Marcia L. Keen

Peripheral Arterial Disease in Patients With End-Stage Renal Disease Observations From the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Background— Patients with end-stage renal disease are at high risk for cardiovascular morbidity and mortality. The aims of the present study were to describe the prevalence of peripheral arterial disease (PAD) and its effects on prognosis and health-related quality of life (HRQOL) in an international cohort of patients on hemodialysis. Methods and Results— Data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective, international, observational study of hemodialysis patients (n=29 873), were analyzed. Associations between baseline clinical variables and PAD were evaluated by logistic regression analysis. Cox regression models were used to test the association between PAD and risk for all-cause mortality, cardiac mortality, and hospitalization. PAD was diagnosed in 7411 patients (25.3%) with significant geographic variation. Traditional cardiovascular risk factors including age, male sex, diabetes, hypertension, and smoking were identified, together with the duration of hemodialysis, as significant correlates of PAD. Diagnosis of PAD was associated with increased all-cause mortality (hazard ratio [HR]=1.36; P<0.0001), cardiac mortality (HR=1.43; P<0.0001), all-cause hospitalization (HR=1.19; P<0.0001), and hospitalization for a major adverse cardiovascular event (HR=2.05; P<0.0001). HRQOL questionnaires revealed physical health scores that were significantly lower in PAD compared with non-PAD patients (P<0.0001). Conclusions— PAD is common in hemodialysis patients and is associated with increased risk of cardiovascular mortality, morbidity, and hospitalization and reduced HRQOL.

Physical exercise among participants in the Dialysis Outcomes and Practice Patterns Study (DOPPS): correlates and associated outcomes

BACKGROUND Levels of physical exercise among haemodialysis patients are low. Increased physical activity in this population has been associated with improved health-related quality of life (HRQoL) and survival. However, results of previous studies may not be applicable to the haemodialysis population as a whole. The present study provides the first description of international patterns of exercise frequency and its association with exercise programmes and clinical outcomes among participants in the Dialysis Outcomes and Practice Patterns Study (DOPPS). METHODS Data from a cross section of 20,920 DOPPS participants in 12 countries between 1996 and 2004 were analysed. Regular exercise was defined as exercise frequency equal to or more than once/week based on patient self-report. Linear mixed models and logistic regression assessed associations of exercise frequency with HRQoL and other psychosocial variables. Mortality risk was calculated in Cox proportional hazard models using patient-level (patient self-reported exercise frequency) and facility-level (the dialysis facility percentage of regular exercisers) predictors. RESULTS Regular exercise frequency varied widely across countries and across dialysis facilities within a country. Overall, 47.4% of participants were categorized as regular exercisers. The odds of regular exercise was 38% higher for patients from facilities offering exercise programmes (adjusted odds ratio = 1.38 [95% confidence interval: 1.03-1.84]; P = 0.03). Regular exercisers had higher HRQoL, physical functioning and sleep quality scores; reported fewer limitations in physical activities; and were less bothered by bodily pain or lack of appetite (P <or= 0.0001 for all). Regular exercise was also correlated with more positive patient affect and fewer depressive symptoms (P <or= 0.0001). In models extensively adjusted for demographics, comorbidities and socio-economic indicators, mortality risk was lower among regular exercisers (hazard ratio = 0.73 [0.69-0.78]; P < 0.0001) and at facilities with more regular exercisers (0.92 [0.89-0.94]; P < 0.0001 per 10% more regular exercisers). CONCLUSIONS Results from an international study of haemodialysis patients indicate that regular exercise is associated with better outcomes in this population and that patients at facilities offering exercise programmes have higher odds of exercising. Dialysis facility efforts to increase patient physical activity may be beneficial.

High alkaline phosphatase levels in hemodialysis patients are associated with higher risk of hospitalization and death

We evaluated risks associated with elevated alkaline phosphatase in hemodialysis patients using longitudinal data from the Dialysis Outcomes and Practice Patterns Study, a prospective observational study of hemodialysis patients in 12 countries. Alkaline phosphatase levels were normalized by the upper limit of the laboratory-reported reference range. Cause-specific hospitalization and mortality risks were evaluated using Cox proportional hazards models, stratified by region and adjusted for phosphorus, calcium, albumin, parathyroid hormone, case mix, and numerous comorbidities. The odds of high normalized alkaline phosphatase were increased twofold in the United States in comparison to Japan. Elevations of normalized alkaline phosphatase were significantly associated with several comorbid conditions, increased fractures, parathyroidectomy, risk of hospitalization due to major adverse cardiac events, higher all-cause cardiovascular, and infection-related mortality risk. Our results also show that elevated serum normalized alkaline phosphatase was associated with higher risks of hospitalization and death in hemodialysis patients, independent of calcium, phosphorus, and parathyroid hormone levels.

A Kinetic Survey of US Hernodialysis Prescriptions

Recent reports indicate increasing mortality correlated to reduced treatment time (t) in hemodialysis (HD) patients. HD prescriptions for 101 patients visiting our unit were subjected to kinetic analysis to assess the amount of dialysis prescribed (Kt/V) and its relationship to t. The analysis showed (1) 98% of the prescriptions were empirical; (2) Kt/V was strongly correlated to protein intake (normalized protein catabolic rate [NPCR], g/kg/d), r = 0.50, N = 101; (3) Kt/V was strongly correlated to t, y = 0.50 + 0.54x, r = 0.54, and fell below 1 when t less than or equal to 3.5 hours; (4) a prescription flux deficit appeared and increased exponentially as t fell below 3.7 hours. These results suggest that in clinical practice, t is individualized as a function of predialysis BUN and is reduced when BUN is low due to low NPCR because of a perceived need for less dialysis. Because of this practice, reduced t is often associated with inadequate dialysis, and kinetic modeling of the interrelationship between blood urea nitrogen (BUN), NPCR, and Kt/V is required to assure adequate dialysis with reduced t.

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

BACKGROUND Limited 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. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS We 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). PREDICTORS At 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. OUTCOME & MEASUREMENTS We 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). RESULTS The 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). LIMITATIONS Potential for residual confounding because of unmeasured factors influencing decision to convert. CONCLUSION Vascular 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

BACKGROUND The 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. METHODS We 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. RESULTS Among 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.

An analysis of thermal regulation in hemodialysis with one and three compartment models

A one compartment model of heat kinetics in hemodialysis (HD) was formulated, solved for the body surface heat transfer coefficient, and used to analyze reported clinical data. The analysis showed a linear relationship between percent change in body surface (y) and fractional dialyzer (x) heat loss, such that y = -25 - 44X, p less than 0.001. Thus, when X = 0, surface heat loss decreases 25% and core temperature (T) rises, and X must equal 45% of heat production to stabilize core T during HD. A three compartment model predicts that skin clothing insulation will have to increase 2.5 times to avoid thermal discomfort when X = 45% of heat production. A theoretic mechanism for decreased symptomatic hypotension resulting from stabilization of core T is proposed.

The Incident Patient Cohort Study Design With Uncontrolled Dose: Substantial Over-estimation of Mortality as a Function of Peritoneal Dialysis Dose?

In the Canada-USA (CANUSA) Study, the dialysis dose was neither randomized nor held constant, was measured at 6 month intervals, and the relative risk of mortality (R) was found to correlate linearly to mean values of weekly peritoneal plus renal urea clearance normalized to volume, (KprT/ V)m, ranging from 1.5 to 2.3. A risk/dose (R/D) function was derived for continuous ambulatory peritoneal dialysis from kinetic criteria for dose equivalency in hemodialysis (HD) and peritoneal dialysis (PD) and the HD R/D function. This PD R/D function was nonlinear with breakpoint from steep to shallow slope at (KprT/V)ud = 2.00, where ud refers to uniform single doses in contrast to mean doses with wide variances on the mean. The predicted decrease in renal urea clearance KrT/V per 6 months of CANUSA follow-up was computed from serial measured KrT/V in the Randomized Dialysis Prescription and Clinical Outcomes Study and showed it to be 0.21 +/- 0.34. The CANUSA (KprT/V)m values were corrected for the distributed values of 3 months decrements in KrT/V, and the population mortality risk at each (KprT/V)m dose level reported in CANUSA was computed from summation of the product of the R/D curve and fractional distribution of (KprT/V)ud values. From these calculations, the authors conclude that maximum (KprT/V)ud level achieved in CANUSA was 2.00, and the study does not define R/D response above this level.

The Current Clinical Database: Is it Complete and Useful?

T HIS WORKSHOP addressed the utility and feasibility of using databases, generated during routine patient care, in clinical research of either a descriptive or experimental nature that focus on morbidity in end-state renal disease (ESRD) patients. The impact of the clinical studies depends on successfully characterizing the morbidity associated with ESRD, describing renal replacement therapy, and assessing the effects of treatment on patient morbidity. All of these studies require that accurate, valid, and pertinent data be collected in the clinical setting, which can only be accomplished if parameters are accurately identified and valid instruments are used for measurement. Regarding the current data collection process, two major points were made. The first was that a large amount of data is currently generated during routine patient care, such as data assessing the patient, describing the equipment associated with renal replacement therapy, and documenting the effectiveness of therapy. The problem with this database is that there is inconsistency in data collection practices throughout the ESRD facilities. For example, not all facilities collect exactly the same data, and the data are recorded in various manners within the patient record, sometimes making the data difficult to access and interpret. However, the value of this database is that its breath is such that a number of the major problems associated with morbidity in ESRD patients might be further characterized, and the impact of interventions examined with minor modifications in the current data collection practices. For example, there is already a large amount of data addressing cardiovascular risk factors, vascular access function, and adequacy of dialysis. Patient quality of life, incidence and types of infections, and status of

Frank Gotch: In Memoriam

With great sadness, we note the passing of one of the pioneers of dialysis, Dr Frank A. Gotch, MD. Dr Gotch was one of many storied nephrologists whose careers were launched at the University of California at San Francisco. Dr Gotch trained as a Fellow under Dr Isidore Edelman, who characterized the distribution of fluids and electrolytes in the body. Dr Gotch shared with Dr Edelman the desire to apply quantitative principles to practical problems in clinical medicine. At UCSF, working with a PhD graduate in engineering, John Sargent, Dr Gotch studied the characteristics of solute and water transport in the artificial kidney. He assisted Ben Lipps and John Sargent, who were working at Dow Chemical at the time, in developing a hollow-fiber kidney that could be used practically without clotting. Dr. Gotch helped organize the first dialysis center in Northern California, at the San Francisco General Hospital, which focused on home hemodialysis training, and later opened the Dialysis Treatment & Research Center at Davies Hospital in San Francisco. In 1972, Dr Gotch chaired the NIH Hemodialyzer Evaluation Study Group which set standards for dialyzer performance, and in 1975, he chaired the National NIH Conference on Adequacy of Hemodialysis. A major trial in dialysis adequacy was launched at the time, the National Cooperative Dialysis Study. Dr Gotch served on the Planning Committee and, with Dr Sargent, reanalyzed the data from that study in terms of the fractional removal of urea, so-called Kt/V, which has been used as a major metric for assessing adequacy over the past 40 years. The use of Kt/V called attention to the roles of protein catabolic rate and dietary protein intake in determining the serum urea nitrogen level, in addition to quantitating the dialysis treatment. Dr Gotch was a member of the Steering Committee of another major randomized trial in hemodialysis, the HEMO Study. He was instrumental in looking at new ways to quantify dialysis, especially when schedules other than three times per week were being used, and expanded the concept that peak concentrations of uremic toxins may be important into a measure called weekly “standard” Kt/V, which is used to this day. One can learn more about this eminent nephrologist from an interview he gave to Dr Dugan W. Maddux in 2008, which is preserved at VoiceExpeditions.com. http://voiceexpeditions.com/noh/gotch/gotch.pdf Dr Gotch had a very creative, inquiring mind, and made many contributions regarding hemodialysis beyond Kt/V. He developed a comprehensive acid-base model that preceded the widespread utilization of bicarbonate dialysate for hemodialysis patients. He became interested in serum sodium, and was among the first, if not the first, with Dr Marcia L. Keen, to point out that most hemodialysis patients had a predialysis serum sodium setpoint level. Together they examined the role of dialysate sodium vs. serum sodium in controlling interdialytic weight gain. He developed methods of quantifying dialysate temperature and heat balance, the solute removal consequences of vascular access recirculation, and creatinine transport during dialysis. Together with Dr Dominik Uehlinger, Dr Gotch developed a pharmacodynamic model of treating anemia of end-stage renal disease, which took into account the effect of erythropoietin and red cell survival duration on the population of red cell throughout their life cycle, and the resulting impact on blood hemoglobin. Toward the end of his life he focused on quantifying calcium and phosphorus mass balance in