RESUMEN
This study investigated the risk profile and the impact of dietary intervention in calcium oxalate stone formers with enteric hyperoxaluria under controlled, standardized conditions. Thirty-seven patients were included in the study. Dietary and 24-h urinary parameters were obtained on the self-selected diet and a balanced, standardized diet. Tests for [13C2]oxalate absorption, calcium- and ammonium chloride-loading were performed. Mean [13C2]oxalate absorption was 18.8%. A significant positive association was observed between urinary oxalate excretion and intestinal oxalate absorption. In addition, urinary oxalate excretion was significantly correlated with dietary oxalate intake. Mean urinary oxalate excretion decreased from 0.841 mmol/24 h on the usual diet to 0.662 mmol/24 h on the balanced diet, corresponding to a reduction of 21.3%. Besides hyperoxaluria, hypocitraturia and hypomagnesuria were the most common urinary abnormalities at baseline, being present in 83.8% and 81.1% of patients, respectively. Urinary citrate increased by 50.9% and magnesium excretion increased by 25.2% on the balanced diet. As a result, the relative supersaturation of calcium oxalate declined significantly (by 36.2%) on the balanced diet. Since 41% of patients on the balanced diet still had a urine volume of less than 2.0 L/24 h, efforts should be made to increase urine volume by increasing fluid intake and reducing intestinal fluid losses. Dietary intervention proved to be effective in reducing urinary oxalate excretion and should be a cornerstone of the treatment of patients with enteric hyperoxaluria.
Asunto(s)
Oxalato de Calcio , Dieta , Hiperoxaluria , Humanos , Masculino , Femenino , Oxalato de Calcio/orina , Oxalato de Calcio/metabolismo , Persona de Mediana Edad , Hiperoxaluria/dietoterapia , Hiperoxaluria/orina , Adulto , Dieta/métodos , Oxalatos/orina , Oxalatos/metabolismo , Anciano , Cálculos Renales/dietoterapia , Cálculos Renales/orina , Cálculos Renales/etiología , Absorción Intestinal , Magnesio/orina , Magnesio/administración & dosificación , Magnesio/metabolismo , Ácido Cítrico/orinaRESUMEN
Magnesium is one of the recommended treatments for calcium stone formers (CSFs) with hyperoxaluria. In this study, we compared the effect of magnesium oxide (MgO) or magnesium citrate (MgCit) with placebo on 24-hour urine (24-U) metabolites and the calcium oxalate supersaturation index (CaOx SS). In a randomized, double-blind, placebo-controlled clinical trial, 90 CSFs with idiopathic hyperoxaluria were recruited from a tertiary stone prevention clinic. Patients were randomly assigned into three groups: 120 mg MgO, 120 mg MgCit or placebo (supplements were taken three times per day, with meals). Finally, 76 patients were included in the final analysis. Analyses of 24-U were performed at baseline and after eight weeks. Study outcomes included changes in 24-U oxalate, magnesium, citrate, and CaOx SS. Dietary factors were controlled by 24-hour food recalls. Repeated measure ANOVA was used to compare the results. After the intervention, both MgO and MgCit supplements decreased 24-U oxalate excretion (-8.13±16.45 in the MgO group and -16.99±18.02 in the MgCit group) and CaOx SS compared to the placebo, with the effects of MgCit reaching statistical significance (p=0.011 and p=0.010, respectively). An increasing trend was observed for 24-U magnesium and citrate excretion without significant differences among groups. Interestingly, MgCit exhibited a significantly greater inhibitory effect on 24-U oxalate in patients with normal urine magnesium levels (p=0.021). Clinically, both MgO and MgCit reduced 24-U oxalate and CaOx SS compared to placebo. However, MgCit demonstrated a greater effect, especially in patients with normal urine magnesium levels.
Asunto(s)
Suplementos Dietéticos , Hiperoxaluria , Cálculos Renales , Óxido de Magnesio , Humanos , Óxido de Magnesio/uso terapéutico , Óxido de Magnesio/administración & dosificación , Femenino , Masculino , Cálculos Renales/orina , Cálculos Renales/prevención & control , Cálculos Renales/tratamiento farmacológico , Cálculos Renales/metabolismo , Adulto , Hiperoxaluria/orina , Hiperoxaluria/tratamiento farmacológico , Hiperoxaluria/complicaciones , Método Doble Ciego , Factores de Riesgo , Persona de Mediana Edad , Ácido Cítrico/orina , Compuestos de Magnesio/uso terapéutico , Compuestos de Magnesio/orina , Compuestos de Magnesio/farmacología , Compuestos de Magnesio/administración & dosificación , Compuestos OrganometálicosRESUMEN
Nedosiran is an N-acetyl-D-galactosamine (GalNAc)-conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative enzyme mediating the final step of oxalate production in all three genetic subtypes of primary hyperoxaluria (PH). This phase I study assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous nedosiran in patients with PH subtype 3 (PH3) and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2. Single-dose nedosiran 3 mg/kg or placebo was administered in a randomized (2:1), double-blinded manner. Safety/tolerability, 24-h urinary oxalate (Uox) concentrations, and plasma nedosiran concentrations were assessed. The main PD endpoint was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox at two consecutive visits. Six participants enrolled in and completed the study (nedosiran, n = 4; placebo, n = 2). Nedosiran was well-tolerated and lacked safety concerns. Although the PD response was not met, 24-h Uox excretion declined 24.5% in the nedosiran group and increased 10.5% in the placebo group at Day 85. Three of four nedosiran recipients had a > 30% reduction in 24-h Uox excretion during at least one visit, and one attained near-normal (i.e., ≥ 0.46 to < 0.60 mmol/24 h; ≥ 1.0 to < 1.3 × upper limit of the normal reference range) 24-h Uox excretion from Day 29 to Day 85. Nedosiran displayed predictable plasma PK. The acceptable safety and trend toward Uox-lowering after single-dose nedosiran treatment enables further clinical development of nedosiran in patients with PH3 who currently have no viable therapeutic options. A plain language summary is available in the supplementary information.
Asunto(s)
Hiperoxaluria Primaria , Hiperoxaluria , Humanos , Hiperoxaluria Primaria/tratamiento farmacológico , Hiperoxaluria Primaria/genética , Hiperoxaluria/orina , Oxalatos/orina , Tasa de Filtración GlomerularRESUMEN
INTRODUCTION: To overcome the data availability hurdle of observational studies on urolithiasis, we linked claims data with 24-hour urine results from a large cohort of adults with urolithiasis. This database contains the sample size, clinical granularity, and long-term follow-up needed to study urolithiasis on a broad level. METHODS: We identified adults enrolled in Medicare with urolithiasis who had a 24-hour urine collection processed by Litholink (2011 to 2016). We created a linkage of their collections results and paid Medicare claims. We characterized them across a variety of sociodemographic and clinical factors. We measured frequencies of prescription fills for medications used to prevent stone recurrence, as well as frequencies of symptomatic stone events, among these patients. RESULTS: In total, there were 11,460 patients who performed 18,922 urine collections in the Medicare-Litholink cohort. The majority were male (57%), White (93.2%), and lived in a metropolitan county (51.5%). Results from their initial urine collections revealed abnormal pH to be the most common abnormality (77.2%), followed by low volume (63.8%), hypocitraturia (45.6%), hyperoxaluria (31.1%), hypercalciuria (28.4%), and hyperuricosuria (11.8%). Seventeen percent had prescription fills for alkali monotherapy, and 7.6% had prescription fills for thiazide diuretic monotherapy. Symptomatic stone events occurred in 23.1% at 2 years of follow-up. CONCLUSIONS: We successfully linked Medicare claims with results from 24-hour urine collections performed by adults that were processed by Litholink. The resulting database is a unique resource for future studies on the clinical effectiveness of stone prevention strategies and urolithiasis more broadly.
Asunto(s)
Hiperoxaluria , Urolitiasis , Estados Unidos/epidemiología , Adulto , Humanos , Masculino , Anciano , Femenino , Factores de Riesgo , Medicare , Urolitiasis/tratamiento farmacológico , Hipercalciuria/orina , Hiperoxaluria/orinaRESUMEN
In primary hyperoxaluria type 1 excessive endogenous production of oxalate and glycolate leads to increased urinary excretion of these metabolites. Although genetic testing is the most definitive and preferred diagnostic method, quantification of these metabolites is important for the diagnosis and evaluation of potential therapeutic interventions. Current metabolite quantification methods use laborious, technically highly complex and expensive liquid, gas or ion chromatography tandem mass spectrometry, which are available only in selected laboratories worldwide. Incubation of ortho-aminobenzaldehyde (oABA) with glyoxylate generated from glycolate using recombinant mouse glycolate oxidase (GO) and glycine leads to the formation of a stable dihydroquinazoline double aromatic ring chromophore with specific peak absorption at 440 nm. The urinary limit of detection and estimated limit of quantification derived from eight standard curves were 14.3 and 28.7 µmol glycolate per mmol creatinine, respectively. High concentrations of oxalate, lactate and L-glycerate do not interfere in this assay format. The correlation coefficient between the absorption and an ion chromatography tandem mass spectrometry method is 93% with a p value < 0.00001. The Bland-Altmann plot indicates acceptable agreement between the two methods. The glycolate quantification method using conversion of glycolate via recombinant mouse GO and fusion of oABA and glycine with glyoxylate is fast, simple, robust and inexpensive. Furthermore this method might be readily implemented into routine clinical diagnostic laboratories for glycolate measurements in primary hyperoxaluria type 1.
Asunto(s)
Hiperoxaluria Primaria , Hiperoxaluria , Ratones , Animales , Hiperoxaluria Primaria/terapia , Oxalatos/orina , Glicolatos/orina , Glioxilatos/metabolismo , Glicina , Hiperoxaluria/diagnóstico , Hiperoxaluria/orinaRESUMEN
Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90-180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs -1664 [1190], respectively; difference, 5172; 95% CI 2929-7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours; <1.3 × ULN) Uox excretion on ≥2 consecutive visits starting at day 90 (50% vs 0; P = 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P < 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P = 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH.
Asunto(s)
Hiperoxaluria Primaria , Hiperoxaluria , Humanos , Hiperoxaluria/orina , Hiperoxaluria Primaria/diagnóstico , Hiperoxaluria Primaria/tratamiento farmacológico , Hiperoxaluria Primaria/genética , Oxalatos/metabolismo , Interferencia de ARN , Método Doble CiegoRESUMEN
We examined how physicians made therapeutic choices to decrease stone risk in patients with bowel disease without colon resection, many of whom have enteric hyperoxaluria (EH), at a single clinic. We analyzed clinic records and 24-h urine collections before and after the first clinic visit, among 100 stone formers with bowel disease. We used multivariate linear regression and t tests to compare effects of fluid intake, alkali supplementation, and oxalate-focused interventions on urine characteristics. Patients advised to increase fluid intake had lower initial urine volumes (L/day; 1.3 ± 0.5 vs. 1.7 ± 0.7) and increased volume more than those not so advised (0.7 ± 0.6 vs. 0.3 ± 0.6 p = 0.03; intervention vs. non-intervention). Calcium oxalate supersaturation (CaOx SS) fell (95% CI -4.3 to -0.8). Alkali supplementation increased urine pH (0.34 ± 0.53 vs. 0.22 ± 0.55, p = 0.26) and urine citrate (mg/d; 83 ± 256 vs. 98 ± 166, p = 0.74). Patients advised to reduce oxalate (mg/day) absorption had higher urine oxalate at baseline (88 ± 44 vs. 50 ± 26) which was unchanged on follow-up (88 (baseline) vs. 91 (follow-up), p = 0.90). Neither alkali (95% CI -1.4 to 2.1) nor oxalate-focused advice (95% CI -1.2 to 2.3) lowered CaOx SS. Physicians chose treatments based on baseline urine characteristics. Advice to increase fluid intake increased urine volume and decreased CaOx SS. Alkali and oxalate interventions were ineffective.
Asunto(s)
Hiperoxaluria , Cálculos Renales , Álcalis , Oxalato de Calcio/orina , Humanos , Hiperoxaluria/complicaciones , Hiperoxaluria/terapia , Hiperoxaluria/orina , Cálculos Renales/etiología , Cálculos Renales/prevención & control , Cálculos Renales/orina , OxalatosRESUMEN
PURPOSE: American Urology Association guidelines recommend genetic testing for patients with recurrent stones and urine oxalate > 75 mg/day. The goal of this study was to examine the treatment of patients in this category in a large multidisciplinary adult stone clinic. METHODS: Patients were evaluated from a single institution between 2006 and 2019. Those with at least one level of urinary oxalate excretion (uOx) above 75 mg/day were identified. A chart review identified enteric risk factors and genetic testing results. Patients without an identifiable enteric cause were considered idiopathic. RESULTS: A total of 4229 separate 24-h urine collections in 1302 patients were reviewed. At least one measurement of uOx above 75 mg/day was found in 103 (7.9%) patients. Enteric hyperoxaluria (EH) was seen in 28 (27%) and idiopathic hyperoxaluria (IH) in 76 (74%). 20 (71%) patients in the EH group had undergone gastric bypass. The median uOx was significantly higher level in the EH group (121.0 vs. 93.0 mg/day). For the entire cohort, there was a drop in uOx (- 33.8 mg/day) with medical and dietary therapy after a follow-up of 46.6 months. The final oxalate was higher in EH (88.9 vs. 60.1 mg/day). Only one patient had referral for genetic testing and was found to have primary hyperoxaluria type 2. CONCLUSIONS: The most common cause of significant hyperoxaluria in patients with recurrent nephrolithiasis remains idiopathic. Patients with IH have more significant improvement in uOx compared to EH; however, both groups had hyperoxaluria at last follow-up. Rate of genetic testing is low despite guideline recommendations.
Asunto(s)
Hiperoxaluria , Cálculos Renales , Nefrolitiasis , Adulto , Estudios de Cohortes , Humanos , Hiperoxaluria/complicaciones , Hiperoxaluria/orina , Cálculos Renales/orina , Nefrolitiasis/genética , Oxalatos/orina , Factores de RiesgoRESUMEN
Ob/ob mice have recently emerged as a model for obesity-related hyperoxaluria as they are obese and excrete more urine oxalate compared to wild type mice. Ob/ob mice are deficient of leptin and develop obesity with hyperphagia and hyperinsulinemia. We hypothesized that insulin resistance and the gut microbiome contribute to hyperoxaluria in ob/ob mice. We developed a new liquid chromatography-mass spectrometry assay for urine oxalate and first compared urine oxalate excretion in ob/ob mice before and after ablation of intestinal bacteria with a standard antibiotic cocktail. We then compared urine oxalate excretion in ob/ob mice before and after leptin replacement or pioglitazone treatment, two maneuvers that reduce insulin resistance in ob/ob mice. Ob/ob mice excreted more oxalate into the urine in a 24-h period compared to wild type mice, but antibiotic, leptin, or pioglitazone treatment did not change urine oxalate excretion in ob/ob mice. Unexpectedly, we found that when food intake was carefully matched between ob/ob and wild type mice, the amount of 24-h urine oxalate excretion did not differ between the two mouse strains, suggesting that ob/ob mice excrete more urine oxalate because of hyperphagia. Since the level of urine oxalate excretion in wild type mice in our study was higher than those reported in prior studies, future work will be needed to standardize the measurement of urine oxalate and to define the range of urine oxalate excretion in wild type mice so that accurate and valid comparisons can be made between wild type mice and ob/ob mice or other mouse models.
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Microbioma Gastrointestinal , Hiperoxaluria , Resistencia a la Insulina , Oxalatos , Animales , Antibacterianos/farmacología , Hiperoxaluria/etiología , Hiperoxaluria/orina , Hiperfagia/orina , Leptina , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Obesos , Obesidad/microbiología , Obesidad/orina , Oxalatos/orina , Pioglitazona/farmacologíaRESUMEN
In the present study, we characterized the probiotic properties of two commercially available bacterial strains, Lactobacillus paragasseri UBLG-36 and Lacticaseibacillus paracasei UBLPC-87, and evaluated their ability to degrade oxalate in vitro and in a hyperoxaluria-induced nephrolithiasis rat model. UBLG-36 harboring two oxalate catabolizing genes, oxalyl coenzyme A decarboxylase (oxc) and formyl coenzyme A transferase (frc), was previously shown to degrade oxalate in vitro effectively. Here, we show that UBLPC-87, lacking both oxc and frc, could still degrade oxalate in vitro. Both these strains harbored several potential putative probiotic genes that may have conferred them the ability to survive in low pH and 0.3% bile, resist antibiotic stress, show antagonistic activity against pathogenic bacteria, and adhere to epithelial cell surfaces. We further evaluated if UBLG-36 and UBLPC-87 could degrade oxalate in vivo and prevent hyperoxaluria-induced nephrolithiasis in rats. We observed that rats treated with 4.5% sodium oxalate (NaOx) developed hyperoxaluria and renal stones. However, when pre-treated with UBLG-36 or UBLPC-87 before administering 4.5% NaOx, the rats were protected against several pathophysiological manifestations of hyperoxaluria. Compared to the hyperoxaluric rats, the probiotic pre-treated rats showed reduced urinary excretion of oxalate and urea (p < 0.05), decreased serum blood urea nitrogen and creatinine (p < 0.05), alleviated stone formation and renal histological damage, and an overall decrease in renal tissue oxalate and calcium content (p < 0.05). Taken together, both UBLG-36 and UBLPC-87 are effective oxalate catabolizing probiotics capable of preventing hyperoxaluria and alleviating renal damage associated with nephrolithiasis.
Asunto(s)
Hiperoxaluria , Cálculos Renales , Lacticaseibacillus paracasei , Probióticos , Animales , Hiperoxaluria/inducido químicamente , Hiperoxaluria/prevención & control , Hiperoxaluria/orina , Cálculos Renales/inducido químicamente , Cálculos Renales/prevención & control , Cálculos Renales/orina , Lactobacillus/metabolismo , Lacticaseibacillus paracasei/metabolismo , Ácido Oxálico/efectos adversos , Ácido Oxálico/metabolismo , Probióticos/farmacología , RatasRESUMEN
Enteric hyperoxaluria (EH) is a metabolic disease caused by excessive absorption of dietary oxalate leading to the formation of chronic kidney stones and kidney failure. There are no approved pharmaceutical treatments for EH. SYNB8802 is an engineered bacterial therapeutic designed to consume oxalate in the gut and lower urinary oxalate as a potential treatment for EH. Oral administration of SYNB8802 leads to significantly decreased urinary oxalate excretion in healthy mice and non-human primates, demonstrating the strain's ability to consume oxalate in vivo. A mathematical modeling framework was constructed that combines in vitro and in vivo preclinical data to predict the effects of SYNB8802 administration on urinary oxalate excretion in humans. Simulations of SYNB8802 administration predict a clinically meaningful lowering of urinary oxalate excretion in healthy volunteers and EH patients. Together, these findings suggest that SYNB8802 is a promising treatment for EH.
Asunto(s)
Hiperoxaluria , Animales , Simulación por Computador , Femenino , Humanos , Hiperoxaluria/etiología , Hiperoxaluria/orina , Masculino , Ratones , Oxalatos/metabolismo , Oxalatos/orinaRESUMEN
Hyperoxaluria, one of the major risk factors for calcium oxalate urolithiasis and nephrocalcinosis, causes significant morbidity and mortality and should therefore be detected and treated as soon as possible. An early, consequent and adequate evaluation, but also a distinction between primary (PH) and secondary hyperoxaluria (SH) is therefore essential. We evaluated the usefulness of three consecutive 24-h urine collections under different diets [usual diet, (A), low oxalate diet, (B), high oxalate diet, (C)] to prove SH, or to find evidence of PH by changes in urinary oxalate excretion (Uox). We retrospectively analyzed results from 96 pediatric patients (47 females and 49 males, age 3-18 years) who presented with a history of nephrolithiasis, nephrocalcinosis and/or persistent hematuria in whom hyperoxaluria was found in an initial urine sample. The typical pattern of SH was found in 34 patients (mean Uox (A) 0.85 ± 0.29, (B) 0.54 ± 0.15 and (C) 0.95 ± 0.28 mmol/1.73m2/d). PH was suspected in 13 patients [(A) 1.21 ± 0.75; (B) 1.47 ± 0.51 and (C) 1.60 ± 0.82 mmol/1.73m2/d], but genetically proven only in 1/5 patients examined. No hyperoxaluria was found in 16 patients. Data were inconclusive in 33 patients. Urine collection under different diets is helpful to diagnose secondary hyperoxaluria and may provide evidence, that urinary oxalate excretion is normal. We have now established this procedure as our first diagnostic step before further, more extensive and more expensive evaluations are performed.
Asunto(s)
Hiperoxaluria , Cálculos Renales , Adolescente , Niño , Preescolar , Dieta/efectos adversos , Femenino , Humanos , Hiperoxaluria/complicaciones , Hiperoxaluria/orina , Cálculos Renales/orina , Masculino , Oxalatos/orina , Estudios Retrospectivos , Toma de Muestras de OrinaRESUMEN
Short bowel (SB) increases the risk of kidney stones. However, the underlying mechanism is unclear. Here, we examined how SB affected renal oxalate and citrate handlings for in vivo hyperoxaluric rats and in vitro tubular cells. SB was induced by small intestine resection in male Wistar rats. Sham-operated controls had no resection. After 7 days of recovery, the rats were divided into control, SB (both fed with distilled water), ethylene glycol (EG), and SB+EG (both fed with 0.75% EG for hyperoxaluric induction) groups for 28 days. We collected the plasma, 24 h of urine, kidney, and intestine tissues for analysis. Hypocitraturia was found and persisted up to 28 days for the SB group. Hypocalcemia and high plasma parathyroid hormone (PTH) levels were found in the 28-day SB rats. SB aggravated EG-mediated oxalate nephropathy by fostering hyperoxaluria and hypocitraturia, and increasing the degree of supersaturation and calcium oxalate (CaOx) crystal deposition. These effects were associated with renal up-regulations of the oxalate transporter solute carrier family 26 (Slc26)a6 and citrate transporter sodium-dependent dicarboxylate cotransporter-1 (NaDC-1) but not Slc26a2. The effects of PTH on the SB kidneys were then examined in NRK-52E tubular cells. Recombinant PTH attenuated oxalate-mediated cell injury and up-regulated NaDC-1 via protein kinase A (PKA) activation. PTH, however, showed no additive effects on oxalate-induced Slc26a6 and NaDC-1 up-regulation. Together, these results demonstrated that renal NaDC-1 upregulation-induced hypocitraturia weakened the defense against Slc26a6-mediated hyperoxaluria in SB kidneys for excess CaOx crystal formation. Increased tubular NaDC-1 expression caused by SB relied on PTH.
Asunto(s)
Oxalato de Calcio/metabolismo , Proteínas Portadoras/metabolismo , Hiperoxaluria/metabolismo , Intestino Delgado/cirugía , Oxalatos/metabolismo , Animales , Calcio/sangre , Oxalato de Calcio/sangre , Cristalización , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Transportadores de Ácidos Dicarboxílicos/metabolismo , Hiperoxaluria/orina , Riñón/metabolismo , Riñón/patología , Masculino , Modelos Biológicos , Hormona Paratiroidea/sangre , Ratas Wistar , Transducción de Señal , Regulación hacia ArribaRESUMEN
BACKGROUND: The aim of the study was to present a case study of a 56-year-old woman with hyperoxaluria induced by calcium-free diet that resulted in kidney stone recurrence. METHODS: A 24-hour urine collection and serum tests for kidney stone risk factors identification were performed. The monitoring of urine risk factors was done by untimed urine samples and 24-hour urine collections. Polarized light microscopy was performed for kidney stone analysis. RESULTS: The results of urine collection showed hyperoxaluria of 0.551 mmoL per 24 hours. After adding calcium-containing products to the diet the oxaluria decreased to reference range value of 0.352 mmoL/24 hours and all untimed oxalate to creatinine ratios returned to reference ranges. Polarized light microscopy revealed 100% calcium oxalate kidney stone composition (It was 50% Weddellite and 50% Whewellite). CONCLUSIONS: The case study shows the importance of calcium intake in the prevention of calcium oxalate kidney stone recurrence. Particularly, unsuitable diet without calcium can induce kidney stone recurrence. Knowledge of diet habits is important for interpretation of kidney stone risk factors and their inhibitors excreted in urine.
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Dieta/efectos adversos , Hiperoxaluria/etiología , Cálculos Renales/etiología , Calcio/sangre , Calcio/orina , Oxalato de Calcio , Femenino , Humanos , Hiperoxaluria/orina , Cálculos Renales/orina , Persona de Mediana Edad , Recurrencia , Factores de RiesgoRESUMEN
BACKGROUND: The incidence of nephrolithiasis in children and adolescents is increasing and appears to double every 10 years. The most important role of the pediatric nephrologist is to diagnose and modify various metabolic and non-metabolic risk factors, as well as prevent long-term complications especially in the case of recurrent nephrolithiasis. OBJECTIVE: The purpose of this review is to summarize the existing literature on the etiology and management of pediatric nephrolithiasis. RESULTS: The incidence of kidney stones is increasing; dietary and environmental factors are probably the main causes for this increased incidence. In most pediatric patients, the etiology for the kidney stones can be identified. Metabolic factors, such as hypercalciuria and hypocitraturia, urinary tract infection, and urinary stasis, constitute leading causes. Herein, we review the etiologies, diagnostic work-up, and treatment options for the most prevalent causes of kidney stones. The detrimental effects of excessive dietary sodium, reduced fluid intake, and the benefits of plant-based over animal-based protein consumption on urinary crystal formation are discussed. We also review the long-term complications. CONCLUSIONS: Pediatric nephrologists have an important role in the diagnostic work-up and prevention of recurring nephrolithiasis.
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Hipercalciuria/diagnóstico , Hiperoxaluria/diagnóstico , Cálculos Renales/diagnóstico , Nefrólogos/organización & administración , Rol Profesional , Adolescente , Niño , Humanos , Hipercalciuria/metabolismo , Hipercalciuria/terapia , Hipercalciuria/orina , Hiperoxaluria/metabolismo , Hiperoxaluria/terapia , Hiperoxaluria/orina , Incidencia , Cálculos Renales/epidemiología , Cálculos Renales/metabolismo , Cálculos Renales/terapia , Recurrencia , Factores de Riesgo , Prevención Secundaria/organización & administraciónRESUMEN
The incidence of urinary stone disease is rapidly increasing, with oxalate being a primary constituent of approximately 80% of all kidney stones. Despite the high dietary exposure to oxalate by many individuals and its potential nephrotoxicity, mammals do not produce enzymes to metabolize this compound, instead relying in part on bacteria within the gut to reduce oxalate absorption and urinary excretion. While considerable research has focused on isolated species of oxalate-degrading bacteria, particularly those with an absolute requirement for oxalate, recent studies have pointed to broader roles for microbiota both in oxalate metabolism and inhibition of urinary stone disease. Here we examined gut microbiota from patients with and live-in individuals without urinary stone disease to determine if healthy individuals harbored a more extensive microbial network associated with oxalate metabolism. We found a gender-specific association between the gut microbiota composition and urinary stone disease. Bacteria enriched in healthy individuals largely overlapped with those that exhibited a significant, positive correlation with Oxalobacter formigenes, a species presumed to be at the center of an oxalate-metabolizing microbial network. Furthermore, differential abundance analyses identified multiple taxa known to also be stimulated by oxalate in rodent models. Interestingly, the presence of these taxa distinguished patients from healthy individuals better than either the relative abundance or colonization of O. formigenes. Thus, our work shows that bacteria stimulated by the presence of oxalate in rodents may, in addition to obligate oxalate users, play a role in the inhibition of urinary stone disease in man.
Asunto(s)
Microbioma Gastrointestinal/fisiología , Hiperoxaluria/microbiología , Oxalatos/metabolismo , Oxalobacter formigenes/aislamiento & purificación , Cálculos Urinarios/microbiología , Anciano , Estudios de Casos y Controles , ADN Bacteriano/aislamiento & purificación , Femenino , Humanos , Hiperoxaluria/complicaciones , Hiperoxaluria/orina , Masculino , Persona de Mediana Edad , Oxalatos/orina , Oxalobacter formigenes/genética , Oxalobacter formigenes/metabolismo , ARN Ribosómico 16S/genética , Cálculos Urinarios/orinaRESUMEN
PURPOSE: To evaluate the potential of ALLN-177, an orally administered, oxalate-specific enzyme therapy to reduce urine oxalate (UOx) excretion in patients with secondary hyperoxaluria. METHODS: Sixteen male and female subjects with both hyperoxaluria and a kidney stone history were enrolled in an open-label study. Subjects continued their usual diets and therapies. During a 3-day baseline period, two 24-h (24-h) urines were collected, followed by a 4-day treatment period with ALLN-177 (7,500 units/meal, 3 × day) when three 24-h urines were collected. The primary endpoint was the change in mean 24-h UOx from baseline. Safety assessments and 24-h dietary recalls were performed throughout. RESULTS: The study enrolled 5 subjects with enteric hyperoxaluria and 11 with idiopathic hyperoxaluria. ALLN-177 was well tolerated. Overall mean (SD) UOx decreased from 77.7 (55.9) at baseline to 63.7 (40.1) mg/24 h while on ALLN-177 therapy, with the mean reduction of 14 mg/24 h, (95% CI - 23.71, - 4.13). The calcium oxalate-relative urinary supersaturation ratio in the overall population decreased from a mean of 11.3 (5.7) to 8.8 (3.8) (- 2.8; 95% CI - 4.9, - 0.79). This difference was driven by oxalate reduction alone, but not any other urinary parameters. Mean daily dietary oxalate, calcium, and fluid intake recorded by frequent diet recall did not differ by study periods. CONCLUSION: ALLN-177 reduced 24-h UOx excretion, and was well tolerated. The results of this pilot study provided justification for further investigation of ALLN-177 in patients with secondary hyperoxaluria. TRIAL REGISTRATION: Clinicaltrials.gov NCT02289755.
Asunto(s)
Carboxiliasas/uso terapéutico , Hiperoxaluria/tratamiento farmacológico , Hiperoxaluria/orina , Oxalatos/orina , Administración Oral , Adulto , Anciano , Carboxiliasas/administración & dosificación , Dieta , Terapia Enzimática , Femenino , Humanos , Hiperoxaluria/complicaciones , Cálculos Renales/complicaciones , Masculino , Persona de Mediana EdadRESUMEN
Hyperoxaluria is characterized by an increased excretion of urinary oxalate which is caused by inherited disorders or high oxalate intake leading to renal stone ailment. Until date, reactive oxygen species and inflammation has been convicted for the progression of kidney stones for which antioxidant therapy has been employed. However, recent studies have linked the association of endoplasmic reticulum stress and oxidative imbalance in the progression of renal diseases. Considering oxidative stress being at forefront in causing hyperoxaluric consequences, current study was designed to correlate the impact of hyperoxaluria and regulation of oxidative imbalance via inhibition of endoplasmic reticulum stress by 4-phenylbutyric acid (4-PBA). Male wistar rats were subdivided into three groups, i.e., normal control (C), hyperoxaluric rats given ethylene glycol (EG), and hyperoxaluric rats treated with 4-PBA (EG + PBA). After 28 days of treatment, assessment of antioxidant defence system, inflammation, ER stress, and subsequent unfolded protein response was studied in renal tissue. It was found that the hyperoxaluric insult led to a marked damage to the renal tissue resulting in compromised antioxidant levels, upregulation of ER stress markers along with a steep surge in the extent of inflammation. However, 4-PBA treatment significantly curtailed the deleterious effects of hyperoxaluria by lowering down the level of stress markers as well as normalizing the antioxidant defence enzymes. Therefore, chemical chaperones can be deemed as a new class of drugs for the treatment of hyperoxaluric induced renal damage.
Asunto(s)
Hiperoxaluria/complicaciones , Cálculos Renales/prevención & control , Riñón/efectos de los fármacos , Fenilbutiratos/farmacología , Respuesta de Proteína Desplegada/efectos de los fármacos , Animales , Biomarcadores/análisis , Oxalato de Calcio/orina , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Glicol de Etileno/toxicidad , Humanos , Hiperoxaluria/inducido químicamente , Hiperoxaluria/orina , Riñón/patología , Riñón/fisiopatología , Cálculos Renales/etiología , Cálculos Renales/fisiopatología , Cálculos Renales/orina , Masculino , Fenilbutiratos/uso terapéutico , Ratas , Ratas WistarRESUMEN
OBJECTIVE: To test the effect of calcium and vitamin B6 therapies on urinary oxalate excretion in a rodent model of enteric hyperoxaluria after Roux-en Y gastric bypass (RYGB) surgery. METHODS: Obese male Sprague-Dawley rats underwent sham (nâ¯=â¯7) or RYGB (nâ¯=â¯10). Animals were maintained on low oxalate (1.5%) and fat (10%; LOF), normal calcium (0.6 %) diet for 8 weeks and then completed a 2-phase crossover metabolic study. In the first 2-week phase, animals were fed a Low oxalate and fat (LOF), high calcium (2.4%; HC) diet. After a 2-week washout, rats were fed a LOF/normal calcium diet highly enriched with vitamin B6. Urine was collected before and after each intervention. Plasma pyridoxal 5'-phosphate (PLP) and metabolites were measured baseline and 11 weeks after sham or RYGB. RESULTS: Compared to baseline, sham animals on LOF/HC diet doubled their urinary calcium excretion but not oxalate. RYGB animals on LOF/HC diet decreased urinary oxalate excretion 28% (P = .001) without a significant rise in urinary calcium. Vitamin B6 supplementation decreased RYGB urinary oxalate by approximately 15% (P = .06), and serum PLP explained 63% of urinary oxalate variability. CONCLUSION: Based on the findings in this model, calcium supplementation appears to be a reasonable therapy to decrease urinary oxalate in RYGB patients who maintain a low fat and oxalate diet. Serum PLP had a fair correlation to urinary oxalate excretion and may be a useful screening tool in hyperoxaluric RYGB patients. Further experimental human studies after RYGB are necessary to determine whether these commonly employed supplements truly provide a benefit in enteric hyperoxaluria.
Asunto(s)
Calcio/uso terapéutico , Suplementos Dietéticos , Derivación Gástrica , Hiperoxaluria/tratamiento farmacológico , Hiperoxaluria/orina , Oxalatos/orina , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/orina , Vitamina B 6/uso terapéutico , Complejo Vitamínico B/uso terapéutico , Animales , Modelos Animales de Enfermedad , Derivación Gástrica/efectos adversos , Hiperoxaluria/etiología , Masculino , Complicaciones Posoperatorias/etiología , Ratas , Ratas Sprague-DawleyRESUMEN
The long pentraxin 3 (PTX3) exerts a variety of regulatory functions in acute and chronic tissue inflammation. In particular, PTX3 acts as an opsonin for a variety of pathogens and endogenous particles. We hypothesized that PTX3 would exhibit opsonin-like functions toward calcium oxalate crystals, too, and inhibit crystal growth. This process is fundamental in kidney stone disease as well as in hyperoxaluria-related nephrocalcinosis, the paradigmatic cause of chronic kidney disease (CKD) in children with primary hyperoxaluria type I due to genetic defects in oxalate metabolism. Direct effects of PTX3 on calcium oxalate crystals were investigated in chemico by adding recombinant PTX3 to supersaturated calcium and oxalate solutions. PTX3, but not isomolar concentrations of albumin, dose-dependently inhibited crystal growth. In vivo, the PTX3 protein was undetectable in tubular epithelial cells and urine of wild-type mice under physiological conditions. However, its levels increased within 3 weeks of feeding an oxalate-rich diet, an exposure inducing hyperoxaluria-related nephrocalcinosis and CKD in selected mouse strains (male and female C57BL/6N and male Balb/c mice) but not in others (male and female 129SV and CD-1, male and female Balb/c mice). Genetic ablation of ptx3 in nephrocalcinosis un-susceptible B6;129 mice was sufficient to raise the oxalate nephropathy phenotype observed in susceptible strains. We conclude that PTX3 is an endogenous inhibitor of calcium oxalate crystal growth. This mechanism limits hyperoxaluria-related nephrocalcinosis, e.g., in primary or secondary hyperoxaluria, and potentially also in the more prevalent kidney stone disease.