Barry M. Wall

INFLUENCES ON RENAL FUNCTION IN CHRONIC SPINAL CORD INJURED PATIENTS

PURPOSE The optimal method of bladder management in the spinal cord injured population remains controversial. We determined the significance of bladder management and other factors on renal function in this population. MATERIALS AND METHODS We retrospectively reviewed the medical records and upper tract imaging studies of 308 patients with a mean followup of 18.7 years since injury. Renal function was assessed by serum creatinine, creatinine clearance and proteinuria measurement, and by upper tract abnormalities on renal ultrasound and nuclear medicine renal scan. Independent variables evaluated for an influence on renal function included patient age, interval since injury, injury level and completeness, vesicoureteral reflux, history of diabetes mellitus and bladder management method. RESULTS Mean serum creatinine plus or minus standard deviation in patients on chronic Foley catheterization, clean intermittent catheterization and spontaneous voiding was 1.08 +/- 0.99, 0.84 +/- 0.23 and 0.97 +/- 0.45 mg./dl. (analysis of variance p = 0.05, Students t test p = 0.10), and mean creatinine clearance was 91.1 +/- 46.5, 113.4 +/- 39.8 and 115 +/- 49 ml. per minute, respectively (analysis of variance and Students t test p <0.01), respectively. Proteinuria was present in 19 patients (6.2%) in the Foley catheterization, 3 (1%) in the clean intermittent catheterization and 4 (1.3%) in the spontaneous voiding group (chi-square test p <0.01), while there were upper tract abnormalities in 56 (18.2%), 20 (6.5%) and 24 (7.8%) patients, respectively (chi-square test p <0.01). Multiple regression analyses revealed no significant predictors of serum creatinine, although older patient age and Foley catheterization significantly predicted low creatinine clearance. Additional logistic regression analyses showed that Foley catheterization was associated with proteinuria and vesicoureteral reflux was associated with upper tract abnormalities. CONCLUSIONS While renal function may be preserved by all forms of bladder management, chronic indwelling catheters may contribute to renal deterioration.

Severe hypernatremia correction rate and mortality in hospitalized patients.

Introduction:Hypernatremia is a common problem in hospitalized patients and is associated with high morbidity and mortality. This study was designed to evaluate whether physicians follow the recommended guidelines for the rate of correction of hypernatremia of ≤0.5 mEq/L/hr and to evaluate the effect of the rate of correction of severe hypernatremia on the mortality of hospitalized patients. Methods:A retrospective chart review of 131 consecutively hospitalized patients with severe hypernatremia (serum sodium ≥155 mEq/L) was performed. Primary outcomes were 30-day patient mortality and 72-hour hypernatremia correction. The first 24-hour serum sodium (Na+) correction rate was tested as a categorical variable; slow rate (<0.25 mEq/L/hr) and fast rate (≥0.25 mEq/L/hr). Results:The mean admission serum Na+ level was 159 ± 3 mEq/L. Ninety percent of patients received the recommended <0.5 mEq/L/hr serum Na+ correction rate; however, hypernatremia was corrected only in 27% of patients after 72 hours of treatment. Thirty-day patient mortality rate was 37%. In multivariable analysis, do not resuscitate status [hazards ratio (HR), 3.85; P < 0.0001], slower correction rate of hypernatremia (HR, 2.63; P = 0.02) and high heart rate (>100 beats/min; HR, 1.99; P = 0.03) were the independent predictors of 30-day mortality. Conclusion:In patients with severe hypernatremia, the rate of correction of hypernatremia was slow and resulted in inadequate correction in majority of the patients. Both slow rate of hypernatremia correction during the first 24 hours and do not resuscitate status were found to be significant predictors of 30-day patient mortality.

Assessment of 24,25(OH)2D levels does not support FGF23-mediated catabolism of vitamin D metabolites

Progressive elevations of fibroblastic growth factor 23 [FGF23] in chronic kidney disease may reduce serum 25-hydroxyvitamin D [25(OH)] and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels, via stimulation of 24-hydroxylase (Cyp24A1) mediated catabolism of these vitamin D metabolites. To test this possibility, we measured serum concentrations of 24,25-dihydroxyvitamin D [24,25(OH)2D], a product of Cyp24A1 hydroxylation of 25(OH)D, in the Col4α3 knockout mouse, a model of Alport syndrome-derived chronic kidney disease, and in patients with chronic kidney disease of variable severity. There was an inverse correlation between serum FGF23 and both 25(OH)D and 1,25(OH)2D in the mouse model but no significant relationship was observed in the cross-sectional patient cohort. The FGF23-dependent increase in Cyp24a1 mRNA expression in the mouse kidneys was consistent with the possibility that FGF23 induces vitamin D catabolism. There was, however, a reduction in serum 24,25(OH)2D levels, rather than the expected elevation, in both the mice and patients with chronic kidney disease. Low 25(OH)D and elevated FGF23 and parathyroid hormone levels were correlated with the reduced serum 24,25(OH)2D concentrations of these patients. Thus, we failed to find support for FGF23-mediated catabolism of vitamin D metabolites in chronic kidney disease assessed by 24,25(OH)2D levels.

Bacteremia In The Chronic Spinal Cord Injury Population: Risk Factors For Mortality

Abstract Background: Individuals with spinal cord injury (SCI) have a lifelong increased risk of systemic infection, which may be associated with episodes of life-threatening bacteremia. Information concerning specific organisms causing bacteremia, the sites of primary infection, and clinical predictors for mortality are necessary to provide optimal treatment. Methods: A retrospective review of positive blood cultures collected over a 3 2-month period in chronic SCI patients treated at the Veterans Affairs Medical Center SCI Unit. Results: One hundred and twenty-three episodes of bacteremia occurred in 63 patients during 83 hospitalizations; 30 patients had multiple episodes of bacteremia. There were 1 ,644 admissions during this period, yielding an incidence of bacteremia of 7 .5% (5.8% after excluding positive cultures that were believed to be caused by contaminants). The patients (31 with paraplegia and 32 with quadriplegia) had a mean age of 59 ± 2 years, and a mean duration of injury of 23 ± 2 years. Bladder management technique consisted of indwelling bladder catheter (n = 53), ileal conduit (n = 6), intermittent catheterization (n = 2), and spontaneous voiding (n = 2). Episodes of bacteremia were nosocomial in 89 out of 123 episodes. Multiple debilitating factors were present, including pressure ulcers in 3 6 out of 63 patients, chronic ventilator dependency in 5 out of 63 patients, recent surgical procedures in 17 out of 63 patients, unde rlying malignancy in 5 out of 63 patients, and evidence of malnutrition in 2 9 out of 63 patients (serum albumin concentration < 2.5 g/dl). Early mortality rate (death within 30 days of bacteremia) occurred in 8 out of 63 patients (13 %) and late mortality (> 1 month following a bacteremic episode) occurred in 1 0 additional participants, such that total mortality was 1 8 out of 63 (2 9%). The sources of bacteremia were urinary tract infection (n = 3 9), presumed contaminant (n = 28), decubitus ulcers (n = 21 ), intravascular catheter (n = 1 9), pneumonia (n = 5), and other (n = 11 ). Gram-negative rods accounted for 2 6 out of 3 9 episodes of bacteremia from a urinary source. Methicillin-resistant Staphylococcus au reus, methicillin-sensitiveS au reus, and coagulase-negative staphylococci were the predominant organi sms when intravascular catheters or pressure ulce rs were the source of bacteremia. Conclusion: In this population, bacteremia predominantly was caused by hospital-associated organisms, and occurred mainly in malnourished patients who required hospitalization for major unde rlying debilitating conditions, particularly pressure ulcers. Chronic indwelling bladder cathet e rs and chronic vascular catheter usage also were highly prevalent in patients with bacteremic episodes. Hypoalbuminemia was the strongest independent predictor for mortality.

INDUCIBLE NITRIC OXIDE SYNTHASE IN THE BLADDER OF SPINAL CORD INJURED PATIENTS WITH A CHRONIC INDWELLING URINARY CATHETER

PURPOSE Spinal cord injured patients are at increased risk for bladder carcinoma. Nitric oxide production in areas of chronic inflammation may provide a stimulus for carcinogenesis by serving as a source of nitrosating agents that generate potentially carcinogenic nitrosamines from secondary amines normally present in urine. MATERIALS AND METHODS To determine whether inducible nitric oxide synthase is expressed as a catalyst for sustained nitric oxide production by cellular elements in chronically inflamed bladder mucosa immunohistochemical studies were performed on mucosal biopsies obtained from 37 adults with spinal cord injury. All participants had required a chronic indwelling urethral or suprapubic catheter for greater than 8 years. RESULTS Histopathological studies revealed active inflammatory infiltrates in all 37 biopsy specimens, squamous metaplasia in 20, epithelial dysplasia in 3 and carcinoma in 1. Inducible nitric oxide synthase was detected in inflammatory cells localized to the lamina propria. Inducible nitric oxide synthase positive cells were identified as macrophages using monoclonal antibodies to macrophage antigen. There was no inducible nitric oxide synthase expression in the urothelial cell layers. Immunostaining for inducible nitric oxide synthase was not detected in bladder mucosal biopsy specimens obtained from cadaveric organ donors. CONCLUSIONS Inducible nitric oxide synthase is expressed in inflammatory macrophages in areas of chronic inflammation in the bladder mucosa of spinal cord injured patients with a chronic indwelling bladder catheter. The expression of inducible nitric oxide synthase may potentially lead to the sustained production of nitric oxide and its oxidative products, the nitrosation of urinary amines and the formation of potentially carcinogenic nitrosamines in the bladder.

Chronic hyponatremia due to resetting of the osmostat in a patient with gastric carcinoma

A 54-year-old schizophrenic patient who presented with hyponatremia and nephrotic-range proteinuria was subsequently discovered to have a gastric adenocarcinoma. Psychogenic water drinking, sodium depletion, and cardiac, adrenal, hepatic, and thyroid disease were excluded as causes of hyponatremia. The serum creatinine concentration was normal, and, although renal biopsy showed changes consistent with immune complex glomerulopathy, proteinuria remitted without treatment. Moderately severe hyponatremia persisted, and the diagnosis of gastric adenocarcinoma was made after the onset of early satiety 1 year later. Surgical exploration at the time of partial gastric resection revealed local metastatic lymph node involvement. Following the patients uneventful recovery from surgery, studies of osmoregulation of vasopressin release and renal water handling were performed to determine the cause of chronic hyponatremia refractory to sodium chloride administration. Oral water loading studies revealed normal urinary diluting ability and appropriate suppression of plasma vasopressin concentrations. However, hypertonic sodium chloride infusion studies revealed a highly significant correlation between plasma osmolality and plasma vasopressin concentration, and a low osmotic threshold for vasopressin release based on linear regression analysis of the plasma vasopressin response to increasing plasma osmolality. Low osmotic threshold for vasopressin release was confirmed by exponential (log linear) and parabolic methods of data analysis. The findings in these studies are consistent with the typical features of the reset osmostat variant of the syndrome of inappropriate antidiuresis. To our knowledge, this is the first report of the occurrence of this syndrome in association with gastric adenocarcinoma.

Diagnosis and treatment of diabetic kidney disease.

Abstract:Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease in the United States. In the last several years, there have been several new developments in the field of the DKD. In 2007, the National Kidney Foundation and Kidney Disease Outcomes Quality Initiative released clinical practice guidelines that included new definitions and summarized diagnostic and therapeutic approaches for DKD. The results of several recent randomized controlled trials provided novel insights regarding effects of glycemic and lipid control on vascular and renal outcomes in patients with diabetes. Additionally, the findings of the Action to Control Cardiovascular Risk in Diabetes—Blood Pressure trial played a critical role in the revision of blood pressure target guidelines in patients with diabetes. The goal of this review article is to summarize recent updates and recommendations for the diagnosis and treatment of DKD.

Effect of Metformin-Containing Antidiabetic Regimens on All-cause Mortality in Veterans With Type 2 Diabetes Mellitus

Objective:There are conflicting reports concerning metformin use and mortality rates in patients with type 2 diabetes (T2DM). The aim of this study was to examine the relationship between metformin use and all-cause mortality in veterans with T2DM. Research design and methods:An observational cohort study involving 2206 patients with T2DM was performed using computerized database from the Veterans Affairs Medical Center, Memphis, TN. All-cause mortality was compared among cohorts of metformin and nonmetformin users. Univariate and multivariate Cox regression models were used to estimate hazard ratios (HR) for all-cause mortality after adjusting for age, race, baseline estimated glomerular filtration rate, glycosylated hemoglobin, use of insulin, use of ACE inhibitors or angiotensin II receptor blockers or statins. Results:The average length of follow-up in metformin and nonmetformin users was 62 ± 17 and 61 ± 18 months, respectively. The mean age was 63 ± 11 years. Crude mortality rates were similar in both groups: 266 (22%) metformin users and 253 (25.3%) nonmetformin users died. There was a trend for improved survival with metformin use (unadjusted HR 0.85, P = 0.07). After multivariate adjustment, metformin users had significantly decreased HR for time to all-cause mortality compared with nonmetformin users (adjusted HR 0.77, P < 0.01). Insulin use was an independent predictor of worsened survival in both univariate and multivariate analyses. In subgroup analysis of patients exposed to insulin, all-cause mortality remained decreased in metformin users (adjusted HR 0.62, P < 0.04). Conclusion:Treatment of T2DM with regimens containing metformin alone or in combination with other hypoglycemic agents was associated with reduced all-cause mortality compared with regimens without metformin.

Inappropriate Antidiuresis and Hyponatremia with Suppressible Vasopressin in Guillain-Barré Syndrome

Studies in which plasma osmolality was altered acutely by oral water loading and hypertonic sodium chloride infusion were performed to further identify the mechanisms involved in the pathogenesis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in a patient with Guillain-Barré syndrome. Although resetting of the osmotic threshold for vasopressin release was demonstrated in these studies, this does not seem to have been a primary factor in the development of SIADH in this patient. Downward resetting of the osmotic threshold by sustained hypoosmolality has been previously demonstrated, and it is possible that this may account for the initially low osmotic threshold identified by our studies. These studies suggest that inappropriate antidiuresis, as shown by the absence of a diuretic response to low threshold suppression of the plasma arginine vasopressin concentration was due either to a vasopressin-independent mechanism or to markedly increased renal tubular sensitivity to vasopressin.

Performance of Simplified Modification of Diet in Renal Disease and Cockcroft-Gault Equations in Patients With Chronic Spinal Cord Injury and Chronic Kidney Disease

Introduction:The purpose of the study was to compare the performance of the simplified Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (CG) equations with 24-hour urinary creatinine clearance (Ccr) in patients with spinal cord injury (SCI) and chronic kidney disease. Methods:A retrospective diagnostic accuracy study of 116 patients with chronic SCI followed at the Memphis Veterans Affairs Medical Center Spinal Cord Injury Unit with measured Ccr (mCcr) <90 mL/min/1.73 m2. Results:Linear regression analysis relating estimated glomerular filtration rate (eGFR) to mCcr showed a highly significant correlation between mCcr and eGFR (n = 116; r = 0.81, r2 = 0.65, P < 0.0001); however, the relationship was more variable in the quadriplegic subjects (n = 52; r = 0.74, r2 = 0.54, P < 0.0001) than in the paraplegic subjects (n = 64; r = 0.86, r2 = 0.73, P < 0.0001). Both eGFR equations overestimated glomerular filtration rate (GFR) at all ranges of GFR in both subgroups of paraplegic subjects and quadriplegic subjects, with an MDRD fractional prediction error of 49% and 62%, respectively. Addition of a correction factor of 0.7 for MDRD and 0.8 for CG equations resulted in clinically acceptable fractional prediction error (below 20%) in both subgroups, especially in paraplegics with 3.9% and 3.6%, respectively. There was marked improvement in the performances of both eGFR equations, with better accuracy and precision after application of the correction factors. Conclusions:Both MDRD and CG equations overestimate GFR in patients with chronic SCI at all stages of chronic kidney disease, particularly in quadriplegic subjects. An empirically derived correction factor markedly improved the performance and accuracy of both prediction equations.