John J. Sim

Mid-Arm Muscle Circumference and Quality of Life and Survival in Maintenance Hemodialysis Patients

BACKGROUND AND OBJECTIVES Maintenance hemodialysis (MHD) patients with larger body or fat mass have greater survival than normal to low mass. We hypothesized that mid-arm muscle circumference (MAMC), a conveniently measured surrogate of lean body mass (LBM), has stronger association with clinical outcomes than triceps skinfold (TSF), a surrogate of fat mass. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS The associations of TSF, MAMC, and serum creatinine, another LBM surrogate, with baseline short form 36 quality-of-life scores and 5-year survival were examined in 792 MHD patients. In a randomly selected subsample of 118 subjects, LBM was measured by dual-energy x-ray absorptiometry. RESULTS Dual-energy x-ray absorptiometry-assessed LBM correlated most strongly with MAMC and serum creatinine. Higher MAMC was associated with better short form 36 mental health scale and lower death hazard ratios (HRs) after adjustment for case-mix, malnutrition-inflammation-cachexia syndrome, and inflammatory markers. Adjusted death HRs were 1.00, 0.86, 0.69, and 0.63 for the first to fourth MAMC quartiles, respectively. Higher serum creatinine and TSF were also associated with lower death HRs, but these associations were mitigated after multivariate adjustments. Using median values of TSF and MAMC to dichotomize, combined high MAMC with either high or low TSF (compared with low MAMC/TSF) exhibited the greatest survival, i.e., death HRs of 0.52 and 0.59, respectively. CONCLUSIONS Higher MAMC is a surrogate of larger LBM and an independent predictor of better mental health and greater survival in MHD patients. Sarcopenia-correcting interventions to improve clinical outcomes in this patient population warrant controlled trials.

Blood Pressure and Mortality in U.S. Veterans With Chronic Kidney Disease: A Cohort Study

BACKGROUND The ideal blood pressure (BP) to decrease mortality rates in patients with non-dialysis-dependent chronic kidney disease (CKD) is unclear. OBJECTIVE To assess the association of BP (defined as the combination of systolic BP [SBP] and diastolic BP [DBP] at the individual level) with death in patients with CKD. DESIGN Historical cohort between 2005 and 2012. SETTING All U.S. Department of Veterans Affairs health care facilities. PATIENTS 651 749 U.S. veterans with CKD. MEASUREMENTS All possible combinations of SBP and DBP were examined in 96 categories from lowest (<80/<40 mm Hg) to highest (>210/>120 mm Hg), in 10-mm Hg increments. Associations with all-cause mortality were examined in time-dependent Cox models with adjustment for relevant confounders. RESULTS Patients with SBP of 130 to 159 mm Hg combined with DBP of 70 to 89 mm Hg had the lowest adjusted mortality rates, and those in whom both SBP and DBP were concomitantly very high or very low had the highest mortality rates. Patients with moderately elevated SBP combined with DBP no less than 70 mm Hg had consistently lower mortality rates than did patients with ideal SBP combined with DBP less than 70 mm Hg. Results were consistent in subgroups of patients with normal and elevated urinary microalbumin-creatinine ratios. LIMITATION Mostly male patients, inability to establish causality, and large number of patients missing proteinuria measurement. CONCLUSION The optimal BP in patients with CKD seems to be 130 to 159/70 to 89 mm Hg. It may not be advantageous to achieve ideal SBP at the expense of lower-than-ideal DBP in adults with CKD. PRIMARY FUNDING SOURCE National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and U.S. Department of Veterans Affairs.

Prevalence of nondiabetic renal disease in diabetic patients.

Background: Diabetic nephropathy is the leading cause of end-stage renal disease in the USA, yet most patients with type 2 diabetes mellitus are not formally evaluated with a renal biopsy. Our aim was to evaluate the prevalence of nondiabetic renal disease (NDRD) in patients with type 2 diabetes mellitus to determine common clinical indicators suggestive of NDRD. Methods: A retrospective analysis was performed on biopsy reports of patients who had undergone native renal biopsy between January 1, 1995, and December 31, 2005. Results: After exclusion of 57 patients, 233 patients with DM2 were included in our analysis. Mean age at the time of biopsy was 58.1 ± 13.7 years, and 53.0% of the study population were male. There were 124 cases (53.2%) with a pathologic diagnosis of NDRD, 64 (27.5%) with pure diabetic glomerulosclerosis (DGS) and 45 (19.3%) with concurrent NDRD and DGS (CD). Patients with NDRD tended to be younger than those with DGS and had significantly less associated diabetic retinopathy. Focal segmental glomerulosclerosis was the most common lesion found in patients with NDRD and accounted for 21.0% of all NDRD, followed by minimal-change disease (15.3%). IgA nephropathy (15.6%) and membranous glomerulonephritis (13.3%) were the most prevalent lesions found in patients with CD. Conclusions: The high prevalence of NDRD found in our population underscores the need for clinicians to consider renal biopsy in diabetic patients with an atypical clinical course, since additional disease-specific therapies may be helpful for this subset of the population.

Sleep Apnea in Early and Advanced Chronic Kidney Disease* Kaiser Permanente Southern California Cohort

BACKGROUND Sleep apnea (SA) has been reported to be highly prevalent in the dialysis population. The reported rates of SA in dialysis are severalfold greater than the 2 to 4% estimated in the general population. This study sought to determine whether an association exists between SA and early stages of chronic kidney disease (CKD) where SA may represent an important comorbidity and potential risk factor in kidney disease. METHODS Cross-sectional study of adults from an integrated health plan with documented serum creatinine levels in the period January 1, 2002, through December 31, 2004. SA diagnosis determined by International Classification of Diseases, ninth revision, coding for SA and Current Procedural Terminology coding for positive airway pressure devices. Kidney function was determined by the estimated glomerular filtration rate (eGFR). Logistic was regression used to estimate the relative risk for SA. RESULTS The overall prevalence of SA was 2.5% in the study population that included subjects with normal renal function and those with CKD. The odds ratios (ORs) for SA by eGFRs of 75 to 89, 60 to 74, 45 to 59, 30 to 44, and 15 to 29 mL/min per 1.73 m(2), respectively, compared to normal kidney function, after adjustment for age, sex, and number of visits, were as follows: 1.22 (95% confidence interval [CI], 1.18 to 1.25); 1.32 (95% CI, 1.27 to 1.37); 1.42 (95% CI, 1.35 to 1.50); 1.37 (95% CI, 1.25 to 1.50); and 1.32 (95% CI, 1.13 to 1.55). The increased ORs for eGFRs > 45 mL/min per 1.73 m(2) were sustained even after controlling for diabetes, heart failure, and hypertension. CONCLUSION This study demonstrated an increased risk of SA in patients with early CKD. Further evidence of a causal relationship should be sought in the hope that the detection and management of SA may improve the course of CKD.

Characteristics of Resistant Hypertension in a Large, Ethnically Diverse Hypertension Population of an Integrated Health System

OBJECTIVE To evaluate the prevalence of and characterize resistant hypertension in a large representative population with successful hypertension management and reliable health information. PATIENT AND METHODS We performed a cross-sectional study using clinical encounter, laboratory, and administrative information from the Kaiser Permanente Southern California health system between January 1, 2006, and December 31, 2007. From individuals older than 17 years with hypertension, resistant hypertension was identified and prevalence was determined. Multivariable logistic regression was used to calculate odds ratios (ORs), with adjustments for demographic characteristics, clinical variables, and medication use. RESULTS Of 470,386 hypertensive individuals, 60,327 (12.8%) were identified as having resistant disease, representing 15.3% of those taking medications. Overall, 37,061 patients (7.9%) had uncontrolled hypertension while taking 3 or more medicines. The ORs (95% CIs) for resistant hypertension were greater for black race (1.68 [1.62-1.75]), older age (1.11 [1.10-1.11] for every 5-year increase), male sex (1.06 [1.03-1.10]), and obesity (1.46 [1.42-1.51]). Medication adherence rates were higher in those with resistant hypertension (93% vs 89.8%; P<.001). Chronic kidney disease (OR, 1.84; 95% CI, 1.78-1.90), diabetes mellitus (OR, 1.58; 95% CI, 1.53-1.63), and cardiovascular disease (OR, 1.34; 95% CI, 1.30-1.39) were also associated with higher risk of resistant hypertension. CONCLUSION In a more standardized hypertension treatment environment, we observed a rate of resistant hypertension comparable with that of previous studies using more fragmented data sources. Past observations have been limited due to nonrepresentative populations, reliability of the data, heterogeneity of the treatment environments, and less than ideal control rates. This cohort, which was established using an electronic medical record-based approach, has the potential to provide a better understanding of resistant hypertension and outcomes.

Viremia, resuppression, and time to resistance in human immunodeficiency virus (HIV) subtype C during first-line antiretroviral therapy in South Africa.

BACKGROUND Episodes of viremia are common in African antiretroviral therapy (ART) programs. We sought to describe viremia, resuppression, and accumulation of resistance during first-line combination ART (cART) in South Africa. METHODS Retrospective analysis of a cohort receiving zidovudine, lamivudine, and either efavirenz or nevirapine with human immunodeficiency virus (HIV) RNA monitoring every 6 months. We assessed viremia (HIV RNA >1000 copies/mL after initial HIV RNA response) and resuppression (HIV RNA <400 copies/mL after viremia). Genotypic resistance testing was performed using stored plasma on a subset of patients at first detection of viremia and subsequently among patients with persistent viremia. RESULTS Between 2002 and 2006, 3727 patients initiated cART (median CD4, 147 cells/mm(3)). Of 1007 patients who developed viremia, 815 had subsequent HIV RNA assays, and 331 (41%) of these resuppressed without regimen switch. At identification of viremia, 45 (66%) of 68 patients had HIV-1 drug resistance, 42 (62%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistance, 25 (37%) had M184V/I, and 4 (6%) had multi-nucleoside analogue drug mutations. By 12 months of persistent viremia among a subset of 14 patients with resistance testing to 12 months, 11 (78%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistance, 8 (57%) had M184V/I, and 2 (14%) had multi-nucleoside analogue drug mutations. Resistance was associated with a reduced probability of resuppression; however, 50% of patients with NNRTI resistance resuppressed while receiving an NNRTI. CONCLUSIONS The majority of patients had NNRTI resistance mutations at detection of viremia. However, 41% resuppressed without regimen switch. Our findings support maximizing first-line use while minimizing risk of significant cross-resistance by implementing intensive adherence support and repeat HIV RNA testing 3-6 months after detecting viremia, with regimen switch only if viremia persists.

Viremia, Resuppression, and Time to Resistance in Human Immunodeficiency Virus (HIV) Subtype C during First-Line Antiretroviral Therapy

BACKGROUND Episodes of viremia are common in African antiretroviral therapy (ART) programs. We sought to describe viremia, resuppression, and accumulation of resistance during first-line combination ART (cART) in South Africa. METHODS Retrospective analysis of a cohort receiving zidovudine, lamivudine, and either efavirenz or nevirapine with human immunodeficiency virus (HIV) RNA monitoring every 6 months. We assessed viremia (HIV RNA >1000 copies/mL after initial HIV RNA response) and resuppression (HIV RNA <400 copies/mL after viremia). Genotypic resistance testing was performed using stored plasma on a subset of patients at first detection of viremia and subsequently among patients with persistent viremia. RESULTS Between 2002 and 2006, 3727 patients initiated cART (median CD4, 147 cells/mm(3)). Of 1007 patients who developed viremia, 815 had subsequent HIV RNA assays, and 331 (41%) of these resuppressed without regimen switch. At identification of viremia, 45 (66%) of 68 patients had HIV-1 drug resistance, 42 (62%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistance, 25 (37%) had M184V/I, and 4 (6%) had multi-nucleoside analogue drug mutations. By 12 months of persistent viremia among a subset of 14 patients with resistance testing to 12 months, 11 (78%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistance, 8 (57%) had M184V/I, and 2 (14%) had multi-nucleoside analogue drug mutations. Resistance was associated with a reduced probability of resuppression; however, 50% of patients with NNRTI resistance resuppressed while receiving an NNRTI. CONCLUSIONS The majority of patients had NNRTI resistance mutations at detection of viremia. However, 41% resuppressed without regimen switch. Our findings support maximizing first-line use while minimizing risk of significant cross-resistance by implementing intensive adherence support and repeat HIV RNA testing 3-6 months after detecting viremia, with regimen switch only if viremia persists.

Why cachexia kills: examining the causality of poor outcomes in wasting conditions

Weight loss is the hallmark of any progressive acute or chronic disease state. In its extreme form of significant lean body mass (including skeletal muscle) and fat loss, it is referred to as cachexia. It has been known for millennia that muscle and fat wasting leads to poor outcomes including death. On one hand, conditions and risk factors that lead to cachexia and inadequate nutrition may independently lead to increased mortality. Additionaly, cachexia per se, withdrawal of nutritional support in progressive cachexia, and advanced age may lead to death via cachexia-specific pathways. Despite the strong and consistent association of cachexia with mortality, no unifying mechanism has yet been suggested as to why wasting conditions are associated with an exceptionally high mortality risk. Hence, the causality of the cachexia–death association, even though it is biologically plausible, is widely unknown. This century-long uncertainty may have played a role as to why the field of cachexia treatment development has not shown major advances over the past decades. We suggest that cachexia-associated relative thrombocytosis and platelet activation may play a causal role in cachexia-related death, while other mechanisms may also contribute including arrhythmia-associated sudden deaths, endocrine disorders such as hypothyroidism, and immune system compromise leading to infectious events and deaths. Multidimensional research including examining biologically plausible models is urgently needed to investigate the causality of the cachexia–death association.

Impact of Achieved Blood Pressures on Mortality Risk and End-Stage Renal Disease Among a Large, Diverse Hypertension Population

BACKGROUND Medical data or clinical guidelines have not adequately addressed the ideal blood pressure (BP) treatment targets for survival and renal outcome. OBJECTIVES This study sought to evaluate ranges of treated BP in a large hypertension population and compare risk of mortality and end-stage renal disease (ESRD). METHODS A retrospective cohort study within the Kaiser Permanente Southern California health system was performed from January 1, 2006, to December 31, 2010. Treated hypertensive subjects ≥ 18 years of age were studied. Cox proportional hazards regression models were used to evaluate the risks (hazard ratios) for mortality and/or ESRD among different BP categories with and without stratification for diabetes mellitus and older age. RESULTS Among 398,419 treated hypertensive subjects (30% with diabetes mellitus), mortality occurred in 25,182 (6.3%) and ESRD in 4,957 (1.2%). Adjusted hazard ratios (95% confidence intervals [CI]) for composite mortality/ESRD in systolic BP <110, 110 to 119, 120 to 129, 140 to 149, 150 to 159, 160 to 169, and ≥ 170 compared with 130 to 139 mm Hg were 4.1 (95% CI: 3.8 to 1.3), 1.8 (95% CI: 1.7 to 1.9), 1.1 (95% CI: 1.1 to 1.1), 1.4 (95% CI: 1.4 to 1.5), 2.3 (95% CI: 2.2 to 2.5), 3.3 (95% CI: 3.0 to 3.6), and 4.9 (95% CI: 4.4 to 5.5) respectively. Diastolic BP 60 to 79 mm Hg were associated with the lowest risk. The nadir systolic and diastolic BP for the lowest risk was 137 and 71 mm Hg, respectively. Stratified analyses revealed that the diabetes mellitus population had a similar hazard ratio curve but a lower nadir at 131 and 69 mm Hg but age ≥ 70 had a higher nadir (140 and 70 mm Hg). CONCLUSIONS Both higher and lower treated BP compared with 130 to 139 mm Hg systolic and 60 to 79 mm Hg diastolic ranges had worsened outcomes. Our study adds to the growing uncertainty about BP treatment targets.

A comparative effectiveness research study of the change in blood pressure during hemodialysis treatment and survival

It is not clear to what extent changes in blood pressure (BP) during hemodialysis affect or predict survival. Studying comparative outcomes of BP changes during hemodialysis can have major clinical implications including the impact on management strategies in hemodialysis patients. Here we undertook a retrospective cohort study of 113,255 hemodialysis patients over a 5 year period to evaluate an association between change in BP during hemodialysis and mortality. The change in BP was defined as post- minus pre-hemodialysis BP and mean of BP change values during the hemodialysis session was used as a mortality predictor. The patients averaged 61 years old and consisted of 45% women, 32% African-Americans and 58% diabetics. Over a median follow-up of 2.2 years, a total of 53,461 (47.2%) all-cause and 21,548 (25.7%) cardiovascular deaths occurred. In fully adjusted Cox regression model with restricted cubic splines, there was a U-shaped association between change systolic BP and all-cause mortality. Post-dialytic drops in systolic BP between −30 to 0 mmHg were associated with greater survival, but large decreases of systolic BP (more than −30 mmHg) and any increase in systolic BP (over 0 mmHg) were related to increased mortality. Peak survival was found at a change in systolic BP of −14 mmHg. The U-shaped association was also found for cardiovascular mortality. Thus, modest declines in BP after hemodialysis are associated with the greatest survival, whereas any rise or large decline in BP is associated with worsened survival.