Multiomics Assessment of the Gut Microbiome in Rare Hyperoxaluric Conditions.

Introduction: Hyperoxaluria is a risk factor for kidney stone formation and chronic kidney disease progression. The microbiome is an important protective factor against oxalate accumulation through the activity of its oxalate-degrading enzymes (ODEs). In this cross-sectional study, we leverage multiomics to characterize the microbial community of participants with primary and enteric hyperoxaluria, as well as idiopathic calcium oxalate kidney stone (CKS) formers, focusing on the relationship between oxalate degrading functions of the microbiome. Methods: Patients diagnosed with type 1 primary hyperoxaluria (PH), enteric hyperoxaluria (EH), and CKS were screened for inclusion in the study. Participants completed a food frequency questionnaire recording their dietary oxalate content while fecal oxalate levels were ascertained. DNA and RNA were extracted from stool samples and sequenced. Metagenomic (MTG) and metatranscriptomic (MTT) data were processed through our bioinformatics pipelines, and microbiome diversity, differential abundance, and networks were subject to statistical analysis in relationship with oxalate levels. Results: A total of 38 subjects were recruited, including 13 healthy participants, 12 patients with recurrent CKS, 8 with PH, and 5 with EH. Urinary and fecal oxalate were significantly higher in the PH and the EH population compared to healthy controls. At the community level, alpha-diversity and beta-diversity indices were similar across all populations. The respective contributions of single bacterial species to the total oxalate degradative potential were similar in healthy and PH subjects. MTT-based network analysis identified the most interactive bacterial network in patients with PH. Patients with EH had a decreased abundance of multiple major oxalate degraders. Conclusion: The composition and inferred activity of oxalate-degrading microbiota were differentially associated with host clinical conditions. Identifying these changes improves our understanding of the relationships between dietary constituents, microbiota, and oxalate homeostasis, and suggests new therapeutic approaches protecting against hyperoxaluria.

Effect of a high-citrate beverage on urine chemistry in patients with calcium kidney stones.

A well-accepted strategy to prevent kidney stones is to increase urine volume by increasing oral intake of fluids, especially water, to lower supersaturation of the relevant, relatively insoluble salts, and thereby lower the risk of precipitation. Randomized controlled trials have shown that this strategy works. It is inexpensive, safe, and intuitively attractive to patients. However, although any beverage can increase urine volume, and citrus juices can increase urine citrate content and pH, no beverage other than water has been clearly shown by randomized controlled trial to prevent kidney stones. We designed an innovative, palatable, low-calorie, high alkali citrate beverage to prevent kidney stones, called Moonstone. One packet of Moonstone powder, mixed in 500 ml of water, contains 24.5 meq of alkali citrate. We administered one packet twice a day to ten calcium stone formers. Moonstone resulted in an increase in mean 24-h urine citrate and urine pH, and a decrease in supersaturation of calcium oxalate in calcium stone formers compared to an equal volume of water. These changes, comparable to those seen in a prior study of a similar amount of (potassium-magnesium) citrate, will likely be associated with a clinically meaningful reduction in kidney stone burden in patients with calcium stones. The effect to increase urine pH would also be expected to benefit patients with uric acid and cystine stones, groups that we hope to study in a subsequent study. The study preparation was well tolerated and was selected as a preferred preventative strategy by about half the participants. Moonstone is an alternative, over-the-counter therapy for kidney stone prevention.

Healthcare utilization, quality of life, and work productivity associated with primary hyperoxaluria: a cross-sectional web-based US survey.

Primary hyperoxaluria (PH) is a family of ultra-rare, autosomal recessive, metabolic disorders associated with frequent kidney stones, chronic kidney disease and kidney failure, and serious complications due to systemic oxalosis, resulting in significant morbidity. We investigated the burden of PH among affected patients and caregivers. This cross-sectional, web-based survey was used to quantify the burden of PH, in terms of healthcare resource utilization, health-related quality of life, and work productivity and activity impairment among adults (≥ 18 years) with PH and caregivers of children (≤ 17 years) with PH in the US. Among the 20 respondents, there were 7 adults with PH and 13 caregivers of children with PH. Adherence to hyperhydration was noted as the most, or one of the most, difficult aspects of PH by 56% of respondents. Most patients (95%) had experienced painful kidney stone events, one-third had visited the emergency room, and 29% were hospitalized for complications due to PH. Of the 24% of patients on dialysis, all found the procedure burdensome. Adult patients' quality of life was negatively affected across several domains. Most respondents (81%) reported that PH had a negative effect on their finances. Employed adult patients and caregivers, and children with PH, had moderate impairment in work productivity, school attendance, and activity. Anxiety about future PH-related sequelae was moderate to high. These findings highlight the need for improvements in PH medical management. A plain language summary is available in the supplementary information.

The longitudinal relationship between patient-reported outcomes and clinical characteristics among patients with focal segmental glomerulosclerosis in the Nephrotic Syndrome Study Network.

BACKGROUND: Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). METHODS: FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. RESULTS: There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (-7.6 points, P = 0.02) and mobility (-4.2, P = 0.02), the number of reported symptoms was associated with worse depression (-2.7 per symptom, P = 0.009) and anxiety (-2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (-2.8 per visit, P < 0.001) and fatigue (-2.4, P = 0.03). Multivariable analyses among adults found the number of reported symptoms was associated with worse function in all eight PROMIS measures and the number of ER visits was associated with worse fatigue, pain interference, sleep impairment, depression, anxiety and social satisfaction. Laboratory markers of disease severity (i.e. proteinuria, estimated glomerular filtration rate and serum albumin) did not predict PRO in multivariable analyses, with the single exception of complete remission and better pain interference scores among children (+9.3, P = 0.03). CONCLUSIONS: PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.

A Descriptive Analysis of an Ambulatory Kidney Palliative Care Program.

Background: Many patients with serious kidney disease have an elevated symptom burden, high mortality, and poor quality of life. Palliative care has the potential to address these problems, yet nephrology patients frequently lack access to this specialty. Objectives: We describe patient demographics and clinical activities of the first 13 months of an ambulatory kidney palliative care (KPC) program that is integrated within a nephrology practice. Design/Measurements: Utilizing chart abstractions, we characterize the clinic population served, clinical service utilization, visit activities, and symptom burden as assessed using the Integrated Palliative Care Outcome Scale-Renal (IPOS-R), and patient satisfaction. Results: Among the 55 patients served, mean patient age was 72.0 years (standard deviation [SD] = 16.7), 95% had chronic kidney disease stage IV or V, and 46% had a Charlson Comorbidity Index >8. The mean IPOS-R score at initial visit was 16 (range = 0-60; SD = 9.1), with a mean of 7.5 (SD = 3.7) individual physical symptoms (range = 0-15) per patient. Eighty-seven percent of initial visits included an advance care planning conversation, 55.4% included a medication change for symptoms, and 35.5% included a dialysis decision-making conversation. Overall, 96% of patients who returned satisfaction surveys were satisfied with the care they received and viewed the KPC program positively. Conclusions: A model of care that integrates palliative care with nephrology care in the ambulatory setting serves high-risk patients with serious kidney disease. This KPC program can potentially meet documented gaps in care while achieving patient satisfaction. Early findings from this program evaluation indicate opportunities for enhanced patient-centered palliative nephrology care.

Assessment of health-related quality of life in patients with cystinuria on tiopronin therapy.

Cystinuria comprises less than 1% of kidney stones and is associated with impaired health-related quality of life (HRQOL). Limited evidence is available regarding HRQOL of patients with cystinuria treated with tiopronin (Thiola®). The objective of this study was to assess the HRQOL of patients with or without tiopronin treatment. For this cross-sectional survey, patients on tiopronin treatment were recruited through the "Thiola® Total Care Hub," a specialty pharmacy used to dispense tiopronin, and compared with patients not taking tiopronin (non-tiopronin group) who were identified from the Cystinuria Contact Registry at New York University School of Medicine. Consented patients responded to a survey that included questions about their experiences with kidney stones, the Wisconsin stone quality of life (WISQOL) (disease-specific) questionnaire, and the short form-36 version 2 (SF-36v2) (generic) HRQOL questionnaire. Statistical analyses included independent-sample t tests, one-way analysis of variance (ANOVA), and correlations. The survey was completed by 312 patients: 267 in the tiopronin group (144 male, 123 female; mean 49 years) and 45 in the non-tiopronin group (10 male, 35 female; mean 48 years). Both groups utilized pain medications similarly (24% overall). Patients on tiopronin had a significantly better HRQOL than patients not on tiopronin for all WISQOL domains (p < 0.001) and all but the physical functioning SF-36v2 domain (p < 0.001), where both groups approached the US normative mean, when controlling for the last stone event. Compared with patients in the non-tiopronin group, patients taking tiopronin reported better HRQOL on both the WISQOL and SF-36v2.

Using PROMIS® to create clinically meaningful profiles of nephrotic syndrome patients.

OBJECTIVE: Nephrotic syndrome (NS) is a kidney disease known to adversely impact health-related quality of life (HRQOL). Patient-reported outcome (PRO) measures are commonly used to characterize HRQOL and the patient disease experience. This study aims to improve the interpretability and clinical utility of the Patient-Reported Outcomes Measurement Information System® (PROMIS®) by identifying distinct meaningful HRQOL profiles in children and adults with NS. METHOD: Patients were from 2 prospective NS cohort studies (PROMIS-II®: 121 children; NEPTUNE: 40 children and 219 adults) with data from 6 PROMIS® domains. Latent Profile Analysis was used to identify subgroups of patients based on PROMIS® score patterns. A 3-step analysis of latent profile predictors was used to determine how clinical parameters predicted HRQOL profile membership. RESULTS: We identified 3 HRQOL profiles (Good, Average, and Poor) with strong indicators of membership classification (entropy >0.86). Complete proteinuria remission, reduction in symptoms, and shorter disease duration, were significant predictors of better HRQOL profile membership. CONCLUSIONS: Patients with NS can be classified by HRQOL into clinically meaningful categories. Integrating this approach into clinic may help in the identification of individuals with poor HRQOL will help clinicians better manage their symptoms and researchers study the causes and possible interventions for these patients. PROMIS® HRQOL profiles were reproducible in replication cohorts. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Effect of increasing doses of cystine-binding thiol drugs on cystine capacity in patients with cystinuria.

Appropriate dosing of cystine-binding thiol drugs in the management of cystinuria has been based on clinical stone activity. When new stones form, the dose is increased. Currently, there is no method of measuring urinary drug levels to guide the titration of therapy. Increasing cystine capacity, a measure of cystine solubility, has been promoted as a method of judging the effects of therapy. In this study, we gave increasing doses of tiopronin or D-penicillamine, depending on the patients' own prescriptions, to ten patients with cystinuria and measured cystine excretion and cystine capacity. The doses were 0, 1, 2, 3 g per day, given in two divided doses, and administered in a random order. Going from 0 to 1 g/day led to an increase in cystine capacity from - 39.1 to 130.4 mg/L (P < 0.009) and decreased 24 h cystine excretion from 1003.9 to 834.8 mg/day (P = 0.039). Increasing the doses from 1 to 2 to 3 g/day had no consistent or significant effect to further increase cystine capacity or decrease cystine excretion. Whether doses higher than 1 g/day have additional clinical benefit is not clear from this study. Limiting doses might be associated with fewer adverse effects without sacrificing the benefit of higher doses if higher doses do not offer clinical importance. However, trials with stone activity as an outcome would be desirable.

Blood volume analysis as a guide for dry weight determination in chronic hemodialysis patients: a crossover study.

BACKGROUND: Volume overload and depletion both lead to high morbidity and mortality. Achieving euvolemia is a challenge in patients with end stage kidney disease on hemodialysis (HD). Blood volume analysis (BVA) uses radiolabeled albumin to determine intravascular blood volume (BV). The measured BV is compared to an ideal BV (validated in healthy controls). We hypothesized that BVA could be used in HD to evaluate the adequacy of the current clinically prescribed "estimated dry weight" (EDW) and to titrate EDW in order to improve overall volume status. We were also interested in the reproducibility of BVA results in end stage kidney disease. METHODS: Twelve adults on chronic HD were recruited; 10 completed the study. BVA (Daxor, New York, NY, USA) was used to measure BV at baseline. EDW was kept the same if the patient was deemed to be euvolemic by BVA otherwise, the prescribed EDW was changed with the aim that measured BV would match ideal BV. A second BVA measurement was done 1-3 months later in order to measure BV again. RESULTS: Based on BVA, 6/10 patients were euvolemic at baseline and 5/10 were euvolemic at the second measurement. When comparing patients who had their prescribed EDW changed after the initial BVA to those who did not, both groups had similar differences between measured and ideal BV (P = 0.75). BV values were unchanged at the second measurement (P = 0.34) and there was no linear correlation between BV change and weight change (r2 = 0.08). CONCLUSIONS: This pilot study is the first longitudinal measurement of BVA in HD patients. It revealed that changing weight did not proportionally change intravascular BV. BV remained stable for 1-3 months. BVA may not be helpful in clinically stable HD patients but studies on patients with hemodynamic instability and uncertain volume status are needed. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02717533), first registered February 4, 2015.

Health-related quality of life (HRQoL) in cystine compared with non-cystine stone formers.

Cystinuria is a genetic cause of recurrent kidney stones which may be more recurrent and larger than more common non-cystine stones. They may have a greater impact on health-related quality of life (HRQoL). We measured this impact by surveying HRQoL in patients with stones, comparing non-cystine stone formers (NCSF) to cystine stone formers (CYSF) and both groups to normative values of the US population. We used SF-36v2 via an internet instrument. CYSF patients were recruited via cystinuria-related websites, two patient advocacy groups, and an active endourology practice. NCSF patients were recruited from the same practice and by email. Total n surveyed with scorable data: 214 CYSF and 81 NCSF. The participants included 128 men and 161 women. The group of CYSF were significantly younger (39 vs. 54 years) and suffered longer from kidney stones (255 vs. 136 months). CYSF patients had significantly more episodes of stones than NCSF patients in the last year (N = 108 CYSF, N = 20 NCSF). More frequent stones in the last year and mental comorbidities most often predicted worse scores in the individual HRQoL domains. However, cystine stone composition was a significant predictor of worse scores only for role emotional. Better scores in all SF-36 domains were associated with greater time since the last kidney stone event. Although kidney stones are often transient, kidney stone formers, regardless of stone composition, have a worse HRQoL than the standard US population, which has a normative score of 50, such as general health (41.2 ± 12.8), bodily pain (46.5 ± 11.8) and mental health (45.1 ± 12.6). CYSF are more frequent and severe stone formers compared with NCSF with a resulting greater, direct impact on the HRQoL of CYSF patients. Whether preventive strategies for cystinuria are being properly utilized by practitioners, and which strategies are most effective, should be established.

Radioisotope blood volume measurement in hemodialysis patients.

Accurate assessment of blood volume (BV) may be helpful for prescribing hemodialysis (HD) and for reducing complications related to hypovolemia and volume overload. Monitoring changes in relative BV (RBV) using hematocrit, e.g., Crit-Line Monitor (CLM-III), an indirect method, cannot be used to determine absolute BV. We report the first study of BV measurement for assessing volume status in HD patients using the indicator dilutional method. Ten adult HD patients were enrolled in this prospective observational study. BV measurement was performed before and after HD using BV analysis (BVA)-100 (Daxor Corporation, New York, NY, USA). BVA-100 calculates BV using radiolabeled albumin (Iodine-131) followed by serial measures of the radioisotope. Fluid loss from the extravascular space was calculated by subtracting the change in BV from total weight loss. Intradialytic changes in RBV were measured by CLM-III. Eight out of 10 cases had significant hypervolemia, two cases were normovolemic. The range of BV variation from predicted normal was 156 to 1990 mL. Significant inter-individual differences in extravascular space fluid loss ranged from 54% to 99% of total weight loss. Spearman correlation showed a good correlation in the measurement of RBV by BVA-100 and CLM-III in 8 out of 10 patients (r(2) = 0.64). BV measurement using BVA-100 is useful to determine absolute BV as well as changes in BV and correlates reasonably well with CLM-III measurements. Individual refilling ability can be determined as well. This may prove useful in prescribing and monitoring ultrafiltration rates, establishment of optimal BV in HD patients and reducing morbidity and mortality associated with chronic HD.

Effects of laparoscopic adjustable gastric banding on sleep and metabolism: a 12-month follow-up study.

BACKGROUND: Obstructive sleep apnea is commonly associated with metabolic changes and obesity, and changes in body weight by either medical or surgical approaches have been considered to affect the severity of sleep apnea and appetite-controlling hormones. This prospective study evaluated the effect of weight loss induced by laparoscopic adjustable gastric banding (LAGB) surgery on respiratory disturbance during sleep, oxygen saturation levels, sleep architecture, and leptin and ghrelin levels. METHODS: Participants were patients at a university-based medical center surgical weight loss program. All participants with a body mass index > 30 kg/m(2) undergoing LAGB surgery for weight reduction were offered the opportunity to participate in the study. Procedures included overnight polysomnography followed by fasting hormone levels at baseline and 12 months postoperatively. RESULTS: Thirty subjects (10 men, 20 women) of mean age 44.0 ± 12.5 years were recruited. At 12 months postoperatively, mean excess weight loss was 44.4% ± 14%. The apnea-hypopnea index decreased from 34.2 ± 35 to 19.0 ± 21.7 events per hour (P < 0.0001), while leptin levels decreased from 24.5 ± 17.42 pg/mL to 11.6 ± 10.6 pg/mL (P = 0.02). Ghrelin levels did not change substantially. Nadir oxygen saturation levels increased from 81% to 84% at 12 months (P = 0.03). Mean oxygen saturation improved and was positively correlated with ghrelin levels at both time points (r = 0.39, P = 0.07, and r = 0.60, P = 0.01). CONCLUSION: LAGB surgery was associated with 44.4% excess weight loss at 12 months, accompanied by a 33.7% improvement in apnea-hypopnea index as well as a reduction in leptin levels by 31.7% in this group. An association between ghrelin and mean oxygen saturation was seen and deserves further investigation.

Predictors of oxidative stress in heart failure patients with Cheyne-Stokes respiration.

PURPOSE: Cheyne-Stokes respiration during sleep is associated with increased mortality in heart failure. The magnitude of oxidative stress is a marker of disease severity and a valuable predictor of mortality in heart failure. Increased oxidative stress associated with periodic breathing during Cheyne-Stokes respiration may mediate increased mortality in these patients. We hypothesized that the presence of Cheyne-Stokes respiration is associated with oxidative stress by increasing the formation of reactive oxygen species in patients with heart failure. METHODS AND RESULTS: Twenty-three patients with heart failure [left ventricular ejection fraction 30.2 ± 9% (mean ± standard deviation)] and 11 healthy controls underwent nocturnal polysomnography. Subjects with obstructive sleep apnea were excluded. The majority (88%) of patients with heart failure had Cheyne-Stokes respiration during sleep. The intensity of oxidative stress in neutrophils was greater in patients with heart failure (4,218 ± 1,706 mean fluorescence intensity/cell vs. 1,003 ± 348 for controls, p < 0.001) and correlated with the duration of Cheyne-Stokes respiration. Oxidative stress was negatively correlated with SaO(2) nadir during sleep (r = -0.43, p = 0.039). The duration of Cheyne-Stokes respiration predicted severity of oxidative stress in patients with heart failure (beta = 483 mean fluorescence intensity/cell, p < 0.02). CONCLUSIONS: Levels of oxidative stress are increased in patients with heart failure and Cheyne-Stokes respiration during sleep compared with healthy controls. The duration of Cheyne-Stokes respiration predicts the magnitude of oxidative stress in heart failure. Increased oxidative stress may mediate increased mortality associated with Cheyne-Stokes respiration in patients with heart failure.

A randomized, controlled trial of lactic acid bacteria for idiopathic hyperoxaluria.

BACKGROUND: Urinary oxalate excretion is an important contributor to calcium oxalate stone formation. Methods of reducing oxalate excretion are not wholly satisfactory, and no controlled trials using them have been performed to prevent stone recurrence. Some lactic acid bacteria can degrade oxalate in vitro. This study sought to reduce urinary oxalate excretion in calcium stone formers with idiopathic hyperoxaluria. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A randomized, double-blind, placebo-controlled trial was performed of Oxadrop, a mix of four lactic acid bacterium species. This preparation previously reduced oxalate excretion in stone formers with idiopathic and enteric hyperoxaluria. Patients were selected from two stone prevention clinics. Twenty people with calcium stones and idiopathic hyperoxaluria (>40 mg/d) were enrolled and randomly assigned 1:1 in placebo and active preparation arms. Both groups took 3.6 g of granulate each day: Either placebo or the experimental preparation. Participants performed two consecutive 24-h urine collections at baseline, at 28 d of therapy, and at 56 d, after being off the preparation for 4 wk. Diet was replicated at each point. RESULTS: There was no effect of the study preparation: Mean 24-h urinary oxalate excretion in placebo-treated patients was 73.9 mg at baseline and 72.7 mg after treatment, whereas the Oxadrop-treated patients had 59.1 mg at baseline and 55.4 mg after treatment. The preparation was well tolerated; three participants on active treatment experienced mild constipation. CONCLUSIONS: In this randomized, placebo-controlled trial, Oxadrop did not reduce urinary oxalate excretion in participants with idiopathic hyperoxaluria.

Respiratory disturbance during sleep in COPD patients without daytime hypoxemia.

Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity and mortality. Its possible association with obstructive sleep apnea is a major cause of concern for clinicians. As the prevalence of both COPD and sleep apnea continues to rise, further investigation of this interaction is needed. In addition, COPD patients are at risk for hypoventilation during sleep due to the underlying respiratory dysfunction. In this study, 13 COPD subjects and 13 non-COPD control subjects were compared for the presence and severity of obstructive sleep apnea and nocturnal hypoventilation. All 26 subjects had presented to a sleep clinic and showed no signs of daytime hypoxemia. After matching for BMI and age, COPD subjects had a similar prevalence of sleep apnea with a lower degree of severity compared to the control subjects. However, less severe events, such as RERA, occurred at similar rates between the two groups. There was no significant difference between groups in the magnitude of oxyhemoglobin desaturation during sleep. Interestingly, severity and presence of nocturnal hypoxemia correlated with that of sleep apnea in the control group, but not in the COPD subjects. In conclusion, COPD without daytime hypoxemia was not a risk factor for sleep apnea or nocturnal hypoventilation in this study.