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Occasional bursts of discovery and innovation have appeared during the otherwise stagnant past several decades of drug development in nephrology. Among other recent drug discoveries, the unexpected kidney benefits observed with sodium/glucose cotransporter 2 inhibitors may herald a renaissance of drug development in kidney disease. This recent progress highlights the need to further promote and stimulate research and development of promising therapies that may ameliorate the morbidity and mortality associated with kidney disease. To help identify and address barriers to drug development in nephrology, the Duke Clinical Research Institute convened a conference in April 2019 that included stakeholders from academia, industry, government agencies, and patient advocacy. From these discussions, several opportunities were identified to improve every stage of drug development for kidney disease from early discovery to implementation into practice. Key topics reviewed in this article are the utility of interconnected data and site research networks, surrogate end points, pragmatic and adaptive trial designs, the promising uses of real-world data, and methods to improve the generalizability of trial results and uptake of approved drugs for kidney-related diseases., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Vascular calcification is common among patients with chronic kidney disease (CKD), and it is associated with all-cause and cardiovascular disease mortality. Deoxycholic acid, a metabolite of circulating bile acids, is elevated in CKD and induces vascular mineralization and osteogenic differentiation in animal models., Study Design: Cohort analysis of clinical trial participants., Setting & Participants: 112 patients with moderate to severe CKD (estimated glomerular filtration rate, 20-45mL/min/1.73m 2 ) who participated in a randomized controlled study to examine the effects of phosphate binders on vascular calcification., Predictor: Serum deoxycholic acid concentration., Outcomes: Baseline coronary artery calcification (CAC) volume score and bone mineral density (BMD) and change in CAC volume score and BMD after 9 months., Measurements: Deoxycholic acid was assayed in stored baseline serum samples using liquid chromatography-tandem mass spectrometry, CAC was measured using a GE-Imitron C150 scanner, and BMD was determined using computed tomographic scans of the abdomen with calibrated phantom of known density., Results: Higher serum deoxycholic acid concentrations were significantly correlated with greater baseline CAC volume and lower baseline BMD. After adjusting for demographics, coexisting illness, body mass index, estimated glomerular filtration rate, and concentrations of circulating markers of mineral metabolism, including serum calcium, phosphorus, vitamin D, parathyroid hormone, and fibroblast growth factor 23, a serum deoxycholic acid concentration > 58ng/mL (the median) was positively associated with baseline CAC volume (β=0.71; 95% CI, 0.26-1.16; P=0.003) and negatively associated with baseline BMD (β = -20.3; 95% CI, -1.5 to -39.1; P=0.04). Serum deoxycholic acid concentration > 58ng/mL was not significantly associated with change in CAC volume score after 9 months (β=0.06; 95% CI, -0.09 to 0.21; P=0.4). The analysis for the relationship between baseline deoxycholic acid concentrations and change in BMD after 9 months was not statistically significant, but was underpowered., Limitations: The use of nonfasting serum samples is a limitation because deoxycholic acid concentrations may vary based on time of day and dietary intake. Few trial participants with complete data to evaluate the change in CAC volume score (n=75) and BMD (n=59). No data for changes in deoxycholic acid concentrations over time., Conclusions: Among patients with moderate to severe CKD, higher serum deoxycholic acid concentrations were independently associated with greater baseline CAC volume score and lower baseline BMD., (Published by Elsevier Inc.)

Background: Serum phosphorus is associated with cardiovascular disease (CVD) in the general population, but may not comprehensively reflect phosphorus homeostasis. Whether urine phosphorus-creatinine ratio (a marker of intestinal absorption) or urine fractional excretion of phosphorus (FEPi; a marker of urinary phosphorus handling) is associated with risk of mortality or CVD is uncertain., Study Design: Prospective observational study., Setting & Participants: 1,325 community-dwelling men 65 years or older participating in the MrOS Study., Predictor: Serum phosphorus, urine phosphorus-creatinine ratio, and FEPi., Outcomes: All-cause and CVD death., Results: Mean age was 74 ± 6 (SD) years, estimated glomerular filtration rate was 75 ± 16 mL/min/1.73 m(2), and serum phosphorus level was 3.2 ± 0.4 mg/dL. During a median follow-up of 9.3 years, there were 364 (120 CVD) deaths. After adjustment for demographics, CVD risk factors, and kidney function, the risks of all-cause death in the highest quartiles of serum phosphorus (≥3.6 mg/dL), urine phosphorus-creatinine ratio (≥0.55), and FEPi (≥18%) were 1.63 (95% CI, 1.23-2.17), 1.22 (95% CI, 0.90-1.65), and 0.88 (95% CI, 0.64-1.23), respectively, compared to the lowest quartiles of each. Results were similar for CVD death. Results also were similar in those with estimated glomerular filtration rate ≥60 and <60 mL/min/1.73 m(2)., Limitations: Older all-male cohort. Few had advanced chronic kidney disease. Spot urine specimens were used., Conclusions: In community-living older men, higher serum phosphorus concentrations are associated with all-cause and CVD death. In contrast, urine phosphorus-creatinine ratio and FEPi are not. These findings do not support using urine phosphorus-creatinine ratio or FEPi as adjuvant measures to predict risk of mortality or CVD in the general population., (Published by Elsevier Inc.)

Background & Aims: Little is known about the effects of alcohol use and sociodemographics on the risk of Barrett's esophagus, a precursor to esophageal adenocarcinoma. We evaluated the association between alcohol use, alcohol type, sociodemographic profiles, other lifestyle factors, and the risk of Barrett's esophagus., Methods: With the use of a case-control study within the Kaiser Permanente Northern California membership, patients with a new diagnosis of Barrett's esophagus (n = 320) diagnosed between 2002 and 2005 were matched to persons with gastroesophageal reflux disease (GERD; n = 316) and to population controls (n = 317). We collected information using validated questionnaires during direct in-person interviews. Analyses used multivariate unconditional logistic regression., Results: Total alcohol use was not significantly associated with the risk of Barrett's esophagus, although stratification by beverage type showed an inverse association for wine drinkers compared with nondrinkers (>/=7 drinks of wine per week vs none: odds ratio, 0.44; 95% confidence interval, 0.20-0.99; multivariate analysis). Among population controls, those who preferred wine were more likely to have college degrees and regularly take vitamin supplements than those who preferred beer or liquor, although adjustment for these factors or GERD symptoms did not eliminate the inverse association between wine consumption and Barrett's esophagus. Education status was significantly inversely associated with the risk of Barrett's esophagus., Conclusions: There are associations between alcohol types, socioeconomic status, and the risk of Barrett's esophagus. Although choice of alcoholic beverages was associated with several factors, multiple adjustments (including for GERD) did not eliminate the association between alcohol and Barrett's esophagus. Further research to evaluate the associations among socioeconomic status, GERD, and Barrett's esophagus is warranted.

Background: Barrett's esophagus is a strong risk factor for esophageal adenocarcinoma, but little is known about its associations with body mass index (BMI) or abdominal obesity., Methods: We conducted a case-control study within the Kaiser Permanente Northern California population. Persons with a new diagnosis of Barrett's esophagus (cases) were matched to subjects with gastroesophageal reflux disease (GERD) without Barrett's esophagus and to population controls. Subjects completed questionnaires and an anthropometric examination., Results: We interviewed 320 cases, 316 patients with GERD, and 317 controls. There was a general association between Barrett's esophagus and a larger abdominal circumference (independent of BMI) compared with population controls (odds ratio, 2.24; 95% confidence interval, 1.21-4.15; circumference, >80 cm vs <80 cm). There was a possible risk plateau, with increased risk evident only at circumferences >80 cm and no significant trend for further increases in circumference. There was a trend for association compared with patients with GERD (test for trend, P = .03). There was no association between Barrett's esophagus and BMI. Abdominal circumference was associated with GERD symptom severity (odds ratio, 1.86; 95% confidence interval, 1.03-3.38; risk of severe weekly GERD, per 10-cm circumference); adjustment for GERD partially attenuated the association between Barrett's esophagus and circumference., Conclusions: Waist circumference, but not BMI, had some modest independent associations with the risk of Barrett's esophagus. The findings provide partial support for the hypothesis that abdominal obesity contributes to GERD, which may in turn increase the risk of Barrett's esophagus.

Protein-energy malnutrition (PEM) and inflammation are common and usually concurrent in maintenance dialysis patients. Many factors that appear to lead to these 2 conditions overlap, as do assessment tools and such criteria for detecting them as hypoalbuminemia. Both these conditions are related to poor dialysis outcome. Low appetite and a hypercatabolic state are among common features. PEM in dialysis patients has been suggested to be secondary to inflammation; however, the evidence is not conclusive, and an equicausal status or even opposite causal direction is possible. Hence, malnutrition-inflammation complex syndrome (MICS) is an appropriate term. Possible causes of MICS include comorbid illnesses, oxidative and carbonyl stress, nutrient loss through dialysis, anorexia and low nutrient intake, uremic toxins, decreased clearance of inflammatory cytokines, volume overload, and dialysis-related factors. MICS is believed to be the main cause of erythropoietin hyporesponsiveness, high rate of cardiovascular atherosclerotic disease, decreased quality of life, and increased mortality and hospitalization in dialysis patients. Because MICS leads to a low body mass index, hypocholesterolemia, hypocreatininemia, and hypohomocysteinemia, a "reverse epidemiology" of cardiovascular risks can occur in dialysis patients. Therefore, obesity, hypercholesterolemia, and increased blood levels of creatinine and homocysteine appear to be protective and paradoxically associated with a better outcome. There is no consensus about how to determine the degree of severity of MICS or how to manage it. Several diagnostic tools and treatment modalities are discussed. Successful management of MICS may ameliorate the cardiovascular epidemic and poor outcome in dialysis patients. Clinical trials focusing on MICS and its possible causes and consequences are urgently required to improve poor clinical outcome in dialysis patients.

Malnutrition inflammation complex syndrome (MICS) occurs commonly in maintenance hemodialysis (MHD) patients and may correlate with increased morbidity and mortality. An optimal, comprehensive, quantitative system that assesses MICS could be a useful measure of clinical status and may be a predictor of outcome in MHD patients. We therefore attempted to develop and validate such an instrument, comparing it with conventional measures of nutrition and inflammation, as well as prospective hospitalization and mortality. Using components of the conventional Subjective Global Assessment (SGA), a semiquantitative scale with three severity levels, the Dialysis Malnutrition Score (DMS), a fully quantitative scoring system consisting of 7 SGA components, with total score ranging between 7 (normal) and 35 (severely malnourished), was recently developed. To improve the DMS, we added three new elements to the 7 DMS components: body mass index, serum albumin level, and total iron-binding capacity to represent serum transferrin level. This new comprehensive Malnutrition-Inflammation Score (MIS) has 10 components, each with four levels of severity, from 0 (normal) to 3 (very severe). The sum of all 10 MIS components ranges from 0 to 30, denoting increasing degree of severity. These scores were compared with anthropometric measurements, near-infrared-measured body fat percentage, laboratory measures that included serum C-reactive protein (CRP), and 12-month prospective hospitalization and mortality rates. Eighty-three outpatients (44 men, 39 women; age, 59 +/- 15 years) on MHD therapy for at least 3 months (43 +/- 33 months) were evaluated at the beginning of this study and followed up for 1 year. The SGA, DMS, and MIS were assessed simultaneously on all patients by a trained physician. Case-mix-adjusted correlation coefficients for the MIS were significant for hospitalization days (r = 0.45; P < 0.001) and frequency of hospitalization (r = 0.46; P < 0.001). Compared with the SGA and DMS, most pertinent correlation coefficients were stronger with the MIS. The MIS, but not the SGA or DMS, correlated significantly with creatinine level, hematocrit, and CRP level. During the 12-month follow-up, 9 patients died and 6 patients left the cohort. The Cox proportional hazard-calculated relative risk for death for each 10-unit increase in the MIS was 10.43 (95% confidence interval, 2.28 to 47.64; P = 0.002). The MIS was superior to its components or different subversions for predicting mortality. The MIS appears to be a comprehensive scoring system with significant associations with prospective hospitalization and mortality, as well as measures of nutrition, inflammation, and anemia in MHD patients. The MIS may be superior to the conventional SGA and the DMS, as well as to individual laboratory values, as a predictor of dialysis outcome and an indicator of MICS.

Hyperphosphatemia is a predictable consequence of chronic renal failure and is present in most patients on dialysis. Traditionally, the risk associated with elevated serum phosphorus has focused on its impact on renal osteodystrophy. A growing body of evidence, however, suggests that abnormalities in serum phosphorus, calcium-phosphorus product (CaxP), and parathyroid hormone (PTH) levels are resulting in vascular and visceral calcification, thereby contributing to the substantially increased risk of cardiovascular death in this population. In this analysis, we review in detail the literature that describes these associations. We show that the current treatment paradigm for serum phosphorus and secondary hyperparathyroidism is ineffective for a large segment of dialysis patients. Currently, 60% of hemodialysis patients have phosphorus greater than 5.5 mg/dL, and 40% have CaxP greater than 60 mg(2)/dL(2). It is our belief that prevention of uremic calcification, cardiac death, and vascular disease should assume primary importance when evaluating the risks associated with elevated levels of phosphorus, CaxP, and PTH. We recommend that target levels should become 9.2 to 9.6 mg/dL for calcium, 2.5 to 5.5 mg/dL for phosphorus, less than 55 mg(2)/dL(2) for CaxP product, and 100 to 200 pg/mL for intact PTH.

Elevated serum phosphorus is a predictable accompaniment of end-stage renal disease (ESRD) in the absence of dietary phosphate restriction or supplemental phosphate binders. The consequences of hyperphosphatemia include the development and progression of secondary hyperparathyroidism and a predisposition to metastatic calcification when the product of serum calcium and phosphorus (Ca x PO4) is elevated. Both of these conditions may contribute to the substantial morbidity and mortality seen in patients with ESRD. We have analyzed the distribution of serum phosphorus in two large national, random, cross-sectional samples of hemodialysis patients who have been receiving dialysis for at least 1 year. Data were obtained from two special studies of the United States Renal Data System, the Case Mix Adequacy Study (1990) and the Dialysis Morbidity and Mortality Study Wave 1 (1993). The relative risk of death by serum phosphorus quintiles is described after adjusting for age at onset of ESRD, race, sex, smoking status, and the presence of diabetes, the acquired immunodeficiency syndrome, and/or neoplasm. Logistic regression analysis is then used to describe the demographic, comorbid, and laboratory parameters associated with high serum phosphorus. Serum phosphorus was similar in these two study populations and averaged 6.2 mg/dL. Ten percent of patients had levels greater than 9 mg/dL and at least 30% of each group had serum phosphorus levels greater than 7 mg/dL. The adjusted relative risk of death by serum phosphorus level was not uniform across all quintiles, being constant below a level of 6.5 mg/dL and increasing significantly above this level. The relative risk of death for those with a serum phosphorus greater than 6.5 mg/dL was 1.27 relative to those with a serum phosphorus of 2.4 to 6.5 mg/dL. This increased risk was not diminished by statistical adjustment for coexisting medical conditions, delivered dose of dialysis, nutritional parameters, or markers of noncompliance. Evaluation of predictors of serum phosphorus greater than 6.5 mg/dL revealed in multivariate analysis that younger age at onset of ESRD, female sex, white race, diabetes, active smoking, and higher serum creatinine levels were all significant predictors. Analysis of serum calcium revealed no correlation with relative risk of death. The Ca x PO4 product, however, showed a mortality risk trend similar to that seen with serum phosphorus alone. Those in the highest quintile of the Ca x PO4 product (>72 mg2/dL2) had a relative mortality risk of 1.34 relative to those with products of 42 to 52 mg2/dL2. The relative mortality risk by log parathyroid hormone (PTH) level was elevated for patients with higher levels, but the mortality risk associated with hyperphosphatemia was independent of PTH. For hemodialysis patients who have been receiving dialysis for at least 1 year, we conclude that a large percentage have a serum phosphorus level above 6.5 mg/dL and that this places them at increased risk of death. This increased risk is independent of PTH. The mechanism(s) responsible for death is unknown, but may be related to an abnormally high Ca x PO4 product. Although mechanisms are not clearly established, this study supports the need for vigorous control of hyperphosphatemia to improve patient survival.

Four cases of desmiod tumors of the anterior abdominal wall recently treated at the University of Chicago Hospitals and Clinics are presented. From our experience we conclude: 1. Inadequate excision of desmoid tumors results in local recurrence. 2. Adequate excision of desmoid tumors ot the abdominal wall sometimes necessitates creation of an abdominal wall defect too large for primary closure. 3. Marlex mesh has been used successfully in reconstruction of the abdominal wall following adequate excision of desmoid tumors. 4. One patient (Case 4) with an abdominal wall desmoid tumor associated with familial polypisis and mesenteric fibromatosis has benefited greatly following wide excision of abdominal wall and reconstriction using Marlex mesh, despite the fact that the mesenteric fibrous tumor was unresectable.

From 1970 to mid-1975, we have operated on 25 consecutive patients with toxic dilatation of the colon with no mortality. This report deals with the principles of management which we follow; primary emphasis is given to aggressive diagnosis and resuscitation, followed by early operative intervention. We prefer total abdominal colectomy with ileostomy and sigmoid mucous fistula for cases of toxic megacolon not complicated by hemorrhage.