Functional Eubacteria Species Along with Trans-domain Gut Inhabitants Favour Dysgenic Diversity in Oxalate Stone Disease

Analyses across all three domains of life are necessary to advance our understanding of taxonomic dysbiosis in human diseases. In the present study, we assessed gut microbiota (eubacteria, archaea, and eukaryotes) of recurrent oxalate kidney stone suffers to explore the extent of trans-domain and functional species dysbiosis inside the gut. Trans-domain taxonomic composition, active oxalate metabolizer and butyrate-producing diversity were explored by utilizing frc-, but-, and buk- functional gene amplicon analysis. Operational taxonomic units (OTUs) level analyses confound with the observation that dysbiosis in gut microbiota is not just limited to eubacteria species, but also to other domains like archaea and eukaryotes. We found that some of healthy eubacterial population retained together with Oxalobacter formigenes and Lactobacillus plantarum colonization in disease condition (p \u3c 0.001 & FDR = 0.05). Interestingly, trans-domain species diversity has been less shared and dysgenic taxa augmentation was found to be higher. Oxalate metabolizing bacterial species (OMBS) and butyrate-producing eubacteria species were found to be decreased in Oxalobacter non-colonizers; and Prevotella and Ruminococcus species which may contribute to oxalate metabolism and butyrate synthesis as well. Our study underscores fact that microbial dysbiosis is not limited to eubacteria only hence suggest the necessity of the trans-domain surveillance in metabolic diseases for intervention studies

Influence of nutrition on feline calcium oxalate urolithiasis with emphasis on endogenous oxalate synthesis

The prevalence of calcium oxalate (CaOx) uroliths detected in cats with lower urinary tract disease has shown a sharp increase over the last decades with a concomitant reciprocal decrease in the occurrence of struvite (magnesium ammonium phosphate) uroliths. CaOx stone-preventative diets are available nowadays, but seem to be marginally effective, as CaOx urolith recurrence occurs in patients fed these diets. In order to improve the preventative measures against CaOx urolithiasis, it is important to understand its aetiopathogenesis. The main research focus in CaOx formation in cats has been on the role of Ca, whereas little research effort has been directed towards the role and origin of urinary oxalates. As in man, the exogenous origin of urinary oxalates in cats is thought to be of minor importance, although the precise contribution of dietary oxalates remains unclear. The generally accepted dietary risk factors for CaOx urolithiasis in cats are discussed and a model for the biosynthetic pathways of oxalate in feline liver is provided. Alanine:glyoxylate aminotransferase 1 (AGT1) in endogenous oxalate metabolism is a liver-specific enzyme targeted in the mitochondria in cats, and allows for efficient conversion of glyoxylate to glycine when fed a carnivorous diet. The low peroxisomal activity of AGT1 in cat liver is compatible with the view that felids utilised a low-carbohydrate diet throughout evolution. Future research should focus on understanding de novo biosynthesis of oxalate in cats and their adaptation(s) in oxalate metabolism, and on dietary oxalate intake and absorption by cats

Obesity and kidney stone disease. A systematic review

INTRODUCTION: Currently, abdominal obesity has reached an epidemic stage and obesity represents an important challenge for worldwide health authorities. Epidemiologic studies have demonstrated that the stone risk incidence increases with Body Mass Index, through multiple pathways. Metabolic syndrome and diabetes are associated with an increased renal stones disease incidence. The aim of this systematic review was to investigate the prevalence, morbidity, risk factors involved in the association between obesity and urolithiasis. EVIDENCE ACQUISITION: The search involved finding relevant studies from MEDLINE, EMBASE, Ovid, the Cochrane Central Register of Controlled Trials, CINAHL, Google Scholar, and individual urological journals between January 2001 and May 2017. The inclusion criteria were for studies written in the English language, reporting on the association between obesity and urinary stones. EVIDENCE SYNTHESIS: The underlying pathophysiology of stone formation in obese patients is thought to be related to insulin resistance, dietary factors, and a lithogenic urinary profile. Uric acid stones and calcium oxalate stones are observed frequently in these patients. Insulin resistance is thought to alter the renal acid-base metabolism, resulting in a lower urine pH, and increasing the risk of uric acid stone disease. Obesity is also associated with excess nutritional intake of lithogenic substances and with an increase in urinary tract infection incidence. Recent studies highlighted that renal stone disease increases the risk of myocardial infarction, progression of chronic kidney disease, and diabetes. Contemporary, bariatric surgery has been shown to be associated with hyperoxaluria and oxalate nephropathy. Certainly, the many health risks of obesity, including nephrolithiasis, will add more burden on urologists and nephrologists. CONCLUSIONS: Obesity related nephrolithiasis seems to necessitate weight loss as primary treatment, but the recognition of the associated complications is necessary to prevent induction of new and equally severe medical problems. The optimal approach to obesity control that minimizes stone risk needs to be determined in order to manage obesity-induced renal stones disease

Transplantation for renal failure secondary to enteric hyperoxaluria: a case report

Enteric hyperoxaluria can lead to renal failure. There have only been a few reports of renal transplantation as treatment of endstage renal disease secondary to enteric hyperoxaluria and results have been mixed. This report describes a patient with Crohn's disease who developed chronic renal failure from enteric hyperoxaluria. He subsequently had a successful renal transplant without any post-operative oxalate related complications and has satisfactory renal function almost three years later. Aggressive pre-transplant hemodialysis was not done. The literature associated with renal transplantation for enteric hyperoxaluria is reviewed

Chemical Chaperones Improve Protein Secretion and Rescue Mutant Factor VIII in Mice with Hemophilia A.

nefficient intracellular protein trafficking is a critical issue in the pathogenesis of a variety of diseases and in recombinant protein production. Here we investigated the trafficking of factor VIII (FVIII), which is affected in the coagulation disorder hemophilia A. We hypothesized that chemical chaperones may be useful to enhance folding and processing of FVIII in recombinant protein production, and as a therapeutic approach in patients with impaired FVIII secretion. A tagged B-domain-deleted version of human FVIII was expressed in cultured Chinese Hamster Ovary cells to mimic the industrial production of this important protein. Of several chemical chaperones tested, the addition of betaine resulted in increased secretion of FVIII, by increasing solubility of intracellular FVIII aggregates and improving transport from endoplasmic reticulum to Golgi. Similar results were obtained in experiments monitoring recombinant full-length FVIII. Oral betaine administration also increased FVIII and factor IX (FIX) plasma levels in FVIII or FIX knockout mice following gene transfer. Moreover, in vitro and in vivo applications of betaine were also able to rescue a trafficking-defective FVIII mutant (FVIIIQ305P). We conclude that chemical chaperones such as betaine might represent a useful treatment concept for hemophilia and other diseases caused by deficient intracellular protein trafficking

Long-Term Transplantation Outcomes in Patients With Primary Hyperoxaluria Type 1 Included in the European Hyperoxaluria Consortium (OxalEurope) Registry

INTRODUCTION: In primary hyperoxaluria type 1 (PH1), oxalate overproduction frequently causes kidney stones, nephrocalcinosis, and kidney failure. As PH1 is caused by a congenital liver enzyme defect, combined liver–kidney transplantation (CLKT) has been recommended in patients with kidney failure. Nevertheless, systematic analyses on long-term transplantation outcomes are scarce. The merits of a sequential over combined procedure regarding kidney graft survival remain unclear as is the place of isolated kidney transplantation (KT) for patients with vitamin B6-responsive genotypes. METHODS: We used the OxalEurope registry for retrospective analyses of patients with PH1 who underwent transplantation. Analyses of crude Kaplan–Meier survival curves and adjusted relative hazards from the Cox proportional hazards model were performed. RESULTS: A total of 267 patients with PH1 underwent transplantation between 1978 and 2019. Data of 244 patients (159 CLKTs, 48 isolated KTs, 37 sequential liver–KTs [SLKTs]) were eligible for comparative analyses. Comparing CLKTs with isolated KTs, adjusted mortality was similar in patients with B6-unresponsive genotypes but lower after isolated KT in patients with B6-responsive genotypes (adjusted hazard ratio 0.07, 95% CI: 0.01–0.75, P = 0.028). CLKT yielded higher adjusted event-free survival and death-censored kidney graft survival in patients with B6-unresponsive genotypes (P = 0.025, P < 0.001) but not in patients with B6-responsive genotypes (P = 0.145, P = 0.421). Outcomes for 159 combined procedures versus 37 sequential procedures were comparable. There were 12 patients who underwent pre-emptive liver transplantation (PLT) with poor outcomes. CONCLUSION: The CLKT or SLKT remains the preferred transplantation modality in patients with PH1 with B6-unresponsive genotypes, but isolated KT could be an alternative approach in patients with B6-responsive genotypes

ALLN-177, oral enzyme therapy for hyperoxaluria

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

Clinical Features and Outcome in Children With Primary Hyperoxaluria; Single Center Experience

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