Mahesh Krishnan

Facility Hemodialysis Vascular Access Use and Mortality in Countries Participating in DOPPS: An Instrumental Variable Analysis

BACKGROUNDnPreviously, the Dialysis Outcomes and Practice Patterns Study (DOPPS) has shown large international variations in vascular access practice. Greater mortality risks have been seen for hemodialysis (HD) patients dialyzing with a catheter or graft versus a native arteriovenous fistula (AVF). To further understand the relationship between vascular access practice and outcomes, we have applied practice-based analyses (using an instrumental variable approach) to decrease the treatment-by-indication bias of prior patient-level analyses.nnnSTUDY DESIGNnA prospective observational study of HD practices.nnnSETTING & PARTICIPANTSnData collected from 1996 to 2004 from 28,196 HD patients from more than 300 dialysis units participating in the DOPPS in 12 countries.nnnPREDICTOR OR FACTORnPatient-level or case-mix-adjusted facility-level vascular access use. OUTCOMES/MEASUREMENTS: Mortality and hospitalization risks.nnnRESULTSnAfter adjusting for demographics, comorbid conditions, and laboratory values, greater mortality risk was seen for patients using a catheter (relative risk, 1.32; 95% confidence interval, 1.22 to 1.42; P < 0.001) or graft (relative risk, 1.15; 95% confidence interval, 1.06 to 1.25; P < 0.001) versus an AVF. Every 20% greater case-mix-adjusted catheter use within a facility was associated with 20% greater mortality risk (versus facility AVF use, P < 0.001); and every 20% greater facility graft use was associated with 9% greater mortality risk (P < 0.001). Greater facility catheter and graft use were both associated with greater all-cause and infection-related hospitalization. Catheter and graft use were greater in the United States than in Japan and many European countries. More than half the 36% to 43% greater case-mix-adjusted mortality risk for HD patients in the United States versus the 5 European countries from the DOPPS I and II was attributable to differences in vascular access practice, even after adjusting for other HD practices. Vascular access practice differences accounted for nearly 30% of the greater US mortality compared with Japan.nnnLIMITATIONSnPossible existence of unmeasured facility- and patient-level confounders that could impact the relationship of vascular access use with outcomes.nnnCONCLUSIONSnFacility-based analyses diminish treatment-by-indication bias and suggest that less catheter and graft use improves patient survival.

Conversion of Vascular Access Type Among Incident Hemodialysis Patients: Description and Association With Mortality

BACKGROUNDnLimited data exist describing vascular access conversions during the first year on dialysis therapy or the effect of converting to and from a catheter on subsequent mortality risk.nnnSTUDY DESIGNnRetrospective cohort study.nnnSETTING & PARTICIPANTSnWe studied a random sample of incident US hemodialysis patients (initiated long-term dialysis < 30 days before study entry) in the Dialysis Outcomes and Practice Patterns Study (DOPPS; 1996-2004).nnnPREDICTORSnAt dialysis therapy initiation, we assessed vascular access type in use (arteriovenous fistula [AVF], arteriovenous graft [AVG], or catheter) and other patient characteristics. We characterized changes in vascular access type (conversions) by using regularly collected functional status information.nnnOUTCOME & MEASUREMENTSnWe assessed time to all-cause mortality. We first described conversions, then used time-dependent Cox regression to estimate mortality hazard ratios (HRs) for conversions from a catheter to a permanent vascular access (versus no conversion) and conversions from a permanent vascular access to a catheter (versus no conversion).nnnRESULTSnThe study included 4,532 patients; 69.2% were dialyzing with a catheter; 17.6%, with an AVG; and 13.1%, with an AVF. In patients initiating therapy with an AVF or AVG, 22% experienced a conversion (failure), and median times to first failure were 62 and 84 days, respectively. In catheter patients, 59% converted to an AVF/AVG (predominantly AVG [57%]); median times to first conversion were 92 and 66 days, respectively. Conversion to a permanent access was associated with an adjusted mortality HR of 0.69 (95% confidence interval, 0.55 to 0.85). The effect was similar for conversion to an AVF or AVG, and these persisted across demographic groups and facilities with different conversion practices. Conversion from a permanent vascular access to a catheter was associated with an adjusted mortality HR of 1.81 (95% confidence interval, 1.22 to 2.68).nnnLIMITATIONSnPotential for residual confounding because of unmeasured factors influencing decision to convert.nnnCONCLUSIONnVascular access conversions are common in incident patients. Continued efforts to increase early nephrologist referral and permanent vascular access placement may help decrease mortality risk in incident dialysis patients.

Hospitalization risks related to vascular access type among incident US hemodialysis patients

BACKGROUNDnThe excess morbidity and mortality related to catheter utilization at and immediately following dialysis initiation may simply be a proxy for poor prognosis. We examined hospitalization burden related to vascular access (VA) type among incident patients who received some predialysis care.nnnMETHODSnWe identified a random sample of incident US Dialysis Outcomes and Practice Patterns Study hemodialysis patients (1996-2004) who reported predialysis nephrologist care. VA utilization was assessed at baseline and throughout the first 6 months on dialysis. Poisson regression was used to estimate the risk of all-cause and cause-specific hospitalizations during the first 6 months.nnnRESULTSnAmong 2635 incident patients, 60% were dialyzing with a catheter, 22% with a graft and 18% with a fistula at baseline. Compared to fistulae, baseline catheter use was associated with an increased risk of all-cause hospitalization [adjusted relative risk (RR) = 1.30, 95% confidence interval (CI): 1.09-1.54] and graft use was not (RR = 1.07, 95% CI: 0.89-1.28). Allowing for VA changes over time, the risk of catheter versus fistula use was more pronounced (RR = 1.72, 95% CI: 1.42-2.08) and increased slightly for graft use (RR = 1.15, 95% CI: 0.94-1.41). Baseline catheter use was most strongly related to infection-related (RR = 1.47, 95% CI: 0.92-2.36) and VA-related hospitalizations (RR = 1.49, 95% CI: 1.06-2.11). These effects were further strengthened when VA use was allowed to vary over time (RR = 2.31, 95% CI: 1.48-3.61 and RR = 3.10, 95% CI: 1.95-4.91, respectively). A similar pattern was noted for VA-related hospitalizations with graft use. Discussion. Among potentially healthier incident patients, hospitalization risk, particularly infection and VA-related, was highest for patients dialyzing with a catheter at initiation and throughout follow-up, providing further support to clinical practice recommendations to minimize catheter placement.

Impact of elevated C-reactive protein levels on erythropoiesis- stimulating agent (ESA) dose and responsiveness in hemodialysis patients

BACKGROUNDnInflammation in an ESRD patient may impact responsiveness to erythropoiesis-stimulating agent (ESA) therapy. We sought to investigate the association between C-reactive protein (CRP) levels and average per-administration epoetin alfa (EPO) dose over 3 months following a CRP measurement.nnnMETHODSnThe study is a retrospective cohort study of hemodialysis patients >or=18 years of age receiving care at a Fresenius Medical Care-North America facility between 1 July 2000 and 30 June 2002 who had no history of peritoneal dialysis. All patients had >or=1 CRP measurement and >or=3 months of recorded information before the CRP measurement (entry period). We evaluated the association between CRP levels and average hemoglobin (Hb) and per-administration EPO dose over the 3 months following the CRP measurement.nnnRESULTSnWe identified 1754 patients with a CRP measurement; mean age was 62.6 years (SD 14.1), 51.5% were male, 56.2% were white and the median CRP value was 2.04 mg/dL (20.4 mg/L). Patients in the upper CRP quartiles were more likely to be older, recently hospitalized; have a catheter vascular access; have lower albumin, Hb and transferrin saturation levels and greater EPO doses. In the subsequent 3 months, EPO doses but not Hb levels were significantly higher for patients in the highest CRP quartile [3.21 mg/dL (32.1 mg/L)] (P = 0.01).nnnCONCLUSIONSnInflammation as measured by an elevated CRP level appears to be an independent predictor of greater ESA dose requirements. Patients with the highest CRP levels required significantly higher ESA doses to achieve comparable Hb levels even after controlling for potential confounding variables.

Effects of Citrate Acid Concentrate (Citrasate ) on Heparin N Requirements and Hemodialysis Adequacy: A Multicenter, Prospective Noninferiority Trial

Background: Citrasate®, citric acid dialysate (CD), contains 2.4 mEq of citric acid (citrate), instead of acetic acid (acetate) as in standard bicarbonate dialysate. Previous studies suggest CD may improve dialysis adequacy and decrease heparin requirements, presumably due to nonsystemic anticoagulant effects in the dialyzer. Methods: We prospectively evaluated 277 hemodialysis patients in eight outpatient facilities to determine if CD with reduced heparin N (HN) would maintain dialyzer clearance. Subjects progressed through four study periods [baseline (B): bicarbonate dialysate + 100% HN; period 1 (P1): CD + 100% HN; period 2 (P2): CD + 80% HN; period 3 (P3): CD + 66.7% HN]. The predefined primary endpoint was noninferiority (margin –8%) of the percent change in mean dialyzer conductivity clearance between baseline and P2. Results: Subjects were 57.4% male, 41.7% white, 54.3% black, and 44.4% diabetic; mean age was 59 ± 14.4 years; mean time on dialysis was 1,498 ± 1,165 days; 65.7% had arteriovenous fistula, 19.9% arteriovenous graft, 14.4% catheters, and 27.8% used antiplatelet agents. Mean dialyzer clearance increased 0.9% (P1), 1.0% (P2), and 0.9% (P3) with CD despite heparin reduction. SpKt/V remained stable (B: 1.54 ± 0.29; P1: 1.54 ± 0.28; P2: 1.55 ± 0.27; P3: 1.54 ± 0.26). There was no significant difference in dialyzer/dialysis line thrombosis, post-HD time to hemostasis, percent of subjects with adverse events (AEs), or study-related AEs. Conclusions: CD was safe, effective, and met all study endpoints. Dialyzer clearance increased approximately 1% with CD despite 20–33% heparin reduction. Over 92% of P3 subjects demonstrated noninferiority of dialyzer clearance with CD and 33% HN reduction. There was no significant difference in dialyzer clotting, bleeding, or adverse events.

Causes and consequences of inflammation on anemia management in hemodialysis patients

Inflammation is common among hemodialysis patients, and evidence is accumulating to suggest that inflammation is a major contributor to morbidity and mortality. Several factors have been suggested as potential causes of inflammation, including infections and the atherosclerosis process, as well as etiologies directly related to kidney disease such as reduced renal function and dialysis. Among several inflammatory biomarkers investigated, serum C‐reactive protein (CRP) is the most widely used. In hemodialysis patients, raised CRP levels have been shown to be predictive of cardiovascular events, hospitalization, and all‐cause and cardiovascular mortality. Elevated CRP levels may correlate with comorbidities and intercurrent events, all of which may impact the response to erythropoiesis‐stimulating agents (ESAs) and lead to higher ESA doses. Most dialysis facilities do not routinely measure CRP, despite recommendations by the National Kidney Foundations Kidney Disease Outcomes Quality Initiative. Regular measurement of CRP levels may help providers to understand change in ESA dosing and identify patients at risk for cardiovascular events. This review explores the inter‐relationships between inflammation, CRP levels, and anemia management in patients receiving hemodialysis.

Changes in Hemoglobin Level Distribution in US Dialysis Patients From June 2006 to November 2008

BACKGROUNDnErythropoiesis-stimulating agents (ESAs) have had a positive effect on anemia treatment in dialysis patients. However, several events in recent years, including new clinical study results, ESA product label revisions, and coverage and reimbursement policy changes, have had an impact on ESA dosing patterns and consequently on hemoglobin (Hb) distribution characteristics in this patient population.nnnSTUDY DESIGNnRetrospective observational study using patient-level data from approximately 87% of dialysis centers in the United States.nnnSETTING & PARTICIPANTSnDialysis patients who were receiving outpatient care at dialysis facilities during June 2006-November 2008 were included in this study.nnnPREDICTORnRecent events affecting ESA treatment practice patterns in US dialysis patients.nnnOUTCOMES & MEASUREMENTSnHb level distribution.nnnRESULTSnMean Hb level decreased by 0.37 g/dL during the indicated period. Additionally, standard deviation (SD) of the Hb level distribution decreased by 0.14 g/dL and skewness increased by -0.10. Hb measurements in specific ranges changed as follows: >12 g/dL, decreased by 11.3 percentage points;10-12 g/dL, increased by 9.4 percentage points; and <10 g/dL, increased by 1.9 percentage points. The percentage of patients with Hb level >13 g/dL for > or =3 months decreased by 2.9 percentage points.nnnLIMITATIONSnPotential bias in dialysis center selection and lack of information for patient characteristics.nnnCONCLUSIONSnRecent events affecting ESA use in dialysis patients have had the desired effect of increasing the proportion of Hb measurements within the US Food and Drug Administration recommended target range of 10-12 g/dL and decreasing the proportion of Hb measurements >12 g/dL. However, the proportion of Hb measurements <10 g/dL also has increased. Benefits of a decrease in Hb measurements in the >12 g/dL range need to be considered, together with risks of having low Hb levels.

A practice-related risk score (PRS): a DOPPS-derived aggregate quality index for haemodialysis facilities

BACKGROUNDnThe Dialysis Outcomes and Practice Patterns Study (DOPPS) database was used to develop and validate a practice-related risk score (PRS) based on modifiable practices to help facilities assess potential areas for improving patient care.nnnMETHODSnRelative risks (RRs) from a multivariable Cox mortality model, based on observational haemodialysis (HD) patient data from DOPPS I (1996-2001, seven countries), were used. The four practices were the percent of patients with Kt/V > or =1.2, haemoglobin > or =11 g/dl (110 g/l), albumin > or =4.0 g/dl (40g/l) and catheter use, and were significantly related to mortality when modelled together. DOPPS II data (2002-2004, 12 countries) were used to evaluate the relationship between PRS and mortality risk using Cox regression.nnnRESULTSnFor facilities in DOPPS I and II, changes in PRS over time were significantly correlated with changes in the standardized mortality ratio (SMR). The PRS ranged from 1.0 to 2.1. Overall, the adjusted RR of death was 1.05 per 0.1 points higher PRS (P < 0.0001). For facilities in both DOPPS I and II (N = 119), a 0.2 decrease in PRS was associated with a 0.19 decrease in SMR (P = 0.005). On average, facilities that improved PRS practices showed significantly reduced mortality over the same time frame.nnnCONCLUSIONSnThe PRS assesses modifiable HD practices that are linked to improved patient survival. Further refinements might lead to improvements in the PRS and will address regional variations in the PRS/mortality relationship.

The effect of epoetin dose on hematocrit

To the Editor: Cotter et al.1 used United States Renal Data System data from 14,001 incident patients to estimate the dose–response relationship between epoetin (EPO) and hematocrit. The authors used their analysis to infer the maximum effective EPO dose and suggested that this should inform Federal reimbursement policy. However, the analytic approach used is inconsistent with FDA guidance and the inferred maximum dose is not likely to be generalizable to the US dialysis population. We think it is inadvisable to support reimbursement policies based on inferential information without careful consideration of the potential clinical consequences.