Robert B. Canada

Observational Modeling of Strict vs Conventional Blood Pressure Control in Patients With Chronic Kidney Disease

IMPORTANCE The effect of strict blood pressure control on clinical outcomes in patients with chronic kidney disease (CKD) is unclear. OBJECTIVE To compare the outcomes associated with a treated systolic blood pressure (SBP) of less than 120 mm Hg vs those associated with the currently recommended SBP of less than 140 mm Hg in a national CKD database of US veterans. DESIGN, SETTING, AND PARTICIPANTS Historical cohort study using a nationwide cohort of US veterans with prevalent CKD, estimated glomerular filtration rate less than 60 mL/min/1.73 m(2), and uncontrolled hypertension, who then received 1 or more additional blood pressure medications with evidence of a decrease in SBP. Propensity scores were calculated to reflect each individuals probability for future SBP less than 120 vs 120 to 139 mm Hg. MAIN OUTCOMES AND MEASURES The effect of SBP on all-cause mortality was evaluated by the log-rank test, and in Cox models adjusted for propensity scores. RESULTS Using a database of 651,749 patients with CKD, we identified 77,765 individuals meeting the inclusion criteria. A total of 5760 patients experienced follow-up treated SBP of less than 120 mm Hg and 72,005 patients had SBP of 120 to 139 mm Hg. During a median follow-up of 6.0 years, 19,517 patients died, with 2380 deaths in the SBP less than 120 mm Hg group (death rate, 80.9/1000 patient-years [95% CI, 77.7-84.2/1000 patient-years]) and 17,137 deaths in the SBP 120 to 139 mm Hg group (death rate, 41.8/1000 patient-years [95% CI, 41.2-42.4/1000 patient-years]; P < .001). The mortality hazard ratio (95% CI) associated with follow-up SBP less than 120 vs 120 to 139 mm Hg was 1.70 (1.63-1.78) after adjustment for propensity scores. CONCLUSIONS AND RELEVANCE Our results suggest that stricter SBP control is associated with higher all-cause mortality in patients with CKD. Confirmation of these findings by ongoing clinical trials would suggest that modeling of therapeutic interventions in observational cohorts may offer useful guidance for the treatment of conditions that lack clinical trial data.

Cystatin C Associates with Arterial Stiffness in Older Adults

Large arteries commonly become stiff in kidney failure, but few studies have investigated arterial stiffness in earlier stages of kidney disease. We evaluated the association between kidney function and aortic pulse wave velocity (aPWV) and its potential modification by race, diabetes, or coronary heart disease in older adults. We measured aPWV in 2468 participants in the Health Aging and Body Composition (Health ABC) study; mean age was 73.7 yr, 40% were black, and 24% had diabetes. After categorizing kidney function into three groups on the basis of cystatin C level, multivariable analysis revealed that the medium and high cystatin C groups associated with a 5.3% (95% confidence interval 0.8 to 10.0%) and 8.0% (95% confidence interval 2.2 to 14.1%) higher aPWV than the low cystatin C group; however, chronic kidney disease, as defined by estimated GFR <60 ml/min per 1.73 m(2), did not significantly associate with aPWV. We did not identify interactions between cystatin C and race, diabetes, or coronary heart disease. In conclusion, stiffness of large arteries, a major risk factor for cardiovascular disease, may partially mediate the association between cystatin C and cardiovascular risk in older adults.

Age and cystatin C in healthy adults: a collaborative study

BACKGROUND Kidney function declines with age, but a substantial portion of this decline has been attributed to the higher prevalence of risk factors for kidney disease at older ages. The effect of age on kidney function has not been well described in a healthy population across a wide age spectrum. METHODS The authors pooled individual-level cross-sectional data from 18 253 persons aged 28-100 years in four studies: the Cardiovascular Health Study; the Health, Aging and Body Composition Study; the Multi-Ethnic Study of Atherosclerosis and the Prevention of Renal and Vascular End-Stage Disease cohort. Kidney function was measured by cystatin C. Clinical risk factors for kidney disease included diabetes, hypertension, obesity, smoking, coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure. RESULTS Across the age range, there was a strong, non-linear association of age with cystatin C concentration. This association was substantial, even among participants free of clinical risk factors for kidney disease; mean cystatin C levels were 46% higher in participants 80 and older compared with those <40 years (1.06 versus 0.72 mg/L, P < 0.001). Participants with one or more risk factors had higher cystatin C concentrations for a given age, and the age association was slightly stronger (P < 0.001 for age and risk factor interaction). CONCLUSIONS There is a strong, non-linear association of age with kidney function, even in healthy individuals. An important area for research will be to investigate the mechanisms that lead to deterioration of kidney function in apparently healthy persons.

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.

Discontinuation of Tenofovir Disoproxil Fumarate for Presumed Renal Adverse Events in Treatment-Naïve HIV-1 Patients: Meta- analysis of Randomized Clinical Studies

Abstract Background: Safety and efficacy of tenofovir disoproxil fumarate (TDF) as a component of antiretroviral therapy (ART) have been demonstrated in clinical trials. TDF nephrotoxicity has been reported in both HIV-infected and noninfected patients. This meta-analysis explored the frequency of discontinuation attributed to renal adverse events (AEs) in randomized, controlled clinical studies that used TDF-containing regimens for ART-naïve, HIV-infected patients. Methods: A literature search of 4 electronic databases through October 31, 2013 was utilized. RCTs included were limited to randomized, prospective, comparative design in ART treatment-naïve adults with HIV-1 infections receiving ART. Studies included trials containing TDF treatment regimens, with or without a non-TDF control group. Study design, follow-up, size of study population, treatment group, patient demographics, number of patients exposed to TDF or non-TDF control, baseline characteristics, investigator-defined criteria for renal AEs, and number of discontinuations due to a presumed renal AEs were extracted. Results: Twenty-one clinical studies met the selection criteria. Treatment duration ranged from 48 to 288 weeks. Renal AEs led to study drug discontinuation in 44 of 10,129 patients exposed to TDF (0.43%; 95% CI, 0.32%-0.58%) and 2 of 2,013 patients exposed to non-TDF-containing regimens (0.10%; 95% CI, 0.01%-0.36%). In 5 randomized, controlled studies that included a non-TDF comparator, the estimated risk difference between the treatment groups (TDF vs non-TDF) was 0.50% (95% CI, 0.13%-0.86%; P = .007). Conclusions: In clinical studies using TDF-containing regimens, the rate of discontinuations due to renal AEs was low, but was slightly higher than in studies using non-TDF comparators.

Polyarteritis nodosa and cryoglobulinemic glomerulonephritis related to chronic hepatitis C

Case Report:A 53-year-old man with hepatitis C virus (HCV) infection underwent cholecystectomy for presumed cholecystitis. Gallstones were not present, and histological examination demonstrated medium-sized arteritis, consistent with polyarteritis nodosa (PAN). The patient later developed rapidly progressive glomerulonephritis. Kidney biopsy demonstrated cryoglobulinemic glomerulonephritis. Because of the severity of the patient’s vasculitic manifestations, treatment included pulse methylprednisolone followed by oral prednisone and monthly intravenous cyclophosphamide for 6 months. During treatment, microhematuria resolved, proteinuria decreased, and serum creatinine concentration stabilized. The patient subsequently underwent treatment for HCV with interferon resulting in a marked decrease in HCV RNA. The patient has had no relapse of his vasculitis, his renal function is stable, and viral load remains low after completing 36 weeks of interferon. Conclusion:Life-threatening vasculitis related to HCV was successfully treated with immunosuppressive therapy. After obtaining clinical remission, antiviral therapy was instituted, resulting in a dramatic decrease in HCV RNA.

Evaluation of vancomycin and gentamicin dialysis clearance using in vivo and in vitro systems

Advances in hemodialysis (HD) techniques have increased the potential for drug removal. Quantifying drug clearance in clinical studies for all possible dialysis conditions is impractical, given the variability in dialysis conditions. The purpose of this study was to determine the dialysis clearance (CLD) of vancomycin and gentamicin using in vitro and in vivo methods and evaluate the applicability of in vitro data. In vitro dialysis was used to determine the CLD of vancomycin and gentamicin under conditions of intermittent HD (IHD) and sustained low-efficiency dialysis (SLED). Two Fresenius polysulfone dialyzers were studied: F180NR for IHD and F50 for SLED. Data were compared with in vivo CLD determined in patients with end-stage renal disease receiving IHD and from the literature for SLED. Under IHD conditions, in vitro CLD of vancomycin and gentamicin was 131 ± 3 and 154 ± 3 mL/min, respectively, and under SLED condition it was 72 ± 9 and 84 ± 11 mL/min, respectively. These values were 11–27% higher than in vivo CLD for IHD (103 ± 15 mL/min for vancomycin and 132 ± 25 mL/min for gentamicin) and SLED (63 mL/min for vancomycin and 76 ± 38 mL/min for gentamicin). There was a statistically significant difference in vancomycin clearance by IHD for the in vitro study compared with in vivo data (p = 0.012), but not for gentamicin (p = 0.18). In vitro methods overestimated in vivo CLD, but are reasonable to assist with drug regimen design if one considers the limitations.

Hypercalcemia Associated With Tertiary Hyperparathyroidism Managed Conservatively With Pamidronate in a Hemodialysis Patient

Secondary hyperparathyroidism and the associated metabolic abnormalities are common complications of chronic kidney disease. When these disorders cannot be managed by conventional measures, including phosphate restriction, phosphate binders, vitamin D therapy, and calcimimetics, tertiary hyperparathyroidism and the associated metabolic abnormalities may develop. In such cases parathyroidectomy is required. We report a case in which a patient with tertiary hyperparathyroidism and refractory hypercalcemia who was not a surgical candidate was managed with the bisphosphonate pamidronate. This patient had failed conventional measures to manage hypercalcemia and presented with mental status changes. Pamidronate therapy was associated with a sustained decrease in serum calcium concentration and improvement in clinical symptoms. This is the first case, to our knowledge, in which pamidronate was used in a patient refractory to all other reasonable medical management, including calcimimetics.

Mechanical haemolysis related to the use of tandem dialyzers

Haemolysis is a well-recognized, rare complication of haemodialysis. The most common reasons for haemodialysis-associated haemolysis are chemical contamination, heat or mechanical injury of erythrocytes from occluded or partially occluded (kinked) haemodialysis lines [1–7]. Tandem dialyzers are occasionally used to improve dialysis dose, especially in patients with high muscle mass [8]. The two dialyzers are aligned in series and connected to each other by a simple blood line. Our patient had a partial occlusion (kink) at this blood line, which resulted in severe haemolysis. Since the changes in venous and arterial pressures were different from those noted with partial occlusion of the venous and arterial lines in standard haemodialysis, the problem was not immediately recognized. This case report describes a serious complication of tandem dialyzers that has not been previously reported.

Predialysis coronary revascularization and postdialysis mortality

Objectives: Coronary artery bypass grafting (CABG) is associated with better survival than percutaneous coronary intervention (PCI) in patients with mild‐to‐moderate chronic kidney disease (CKD) and end‐stage renal disease (ESRD). However, the optimal strategy for coronary artery revascularization in patients with advanced CKD who transition to ESRD is unclear. Methods: We examined a contemporary national cohort of 971 US veterans with incident ESRD who underwent first CABG or PCI up to 5 years before dialysis initiation. We examined the association of a history of CABG versus PCI with all‐cause mortality following transition to dialysis using Cox proportional hazards models adjusted for time between procedure and dialysis initiation, sociodemographics, comorbidities, and medications. Results: In total, 582 patients underwent CABG and 389 patients underwent PCI. The mean age was 64 ± 8 years, 99% of patients were male, 79% were white, 19% were African American, and 84% had diabetes. The all‐cause post‐dialysis mortality rates after CABG and PCI were 229 per 1000 patient‐years (95% confidence interval [CI], 205‐256) and 311 per 1000 patient years (95% CI, 272‐356), respectively. Compared with PCI, patients who underwent CABG had 34% lower risk of death (multivariable adjusted hazard ratio, 0.66; 95% CI, 0.51‐0.86, P = .002) after initiation of dialysis. Results were similar in all subgroups of patients stratified by age, race, type of intervention, presence/absence of myocardial infarction, congestive heart failure, and diabetes. Conclusions: CABG in patients with advanced CKD was associated lower risk of death after initiation of dialysis compared with PCI.