Faculty Bibliography

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.

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/METHODS: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).

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: = 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/BACKGROUND:ClinicalTrials.gov (NCT02717533), first registered February 4, 2015.

Background: Potassium citrate is a mainstay of treatment to prevent calcium stones. However, it can increase urine pH and calcium phosphate (CaP) supersaturation (SS). HCA, extracted from garcinia cambogia, is a potent inhibitor of calcium oxalate (CaOx) crystal growth in vitro and may not yield HCO3. It is "generally regarded as safe" and available over the counter. We studied how HCA supplementation affects urine chemistry.
Method(s): We enrolled 2 groups: calcium stone formers (SF) and non-stone forming (NSF) controls. Thiazides and potassium citrate were held for 2 weeks prior to study. Participants recorded a self-selected diet for 2 days and performed 24-hour urine collection on day 2. HCA 300 mg 3 times daily was taken orally for 7 days, and 24-hour urine collected on day 7 while the patient replicated the initial, self-selected diet.
Result(s): 13 people, aged 26-76 years, participated. There were 6 SF and 7 NSF, combined into 1 group of 13. Patients replicated their diets well, as urine Na, volume, and creatinine were similar (data not shown). Results presented in Table. HCA increased urine K and citrate (P < 0.001 and 0.013 respectively). Mean urine pH was unchanged (6.25 to 6.47, P=0.14), while urinary NH4 fell (P = 0.017). 24h excretion of Ca and Ox did not change. SS of CaOx and CaP did not change. Serum values did not change: baseline HCO3 and K were 23.5 +/- 2.5 and 4.0 +/- 0.2 meq/L and 23.7 +/- 1.8 and 4.4 +/- 0.6 meq/L after HCA.
Conclusion(s): Urine K excretion rose by 29 meq/day compared with an expected increase based on the label of 14 meq, suggesting the label was not accurate. Increased citrate and lower NH4 suggest some K is in the form of alkali salts or that some HCA is metabolized to bicarbonate. There was no change in CaP or CaOx SS. The lack of effect on SS may not reflect the potential ability of HCA to inhibit calcium crystallization, as it inhibits Ca crystal growth in vitro in supersaturated media

Background: We have shown previously that PH has better HRQoL compared to cystine stone formers and the US Standard Population. Now we show the first crosssectional HRQoL profiles of PH patients.
Method(s): PH participants were enrolled from the Rare Kidney Stone Consortium (RKSC) registry. The group of PH participants consist of PH 1, 2, 3, and PH-NMD (no mutation detected). PH-NMD met clinical criteria for PH. HRQoL was measured with the generic non-disease specific instrument (SF-36v2). Results were calculated as norm-based scores (NBS) based on US Standard Population (mean domain score = 50). We created three stone event groups (<= 30 days, 31-365 days, >=366 days). We compared HRQoL by last stone event for PH participants without a liver and/or kidney transplant. Group means < 47 indicate the presence of impaired functioning in associated dimensions.
Result(s): We used 184 surveys of adults with PH at different time points, adjusted for the last stone event, and compared SF-36 domain profiles. 56 participants were included with multiple surveys (PH1 26, PH2 8, PH3 13, PH-NMD 9; 30 males, 26 females; 42 years old, males 42 years, females 41 years). Lowest domain results were found in participants that experienced a stone event <= 30 days before the survey. Participants with no stone event within a year had the best HRQoL with domain scores above the US Standard Population. PH-NMD compared to PH1, PH2 and PH3 had the highest stone event rate within one year of the survey (58.1 vs 35 vs 3 vs 29.5%). All PH patients with a stone event within 30 days of the survey trended towards higher urine oxalate excretion and lower eGFR (underpowered, not significant). Figure 1 shows that time since the last stone significantly affected HRQoL.
Conclusion(s): PH participants as a group are not homogeneous and experience different HRQoL based on proximity to stone event. PH type is a covariate. Overall PH2 has fewer stone events compared to other PH participants, with an expected direct impact on HRQoL

Background: Patients with advanced kidney disease have an elevated symptom burden, increased mortality, and poor quality of life. While palliative care can address these issues, nephrology patients infrequently receive such care. To address this, we implemented an ambulatory kidney palliative care program. We describe our initial outcomes.
Method(s): Utilizing chart abstractions, we characterized the clinic population and symptom burden for patients seen from May 6, 2016-July 6, 2018.
Result(s): Ninety-four patients were referred; 74 (78.7%) patients seen. Forty (54.1%) had follow-up appointments (range 2-13). Mean patient age was 72.7 +/-16 years with 32 (43.2%) on dialysis. The mean symptom burden (n=65) was 12 (+/- 4.9) symptoms (out of 17) with mean severity of 2 (range 0-4), representing moderate severity. The most common physical symptoms were nausea (78%), dyspnea (72%), pain (68%) and itch (66%). Eighty-seven percent reported anxiety and 73% reported depression. There was no difference in symptom burden between patients on dialysis and those on conservative management (n=22). Patients on conservative management were significantly older and had more comorbidities. By visit two, there was a significant reduction in global symptom score (21.9 vs 19.0, p=0.01) in addition to a reduction in anxiety (2.1 vs 1.7, p=0.03), vomiting (0.8 vs 0.2, p=0.04), and restless legs syndrome (1.3 vs 0.8, p = 0.02).
Conclusion(s): Patients with serious kidney disease treated in a kidney palliative care clinic have a high symptom burden regardless of treatment choice. The decision to pursue conservative management is more prevalent in older patients with more comorbidities. Follow up visits to the clinic demonstrated a decrease in symptom burden, suggesting that a dedicated kidney-palliative care clinic may be successful in managing symptoms and addressing unmet need

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: 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: 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)