Faculty Bibliography

INTRODUCTION: and Objectives: To examine kidney stone disease as a potential risk factor for chronic kidney disease (CKD), end-stage kidney disease and treatment with dialysis (ESKD). METHODS: The National Health and Nutrition Examination Survey (NHANES 2007-2010) database was interrogated for patients with a history of kidney stones. Demographics and comorbid conditions including age, sex, body mass index (BMI), diabetes, hemoglobin A1c, hypertension, gout and smoking were also assessed. Multivariate analysis adjusting for patient demographics and comorbidities was performed to assess differences in the prevalence of CKD and treatment with dialysis between the two groups. History of nephrolithiasis was assessed by the question "Have you ever had kidney stones?" CKD was defined as patients with either an eGFR of < 60 mL/min/1.73 m2 or a urinary albumin to creatinine ratio >30 mg/g or both. Statistical calculations were performed using Stata software (StataCorp LP, Texas) with determinations of p-values and 95% confidence intervals where appropriate. RESULTS: The study included an analysis of 5,971 NHANES participants for whom data on CKD and kidney stones was available, of whom 521 reported a history of kidney stones. On multivariate analysis, a history of kidney stones was associated with CKD and treatment with dialysis (OR 1.50 (1.10-2.04) p= 0.013, and 2.37 (1.13- 4.96) p=0.025). This difference appeared to be driven by women, where a history of kidney stones was associated with a higher prevalence of CKD (OR 1.76 (1.13-2.763) p=0.016) and treatment with dialysis (OR 3.26 (1.48-7.16) p=0.004). There was not a significant association between kidney stone history and CKD or treatment with dialysis in men. CONCLUSIONS: Kidney stone history is associated with an increased risk of CKD and treatment with dialysis among women even after adjusting for co-morbid conditions. Large-scale prospective studies are needed to further characterize the relationship between nephrolithiasis and CKD.

OBJECTIVE: To assess the effectiveness of l-cystine dimethyl ester (CDME), an inhibitor of cystine crystal growth, for the treatment of cystine urolithiasis in an Slc3a1 knockout mouse model of cystinuria. MATERIALS AND METHODS: CDME (200 mug per mouse) or water was delivered by gavage daily for 4 weeks. Higher doses by gavage or in the water supply were administered to assess organ toxicity. Urinary amino acids and cystine stones were analyzed to assess drug efficacy using several analytical methods. RESULTS: Treatment with CDME led to a significant decrease in stone size compared with that of the water group (P = .0002), but the number of stones was greater (P = .005). The change in stone size distribution between the 2 groups was evident by micro computed tomography. Overall, cystine excretion in urine was the same between the 2 groups (P = .23), indicating that CDME did not interfere with cystine metabolism. Scanning electron microscopy analysis of cystine stones from the CDME group demonstrated a change in crystal habit, with numerous small crystals. l-cysteine methyl ester was detected by ultra-performance liquid chromatography-mass spectrometer in stones from the CDME group only, indicating that a CDME metabolite was incorporated into the crystal structure. No pathologic changes were observed at the doses tested. CONCLUSION: These data demonstrate that CDME promotes formation of small stones but does not prevent stone formation, consistent with the hypothesis that CDME inhibits cystine crystal growth. Combined with the lack of observed adverse effects, our findings support the use of CDME as a viable treatment for cystine urolithiasis.

Introduction: We assessed (1) the differences in the function of urinary proteins between children with cystinuria and kidney stones (CYS), and healthy controls (HC), and (2) the presence of diagnostic biomarkers for CYS. Material and methods: We compared urinary proteomes of 2 children with CYS and 2 age- and gender-matchedHC, using liquid chromatography-mass spectrometry (LC-MS/MS). Relative protein abundance was estimated using spectral counting. Proteins of interest were selected using the following criteria: 1) >5 spectral counts; 2) >2-fold difference in spectral counts; and 3) <0.05 p-value for the Fisher's Exact Test. Protein function was analyzed using the DAVID online bioinformatics resource, and Cytoscape was used to investigate the key nodes of unique proteins. Results: Of the 623 proteins identified by proteomic analysis, 180 exhibited at least 2-fold difference between CYS and HC. Of those, 94 proteins were up-regulated in CYS, 26 of which were involved in response to wounding, 21 in inflammatory response, 18 in immune response, and 4 in cellular response to oxidative stress. 86 proteins were down-regulated in CYS, 26 of which were involved in cell adhesion. 140 proteins were found only in children with CYS, 33 of which met the selection criteria. Proteinprotein interaction modeling of CYS unique proteins identified actin, vimentin, heat shock 70 kDa protein (HSP70), inter-alpha-trypsin-inhibitor heavy chain (ITIH), and matrix metalloproteinase-9 (MMP-9) as the key nodes, proteins associated with fibrosis pathways. Conclusions: We provide proteomic evidence of oxidative injury, inflammation, wound healing and fibrosis in children with cystinuria and kidney stones. We speculate that oxidative stress and inflammation may cause remodeling via actin and vimentin pathways, leading to fibrosis. Additionally, we identified ITIH and MMP-9 as potential diagnostic biomarkers and novel therapeutic targets in CYS. These unique proteins merit further investigation

Mortality is highest in the first months of maintenance hemodialysis (HD) therapy. In many Western countries, patients who transition to kidney replacement therapy usually begin thrice-weekly HD regardless of their level of residual kidney function (RKF). RKF is a major predictor of survival. RKF may decline more rapidly with thrice-weekly HD treatments, is associated with a reduced need for dialytic solute clearance, and is an important factor in the prescription of peritoneal dialysis. In this article, we review the concept of incremental HD, in which weekly dialysis dose, in particular HD treatment frequency, is based on a variety of clinical factors, such as RKF (including urine output > 0.5L/d), volume status, cardiovascular symptoms, body size, potassium and phosphorus levels, nutritional status, hemoglobin level, comorbid conditions, hospitalizations, and health-related quality of life. These 10 clinical criteria may identify which patients might benefit from beginning maintenance HD therapy twice weekly. Periodic monitoring of these criteria will determine the timing for increasing dialysis dose and frequency. We recognize that twice-weekly HD represents a major paradigm shift for many clinicians and jurisdictions. Therefore, we propose conducting randomized controlled trials of twice-weekly versus thrice-weekly HD to assess the potential of twice-weekly HD to improve survival and health-related quality of life while simultaneously reducing costs, protecting fragile vascular accesses, and optimizing resource use during the first year of hemodialysis therapy. Such incremental and individualized HD therapy may prove to be the most appropriate approach for transitioning to dialytic therapy.

PURPOSE: The purpose of this guideline is to provide a clinical framework for the diagnosis, prevention and follow-up of adult patients with kidney stones based on the best available published literature. MATERIALS AND METHODS: The primary source of evidence for this guideline was the systematic review conducted by the Agency for Healthcare Research and Quality on recurrent nephrolithiasis in adults. To augment and broaden the body of evidence in the AHRQ report, the AUA conducted supplementary searches for articles published from 2007 through 2012 that were systematically reviewed using a methodology developed a priori. In total, these sources yielded 46 studies that were used to form evidence-based guideline statements. In the absence of sufficient evidence, additional statements were developed as Clinical Principles and Expert Opinions. RESULTS: Guideline statements were created to inform clinicians regarding the use of a screening evaluation for first-time and recurrent stone formers, the appropriate initiation of a metabolic evaluation in select patients and recommendations for the initiation and follow-up of medication and/or dietary measures in specific patients. CONCLUSIONS: A variety of medications and dietary measures have been evaluated with greater or less rigor for their efficacy in reducing recurrence rates in stone formers. The guideline statements offered in this document provide a simple, evidence-based approach to identify high-risk or interested stone-forming patients for whom medical and dietary therapy based on metabolic testing and close follow-up is likely to be effective in reducing stone recurrence.

A literature review performed by the EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup highlighted deficiencies in the existing literature, especially the reporting of case studies. Although general reporting guidelines exist for case studies, there are none in the specific field of extracorporeal treatments in toxicology. Our goal was to construct and propose a checklist that systematically outlines the minimum essential items to be reported in a case study of poisoned patients undergoing extracorporeal treatments. Through a modified two-round Delphi technique, panelists (mostly chosen from the EXTRIP workgroup) were asked to vote on the pertinence of a set of items to identify those considered minimally essential for reporting complete and accurate case reports. Furthermore, independent raters validated the clarity of each selected items between each round of voting. All case reports containing data on extracorporeal treatments in poisoning published in Medline in 2011 were reviewed during the external validation rounds. Twenty-one panelists (20 from the EXTRIP workgroup and an invited expert on pharmacology reporting guidelines) participated in the modified Delphi technique. This group included journal editors and experts in nephrology, clinical toxicology, critical care medicine, emergency medicine, and clinical pharmacology. Three independent raters participated in the validation rounds. Panelists voted on a total of 144 items in the first round and 137 items in the second round, with response rates of 96.3% and 98.3%, respectively. Twenty case reports were evaluated at each validation round and the independent raters' response rate was 99.6% and 98.8% per validation round. The final checklist consists of 114 items considered essential for case study reporting. This methodology of alternate voting and external validation rounds was useful in developing the first reporting guideline for case studies in the field of extracorporeal treatments in poisoning. We believe that this guideline will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports may provide early signals of effectiveness and/or harm, thereby improving healthcare decision-making.

BACKGROUND: In order to develop clinical reasoning, medical students must be able to integrate knowledge across traditional subject boundaries and multiple disciplines. At least two dimensions of integration have been identified: horizontal integration, bringing together different disciplines in considering a topic; and vertical integration, bridging basic science and clinical practice. Much attention has been focused on curriculum overhauls, but our approach is to facilitate horizontal and vertical integration on a smaller scale through an interdisciplinary case study discussion and then to assess its utility. METHODS: An interdisciplinary case study discussion about a critically ill patient was implemented at the end of an organ system-based, basic sciences module at New York University School of Medicine. Three clinical specialists-a cardiologist, a pulmonologist, and a nephrologist-jointly led a discussion about a complex patient in the intensive care unit with multiple medical problems secondary to septic shock. The discussion emphasized the physiologic underpinnings behind the patient's presentation and the physiologic considerations across the various systems in determining proper treatment. The discussion also highlighted the interdependence between the cardiovascular, respiratory, and renal systems, which were initially presented in separate units. After the session students were given a brief, anonymous three-question free-response questionnaire in which they were asked to evaluate and freely comment on the exercise. RESULTS: Students not only took away physiological principles but also gained an appreciation for various thematic lessons for bringing basic science to the bedside, especially horizontal and vertical integration. The response of the participants was overwhelmingly positive with many indicating that the exercise integrated the material across organ systems, and strengthened their appreciation of the role of physiology in understanding disease presentations and guiding appropriate therapy. CONCLUSIONS: Horizontal and vertical integration can be presented effectively through a single-session case study, with complex patient cases involving multiple organ systems providing students opportunities to integrate their knowledge across organ systems while emphasizing the importance of physiology in clinical reasoning. Furthermore, having several clinicians from different specialties discuss the case together can reinforce the matter of integration across multiple organ systems and disciplines in students' minds.

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.