Faculty Bibliography

Patients with complex chronic diseases usually must make multiple lifestyle changes to limit and manage their conditions. Numerous studies have shown that education alone is insufficient for engaging people in lifestyle behavior change, and that theory-based behavioral approaches also are necessary. However, even the most motivated individual may have difficulty with making lifestyle changes because of the information complexity associated with multiple behavior changes. The goal of the current Healthy Hearts and Kidneys study was to evaluate, different mobile health (mHealth)-delivered intervention approaches for engaging individuals with type 2 diabetes (T2D) and concurrent chronic kidney disease (CKD) in behavior changes. Participants were randomized to 1 of 4 groups, receiving: (1) a behavioral counseling, (2) technology-based self-monitoring to reduce information complexity, (3) combined behavioral counseling and technology-based self-monitoring, or (4) baseline advice. We will determine the impact of randomization assignment on weight loss success and 24-hour urinary excretion of sodium and phosphorus. With this report we describe the study design, methods, and approaches used to assure information security for this ongoing clinical trial. Clinical Trials.gov Identifier: NCT02276742.

Background: Cystic fibrosis (CF) may predispose patients to urinary stone disease (USD) via several proposed mechanisms including antibiotic exposure and intestinal malabsorption. Prevalence of USD in patients with CF was estimated at 2-6% in studies with mean age 16-27 years. These data are limited by small sample sizes and single-center settings. The CF Foundation Patient Registry (CFFPR) began collecting prevalence data on USD in 2006.
Method(s): We studied 29,396 patients in the CFFPR living in 2016 to calculate age-stratified prevalence of USD.USD was assessed by trained CF clinic staff at each encounter. For 15,531 patients age 18 or older we examined associations between age, BMI, demographics, CFTR mutation class, other clinical parameters, and prevalent USD using multivariate logistic regression.
Result(s): Overall prevalence of USD was 3.1% (95% CI 2.9-3.3%). Prevalence under age 18 years was 0.4% (0.3-0.5%), 18 to 24 years, 3.1% (2.7-3.6%), 25 to 34 years, 6.4% (5.8-7.1%), 35 to 44 years, 7.5% (6.5-8.5%), and 45 years and older, 6.7% (5.8-7.8%). Mean age of all patients was 21.3 years. We also calculated prevalence for age ranges 20-29, and 30-39 years to compare with published NHANES data for the general population. Stone prevalence was 4.8% and 7.1% in in CF patients within these two age cohorts, respectively, compared to 3.4 and 6.4% in NHANES. Multivariate adjusted odds ratios for stone prevalence were significant for female sex, OR 1.4 (95% CI 1.2-1.7), severe CFTR mutations, OR 1.8 (1.2-2.5), diabetes, OR 1.2 (1.0-1.5), hypertension, OR 1.4 (1.0-1.9), and chronic macrolide therapy, OR 1.3 (1.1-1.6). BMI was not associated with USD.
Conclusion(s): USD prevalence in CFFPR may be higher than in the general population and increased with age. Some risk factors for stone disease in the general population appear significant for adult patients with CF, including hypertension and diabetes. However, BMI did not show the same relationship. Several novel associations with USD in CF patients also were identified, including a greater prevalence in women. This study is limited by the method of USD assessment; it is possible patients with more severe CF had higher rates of reported asymptomatic stones incidentally diagnosed due to more frequent imaging. As life expectancy of people with CF increases, the prevalence of USD may also increase

Background: CSF have lower HRQoL compared to US Standard Population. We have shown previously that HRQoL results need to be controlled for the last stone event and comorbidities. We now show the first longitudinal HRQoL domain profiles for baseline and two yearly follow-ups.
Method(s): CSF were enrolled from the RKSC registry. HRQoL was measured with the generic non-disease specific SF-36v2. Results were calculated as norm-based scores (NBS) based on US Standard Population (Domain score mean = 50). We selected 3 stone frequency groups (SFG): low (stone-free during observation period), medium (minimum of one stone event between 31-365 days) and high (stone event always present within 30 days of the survey), and compared the groups' HRQoL at baseline and second follow-up.
Result(s): We scored 386 surveys. 78 participants (32 males and 46 females) were compared at baseline and 2 follow-up assessments. Mean age was 45 years (male 44/ female 46). Repeated measure ANOVA showed no difference within each SFG over time (Fig 1). However, domain scores were significantly different between SFG's (p<0.05) at each time point, with low>medium>high stone frequency. Whether surgical intervention was required, and type, were not predictors of HRQoL outcomes. Better HRQoL tracked with lower cystine excretion per liter on 24h urine collections; lower cystine capacity and higher citrate doses were underpowered (NS).
Conclusion(s): CSF with high stone event rates experience worse HRQoL over time, while CSF with no stone events achieved better HRQoL than US standard. Clinnical data suggest that the high SFG is undertreated

Background: About 60-80% of kidney stones are composed of calcium oxalate (CaOx); idiopathic CaOx kidney stones (CaOPx), primary hyperoxaluria (PH) and enteric hyperoxaluria (EH) are diseases predisposing to stones. Oxalobacter formigenes (Oxf) is a human gut commensal that depends on oxalate for its carbon and energy, and may be protective against CaOx stones. We hypothesize that the microbiome community structure differs between patients with CaOx, PH, EH and normal subjects (NS). We also expect that Oxf isolates from PH patients will result in further reduction in urinary oxalate when compared to Oxf reference strain CC13, in a germ-free (GF) mouse model.
Method(s): We collected fecal specimens from 34 subjects (mean age: 39.1 +/- 11.9 years) with PH (n=6), CaOPx (n=10), EH (n= 5) and NS (n=13) in a cross-sectional observational study, and tested fecal samples from the groups by: 1)16S rRNA sequencing to determine the microbiome community structure, 2)PCR and qPCR for Oxf colonization and, 3) culturing in high oxalate selective media for indication of Oxf presence and subsequent isolation. We isolated Oxf from 4 PH (Oxf PH) subjects. We gavaged a growing culture of PH Oxf (n=6), Oxf reference strain CC13 (Oxf CC13) (n=5), and sham (n=6) into adult C5B6 GF mice, observing them for 4 weeks. We collected urine from mice for 48 hours before sacrifice to be tested for oxalate and creatinine (Uox/cr).
Result(s): Oxf was detected in 6 (46%) of 13 NS, 1 (10%) of 10 CaOPx, 0 (0%)of 4 EH, and 5 (83%) of 6 PH. Microbiome analysis revealed that the 4 groups differed in beta diversity, based on Bray-Curtis dissimilarity (p=0.08). Alpha diversity analysis trended toward lower Shannon and phylogenetic diversity index in the CaOPx and EH subjects compared to PH and NS. Introducing the PH Oxf to GF mice led to lower Uox/cr than in uninoculated controls (0.68 +/- 0.14, and 2.26 +/-0.49, respectively, p=0.04 by Mann-Whitney U test), but not significantly different from the Oxf CC13-innoculated mice (0.68 +/- 0.14, and 0.91 +/-0.24, respectively, p=0.26 by Mann-Whitney U test).
Conclusion(s): These studies provide evidence of differences in Oxf colonization rates and in microbiome composition in patients with CaOx stones and show the functional capacity of a PH Oxf strain to ameliorate hyperoxaluria. Studies to expand these patient groups are on-going

Background: Behavioral methods enhance the effectiveness of lifestyle interventions, but are often resource intensive. Although mobile health (mHealth) technology can help create lower input interventions, their feasibility, acceptability and efficacy have not been adequately evaluated in hemodialysis (HD) patients.
Method(s): Maintenance HD patients with persistent hyperphosphatemia (n=40) were randomized to receive: (1) educational (Edu) videos (EDU), (2) Edu + mobile selfmonitoring (SM) with MyNetDiary (MON), or (3) Edu + SM + social cognitive theory (SCT)-based behavioral counseling videos (SCT) over a 12-week period with videos for each group delivered using iPads. Serum phosphorus concentrations (sPO4) were measured at baseline, 12 and 24 weeks, and a 5-point Likert scale survey on the mHealth technology was completed at 24-weeks. Two participants in the EDU group with no follow-up sPO4 measurements were excluded; missing sPO4 measurements at 12-and 24-weeks were imputed by carrying forward the most recent sPO4 values.
Result(s): At the end of the intervention phase (12-weeks), there was a non-significant trend towards greater decreases in sPO4 in the MON (-0.5+/-1.6 mg/dL, p=0.32) and SCT (-0.3+/-2.1 mg/dL, p=0.56) groups compared to the EDU group (+0.2+/-1.4 mg/dL), but these differences had mostly disappeared by the end of the monitoring phase (24-weeks) (EDU +0.1+/-1.2 mg/dL, MON -0.1+/-1.9 mg/dL, SCT -0.1+/-2.1 mg/dL). Most participants agreed or strongly agreed that the iPads were convenient (64%), and SM helped them stay motivated (68%), take binders (61%), and limit phosphorus intake (68%). Relatively few participants reported that they agreed or strongly agreed that they sometimes "got lost" maneuvering the iPad programs (24%), felt that SM wasn't worthwhile (16%), or would have preferred face-to-face meetings offsite (4%).
Conclusion(s): Many HD patients are willing, able and report benefits of engaging in technology-supported behavioral interventions involving SM and SCT. Although these programs are easy to disseminate with limited resources once developed, any benefits for phosphorus management in HD patients may last only as long as the intervention is active

Background: Cystinuria is an inherited kidney stone disorder caused by mutations to the SLC3A1 and SLC7A9 genes. While most cases are due to biallelic mutations to either gene, monoallelic and digenic families have been described, with overall considerable disease variability. Nevertheless, clear genotype/phenotype correlations have not been described to date.
Method(s): A next generation sequencing (NGS) panel consisting of 90 known and candidate kidney stone genes was developed and validated. A total of 49 unrelated, genetically unscreened individuals with a clinical diagnosis of cystinuria were analyzed using this panel. Preliminary correlations with phenotype were made with the genic groups.
Result(s): The baseline mean (SD) characteristics of the cohort were: age at diagnosis = 19.6y (12.5), number of stones = 5.8 (6.6), cystine excretion = 939.9mg (323.6), eGFR = 82.1ml/min/1.73m² (24.5), with age at last follow up = 43.8y (14). A total of 34 patients (69.4%) had biallelic SLC3A1 and 11 (22.4%) biallelic SLC7A9 mutations. One SLC3A1 and two SLC7A9 cases had a single detected mutation, and one case had no mutations detected. Large rearrangements, detected by LOG2 ratio analysis of the sequence data and confirmed by Multiplex Ligation-dependent Probe Amplification (MLPA), accounted for 31.9% of all SLC3A1 mutations, mainly the common ex5-9 duplication. Other common mutations were the SLC3A1 missense change p.Met467Thr (21.7% alleles) and the nonsense mutation p.Arg270* (18.8%), while for SLC7A9 the missense mutation p.Gly105Arg accounted for 29.2% of pathogenic alleles. Ten novel mutations were identified for each gene. The only detected correlation with genotype was with baseline mean stone number, SLC3A1 = 7.1 (7.1), SLC7A9 = 2.0 (2.1; p=0.05) in this cohort.
Conclusion(s): This analysis shows the utility of a panel-based NGS approach in cystinuria populations and more broadly in patients with suspected monogenic stone disease. Other genetic and/or environmental factors likely also contribute to the observed phenotypic variability

Background: Kidney stones represent a disease of worldwide prevalence with significant public health implications. About 60-80% of stones are composed of calcium oxalate (CaOx); hyperoxaluria is a major risk factor for CaOx stones. Oxalate is an endproduct of mammalian digestion and as with urea, must be excreted. We obtain oxalate from diet, or from endogenous production. Certain intestinal bacteria have the ability to degrade oxalate, protecting against oxalate nephropathy, including nephrolithiasis. To understand the role of the gut microbiome in oxalate metabolism, we compared conventional mice with germ-free mice (that lack a microbiota). In addition to the stress of endogenous oxalate production, we challenged groups with dietary and metabolic (via hydroxyproline (Hyp) supplementation) oxalate loads.
Method(s): Conventional (CO) and germ-free (GF) mice were fed normal chow diets supplemented with either 1% Oxalate (Ox), 1% Hydroxyproline (Hyp) or were unsupplemented (NC) for 6 weeks (n=3-4/mice group). After 6 weeks, we obtained 48-hour urine collections for measurement of the oxalate/creatinine ratio (Uox/cr).
Result(s): In CO mice, Uox/cr increased with the Ox diet compared with NC (0.57 + 0.17 vs 0.16 + 0.05, p= 0.03 by Student's t test), but not with the Hyp diet (0.14 +0.03 vs 0.16 +0.05, p=ns). However, in germ-free mice, both dietary Hyp and Ox led to increased Uox/ cr compared to NC diet (0.50 +/- 0.04, 0.85 +/- 0.11, vs. 0.31+/- 0.06, p<0.05 by ANOVA, respectively). Uox/Cr was lower in CO mice than GF mice when receiving Hyp (p=0.01, by Student's t test), Ox (p=0.06), and NC diets (0.06).
Conclusion(s): In conclusion, oxalate excretion was higher in the germ-free than in the conventional mice under all three dietary conditions (Ox, Hyp, NC), providing direct evidence that the normal gut microbiome plays a protective (symbiotic) role in oxalate metabolism. With the metabolic stress of the Hyp diet, the CO mice but not the germfree mice could compensate. Since mice are not colonized with O. formigenes, this work indicates that other members of their microbiota have the functional capacity to alter oxalate metabolism

Background: Urine chemistry is a determinant of stone formation in cystinuria. We previously showed that positive cystine capacity (CysCap), a measure of higher cystine solubility, led to fewer stone events. We queried the RKSC Cystinuria Registry to determine urinary and medication variables associated with positive (CysCap+), rather than negative (CysCap-) values.
Method(s): This is the 1st report from the Cystinuria Registry, with data on 300 people with cystinuria (142 males, 158 females; age at enrollment 38 +/- 17 years). 112 participants had 306 determinations of CysCap, measured by Litholink (Chicago, IL). In this cross-sectional study we compared variables associated with CysCap+ vs CysCap-.
Result(s): Lower urine Na (r=0.48; Fig 1A) and creatinine (r=0.62, not shown) were associated with lower 24h urine cystine (UC; P<0.001). Increasing CysCap values were seen with increasing urine pH (rs=0.45, Fig 1B), volume (rs=0.44) and decreasing UC (rs=-0.44 Fig 1C; all P<0.001). Dividing Cyscap determinations into CysCap+ and CysCapgroups (Table), only higher urine volume and greater daily citrate doses were different. Relatively few participants were taking citrate or tiopronin.
Conclusion(s): Higher urine pH and volume and lower UC were associated with less lithogenic urine; lower UC was seen with less Na and creatinine. Higher volume and citrate doses distinguished patients with less lithogenic urine. Many patients with cystinuria may be undertreated and would benefit from better dietary adherence. (Table Presented)

Background: USD is a preventable disease characterized by significant risk of recurrence. A "cascade of care" shows how many patients are lost to follow-up at diagnosis, referral, and treatment and is a useful tool in delivering HIV care. We can analyze our success, or failure, in the secondary prevention of kidney stones and retention of patients by constructing a cascade of care.
Method(s): We abstracted data from observational studies to identify impediments to care of patients with USD Results: In the US there are about 1.2 million ER visits per year. 37% of patients diagnosed with stones receive a follow-up consultation with a urologist and fewer see a nephrologist. Although 24h urine collection results may decrease stone recurrence rate, only 7.4% do them. 50% of patients experience a recurrent 2nd episode within 5 years. Of these 24% undergo a complete evaluation, 18% are referred to a nephrologist and 13.8% are prescribed medical therapy. 30% remain adherent to this pharmacotherapy. Of patients that are adherent 27% have lower odds of an ER visit than non-adherent patients. The cascade of care demonstrates that a low prevalence of patients receive proper followup. The impediments to the care of patients with kidney stones are (1) the unrecognized comorbidities of stones (2) disconnect between the ER and stone experts and (3) the low prevalence of 24h urine collections and prescribed medical therapy.
Conclusion(s): It is important to identify loci in the cascade of care that could represent opportunities to change practice. Prescription of appropriate fluid therapy and dietary changes and a referral to an expert should 1st be initiated by the ER. The low prevalence of 24h urine collections may reflect that the data are intimidating for some. Empiric therapy for calcium stones with fluids, diet, thiazides and potassium citrate may be a rational therapy to achieve significant supersaturation reductions and could be compared with targeted medical therapy in a randomized controlled trial. A greater effort needs to be devoted to develp a comprehensive flow of participants to retain patients in the cascade of care for USD. (Table Presented)

Background: The assessment of HRQoL in RKSF is important for following disease course and evaluating treatment. Previously, using a non-disease specific instrument we showed that RKSF present differently, with the worst domain scores in cystinuria. These are the first follow-up data based on summary scores for adults in a cross-sectional comparison.
Method(s): RKSF were enrolled from 4 RKSC registries: primary hyperoxaluria, cystinuria, Dent disease and APRTd. HRQoL is measured with the generic non-disease specific SF-36v2. Results are norm-based scores (NBS) based on US Standard Population (Domain score mean = 50). Group means < 47 indicate the presence of impaired functioning in associated dimension.
Result(s): We scored 545 surveys of the adult population at different time points, adjusted for the last stone event and compared the Physical and Mental Component Scores (PCS and MCS). We found the lowest PCS in Dent, and the highest in PH. The lowest MCS was found in cystinuria, the highest was found in PH. Low PCS indicate restrictions in self-care, physical, social and role activities; bodily pain, tiredness and poor rated health. Low MCS are associated with frequent psychological distress, social and role disability due to emotional problems, and poor rated health. Participants with cystinuria reported more stone events with related procedures than other RKSF (X2 (9) 23.375, p=.005).
Conclusion(s): HRQoL in RKSF is influenced by stone events and can be assessed with a non-disease specific SF-36v2. Adjusting for time between the survey and last event allows for the interpretation of more meaningful HRQoL profiles. The time from the last stone event and related procedures affect HRQOL in RKSF significantly. (Table Presented)