Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Men have more kidney stones compared with women; however, the difference is progressively decreasing. The reasons for higher prevalence of stones in men, as well as increasing prevalence in women, is a subject of ongoing speculation. In this review, we summarize the evidence of differences between men and women and expand on the speculative causes. RECENT FINDINGS/RESULTS:Stone incidence is rising in women and adolescent girls. Stone disease is more heritable among men than women, and women demonstrate greater influence of the unique environment. Women under the age of 50 years who have been pregnant, have more than double the odds of kidney stones compared with those who have never been pregnant. Women are more burdened with obesity, bariatric surgery and dieting, all associated with increased stones. Women have higher urinary pH because of greater absorption of dietary organic anions leading to increased urinary citrate, compared with men, and they differ in tubular calcium handling. SUMMARY/CONCLUSIONS:It is obvious that the cause of stones in men and women is complex and requires further study. Potential clues offered are in the change of the female environment, influencing increasing incidence in stones, particularly of younger women and female adolescents.

People with chronic kidney disease (CKD) are at increased risk of hyperkalemia, an electrolyte abnormality that can cause serious, sometimes fatal, cardiac arrhythmias. Muscle contraction causes potassium to be released from cells, increasing serum potassium concentrations. However, these effects are transient, and the long-term impact of exercise training on hyperkalemia risk in CKD patients is largely unknown. In this review, we examine the effects of exercise on factors affecting potassium balance in people with CKD, highlighting the potential benefits of regular exercise on hyperkalemia risk in this population. Although regular exercise is already recommended for people with CKD, research examining this hypothesis may lead to novel therapeutic treatments for this life-threatening condition.

BACKGROUND:A scarcity of organs has driven the transplant community to broaden selection criteria for both living and deceased donors. Living donor transplants offer better patient and allograft survival when compared with deceased donor transplants. Many transplant centers now allow complex living donors such as those with nephrolithiasis to undergo nephrectomy. METHODS:We conducted a survey of medical and surgical directors of kidney transplant programs in the United States to shed light on current practices pertaining to medical evaluation of living kidney donors with nephrolithiasis. 353 surveys were e-mailed to medical directors and surgical directors of transplant programs after contacts were obtained from UNOS. RESULTS:49 completed surveys were returned (13.9%). 77.7% (38/49) of survey participants said their centers will consider living kidney donor candidates with a history of symptomatic kidney stones, 69.4% (34/49) said their centers will consider candidates who are incidentally found to have kidney stones and 10.2% (5/49) said their centers decline all potential donors with nephrolithiasis. CONCLUSIONS:Several programs are still reluctant to allow potential donors with nephrolithiasis to donate. There is an unmet need to develop evidence-based guidelines to optimize outcomes in this population of kidney donors with nephrolithiasis and their recipients.

Previous studies assumed a uniform relationship between heat and kidney stone presentations. Determining whether sex and other characteristics modify the temperature dependence of kidney stone presentations has implications for explaining differences in nephrolithiasis prevalence and improving projections of the effect of climate change on nephrolithiasis. We performed an aggregated case-crossover study among 132,597 children and adults who presented with nephrolithiasis to 68 emergency departments throughout South Carolina from 1997 to 2015. We used quasi-Poisson regression with distributed lag non-linear models to estimate sex differences in the cumulative exposure and lagged response between maximum daily wet-bulb temperatures and emergent kidney stone presentations, aggregated at the ZIP-code level. We also explored interactions by age, race, payer, and climate. Compared to 10 °C, daily wet-bulb temperatures at the 99th percentile were associated with a greater increased relative risk (RR) of kidney stone presentations over 10 days for males (RR 1.73; 95% CI 1.56, 1.91) than for females (RR 1.15; 95% CI 1.01, 1.32; interaction P < 0.001). The shape of the lagged response was similar for males and females, with the greatest risk estimated for the 2 days following high temperatures. There were weak differences by age, race, and climatic zone, and no differences by payer status. The estimated risk of presenting emergently with kidney stones within 10 days of high daily wet-bulb temperatures was substantially greater among men than women, and similar between patients with public and private insurance. These findings suggest that the higher risk among males may be due to sexually dimorphic physiologic responses rather than greater exposure to ambient temperatures.

BACKGROUND:Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. METHODS:M/TP, and A/TP from the CKiD cohort were compared with DD1 and DC. RESULTS:M/Cr of ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease. CONCLUSIONS:M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.

Background: Kidney stones commonly affect US adults. In recent years, there has been increasing interest in the human anaerobic colonic bacterium Oxalobacter formigenes because of its ability to metabolize oxalate, and its potential to protect against calcium oxalate kidney stones. Currently, there are two known groups of O. formigenes (Group 1 and Group 2) with only a few isolates from each group characterized. In our experiments, we aimed to isolate O. formigenes from subjects with primary hyperoxaluria (PH), enteric hyperoxaluria (EH) and healthy controls (HC) to compare their metabolic activities. Understanding these differences will help expand our knowledge about this important organism and its effect on oxalate homeostasis in humans.
Method(s): We collected fecal samples from 37 patients via clinical trials at New York University Langone Medical Center and Mayo Clinic with PH, EH and HC. We cultured fecal samples in 25mM oxalate-rich selective media, then isolated O. formigenes by picking characteristic colonies from calcium oxalate agar. We identified and grouped isolates using PCR and Sanger sequencing of the oxc gene. We then tested their oxalate consumption via Oxalate Degradation Assay to compute mean oxalate degradation rates (ODR) for each group of isolates.
Result(s): We isolated 25 O. formigenes colonies from 14 subjects, with all isolates belonging to either HC (n=11) or PH (n= 14) patients, and none from EH patients. Based on oxc sequences, we identified Group 1 (n=17) and Group 2 (n=5) strains, and potentially a new taxonomic group Group 3 (n=3). We were able to regrow 13 (76%) of 17, 1 (20%) of 5, and 1 (33%) of 3 Group 1, 2, and 3 strains, respectively. All 14 PH patient colonies were identified as Group 1, while HC had a mix of all three groups. Mean ODR was significantly higher in Group 1 vs Group 2 isolates (8.5 +/- 3.3 vs 2.8 +/- 1.9 micromole/ hour, p=0.02). Group 3 isolates had intermediate ODR (5.7 +/- 3.1) values. As expected, the ODRs of our Group 1 isolates were similar to the control group 1 strain OXCC13 (11.1 +/- 1.2). Mean ODR between PH, EH and HC did not differ significantly.
Conclusion(s): We were able to isolate and characterize 25 colonies of O. formigenes, including a potential new group of O. formigenes. Group 1 strains appear to be most metabolically active in vitro, and were exclusively present in PH patients

Background: Cystinuria is a disease of impaired absorption of cystine and dibasic amino acids (DAA) from the intestine and renal tubule leading to formation of cystine kidney stones. However, the metabolic impact of reduced amino acid absorption and excessive loss in the urine is poorly understood. We measured endogenous, gut microbial, and xenobiotic metabolites, providing insight into consequences of the disease and its treatment.
Method(s): Urinary biochemicals were assayed using LC-MS in 293 urine specimens from patients with cystinuria or control urinary phenotypes. Multivariate statistical analyses were conducted to reveal statistically significant biochemical signatures of the disease and products of cysteine-binding thiol drugs (CBTDs). 16s rRNA gene sequencing was performed on fecal samples from 12 wildtype (WT) and 12 cystinuric (Slc3a1 knockout; KO) mice to evaluate their gut microbial composition.
Result(s): Cystinuric urine samples had elevated levels of cysteine-gamma-glutamyl cystine disulfide (glutathione precursor), indole-3-acetic acid (microbial tryptophan metabolism), and novel conjugated forms of putrescine (microbial DAA decomposition). Conversely, taurine (sulfur metabolism), indole-3-acetic acid-glucuronide, and novel urinary metabolite N-methyl pipecolic acid (lysine metabolism) were reduced in cystinuric urine. Where cysteine-bound CBTDs were observed, substantial amounts of "wasted" drug were also detected as CBTD homodimers, non-cysteine disulfides, and mixed drug disulfides. The differentiation of gut microbially-derived metabolites led us to evaluate the gut microbiome diversity and composition in a mouse model of cystinuria revealing clear beta diversity and taxa differentiation between WT and KO mice.
Conclusion(s): Cystinuria is associated with unique urinary metabolic profiles beyond hyperexcretion of cystine and DAA, indicating perturbed metabolic processes and potential gut microbial effects. Study of the gut microbiome of WT and KO mice provides the first evidence for them having distinct taxa, perhaps due to poorly absorbed DAA present in the intestinal lumen. Urinary profiles allow us to characterize the excretion profiles of CBTDs, providing insight which may be helpful to tailor treatment

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: 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