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Frontiers in Genetics 2023Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive accumulation of oxalate in plasma and urine, resulting in various phenotypes due to...
Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive accumulation of oxalate in plasma and urine, resulting in various phenotypes due to allelic and clinical heterogeneity. This study aimed to analyze the genotype of 21 Chinese patients with primary hyperoxaluria (PH) and explore their correlations between genotype and phenotype. Combined with clinical phenotypic and genetic analysis, we identified 21 PH patients from highly suspected Chinese patients. The clinical, biochemical, and genetic data of the 21 patients were subsequently reviewed. We reported 21 cases of PH in China, including 12 cases of PH1, 3 cases of PH2 and 6 cases of PH3, and identified 2 novel variants (c.632T > G and c.823_824del) in gene and 2 novel variants (c.258_272del and c.866-34_866-8del) in gene, respectively. A possible PH3 hotspot variant c.769T > G was identified for the first time. In addition, patients with PH1 showed higher levels of creatinine and lower eGFR than those with PH2 and PH3. In PH1, patients with severe variants in both alleles had significantly higher creatinine and lower eGFR than other patients. Delayed diagnosis still existed in some late-onset patients. Of all cases, 6 had reached to end-stage kidney disease (ESKD) at diagnosis with systemic oxalosis. Five patients were on dialysis and three had undergone kidney or liver transplants. Notably, four patients showed a favorable therapeutic response to vitamin B6, and c.823_824dup and c.145A > C may be identified as potentially vitamin B6-sensitive genotypes. In brief, our study identified 4 novel variants and extended the variant spectrum of PH in the Chinese population. The clinical phenotype was characterized by large heterogeneity, which may be determined by genotype and a variety of other factors. We first reported two variants that may be sensitive to vitamin B6 therapy in Chinese population, providing valuable references for clinical treatment. In addition, early screening and prognosis of PH should be given more attention. We propose to establish a large-scale registration system for rare genetic diseases in China and call for more attention on rare kidney genetic diseases.
PubMed: 37139236
DOI: 10.3389/fgene.2023.1124745 -
Frontiers in Medicine 2021Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that can result in irreversible damage to the kidneys and, eventually, extrarenal organs. While kidney...
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that can result in irreversible damage to the kidneys and, eventually, extrarenal organs. While kidney failure is a known consequence of PH1, few studies to date have characterized clinical consequences of PH1 prior to kidney failure, and data on healthcare resource use outcomes across different stages of disease severity in PH1 are also limited. To help fill this knowledge gap, this study characterized the clinical and healthcare resource use (HRU) burden in patients with PH1 with varying stages of kidney disease. Nephrologists in the United States, Canada, United Kingdom, France, Germany, and Italy abstracted chart data from patients with PH1 under their care via an online questionnaire. Eligible patients had confirmed PH1 and ≥2 office visits from 2016 to 2019. A total of 120 patients were analyzed (median age at diagnosis, 17.4 years old, median age at index 19.5 years old, median eGFR at index 45 ml/min/1.73 m; median follow-up 1.7 years). During follow-up, the most common PH1 manifestations were kidney stones and urinary tract infections (UTIs, both 56.8%), and the most common symptoms were fatigue/weakness (71.7%) and pain (64.6%). With regard to HRU during follow-up, 37.4% required lithotripsy, 31.3% required ureteroscopy, and 9.6% required nephrolithotomy. PH1-related hospitalizations and emergency/urgent care visits were noted for 84.0 and 81.6% of patients, respectively. The current study demonstrated that patients with PH1 across various stages of kidney disease exhibited a substantial clinical burden, including kidney stones, UTIs, fatigue/weakness, and pain, and required frequent HRU, including kidney stone procedures, hospitalizations, and emergency visits. These findings highlight the significant morbidity and HRU burden in patients with PH1.
PubMed: 34616753
DOI: 10.3389/fmed.2021.703305 -
Urology Annals 2018The aim of the study is to identify the prevalence of metabolic abnormalities in children with urolithiasis.
AIM
The aim of the study is to identify the prevalence of metabolic abnormalities in children with urolithiasis.
MATERIALS AND METHODS
This is a prospective study; all children below 15 years who are found to have urolithiasis were prospectively evaluated with relevant history, clinical examination, and urine and serum testing. Metabolic workup includes complete urine examination, urine culture and sensitivity, and 24-h urinary analysis (lithorisk profile).
RESULTS
A total of 55 patients are included in the study. Forty-two are boys and 13 are girls aged between from 8 months to 15 years. Thirty-three patients underwent stone analysis, primary composition of calcium oxalate stones in 19 (58%), ammonium urate in 4, dahlite in 3 and uric acid in 3, silicon oxide in 2, and struvite in 2 cases. Lithorisk profile was performed in 40 cases (72.7%). The pH range is 5.6-6.2. We noted hypercalciuria in 20 patients (50%), hyperuricosuria in 23 (57.5%), hyperoxaluria in 20 (50%), hypernatriuria in 26 (65%), hypocitraturia in 9 (23%), and hypomagnesuria in 3 (7.5%). Urine calcium-to-creatinine ratio >0.2 was found in 22 (55%) patients. Statistically significant association between hyperoxaluria and hyperuricosuria ( < 0.04, = 0.32) and hypercalciuria and hyperuricosuria ( < 0.001, = 0.51) found in this study. Hyperuricosuria is seen in 75% and 73% of patients with hypercalciuria and hyperoxaluria, respectively. Twenty-five children have both lithorisk profile and stone analysis. Hypercalciuria and hyperoxaluria were noted in 60% of calcium oxalate stone formers each. Elevated urinary calcium/creatinine ratio (>0.2) was seen in 73% of calcium oxalate stone formers.
CONCLUSION
Because of high prevalence of metabolic risk factors and the significant risk of lifelong recurrence, all children with urolithiasis need complete evaluation with metabolic workup.
PubMed: 29416283
DOI: 10.4103/UA.UA_98_17 -
International Journal of Nephrology and... 2022Primary hyperoxaluria (PH) is a rare genetic disease caused by excessive hepatic production and elevated urinary excretion of oxalate that leads to recurrent... (Review)
Review
Primary hyperoxaluria (PH) is a rare genetic disease caused by excessive hepatic production and elevated urinary excretion of oxalate that leads to recurrent nephrolithiasis, nephrocalcinosis and, eventually, kidney failure. As glomerular filtration rate declines, oxalate accumulates leading to systemic oxalosis, a debilitating condition with high morbidity and mortality. Although PH is usually diagnosed during infancy, it can present at any age with different phenotypes, ranging from mild symptoms to extremely debilitating manifestations. PH is an autosomal recessive disorder and, to date, three types have been identified: PH1, PH2 and PH3. PH1 is the most common and most aggressive type, accounting for almost 80% of primary hyperoxaluria diagnoses. Until 2020, general treatment for PH1 consisted mainly in high fluid intake, urine alkalization, surgical management of recurrent nephrolithiasis and eventually, if and when kidney failure occurred, intensive dialysis regimens and transplantation strategies (simultaneous or sequential liver-kidney transplant or isolated liver/kidney transplant in carefully selected patients). Specific treatment did and still consists in administration of pyridoxine hydrochloride, although it is only effective in a subset of PH1 patients. Lumasiran, a novel biological drug based on mRNA interference that has been recently approved in the US and European Union, showed promising results and is set to be a turning point in the management of PH1. This literature review aims to summarize the available evidence on PH1 treatment with lumasiran, in order to provide both pediatric and adult nephrologists and clinicians with the knowledge for the identification and management of PH1 patients suitable for treatment.
PubMed: 35747094
DOI: 10.2147/IJNRD.S293682 -
Nutrients Nov 2023Nephrolithiasis affects around 10% of the population and is frequently associated with impaired dietary factors. The first one is insufficient fluid intake inducing... (Review)
Review
Nephrolithiasis affects around 10% of the population and is frequently associated with impaired dietary factors. The first one is insufficient fluid intake inducing reduced urine volume, urine supersaturation, and subsequently urinary lithiasis. Kidneys regulate 24 h urine volume, which, under physiological conditions, approximately reflects daily fluid intake. The aim of this study is to synthesize and highlight the role of hydration in the treatment of nephrolithiasis. Increasing fluid intake has a preventive effect on the risk of developing a first kidney stone (primary prevention) and also decreases the risk of stone recurrence (secondary prevention). Current guidelines recommend increasing fluid intake to at least at 2.5 L/day to prevent stone formation, and even to 3.5-4 L in some severe forms of nephrolithiasis (primary or enteric hyperoxaluria or cystinuria). Fluid intake must also be balanced between day and night, to avoid urinary supersaturation during the night. Patients should be informed and supported in this difficult process of increasing urine dilution, with practical ways and daily routines to increase their fluid intake. The liquid of choice is water, which should be chosen depending on its composition (such as calcium, bicarbonate, or magnesium content). Finally, some additional advice has to be given to avoid certain beverages such as those containing fructose or phosphoric acid, which are susceptible to increase the risk of nephrolithiasis.
Topics: Adult; Humans; Kidney Calculi; Kidney; Calcium, Dietary; Cystinuria; Hyperoxaluria
PubMed: 38068743
DOI: 10.3390/nu15234885 -
Kidney International Dec 2015Nephrolithiasis is a highly prevalent disorder affecting approximately one in eleven people and is associated with multiple complications including hypertension,... (Review)
Review
Nephrolithiasis is a highly prevalent disorder affecting approximately one in eleven people and is associated with multiple complications including hypertension, cardiovascular disease, and chronic kidney disease. Significant epidemiologic associations with chronic kidney disease and ESRD have been noted and are reviewed herein, but debate persists in the literature as to whether kidney stone formation is a pathogenic process contributing to kidney disease. Corroborating evidence supporting the presence of kidney disease in stone formers includes the variability of renal function by stone type, the positive association of stone size with renal dysfunction, the presence of markers of renal injury in the urine of even asymptomatic stone formers, and direct evidence of renal tissue injury on histopathology. Proposed pathogenic mechanisms include recurrent obstruction and comorbid conditions such as recurrent urinary tract infections and structural abnormalities. Recent work evaluating the renal histopathology of different groups of stone formers adds further granularity, suggesting variability in mechanisms of renal injury by stone type and confirming the pathogenic effects of crystal formation. Genetic abnormalities leading to stone formation including cystinuria and primary hyperoxaluria, among others, contribute to the burden of disease in the stone-forming population.
PubMed: 26376133
DOI: 10.1038/ki.2015.254 -
Nephrology, Dialysis, Transplantation :... Apr 2022Primary hyperoxaluria (PH) type 3 (PH3) is caused by mutations in the hydroxy-oxo-glutarate aldolase 1 gene. PH3 patients often present with recurrent urinary stone...
BACKGROUND
Primary hyperoxaluria (PH) type 3 (PH3) is caused by mutations in the hydroxy-oxo-glutarate aldolase 1 gene. PH3 patients often present with recurrent urinary stone disease in the first decade of life, but prior reports suggested PH3 may have a milder phenotype in adults. This study characterized clinical manifestations of PH3 across the decades of life in comparison with PH1 and PH2.
METHODS
Clinical information was obtained from the Rare Kidney Stone Consortium PH Registry (PH1, n = 384; PH2, n = 51; PH3, n = 62).
RESULTS
PH3 patients presented with symptoms at a median of 2.7 years old compared with PH1 (4.9 years) and PH2 (5.7 years) (P = 0.14). Nephrocalcinosis was present at diagnosis in 4 (7%) PH3 patients, while 55 (89%) had stones. Median urine oxalate excretion was lowest in PH3 patients compared with PH1 and PH2 (1.1 versus 1.6 and 1.5 mmol/day/1.73 m2, respectively, P < 0.001) while urine calcium was highest in PH3 (112 versus 51 and 98 mg/day/1.73 m2 in PH1 and PH2, respectively, P < 0.001). Stone events per decade of life were similar across the age span and the three PH types. At 40 years of age, 97% of PH3 patients had not progressed to end-stage kidney disease compared with 36% PH1 and 66% PH2 patients.
CONCLUSIONS
Patients with all forms of PH experience lifelong stone events, often beginning in childhood. Kidney failure is common in PH1 but rare in PH3. Longer-term follow-up of larger cohorts will be important for a more complete understanding of the PH3 phenotype.
Topics: Female; Humans; Hyperoxaluria; Hyperoxaluria, Primary; Male; Mutation; Nephrolithiasis; Phenotype; Renal Insufficiency
PubMed: 33543760
DOI: 10.1093/ndt/gfab027 -
Kidney360 Jan 2024Oxalate nephropathy is an underrecognized cause of CKD and ESKD. We present one of the largest native oxalate nephropathy cohorts to date from a tertiary care...
KEY POINTS
Oxalate nephropathy is an underrecognized cause of CKD and ESKD. We present one of the largest native oxalate nephropathy cohorts to date from a tertiary care institution in the United States. Oxalate nephropathy has multiple etiologies and given its clinical course and poor prognosis, attention must be paid to screening for risk factors to guide prompt diagnosis and management.
BACKGROUND
Oxalate nephropathy (ON) is characterized by deposition of calcium oxalate crystals in the kidney and is commonly under-recognized. Causes of ON include primary hyperoxaluria, enteric hyperoxaluria, and ingestion of excess oxalate or its precursors.
METHODS
We report the clinical and pathological characteristics of one of the largest series of native kidney ON to date, from January 2015 to March 2023 at the Cleveland Clinic.
RESULTS
We identified 60 native biopsies with oxalate deposits and excluded patients with clinically insignificant biopsies (=12) or lack of data (=17). Thirty-one patients with native ON were described. The mean age at diagnosis was 66.2 years (±12.1), and 58.1% were female. 87.1% had hypertension, 58.1% had diabetes, 42% had nephrolithiasis, and 77.4% had underlying CKD, with a mean baseline creatinine of 1.8 mg/dl ±1.3. The mean creatinine at biopsy was 5.2 mg/dl ±1.7. Kidney biopsies showed abundant calcium oxalate crystal deposits, and 27 of 31 biopsies had additional diagnoses, the most common of which were acute tubular injury =17 (54.8%) and diabetic glomerulosclerosis =7 (22.6%). Severe and moderate interstitial fibrosis was present in 38.7% (=12) and 51.6% (=16) of biopsies, respectively. Ten had a single etiology of ON, ten had a multifactorial etiology (both enteric hyperoxaluria and high precursor intake), and 11 had an unclear etiology. Notably, only seven patients had a history of gastric bypass. The mean duration of follow-up was 26.8 months, and 26 patients had follow-up data >1 year. Of these, 21 required dialysis, and five were dialysis-free at presentation. Five of the 26 were deceased at 1 year, with 12 patients (38.7%) deceased at last follow-up. Seventeen patients received targeted management, while nine patients did not receive targeted treatment, and all nine required hemodialysis. More patients (31.6%) had vitamin C intake after the coronavirus disease 2019 pandemic (2020–2023) versus 16.7% before 2020.
CONCLUSIONS
ON presents as AKI or acute on CKD. The prognosis is poor with most patients requiring dialysis at presentation with high morbidity and mortality. Clinicians need to be aware of the risk factors associated with ON to aid prompt diagnosis and management.
PODCAST
This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/K360/2024_01_26_KID0000000000000340.mp3
Topics: Humans; Hyperoxaluria; Renal Insufficiency; Oxalates
PubMed: 38095544
DOI: 10.34067/KID.0000000000000340 -
Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up.Kidney International Dec 2019Primary hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure....
Primary hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure. Previously, primary hyperoxaluria type 2 was considered to have a more favorable prognosis than primary hyperoxaluria type 1, but earlier reports are limited by low patient numbers and short follow up periods. Here we report on the clinical, genetic, and biochemical findings from the largest cohort of patients with primary hyperoxaluria type 2, obtained by a retrospective record review of genetically confirmed cases in the OxalEurope registry, a dataset containing 101 patients from eleven countries. Median follow up was 12.4 years. Median ages at first symptom and diagnosis for index cases were 3.2 years and 8.0 years, respectively. Urolithiasis was the most common presenting feature (82.8% of patients). Genetic analysis revealed 18 novel mutations in the GRHPR gene. Of 238 spot-urine analyses, 23 (9.7%) were within the normal range for oxalate as compared to less than 4% of 24-hour urine collections. Median intra-individual variation of 24-hour oxalate excretion was substantial (34.1%). At time of review, 12 patients were lost to follow-up; 45 of the remaining 89 patients experienced chronic kidney disease stage 2 or greater and 22 patients had reached stage 5. Median renal survival was 43.3 years, including 15 kidney transplantations in 11 patients (1 combined with liver transplantation). Renal outcome did not correlate with genotype, biochemical parameters or initially present nephrocalcinosis. Thus, primary hyperoxaluria type 2 is a disease with significant morbidity. Accurate diagnosis by 24-hour urine analysis and genetic testing are required with careful follow-up.
Topics: Adolescent; Adult; Age of Onset; Child; Child, Preschool; Europe; Female; Humans; Hyperoxaluria, Primary; Infant; Kidney Failure, Chronic; Kidney Transplantation; Male; Registries; Retrospective Studies; Young Adult
PubMed: 31685312
DOI: 10.1016/j.kint.2019.08.018 -
Revue Medicale de Liege Jul 2022Primary hyperoxaluria type 1 is a rare autosomal recessive disorder leading to oxalate overproduction by deficiency in the liver-specific enzyme alanine-glyoxylate...
Primary hyperoxaluria type 1 is a rare autosomal recessive disorder leading to oxalate overproduction by deficiency in the liver-specific enzyme alanine-glyoxylate transaminase (AGT). Oxalate is a poorly soluble molecule that binds calcium and deposits in the entire organism leading to oxalosis. Its elimination is mainly carried out by kidneys. Hence the first manifestations are frequently of urinary concern and whitout any early care, progression of the disease to end-stage renal failure cannot be avoided. The only etiological treatment has long been combined liver-kidney transplantation because it restaures enzymatic function and replaces pathological kidneys. However, for a few years now, numerous studies are carried out on this subject and promising results have already been published with a new drug, lumasiran. From a clinical case, we describe the different options for the therapeutic management of primary hyperoxaluria type 1.
Topics: Humans; Hyperoxaluria, Primary; Nephrocalcinosis; Oxalates; RNA, Small Interfering
PubMed: 35924494
DOI: No ID Found