFR at diagnosis (median = 52 mL/min/1.73 m vs 114 mL/min/1.73 m), and have normal mobility. Patients with PH1 had higher proportion of calcium oxalate monohydrate kidney stones than controls (median = 100 % vs 10 %). There were no differences in diagnosis of failure to thrive, stone size, or echocardiography results.
CONCLUSIONS
Children with PH1 are characterized by presentation before adolescence, nephrocalcinosis, decreased eGFR at diagnosis, and calcium oxalate monohydrate stone composition. If externally validated, these characteristics could facilitate earlier diagnosis and treatment of children with PH1.
Topics: Adolescent; Humans; Child; Nephrocalcinosis; Calcium Oxalate; Case-Control Studies; Kidney Failure, Chronic; Kidney Calculi; Hyperoxaluria, Primary; Nephrolithiasis
PubMed: 37848358
DOI: 10.1016/j.jpurol.2023.10.001 -
Frontiers in Pediatrics 2023Incidence and prevalence of urolithiasis is apparently increasing worldwide, also among children and adolescents. Nevertheless, robust data have only been obtained in a...
Incidence and prevalence of urolithiasis is apparently increasing worldwide, also among children and adolescents. Nevertheless, robust data have only been obtained in a few countries. In Spain, a voluntary Registry for Pediatric Renal Lithiasis has been active since 2015. Irregular participation limits its applicability, as well as its limitation to patients with a stone available for morphocompositional study, to obtain data about incidence and prevalence. On the other hand, findings about typology of stones and clinical and analytical characteristics of these subjects have been communicated in several meetings. Other valuable efforts in this field are the elaboration of guidelines for the collection and processing of urine samples for the study of urolithiasis in pediatric patients with the consensus of the Spanish Society for Pediatric Nephrology (AENP) as well as the Spanish Society for Laboratory Medicine (SEQC), the collaborative network RenalTube for the diagnosis of primary tubulopathies and the registry of patients with Primary Hyperoxaluria (OxalSpain). In many hospitals from the public healthcare system, pediatric nephrologists are the specialists in charge of the management of children with kidney stones, but there is no formal regulation on this competence. Other specialists, such as urologists, pediatric surgeons or pediatric urologists, in many cases do not offer a complete insight into the etiopathogenic mechanisms and the consequent medical treatment. Access to medication according to standards of treatment is warranted, provided a correct diagnosis is achieved, but criteria for the reimbursement of certain therapies, such as RNAi drugs for primary hyperoxaluria, are arguable.
PubMed: 38143536
DOI: 10.3389/fped.2023.1294319 -
Indian Journal of Nephrology 2023Hypercalcemia in infants presents with a variety of clinical features and the etiology of hypercalcemia varies with age. Here we present a case of hypercalcemia in an...
Hypercalcemia in infants presents with a variety of clinical features and the etiology of hypercalcemia varies with age. Here we present a case of hypercalcemia in an infant presenting with nephrocalcinosis and nephrolithiasis. Our investigations led us to a diagnosis of primary hyperoxaluria (PH) type 2, a rare metabolic disorder, along with hypercalcemia, a never before reported association. A 9-month-old female presented with urinary tract infection and systemic features requiring hospitalization and parenteral antibiotics. Investigations revealed bilateral medullary nephrocalcinosis. Genetic testing revealed a diagnosis of Primary hyperoxaluria type 2 with two possible mutations. Sanger sequencing of the parents identified the pathogenic mutation in the mother. This is the first report of a genetically proven case of primary hyperoxaluria type 2 associated with hypercalcemia.
PubMed: 37881736
DOI: 10.4103/ijn.ijn_140_22 -
Ophthalmology Dec 2023
PubMed: 38099910
DOI: 10.1016/j.ophtha.2023.11.012 -
BMC Nephrology Oct 2023Without effective intervention, primary hyperoxaluria type 1 (PH1) causes oxalate-induced kidney damage, leading to end-stage kidney disease and serious complications... (Observational Study)
Observational Study
BACKGROUND
Without effective intervention, primary hyperoxaluria type 1 (PH1) causes oxalate-induced kidney damage, leading to end-stage kidney disease and serious complications throughout the body. Although PH1 carries a heavy burden that impacts quality of life, literature on the experiences of those living with PH1 and caring for patients with PH1 is limited. This study aimed to describe the diagnostic journey in PH1 and characterize patients' and caregivers' self-reported experiences throughout the disease course.
METHODS
This was an observational study involving in-depth, semi-structured telephone interviews. Dominant trends were assessed using constant comparative analysis to identify themes in interviewees' descriptions of their experiences. Individuals aged ≥ 12 years and caregivers of children aged 6-17 years with genetically confirmed PH1 were eligible. Informed consent/assent and ability to read and speak English were required.
RESULTS
Interviewees (16 patients, 12 caregivers) reported a prolonged diagnostic journey due to low disease awareness, among other factors. Upon diagnosis, PH1 was frequently symptomatic, typically involving kidney stone-related symptoms but also potentially symptoms arising beyond the kidneys. PH1 most commonly led to worry and social impairment in adolescents, impaired physical function in adults, and a range of impacts on caregivers. In late-stage disease, dialysis was the most burdensome aspect of living with PH1 (due to time requirements, limitations from living with a catheter, etc.), and this burden was exacerbated by the COVID-19 pandemic. Benefits desired from PH1 management included reductions in laboratory measures of oxalate burden, kidney stone and urination frequency, and oxalate-related skin ulcers.
CONCLUSIONS
PH1 greatly impacts patients' and caregivers' lives, primarily due to burdensome disease manifestations and associated emotional, physical, and practical impacts, as well as disease management challenges - particularly those related to dialysis in late-stage disease.
Topics: Child; Adult; Adolescent; Humans; Pandemics; Quality of Life; Renal Dialysis; Hyperoxaluria, Primary; Oxalates; Kidney Calculi; Patient Outcome Assessment
PubMed: 37884879
DOI: 10.1186/s12882-023-03365-1 -
Case Reports in Nephrology and Dialysis 2023The primary hyperoxalurias (PHs) are a group of diseases characterized by kidney stones, nephrocalcinosis, and chronic kidney disease. At stages of advanced kidney...
The primary hyperoxalurias (PHs) are a group of diseases characterized by kidney stones, nephrocalcinosis, and chronic kidney disease. At stages of advanced kidney disease, glomerular filtration of oxalate becomes insufficient, plasma levels increase, and tissue deposition may occur. Hemodialysis is often unable to overcome the excess hepatic oxalate production. The current surgical management of primary hyperoxaluria type 1 (PH1) is combined liver kidney transplantation. In a subset of PH1 patients who respond to pyridoxine, kidney-only transplantation has been successfully performed. Recently, kidney-only transplantation has also been performed in PH1 patients receiving a small interfering RNA therapy called lumasiran. This drug targets the hepatic overproduction of oxalate, making kidney-only transplantation a potentially practical novel approach for managing PH1 patients with advanced kidney disease. It is unknown if similar effects could be seen with a different small interfering RNA agent called nedosiran. This article will briefly review PH1, describe the small interfering RNA therapies being used to treat PH, summarize the reported cases of kidney-only transplantation performed with lumasiran, and detail a case of kidney-only transplantation performed in a PH1 patient receiving nedosiran.
PubMed: 37497389
DOI: 10.1159/000531053 -
Clinical Case Reports Jan 2024Cutaneous oxalosis is a rare manifestation of systemic oxalosis, typically associated with primary or secondary hyperoxaluria. We present a rare case of a 23-year-old...
Cutaneous oxalosis is a rare manifestation of systemic oxalosis, typically associated with primary or secondary hyperoxaluria. We present a rare case of a 23-year-old female diagnosed with primary hyperoxaluria and end-stage renal disease, who presented with papules on the palms without any vascular complications. The skin can be affected by oxalate deposition, resulting in various manifestations such as vascular complications or calcified nodules. In our case, the patient had primary hyperoxaluria and end-stage renal disease but exhibited atypical features of cutaneous oxalosis. Histopathology confirmed the presence of oxalate crystals in the dermis, subcutis, and medium-sized arteries. The mechanism of oxalate deposition in this case remains unclear. This case underscores the importance of considering cutaneous oxalosis in the differential diagnosis of patients with renal failure and skin lesions, and highlights the variability of clinical presentations in primary hyperoxaluria.
PubMed: 38188849
DOI: 10.1002/ccr3.8423 -
Cureus Jul 2023Primary hyperoxaluria (PH) is a rare genetic condition that disrupts the normal process of glyoxylate metabolism, resulting in an overproduction of oxalate. This...
Primary hyperoxaluria (PH) is a rare genetic condition that disrupts the normal process of glyoxylate metabolism, resulting in an overproduction of oxalate. This excessive oxalate production leads to the accumulation of calcium oxalate (known as oxalosis) throughout various organs in the body. The urinary tract, specifically the renal parenchyma, is the first location where the deposition of calcium oxalate begins in PH. These deposits are responsible for nephrocalcinosis and tubule‑interstitial nephritis which leads to end‑stage renal failure. This is then followed by the accumulation of oxalate in other organs including the bone marrow. Herein, we report the case of a 22-year-old male patient who presented with bicytopenia; he had a history of end-stage renal disease preceded by recurrent urolithiasis and nephrolithiasis episodes since the age of 3 years. A bone marrow biopsy was performed for evaluation of the bicytopenia which led to the diagnosis of PH.
PubMed: 37637636
DOI: 10.7759/cureus.42469 -
Cureus Oct 2023Primary hyperoxaluria-1 (PH1) is an autosomal recessively inherited rare genetic condition due to the deficiency of the hepatic enzyme alanine:glyoxylate...
Primary hyperoxaluria-1 (PH1) is an autosomal recessively inherited rare genetic condition due to the deficiency of the hepatic enzyme alanine:glyoxylate aminotransferase which leads to high systemic levels of oxalate and subsequently, early end-stage renal disease and death. Here, we present a case of a three-month-old male infant who presented with loose stools, reduced oral intake, and decreased activity for 12-13 days along with edema and a peeling rash on cheeks, lips, and genitalia. During the entire duration of the inpatient stay, the child was oligoanuric. Kidney ultrasound (USG) was suggestive of bilateral hyperechoic kidneys with increased cortical echogenicity and a computed tomography scan showed bilateral diffusely calcified renal cortices with well-preserved renal architecture. A diagnosis of "oxalate nephropathy" was made from renal biopsy and genetic testing confirmed it to be "primary hyperoxaluria-1". The child was initially managed conservatively, and then peritoneal dialysis was done, following which the child was shifted to intermittent hemodialysis.
PubMed: 37954792
DOI: 10.7759/cureus.46827