Predialysis nephrologist care and access to kidney transplantation in the United States.

Predialysis nephrologist care is associated with morbidity and mortality in incident dialysis patients, but the relationship with access to kidney transplantation (KT) is unclear. From a national study of incident US dialysis patients, we identified 2253 patients with detailed information about predialysis care, sociodemographic characteristics and comorbidities. We used multivariate Cox proportional hazards models to study associations between predialysis nephrology care and two outcomes: time from first dialysis to the first day on the KT wait-list, and time to first KT. Two-thirds of patients first encountered a nephrologist >3 months prior to dialysis and one-third

Associations between CMS's Clinical Performance Measures project benchmarks, profit structure, and mortality in dialysis units.

Prior studies observing greater mortality in for-profit dialysis units have not captured information about benchmarks of care. This study was undertaken to examine the association between profit status and mortality while achieving benchmarks. Utilizing data from the US Renal Data System and the Centers for Medicare & Medicaid Services' end-stage renal disease (ESRD) Clinical Performance Measures project, hemodialysis units were categorized as for-profit or not-for-profit. Associations with mortality at 1 year were estimated using Cox regression. Two thousand six hundred and eighty-five dialysis units (31,515 patients) were designated as for-profit and 1018 (15,085 patients) as not-for-profit. Patients in for-profit facilities were more likely to be older, black, female, diabetic, and have higher urea reduction ratio (URR), hematocrit, serum albumin, and transferrin saturation. Patients (19.4 and 18.6%) in for-profit and not-for-profit units died, respectively. In unadjusted analyses, profit status was not associated with mortality (hazard ratio (HR)=1.04, P=0.09). When added to models with profit status, the following resulted in a significant association between profit status (for-profit vs not-for-profit) and increasing mortality risk: URR, hematocrit, albumin, and ESRD Network. In adjusted models, patients in for-profit facilities had a greater death risk (HR 1.09, P=0.004). More patients in for-profit units met clinical benchmarks. Survival among patients in for-profit units was similar to not-for-profit units. This suggests that in the contemporary era, interventions in for-profit dialysis units have not impaired their ability to deliver performance benchmarks and do not affect survival.

Determinants of delayed nephrologist referral in patients with chronic kidney disease.

Late referral to nephrologists of patients with chronic kidney disease (CKD) is a major public health problem because it is prevalent and associated with increased morbidity, mortality, and greater healthcare costs. To identify factors associated with delayed nephrologist referral (first nephrologist visit < 90 days before the onset of renal replacement therapy), we identified a cohort of patients with preexisting CKD that progressed to end-stage renal failure. We developed a logistic regression model to measure the association of specific demographic and clinical covariates with delayed nephrologist referral. Delayed referral was highly associated with older age (P < 0.001), race other than white or black (P = 0.002), and the absence of certain comorbidities: hypertension (P < 0.001), coronary artery disease (P < 0.001), malignancy (P = 0.005), and diabetes (P = 0.02). Associations of late referral with male sex (P = 0.07) and lower socioeconomic status (P = 0.09) were of borderline significance. Patients who were predominantly cared for by a general internist were more likely to be referred late to a nephrologist compared with those cared for by a family or primary care practitioner (P = 0.002) or another subspecialist (P = 0.019). These findings suggest that several factors increase the risk that patients with CKD will have the first nephrologist consultation excessively late in the course of their disease. Although timely access to nephrologist services is important for all patients with advanced CKD, this is of particular concern in older patients, those in certain minority populations, and those in whom the absence of comorbidity may provide a false sense of true risk status.

Association between prevalent care process measures and facility-specific mortality rates.

BACKGROUND: Medical communities often develop practice guidelines recommending certain care processes intended to promote better clinical outcome among patients. Conformance with those guidelines by facilities is then monitored to evaluate care quality, presuming that the process is associated with and can be used reliably to predict clinical outcome. Outcome is often monitored as a facility-specific mortality rate (SMR) standardized to the mix of patients treated, also presuming that inferior outcome implies a suboptimal process. The U.S. Health Care Financing Administration monitors three practice guidelines, called Core Indicators, in dialysis facilities to assist management of its end-stage renal disease program: (1) patients' hematocrit values should exceed 30 vol%, (2) the urea reduction ratio (URR) during dialysis should equal or exceed 65%, and (3) patients' serum albumin concentrations should equal or exceed 3.5 g/dL. METHODS: The associations of a facility-specific SMR were evaluated with the fractions of hemodialysis patients not conforming to (that is, at variance with) the Core Indicators during three successive years (1993 to 1995) in large numbers of facilities (394, 450, and 498) using one-variable and multivariable statistical models. Three related strategies were used. First, the association of the SMR with the fraction of patients not meeting the guideline was evaluated. Second, each facility was classified by whether its SMR exceeded the 80% confidence interval above 1.0 (worse than 1.0, Group 3), was less than the interval below 1.0 (better than 1.0, Group 1), or was within the interval (Group 2). The fraction of those patients who did not meet the Indicator guidelines was then evaluated in each group. Third, the ability of variance from Indicator guidelines to predict into which of the three SMR groups a facility would be categorized was evaluated. RESULTS: SMR was directly correlated with variance from the Indicator guidelines, but the strengths of the associations were weak particularly for the hematocrit (R(2) = 2.2%, 5.6, and 2.2 for each of the 3 years) and URR Indicators (R(2) = 2.6, 0.6, 3.3). It was stronger for the albumin Indicator (R(2) = 11.6, 20.4, 21.8). The fractions of patients falling outside of the Indicator guidelines tended to be higher in the highest SMR group. The groups were not well separated, however, particularly for the hematocrit and URR Indicators, and there was substantial overlap between them. Finally, although the likelihood that a facility would be a member of the high or low SMR group was associated with fractional variance from Core Indicator guidelines, the strengths of association were weak, and the probability that a facility would be a member of the high or low group could not be easily distinguished from the probability that it would be a member of the middle group. CONCLUSIONS: While there were statistical associations between SMR and the fraction of patients in facilities who were at variance with these guidelines, they were weak and variances from the guidelines could not be used reliably to predict high or low SMR. Such findings do not imply that measures reflecting anemia, dialysis dose, or medical processes that influence serum albumin concentration are irrelevant to the quality of care. They do suggest, however, that more attention needs be paid to these and other associates and causes of mortality among dialysis patients when developing care process indicator guidelines.

Explaining counter-intuitive clinical outcomes predicted by Kt/V.

Population-based studies of maintenance hemodialysis patients have demonstrated a reproducible relationship between the dose of hemodialysis and mortality and morbidity outcomes. In these analyses, which have aggregated hemodialysis patient subgroups, improved outcomes are associated with greater doses of hemodialysis. However, remarkable counterintuitive findings are observed if patients are analyzed by subgroups based on their race, gender, and anthropometric and blood-based biomarkers of nutritional state. For example, blacks generally receive lower doses of hemodialysis than whites, but enjoy relatively improved survival; patients who receive the highest doses of hemodialysis have an increased death risk; and the dose response curve between hemodialysis and survival is altered based on the patients' body mass index. These seemingly paradoxical relationships between hemodialysis dose and patient survival can be explained because of the use of mathematical urea kinetic constructs as clinical outcome predictors; they integrate a measure of solute removal (K x t) with an anthropometric surrogate of nutrition, the urea distribution volume (V). Both these measures have an independent influence on patient survival and in some clinical circumstances are of unequal power as clinical outcome predictors. These complex interactions must be kept in perspective as clinical care is delivered in the context of hemodialysis dose.

Role of the nephrologist in the intensive care unit.

Intensive care units (ICUs) are increasingly becoming a focal point for tension between medical specialists. In an extreme approach to this issue, some ICUs have become closed units managed by intensivists, with other specialists, such as nephrologists, having a restricted supportive role. The nephrologist, a subspecialist with broad skills in general internal medicine, has trained and appropriately can serve as the primary physician for patients with significant renal failure and end-stage renal disease in multiple hospital settings, including the ICU. Sick and complex hospitalized patients offer ample opportunity for a collaborative interaction between the nephrologist and intensivist in the ICU.

Funding ESRD care through charity: the paradigm of the National Kidney Foundation of Singapore.

Given the prohibitive costs of end-stage renal disease (ESRD) care for certain countries and the increasing incidence of ESRD worldwide, alternative methods of funding dialysis care are increasingly necessary. We describe the paradigm of the National Kidney Foundation of Singapore (NKF-S), the provider of subsidized dialysis care and comprehensive rehabilitative services to approximately 60% of all ESRD patients in the country, whose activities are funded entirely by charitable public donations. Unique to the NKF-S model are the considerations of the donor as an "investor" in the health care of NKF-S dialysis patients, the personal responsibility of the dialysis patient as a recipient of this "investment" to play an active role in achieving good clinical and rehabilitative outcomes, and the fostering of community-based support systems to facilitate patient rehabilitation such as partnerships with employers willing to employ dialysis patients. The success of the system is shown by its clinical outcomes, which approximate those observed in the United States. We believe that several aspects of the NKF-S model for ESRD care may be implemented in other communities, particularly in countries that have yet to develop financially and clinically mature dialysis programs.

Long-term outcomes of revascularization for peripheral vascular disease in end-stage renal disease patients.

The occurrence of peripheral vascular disease (PVD) and atraumatic lower-extremity amputations is significantly greater in patients with end-stage renal disease (ESRD) than those with normal renal function. Moreover, the mortality for dialysis patients undergoing atraumatic lower-extremity amputations is far greater. Because PVD requiring amputation is an extreme form of PVD, we tested the hypothesis that mortality and intermediate outcomes for patients with ESRD undergoing lower-extremity revascularization, a less extreme form of PVD, would be equivalent to that for patients without ESRD. This is a retrospective case-control analysis of lower-extremity revascularization in patients with ESRD. Procedures in patients with ESRD were matched with procedures in non-ESRD controls for patient age, sex, race, diabetes mellitus, and hospital setting. Patient survival, graft survival, and limb salvage rates were determined using Kaplan-Meier analysis. Subjective interpretation of functional and symptomatic improvement was determined by telephone interviews with patients or relatives. Thirty-one procedures were performed on 20 patients with ESRD and 64 matched procedures were performed on 57 patients without ESRD. In the ESRD group, median patient survival was 1.72 years compared with 5.17 years for the control group (P < 0.001). Time to 50% limb loss was 1.24 years in the ESRD group and longer than 5.65 years in the control group (P < 0.001). Time to 50% graft patency loss was 0.70 years in the ESRD group and longer than 5.5 years in the control group (P < 0.05). Subjective improvement was less in patients with ESRD. Outcomes of lower-extremity revascularization in patients with ESRD are inferior to those in non-ESRD controls. The mortality rate for patients with ESRD who undergo revascularization is extremely high. Patient-related variables (eg, increased prevalence of hypertension and cardiovascular disease) and/or provider-specific factors (eg, timing of surgery in the course of PVD) may be responsible for poorer outcomes.

Differential survival after coronary revascularization procedures among patients with renal insufficiency.

BACKGROUND: Acute myocardial infarction, cardiac arrest, and other cardiac events are the major cause of mortality among patients with renal insufficiency. Previous studies of interventions for coronary artery disease among patients with renal insufficiency have not controlled for potentially confounding factors such as coronary artery disease severity and left ventricular function. This study investigates the comparative survival for patients with renal insufficiency and coronary artery disease following coronary artery bypass graft (CABG) surgery as compared with percutaneous coronary artery intervention (PCI), while controlling for confounding factors. METHODS: This retrospective cohort study of patients undergoing CABG surgery or PCI discharged between 1993 and 1995 uses the New York Department of Health databases and Cox proportional hazards analyses to estimate the mortality risk associated with CABG as compared with PCI for patients with renal insufficiency. Renal function was categorized as creatinine <2.5 mg/dL (N = 58,329), creatinine > or =2.5 mg/dL (N = 840), and end-stage renal disease (ESRD) requiring dialysis (N = 407). RESULTS: Patients with either ESRD or serum creatinine > or =2.5 mg/dL had more severe coronary artery disease and a greater frequency of comorbid conditions as compared with patients with creatinine <2.5 mg/dL. Creatinine > or =2.5 mg/dL and ESRD were both associated with an increased mortality risk among all distributions of coronary artery disease anatomy. Among patients with ESRD, the risk ratio (RR) of mortality for patients undergoing CABG compared with PCI was 0.39 (95% CI, 0.22 to 0.67, P = 0.0006). Among patients with creatinine > or =2.5 mg/dL, CABG surgery did not convey a survival benefit over PCI (RR, 0.86, 95% CI, 0.56 to 1.33, P = 0.50). CONCLUSIONS: This study demonstrates a survival benefit among patients with ESRD undergoing CABG surgery as compared with PCI, while controlling for severity of coronary artery disease, left ventricular dysfunction, and other comorbid conditions. These results suggest that management decisions among patients with coronary artery disease should be made in the context of not only location and severity of coronary artery lesions, but also on the presence and severity of renal dysfunction.

Evaluation of disease-state management of dialysis patients.

Dialysis patients are the only Medicare beneficiaries prohibited from joining managed care plans. Concerns have been raised about the ability of such plans to provide the comprehensive care required by patients with this complex condition. However, more than 20,000 dialysis patients belong to such plans because they were enrolled before developing end-stage renal disease (ESRD). Disease-state management, successfully applied to patients with diabetes mellitus and congestive heart failure, is now being used in patients with ESRD. Standardized mortality ratios (SMRs) and standardized hospitalization ratios (SHRs) were calculated for 1998 and 1999 in 1,541 patients enrolled in the RMS Disease Management program of renal disease-state management using US Renal Data System methods. SMRs were 0.643 and 0.806 for 1998 and 1999, respectively, significantly different from 1.0 for both years (P < 0.001). SHRs were 0.620 and 0.503 for 1998 and 1999, respectively, significantly different from 1.0 for both years (P < 0.001). Although additional studies are needed to define the aspects of care that are most important for the outcomes seen, this study shows that favorable outcomes are achievable for this vulnerable patient population within a managed care setting that applies coordinated approaches to care.

Subcutaneous erythropoietin results in lower dose and equivalent hematocrit levels among adult hemodialysis patients: Results from the 1998 End-Stage Renal Disease Core Indicators Project.

The National Kidney Foundation's Dialysis Outcome Quality Initiative (NKF-DOQI) guidelines recommend that epoetin alfa should be administered by the subcutaneous route in hemodialysis patients. We determined whether hematocrit levels in hemodialysis patients differed by route of epoetin alfa administration after controlling for demographic factors and iron status. Data were available for 7,092 of the 7,658 patients randomly chosen for inclusion in the 1997 Health Care Financing Administration Core Indicators sample. Epoetin alfa was administered to 96% of the study cohort and was administered subcutaneously in 10% of patients. After controlling for hematocrit, patient characteristics, adequacy of dialysis, iron status, serum albumin, postdialysis weight, and duration of dialysis, the epoetin alfa dose by the intravenous route was 193.6 units/kg/wk (95% confidence interval, 189.5 to 197.8 units/kg/wk) compared with 167.4 units/kg/wk (95% confidence interval, 153.9 to 180.8 units/kg/wk) for the subcutaneous route (P < 0.001). The mean hematocrit for the subcutaneous route was 32.7% +/- 3.4% and for the intravenous route was 33.0% +/- 3.2% (P < 0.05). Factors independently associated with increased hematocrit included male gender, white race, older patient age, greater number of years on dialysis, higher serum albumin concentration, higher urea reduction ratio, and percent transferrin saturation (all P < 0.001). After controlling for patient factors and weekly epoetin alfa dose, there was no association between route of epoetin alfa administration and hematocrit level (P = 0.144). Patients receiving epoetin alfa by the subcutaneous route had comparable hematocrit values using a lower epoetin alfa dose than patients receiving epoetin alfa intravenously. These data support the NKF-DOQI recommendation that epoetin alfa be administered subcutaneously in long-term hemodialysis patients.

Pathogenesis of beta(2)-microglobulin amyloidosis: role of monocytes/macrophages.

beta(2)-microglobulin (beta(2)M) amyloidosis (A beta(2)M) is a serious, often incapacitating complication for patients undergoing long-term hemodialysis. Amyloid deposits composed of beta(2)M fibrils as the major constituent protein are mainly localized in joints and periarticular bone and lead to chronic arthralgias, carpal tunnel syndrome, and eventually destructive arthropathy. Although recent histologic studies have shown the accumulation of monocytes/macrophages around amyloid deposits, the factor(s) causing their infiltration and pathologic involvement have yet to be fully elucidated. Immunohistochemical staining reveals that macrophages in tenosynovial tissues express CD13, CD14, CD33, HLA-DR, and CD68 antigens on their surfaces and express interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, and IL-6. Many of these cells also express LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), and VLA-4 (CD49d/CD29) on their surfaces. AGE-modified beta(2)M enhances chemotaxis of monocytes and stimulates macrophages to release bone-resorbing cytokines, such as IL-1 beta, TNF-alpha and IL-6. Via a RAGE-mediated pathway, AGE-modified, but not unmodified beta(2)M, significantly delays constitutive apoptosis of human peripheral blood monocytes. Monocytes survival in an advanced glycation end product (AGE) beta(2)M-containing microenvironment is associated with their phenotypic alteration into macrophage-like cells that generate more reactive oxygen species and elaborate greater quantities of IL-1 beta and TNF-alpha. Thus through regulation of their survival and differentiation, AGE beta(2)M in amyloid deposits may be able to influence the presence and quantity of infiltrated monocytes, and hence their biologic effects.

beta(2)-Microglobulin modified with advanced glycation end products delays monocyte apoptosis.

BACKGROUND: A local inflammatory reaction to beta(2)-microglobulin (beta(2)m) amyloid deposits by monocytes/macrophages is a characteristic histologic feature of dialysis-related amyloidosis (DRA). Since beta(2)m modified with advanced glycation end products (AGE-beta(2)m) is a major constituent of amyloid in DRA, we tested the hypothesis that AGE-beta(2)m affects apoptosis and phenotype of human monocytes. METHODS: Human peripheral blood monocytes were incubated with or without in vitro-derived AGE-beta(2)m, and their viability, extent of apoptosis, morphology, and function examined over the subsequent four days. RESULTS: AGE-modified but not unmodified beta(2)m significantly delayed spontaneous apoptosis of human peripheral blood monocytes in adherent and nonadherent cultures. The effect of AGE-beta(2)m on monocytes apoptosis was time- and dose-dependent and was attenuated by a blocking antibody directed against the human AGE receptor (RAGE). There was no difference in effect between AGE-beta(2)m and that of AGE-modified human serum albumin. Culture of monocytes with AGE-beta(2)m did not alter membrane expression of Fas or Fas ligand. Monocytes cultured with AGE-beta(2)m underwent substantial changes in morphology similar to those observed when monocytes differentiate into macrophages. The cultured cells increased in size and vacuolization, and their content of beta-glucuronidase and acid phosphatase increased by 5- to 10-fold at day 4. Expression of the monocyte--macrophage membrane antigens HLA-DR, CD11b, and CD11c also increased at day 4. Although exhibiting phenotypic characteristics of macrophages, monocytes cultured with AGE-beta(2)m functioned differently than macrophages cultured with serum. Superoxide production in response to phorbol myristic acetate was maintained in monocytes cultured with AGE-beta(2)m, but declined with time in cells cultured with serum. Constitutive synthesis of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and prostaglandin E2 (PGE2) increased in monocytes cultured for four to six days with AGE-beta(2)m. CONCLUSIONS: These findings support a novel role for AGE-modified proteins such as AGE-beta(2)m that may contribute to the development of a local inflammatory response, with predominant accumulation of monocytes/macrophages, in DRA.

A novel immunoadsorption device for removing beta2-microglobulin from whole blood.

BACKGROUND: High plasma levels of beta2-microglobulin (beta2m) have been implicated in the formation of the severely destructive and potentially fatal amyloid deposits that are characteristic of dialysis-related amyloidosis (DRA). Conventional renal replacement technologies remove insufficient quantities of beta2m to normalize plasma levels. This limitation arises because of nonspecific adsorptive qualities and reliance on size exclusion, which can also remove other middle molecular weight proteins. These nonspecific approaches also make it difficult to evaluate the role and contribution of middle molecular weight molecules to the pathology of DRA and other morbidities of end-stage renal disease. A high-affinity and biologically specific approach could target a protein, prevent a significant loss of other important molecules, and improve the apparent adsorption rate within an extracorporeal device. METHODS: Agarose-immobilized murine anti-human beta2m monoclonal antibodies were used in a Vortex Flow Plasmapheretic Reactor (VFPR) to remove donor baseline and controlled amounts of recombinant beta2m from human blood in vitro. The extracorporeal circuit was hemoperfused at 200 mL/min for two hours. RESULTS: The immunoadsorptive media had a binding site density of 30 microg beta2m per mL of settled gel. The VFPR cleared baseline quantities of donor beta2m below detectable limits of the assay. The experiments with higher initial beta2m concentrations reached an equilibrium concentration within 20 minutes, corresponding to a 92% clearance. No deleterious hemocompatibility issues were observed (complete blood count, total protein, and plasma free hemoglobin). CONCLUSIONS: The adsorptive kinetics of the VFPR are optimal for the conditions used and support the use of immunoadsorption for the removal of beta2m.

Changing hemodialysis thresholds for optimal survival.

BACKGROUND: The urea reduction ratio (URR), a measure quantitating solute removal during hemodialysis, is the fractional reduction of the blood urea concentration during a single hemodialysis treatment. The URR is the principal measure of hemodialysis dose in the United States. Based on studies of patients dialyzed prior to 1994, a minimum URR value of 65% was recommended to optimize survival. Because of new hemodialysis technologies and evolving demographics of the hemodialysis population, the relationship between the amount of hemodialysis and mortality was examined in contemporary cohorts. METHODS: This retrospective cohort included> 15,000 patients per year receiving hemodialysis during 1994 through 1997. Each patient's URR was averaged for the three months prior to the beginning of each year. Mortality odds ratios were calculated for patients by URR. To determine the URR value above which no further improvement in mortality was seen ("threshold"), spline functions were tested in logistic regression models, both unadjusted and adjusted for case mix measures. The strength of fit for URR, defined by a range of candidate thresholds from 55 to 75%, was evaluated in increments of 1% for each year using spline functions. RESULTS: The median URR was 63.2, 65.4, 67.4, and 68.1% for 1994 through 1997, respectively. The median length of hemodialysis treatments increased only six minutes from the beginning to the end of the period of analysis. Using spline functions, the threshold URR values were 61.1, 65.0, 68.0, and 71.0% for 1994 through 1997 in models adjusted for case mix. The ratio of median URR to URR threshold decreased from 1.03 in 1994 to 0.97 in 1997. CONCLUSIONS: From 1994 to 1997, the median URR and the URR threshold for mortality benefit increased. Although an increased need in the amount of hemodialysis may be a consequence of changes in patients' demographic characteristics, the likely explanation(s) is a change in the dialysis procedure and/or blood sampling favoring higher URR values without changing the amount of dialysis provided. The recommended minimum URR of 65% appears to be too low to confer an optimal mortality benefit in the context of current practices.