Faculty Bibliography

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

Diet is a key determinant of several common and serious disease complications in hemodialysis (HD) patients. The recommended balance and variety of foods in the HD diet is designed to limit high potassium and phosphorus foods while maintaining protein adequacy. In this report, we examine the potassium, phosphorus, and protein content of foods, and identify critical challenges, and potential pitfalls when translating nutrient prescriptions into dietary guidelines. Our findings highlight the importance of individualized counseling based on a comprehensive dietary assessment by trained diet professionals, namely renal dietitians, for managing diet-related complications in HD patients.

Medullary sponge kidney (MSK) is a cause of nephrocalcinosis, associated with hematuria, renal colic, pyelonephritis. There are rare and atypical MSK cases characterized by chronic severe pain (CP), whose features are unknown, in particular the relationship with the stone disease activity. This study analyzes a cohort of MSK-CP patients belonging to three North-America self-support Facebook groups. Patients had to self-administer an on-line questionnaire (on intensity, progression and MSK-associated conditions, stone-related disease, pain features, drug use), the Brief Pain Inventory, the Fatigue Severity Score, and Wisconsin Quality of Life (WQL) in stone formers questionnaires. Ninety-two patients with a diagnosis of MSK joined our survey. Stone rate was very high (3.1 stones per patient-year, < 15% of patients had ≤ 1 stone per year). Most patients had repeated hospitalizations for stones symptoms (p < 0.001) or pain (p < 0.005). 71% of participants referred a daily pain that interfered strongly with everyday life and quality of life (WQL mean value 29.4). 69% used pain medications daily (70% opioids). In most cases, pain was associated with stone passage, while 15% referred a sine materia pain. We showed how MSK-CP symptoms affect very negatively on the quality of life of these patients. They also have a definite risk of progressing to end-stage kidney disease. Generally, CP seems to be associated with an exceptionally high lithogenic activity, suggesting that a better and earlier metabolic treatment for stone prevention should be the first approach in these patients before mini-invasive treatments to prevent pain.

Expression of Tamm-Horsfall protein (THP or uromodulin) is highly restricted to the kidneys' thick ascending limb (TAL) of loop of Henle. Despite the unique location and recent association of THP gene mutations with hereditary uromodulin-associated kidney disease and THP single nucleotide polymorphisms with chronic kidney disease and hypertension, the physiological function(s) of THP and its pathological involvement remain incompletely understood. By studying age-dependent changes of THP knockout (KO) mice, we show here that young KO mice had significant salt and water wasting but were partially responsive to furosemide, due to decreased luminal translocation of Na-K-Cl cotransporter 2 (NKCC2) in the TAL. Aged THP KO mice were, however, markedly oliguric and unresponsive to furosemide, and their NKCC2 was localized primarily in the cytoplasm as evidenced by lipid raft floatation assay, cell fractionation, confocal and immunoelectron microscopy. These aged KO mice responded to metolazone and acetazolamide, known to target distal and proximal tubules, respectively. They also had marked upregulation of renin in juxtaglomerular apparatus and serum, and they were hypertensive. Finally, the aged THP KO mice had significant upregulation of Na-coupled urate transporters Slc5a8 and Slc22a12 as well as sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule and elevated serum uric acid and allantoin. Collectively, our results suggest that THP deficiency can cause progressive disturbances in renal functions via initially NKCC2 dysfunction and later compensatory responses resulting in prolonged activation of the renin-angiotensin-aldosterone axis and hyperuricema.

Background Although intestinal and urinary microbiome perturbations are associated with nephrolithiasis, whether antibiotics are a risk factor for this condition remains unknown.Methods We determined the association between 12 classes of oral antibiotics and nephrolithiasis in a population-based, case-control study nested within 641 general practices providing electronic health record data for >13 million children and adults from 1994 to 2015 in the United Kingdom. We used incidence density sampling to match 25,981 patients with nephrolithiasis to 259,797 controls by age, sex, and practice at date of diagnosis (index date). Conditional logistic regression models were adjusted for the rate of health care encounters, comorbidities, urinary tract infections, and use of thiazide and loop diuretics, proton-pump inhibitors, and statins.Results Exposure to any of five different antibiotic classes 3-12 months before index date was associated with nephrolithiasis. The adjusted odds ratio (95% confidence interval) was 2.33 (2.19 to 2.48) for sulfas, 1.88 (1.75 to 2.01) for cephalosporins, 1.67 (1.54 to 1.81) for fluoroquinolones, 1.70 (1.55 to 1.88) for nitrofurantoin/methenamine, and 1.27 (1.18 to 1.36) for broad-spectrum penicillins. In exploratory analyses, the magnitude of associations was greatest for exposure at younger ages (P<0.001) and 3-6 months before index date (P<0.001), with all but broad-spectrum penicillins remaining statistically significant 3-5 years from exposure.Conclusions Oral antibiotics associated with increased odds of nephrolithiasis, with the greatest odds for recent exposure and exposure at younger age. These results have implications for disease pathogenesis and the rising incidence of nephrolithiasis, particularly among children.

Temperature and relative humidity have opposing effects on evaporative water loss, the likely mediator of the temperature-dependence of nephrolithiasis. However, prior studies considered only dry-bulb temperatures when estimating the temperature-dependence of nephrolithiasis. We used distributed lag non-linear models and repeated 10-fold cross-validation to determine the daily temperature metric and corresponding adjustment for relative humidity that most accurately predicted kidney stone presentations during hot and cold periods in South Carolina from 1997 to 2015. We examined three metrics for wet-bulb temperatures and heat index, both of which measure the combination of temperature and humidity, and for dry-bulb temperatures: (1) daytime mean temperature; (2) 24-h mean temperature; and (3) most extreme 24-h temperature. For models using dry-bulb temperatures, we considered four treatments of relative humidity. Among 188,531 patients who presented with kidney stones, 24-h wet bulb temperature best predicted kidney stone presentation during summer. Mean cross-validated residuals were generally lower in summer for wet-bulb temperatures and heat index than the corresponding dry-bulb temperature metric, regardless of type of adjustment for relative humidity. Those dry-bulb models that additionally adjusted for relative humidity had higher mean residuals than other temperature metrics. The relative risk of kidney stone presentations at the 99th percentile of each temperature metric compared to the respective median temperature in summer months differed by temperature metric and relative humidity adjustment, and ranged from an excess risk of 8-14%. All metrics performed similarly in winter. The combination of temperature and relative humidity determine the risk of kidney stone presentations, particularly during periods of high heat and humidity. These results suggest that metrics that measure moist heat stress should be used to estimate the temperature-dependence of kidney stone presentations, but that the particular metric is relatively unimportant.

PURPOSE/OBJECTIVE:Treatment of a first-time renal stone consists of acute management followed by medical efforts to prevent stone recurrence. Although nephrolithiasis is roughly 50% heritable, the presence of a family history usually does not affect treatment since most stone disease is regarded as polygenic, ie not attributable to a single gene. Recent evidence has suggested that single mutations could be responsible for a larger proportion of renal stones than previously thought. This intriguing possibility holds the potential to change the management paradigm in stone prevention from metabolically directed therapy to more specific approaches informed by genetic screening and testing. This review synthesizes new findings concerning monogenic kidney stone disease, and provides a concise and clinically useful reference for monogenic causes. It is expected that increased awareness of these etiologies will lead to increased use of genetic testing in recurrent stone formers and further research into the prevalence of monogenic stone disease. MATERIALS AND METHODS/METHODS:We assembled a complete list of genes known to cause or influence nephrolithiasis based on recent reviews and commentaries. We then comprehensively searched PubMed® and Google Scholar™ for all research on each gene having a pertinent role in nephrolithiasis. We determined which genes could be considered monogenic causes of nephrolithiasis. One gene, ALPL, was excluded since nephrolithiasis is a relatively minor aspect of the disorder associated with the gene (hypophosphatasia). We summarized selected studies and assembled clinically relevant details. RESULTS:A total of 27 genes were reviewed in terms of recent findings, mode of inheritance of stone disease, known or supposed prevalence of mutations in the general population of stone patients and specific therapies or considerations. CONCLUSIONS:There is a distinct opportunity for increased use of genetic testing to improve the lives of pediatric and adult stone patients. Several genes first reported in association with rare disease may be loci for novel mutations, heterozygous disease and forme frustes as causes of stones in the broader population. Cases of idiopathic nephrolithiasis should be considered as potentially having a monogenic basis.

INTRODUCTION/BACKGROUND:Adenine phosphoribosyltransferase (APRT) deficiency is a rare, but significant, cause of kidney stones and progressive chronic kidney disease. The optimal treatment has not been established. The purpose of this pilot study was to compare the effect of the xanthine oxidoreductase inhibitors allopurinol and febuxostat on urinary 2,8-dihydroxyadenine (DHA) excretion in APRT deficiency patients. MATERIALS AND METHODS/METHODS:Patients listed in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, currently receiving allopurinol therapy, were invited to participate. The trial endpoint was the 24-h urinary DHA excretion following treatment with allopurinol (400mg/day) and febuxostat (80mg/day). Urinary DHA was measured using a novel ultra-performance liquid chromatography - electrospray tandem mass spectrometry assay. RESULTS:Eight of the 10 patients invited completed the study. The median (range) 24-h urinary DHA excretion was 116 (75-289) mg at baseline, and 45 (13-112) mg after 14days of allopurinol therapy (P=0.036). At the end of the febuxostat treatment period, 4 patients had urinary DHA below detectable limits (<20ng/mL) compared with none of the participants following allopurinol treatment (P=0.036). The other 4 participants had a median 24-h urinary DHA excretion of 13.2 (10.0-13.4) mg at the completion of febuxostat therapy (P=0.036). CONCLUSION/CONCLUSIONS:Urinary DHA excretion in APRT deficiency patients decreased with conventional doses of both allopurinol and febuxostat. Febuxostat was, however, significantly more efficacious than allopurinol in reducing DHA excretion in the prescribed doses. This finding, which may translate into improved outcomes of patients with APRT deficiency, should be confirmed in a larger sample.

Because salicylism is a clinical diagnosis, the serum concentration should be interpreted in conjunction with the clinical presentation. A 26-year-old man presented to the Emergency Department with abdominal painand had extremely elevated serum triglycerides (>7000 mg/dL). Ethanol, acetaminophen, and salicylate concentrations were checked because of concern of self-injurious behavior, which returned at 13.1 mg/dL, undetectable, and >100 mg/dL, respectively. His basic metabolic panel revealed a bicarbonate of 23 mEq/L and an anion gap of 11. An arterial blood gas showed a pH 7.39 and a PCO2 of 36.6 mmHg. On physical examination, he was awake and alert, and had a respiratory rate of 12–14/min. The possible effect of hyperlipidemia to falsely elevate the salicylate concentration was recognized. He was treated for severe hypertriglyceridemia and as his triglyceride level dropped, his repeat salicylate concentration was <1 mg/dL. Since dfferent sized lipoproteins contribute variably to serum sample turbiditythey have the potential to interfere with the absorption of light thereby producing erroneous laboratory results . Clinicians need to be aware of the implications of severe hyperlipidemia and interference to prevent clinical errors based on false positive laboratory results