Diet-related urine collections: assistance in categorization of hyperoxaluria

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.

Effect of antibiotic treatment on Oxalobacter formigenes colonization of the gut microbiome and urinary oxalate excretion

The incidence of kidney stones is increasing in the US population. Oxalate, a major factor for stone formation, is degraded by gut bacteria reducing its intestinal absorption. Intestinal O. formigenes colonization has been associated with a lower risk for recurrent kidney stones in humans. In the current study, we used a clinical trial of the eradication of Helicobacter pylori to assess the effects of an antibiotic course on O. formigenes colonization, urine electrolytes, and the composition of the intestinal microbiome. Of 69 healthy adult subjects recruited, 19 received antibiotics for H. pylori eradication, while 46 were followed as controls. Serial fecal samples were examined for O. formigenes presence and microbiota characteristics. Urine, collected serially fasting and following a standard meal, was tested for oxalate and electrolyte concentrations. O. formigenes prevalence was 50%. Colonization was significantly and persistently suppressed in antibiotic-exposed subjects but remained stable in controls. Urinary pH increased after antibiotics, but urinary oxalate did not differ between the control and treatment groups. In subjects not on antibiotics, the O. formigenes-positive samples had higher alpha-diversity and significantly differed in Beta-diversity from the O. formigenes-negative samples. Specific taxa varied in abundance in relation to urinary oxalate levels. These studies identified significant antibiotic effects on O. formigenes colonization and urinary electrolytes and showed that overall microbiome structure differed in subjects according to O. formigenes presence. Identifying a consortium of bacterial taxa associated with urinary oxalate may provide clues for the primary prevention of kidney stones in healthy adults.

In Search of an Efficient Complexing Agent for Oxalates and Phosphates: A Quantum Chemical Study

Limiting gastrointestinal oxalate absorption is a promising approach to reduce urinary oxalate excretion in patients with idiopathic and enteric hyperoxaluria. Phosphate binders, that inhibit gastrointestinal absorption of dietary phosphate by the formation of easily excretable insoluble complexes, are commonly used as a treatment for hyperphosphatemia in patients with end-stage renal disease. Several of these commercially available phosphate binders also have affinity for oxalate. In this work, a series of metallic cations (Li+, Na+, Mg2+, Ca2+, Fe2+, Cu2+, Zn2+, Al3+, Fe3+ and La3+) is investigated on their binding affinity to phosphate and oxalate on one side and anionic species that could be used to administer the cationic species to the body on the other, e.g., acetate, carbonate, chloride, citrate, formate, hydroxide and sulphate. Through quantum chemical calculations, the aim is to understand the competition between the different complexes and propose possible new and more efficient phosphate and oxalate binders.

Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1

Background and objectivesIn the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1.Design, setting, participants, & measurementsThis phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3–6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics.ResultsThirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal.ConclusionsLumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels.Clinical Trial registry name and registration number:Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886

MO113CALCULATED URINARY CALCIUM-OXALATE SATURATION (ßCAOX) IS NOT SPECIFICALLY ELEVATED IN PATIENTS WITH PRIMARY HYPEROXALURIA

Background and Aims In the primary hyperoxalurias (PH; types 1-3) recurrent urolithiasis (UL) and/or progressive nephrocalcinosis (NC) are the clinical hallmarks. Three different enzyme defects lead to endogenous oxalate overproduction and to extremely elevated urinary oxalate excretion (UOx). Thus, it seems logical that urine is supersaturated for calcium-oxalate (CaOx). It was, hence, speculated that urinary CaOx saturation (ßCaOx), calculated by computed programs, is significantly higher as compared to that of patients with idiopathic CaOx stones. We now aimed to evaluate and calculate urinary ßCaOx in PH patients according to type, as well as in non-PH patients with UL or NC. Method The computed equilibrium program EQUIL2 was used for the calculation of ßCaOx. For this, 24 h urine specimen of 70 patients with non-PH NC (46 male, 24 female, median age 6.06 (range 0.3-31.4 years)), of 149 idiopathic CaOx UL (90/59 m/f, age 8.5 (0.1-68.6)), of 51 PH 1 patients (31/21, age 12.33 (0.8-63.8)), of 5 PH 2 patients (3/2, age 5.41 (4.3-12.9)) and of 14 PH 3 patients (8/6, age 8.5 (2.9-29.3)) were analyzed for all necessary components. All patients were in stable kidney function (eGFR > 45 ml/min). Results Uox was higher in the PH patients as compared to the non-PH UL or NC patients (p < 0.05). However, there was no statistical difference between the Uox in PH 1 vs PH 2 or PH 3 patients, although, a clear effect of B6 medication was visible in PH1 patients. Urinary calcium excretion was lower (not significant) in PH patients as compared to NC/UL. There was no difference in ßCaOx when PH were compared to non-PH patients and it mostly remained in the normal range. Conclusion Urine ßCaOx is similar in PH and non-PH stone formers. Therefore, calculation of ßCaOx using computed programs is not a reliable parameter to define the definitively extreme CaOx supersaturation of urine from PH patients. This miscalculation is related to a rather lowish urinary calcium excretion in PH as compared to other UL/NC patients. Therefore, we recommend not to use such programs to express the risk of recurrent stone disease or nephrocalcinosis in PH.

Plasma oxalate and eGFR are correlated in primary hyperoxaluria patients with maintained kidney function—data from three placebo-controlled studies

Background In patients with primary hyperoxaluria (PH), endogenous oxalate overproduction increases urinary oxalate excretion, leading to compromised kidney function and often kidney failure. Highly elevated plasma oxalate (Pox) is associated with systemic oxalate deposition in patients with PH and severe chronic kidney disease (CKD). The relationship between Pox and estimated glomerular filtration rate (eGFR) in patients with preserved kidney function, however, is not well established. Our analysis aimed to investigate a potential correlation between these parameters in PH patients from three randomized, placebo-controlled trials (studies OC3-DB-01, OC3-DB-02, and OC5-DB-01). Methods Baseline data from patients with a PH diagnosis (type 1, 2, or 3) and eGFR > 40 mL/min/1.73 m2 were analyzed for a correlation between eGFR and Pox using Spearman’s rank and Pearson’s correlation coefficients. Data were analyzed by individual study and additionally were pooled for Studies OC3-DB-02 and OC5-DB-01 in which the same Pox assay was used. Results A total of 106 patients were analyzed. A statistically significant inverse Spearman’s correlation between eGFR and Pox was observed across all analyses; correlation coefficients were − 0.44 in study OC3-DB-01, − 0.55 in study OC3-DB-02, − 0.51 in study OC5-DB-01, and − 0.49 in the pooled studies (p < 0.0064). Conclusions Baseline evaluations showed a moderate and statistically significant inverse correlation between eGFR and Pox in patients with PH already at early stages of CKD (stages 1–3b), demonstrating that a correlation is present before substantial loss in kidney function occurs. Graphical abstract

Effect of antibiotic treatment on Oxalobacter formigenes colonization of the gut microbiome and urinary oxalate excretion

Background: The incidence of kidney stones is increasing in the US population. Oxalate, a major factor for stone formation, is degraded by gut bacteria reducing its intestinal absorption. Intestinal O. formigenes colonization has been associated with a lower risk for recurrent kidney stones in humans. In the current study, we used a clinical trial of the eradication of Helicobacter pylori to assess the effects of an antibiotic course on O. formigenes colonization, urine electrolytes, and the composition of the intestinal microbiome. Methods: Of 69 healthy adult subjects recruited, 19 received antibiotics for H. pylori eradication, while 46 were followed as controls. Serial fecal samples were examined for O. formigenes presence and microbiota characteristics. Urine, collected serially fasting and following a standard meal, was tested for oxalate and electrolyte concentrations. Results: O. formigenes prevalence was 50%. Colonization was significantly and persistently suppressed in antibiotic-exposed subjects but remained stable in controls. Urinary pH increased after antibiotics, but urinary oxalate did not differ between the control and treatment groups. The O. formigenes-positive samples had higher alpha-diversity and significantly differed in Beta-diversity from the O. formigenes-negative samples. Specific taxa varied in abundance in relation to urinary oxalate levels.Conclusions: These studies identified significant antibiotic effects on O. formigenes colonization and urinary electrolytes and showed that overall microbiome structure differed in subjects according to O. formigenes presence. Identifying a consortium of bacterial taxa associated with urinary oxalate may provide clues for the primary prevention of kidney stones in healthy adults.

Contribution of Dietary Oxalate and Oxalate Precursors to Urinary Oxalate Excretion

Kidney stone disease is increasing in prevalence, and the most common stone composition is calcium oxalate. Dietary oxalate intake and endogenous production of oxalate are important in the pathophysiology of calcium oxalate stone disease. The impact of dietary oxalate intake on urinary oxalate excretion and kidney stone disease risk has been assessed through large cohort studies as well as smaller studies with dietary control. Net gastrointestinal oxalate absorption influences urinary oxalate excretion. Oxalate-degrading bacteria in the gut microbiome, especially Oxalobacter formigenes, may mitigate stone risk through reducing net oxalate absorption. Ascorbic acid (vitamin C) is the main dietary precursor for endogenous production of oxalate with several other compounds playing a lesser role. Renal handling of oxalate and, potentially, renal synthesis of oxalate may contribute to stone formation. In this review, we discuss dietary oxalate and precursors of oxalate, their pertinent physiology in humans, and what is known about their role in kidney stone disease.

Association of urinary sex steroid hormones with urinary calcium, oxalate and citrate excretion in kidney stone formers

Background Sex-specific differences in nephrolithiasis with respect to both distribution of prevalence and stone composition are widely described and may be influenced by sex hormones. Methods We conducted a cross-sectional analysis of the relationship between 24-hour urinary sex hormone metabolites measured by gas chromatography–mass spectrometry with urinary calcium, oxalate and citrate excretion in a cohort of 628 kidney stone formers from a tertiary care hospital in Switzerland, taking demographic characteristics, kidney function and dietary factors into account. Results We observed a positive association of urinary calcium with urinary testosterone and 17β-estradiol. Positive associations of urinary calcium with dehydroepiandrosterone, 5α-DH-testosterone, etiocholanolone, androsterone, and estriol were modified by net gastrointestinal alkali absorption or urinary sulfate excretion. As the only sex hormone, dehydroepiandrosterone was inversely associated with urinary oxalate excretion in adjusted analyses. Urinary citrate correlated positively with urinary testosterone. Associations of urinary citrate with urinary androsterone, 17β-estradiol and estriol were modified by urinary sulfate or sodium, or by sex. Conclusions Urinary androgens and estrogens are significantly associated with urinary calcium and citrate excretion, and associations are in part modified by diet. Our data furthermore reveal dehydroepiandrosterone as a novel factor associated with urinary oxalate excretion in humans.