Predicting decline of kidney function in lupus nephritis using urine biomarkers.

OBJECTIVE: To evaluate candidate biomarkers to predict future renal function decline (RFD) in children and adults with lupus nephritis (LN). METHODS: At the time of enrollment into prospective observational LN cohort studies liver-type fatty acid binding protein (LFABP), albumin, monocyte chemoattractant protein-1 (MCP-1), uromodulin, transferrin, and hepcidin were measured in urine samples of two cohorts of patients with LN, one followed at a pediatric (cohort-1; n = 28) and one at an adult institution (cohort-2; n = 69). The primary outcome was RFD, defined in cohort-1 as a decrease in estimated glomerular filtration rate (eGFR) of ≥20% and in cohort-2 as a sustained increase of ≥25% in serum creatinine concentration (SCr), both from baseline. RESULTS: All patients (n = 97) had normal eGFR or SCr at the time of urine collection at baseline. RFD occurred in 29% (8/28) of patients in cohort-1 during a mean follow-up of 6.1 months, and in 30% (21/69) of those in cohort-2 during a mean follow-up of 60 months. Individually, in cohort-1, levels of MCP-1, transferrin, LFABP, and albumin were higher in the RFD group than those who maintained renal function, with statistical significance for LFABP and albumin. In cohort-2 the RFD group also had higher levels of urine MCP-1 and albumin than others. The combination of LFABP, MCP-1, albumin, and transferrin had good predictive accuracy for RFD in both cohorts (area under the ROC curve = 0.77-0.82). CONCLUSION: The combinatorial urine biomarker LFABP, MCP-1, albumin, and transferrin shows promise as a predictor of renal functional decline in LN, and warrants further investigation.

Satisfaction with care in peritoneal dialysis patients.

Patient satisfaction is an important aspect of dialysis care, only recently evaluated in clinical studies. We developed a tool to assess peritoneal dialysis (PD) customer satisfaction, and sought to evaluate and validate the Customer Satisfaction Questionnaire (CSQ), quantifying PD patient satisfaction. The CSQ included questions regarding administrative issues, Delivery Service, PD Training, Handling Requests, and transportation. The study was performed using interviews in all Hungarian Fresenius Medical Care dialysis centers offering PD. CSQ results were compared with psychosocial measures to identify if patient satisfaction was associated with perception of social support and illness burden, or depression. We assessed CSQ internal consistency and validity. Factor analysis explored potential underlying dimensions of the CSQ. One hundred and thirty-three patients treated with PD for end-stage renal disease for more than 3 months were interviewed. The CSQ had high internal consistency. There was high patient satisfaction with customer service. PD patient satisfaction scores correlated with quality of life (QOL) and social support measures, but not with medical or demographic factors, or depressive affect. The CSQ is a reliable tool to assess PD customer satisfaction. PD patient satisfaction is associated with perception of QOL. Efforts to improve customer satisfaction may improve PD patients' quantity as well as QOL.

The predictive value of self-report scales compared with physician diagnosis of depression in hemodialysis patients.

The prevalence of depression in end-stage renal disease (ESRD) patients on hemodialysis has not been definitively determined. We examined the prevalence of depression and the sensitivity, specificity, positive, and negative likelihood ratios (+LR and -LR) of self-report scales using the physician-administered Structured Clinical Interview for Depression (SCID) as the comparison. Ninety-eight consecutive patients completed the Beck Depression Inventory (BDI) and the Center for Epidemiological Study of Depression (CESD) scales. A physician blinded to BDI and CESD scores administered the SCID. Receiver/responder operating characteristic curves determined the best BDI and CESD cutoffs for depression. Depressed patients had more co-morbidities and lower quality of life, P<0.05. The prevalence of depression by SCID was 26.5% and of major depression was 17.3%. The CESD cutoff with the best diagnostic accuracy was 18, with sensitivity 69% (95% confidence interval (CI) (51%, 87%)), specificity 83% (95% CI (74%, 92%)), positive predictive value (PPV) 60%, negative predictive value (NPV) 88%, +LR 4.14, and -LR 0.37. The best BDI cutoff was 14, with sensitivity 62% (95% CI (43%, 81%)), specificity 81% (95% CI (72%, 90%)), PPV 53%, NPV 85%, +LR 3.26, and -LR 0.47. Self-report scales have high +LR but low -LR for diagnosis of depression. When used for screening, the threshold for depression should be higher for ESRD compared with non-ESRD patients. Identifying depression using physician interview is important, given the low -LR of self-report scales.

Depression and marital dissatisfaction in patients with end-stage renal disease and in their spouses.

Little research has been performed assessing patients with end-stage renal disease (ESRD) as parts of marital dyads or within family structures. Recent findings suggest patient interactions within such systems are associated with patient outcomes. To evaluate the relationship between level of patient depression and spouse psychosocial status, 55 couples in which one partner was undergoing chronic hemodialysis therapy for ESRD were interviewed. Two variables that alone and in interaction with one another were expected to relate to the spouse's level of depression and marital satisfaction were investigated: patient depression level and spouse's perceived social support. Depression was assessed using the Beck Depression Inventory (BDI). Spouses' levels of depressive affect correlated directly with patient BDI scores. A significant two-way interaction for spousal depression (patient depression and spousal support) supported viewing spouses' adjustment as a function of the interaction between spouse and patient factors. Additionally, a main effect of perceived spousal social support on spousal marital satisfaction indicated that spouses reporting high levels of social support had the least marital strain. The severity of the patient's illness did not correlate with any of the predictor variables or measures of spousal adjustment, but spouses reported significantly lower functional status for patients than did nephrologists. Spouse and patient levels of depression are related, although causal relationships cannot be determined by these studies. Moreover, spouse perception of marital satisfaction is related to depression scores. These findings suggest the patient with ESRD functions in a psychosocial dyad. Spouse psychosocial status could impact on the level of patient depression, and the spouse might be amenable to interventions that could improve patient outcome.

Biocompatibility of hemodialysis membranes: interrelations between plasma complement and cytokine levels.

Hemodialysis (HD) membrane biocompatibility is defined as absence of complement activation. We have recently shown that circulating levels of interleukin (IL) 1 and IL-2 predict death and survival, respectively, of HD patients. Studies have assessed IL-1 in treatments with biocompatible and less biocompatible dialysis membranes, but no study has correlated circulating levels of all these immunoreactants. We assessed these immunoreactants, and temperature as an outcome, during HD in patients treated with different membranes. Twelve stable patients, receiving thrice-weekly chronic bicarbonate HD, were randomly dialyzed with three different types of membranes, composed of: Cuprophan, cuprammonium rayon modified cellulose, and Hemophan. Blood was drawn from the arterial line port before (Pre) and 15, 30, and 60 min during and after (Post) HD. Patients' temperatures were measured before and after each treatment. The plasma concentrations of IL-1 and IL-2 and factors C3a and C5a were assessed by ELISA. There were no differences between baseline levels of any of the immunoreactants in patients treated with different dialyzers. C3a, C5a, and IL-1 levels increased significantly during HD treatments with all three different membranes. C3a, C5a, and IL-1 levels during Cuprophan and Hemophan treatments were significantly higher than the levels during modified cellulose treatment at 30 and 60 min and Post (p < 0.01). For all the immunoreactants, however, the Post levels were higher than the Pre levels. In contrast to IL-1, there were no differences in mean IL-2 levels during treatments when different membranes were compared. There were few correlations of plasma C3a and C5a levels with plasma IL-1 levels, but there was only one treatment time in one dialyzer group during which IL-2 and any of the other factors were correlated. Pre and Post temperature values and percent change in temperature were not correlated with any of the immunoreactants measured. These data show that C3a, C5a, and IL-1 responses are similar, but not identical, during treatments with different membranes. The response of circulating IL-2 levels to treatments is quite different from that of plasma C3a, C5a and IL-1 levels and suggests that these changes are not solely due to treatment factors. Treatment with modified cellulose membranes is associated with a different immunoreactive profile as compared with patients dialyzed using other cellulose membranes. We suggest that circulating IL-1 levels are good biocompatibility markers.

Compliance in hemodialysis patients: multidimensional measures in search of a gold standard.

The gold standard to assess the compliance of hemodialysis (HD) patients has not been established. Compliance parameters should be easily measured and verified, reproducible, clearly interpretable, and accurate. They should have meaning for the patient, clear pathophysiological significance unrelated to other factors, and be related to important outcomes. There is poor correlation of subjective and objective measures and poor correlation of laboratory compliance measures. Different factors have been associated with differential compliance in different patient populations, depending on the measures assessed. Recently, behavioral measures of compliance with dialysis prescription, such as shortening or skipping HD treatments, have been developed. New data confirm that many compliance measures, including both laboratory and behavioral compliance indices, are associated with patient outcomes. It is the duty of the nephrologist and staff to make the importance of compliance understandable to patients. It is important for the health care team to understand patients' expectations and attitudes about their illness and their beliefs about the efficacy and importance of the treatment, as well as patients' demographic, medical, psychological, familial, and socioeconomic status, before realistically evaluating compliance. Such knowledge and approaches may be critical in achieving mutually agreed on compliance goals. We suggest that although assessment of indirect indices is useful, behavioral compliance measures that quantify shortening and skipping behaviors generally should be used in HD patients. Hopefully, analyses of results that control for multiple potentially confounding factors and effective interventions to improve compliance will be developed in the near future.

Zinc nutritional status modifies renal osteodystrophy in uremic rats.

BACKGROUND: Previous studies from our laboratories suggested that zinc depletion reduces the circulating level of 1,25-dihydroxycholecalciferol (1,25(OH)2D, calcitriol) in calcium- and phosphorus-depleted rats with normal renal function, and rats with uremia. Since calcitriol synthesis is in part dependent on renal function, we studied levels of circulating vitamin D metabolites, PTH response, mineral balance and bone histomorphometry in animals with different zinc nutritional and renal functional status. METHODS: Fifty-eight male Sprague-Dawley rats were pair-fed zinc-replete (+) or -deplete (-) diets for two weeks. Thereafter, half of each paired group underwent nephrectomy (N), while half had sham (S) operations. Animals were observed for eight weeks after surgery. External mineral balances of zinc, calcium, phosphate and magnesium were determined before surgery, and 1, 2 and 7 weeks after surgery. Plasma creatinine, zinc, calcium, phosphorus, magnesium, 25-hydroxycholecalciferol, calcitriol and PTH were determined at sacrifice. Static and dynamic bone histomorphometry was determined by standard techniques. RESULTS: After an 8-week observation period, zinc-depleted animals had lower plasma zinc levels, and nephrectomized animals had lower creatinine clearances than respective controls at sacrifice. Plasma calcium and phosphorus concentrations were similar in all four groups at sacrifice. Plasma magnesium concentrations were similar in groups with renal insufficiency, regardless of zinc nutritional status. Plasma 25-hydroxycholecalciferol and calcitriol levels were similar in all groups. There was no difference between mean PTH concentration in sham-operated animals, regardless of zinc nutritional status. Although nephrectomized groups' PTH levels were increased compared to S controls, PTH levels were increased in +Zn/N animals compared to the -Zn/N group. Zinc-deplete groups had consistent negative net zinc balance, however, there was no consistent effect of nephrectomy on external calcium, phosphorus, or magnesium balance, when nephrectomized groups of different zinc nutritional status were compared. Nephrectomized animals had histomorphometric changes indicative of higher bone turnover and abnormal mineralization. Zinc deficiency was associated with less evidence of increased parathyroid hormone activity on bone in nephrectomized rats. CONCLUSIONS: Zinc depletion limits the increase in plasma PTH concentration and the expression of secondary hyperparathyroid bone disease during the development of renal insufficiency in the renal ablation model of uremia in rats. The mechanism underlying this effect is unknown, but may involve a direct effect of zinc on the synthesis, release, metabolic clearance, and/or action of PTH on the cellular level, on the interrelationship of calcitriol and PTH, or a direct effect of zinc on bone mineral metabolism. These data highlight the potential relevance of zinc nutritional status to mineral metabolism in patients with chronic renal insufficiency and end-stage renal disease.

Trends in erythropoietin therapy in the U.S. dialysis population: 1995 to 1998.

Anemia is an important cause of morbidity, and may be associated with increased mortality in patients with end-stage renal disease (ESRD) receiving dialysis. Therapy with recombinant human erythropoietin (rHuEPO) has revolutionized the care of ESRD patients, but this is a costly medication and concerns have been expressed about whether the outcome, as measured by achieved hematocrit (Hct), could be improved. The number and proportion of ESRD patients receiving rHuEPO increased steadily from 1995 to 1998, as did the dose of rHuEPO per patient. The amount of intravenous iron administered to patients increased markedly over the study period. The patients' mean hematocrit also rose, but proportionally less over the study period. The increase in both the amounts of payments per patient for rHuEPO, and the number of patients receiving rHuEPO over this time has resulted in a marked increase in the total costs to Medicare for this therapy. We suggest that a combination of payment regulations, provider financial opportunities and disincentives, and patient resistance to the effects of rHuEPO, as a result of both iron deficiency and inflammation, largely explain the findings.

Multiple measurements of depression predict mortality in a longitudinal study of chronic hemodialysis outpatients.

BACKGROUND: The medical risk factors associated with increased mortality in hemodialysis (HD) patients are well known, but the psychosocial factors that may affect outcome have not been clearly defined. One key psychosocial factor, depression, has been considered a predictor of mortality, but previous studies have provided equivocal results regarding the association. We sought to determine whether depressive affect is associated with mortality in a longitudinal study of end-stage renal disease (ESRD) patients treated with HD, using multiple assessments over time. METHODS: Two hundred ninety-five outpatients with ESRD treated with HD were recruited from three outpatient dialysis units in Washington D.C. to participate in a prospective cohort study with longitudinal follow-up. Patients were assessed every six months for up to two years using the Beck Depression Inventory (BDI), age, serum albumin concentration, Kt/V, and protein catabolic rate (PCR). A severity index, previously demonstrated to be a mortality marker, was used to grade medical comorbidity. The type of dialyzer with which the patient was treated was noted. Patient mortality status was tracked for a minimum of 20 and a maximum of 60 months after the first interview. Cox proportional hazards models, treating depression scores as time-varying covariates in a univariable analysis, and controlling for age, medical comorbidity, albumin concentration, and dialyzer type and site in multivariable models, were used to assess the relative mortality risk. RESULTS: The mean (+/- SD) age of our population at initial interview was 54.6 +/- 14.1 years. The mean PCR was 1.06 +/- 0.27 g/kg/day, and the mean Kt/V was 1.2 +/- 0.4 at baseline, suggesting that the patients were well nourished and dialyzed comparably to contemporary U.S. patients. The patients' mean BDI at enrollment was 11.4 +/- 8.1, in the range of mild depression. Patients' baseline level of depression was not a significant predictor of mortality at 38.6 months of follow-up. In contrast, when depression was treated as a time-varying covariate based on periodic follow-up assessments, the level of depressive affect was significantly associated with mortality in both single variable and multivariable analyses. CONCLUSIONS: Higher levels of depressive affect in ESRD patients treated with HD are associated with increased mortality. The effects of depression on patient survival are of the same order of magnitude as medical risk factors. Our findings using both controls for factors possibly confounded with depressive affect in patients with ESRD and time-varying covariate analyses may explain the inconsistent results of previous studies of depression and mortality in ESRD patients. Time-varying analyses in longitudinal studies may add power to defining and sensitivity to establishing the association of psychosocial factors and survival in ESRD patients. The mechanism underlying the relationship of depression and survival and the effect of interventions to improve depression in HD outpatients and general medical inpatients should be studied.

Psychosocial factors in adult end-stage renal disease patients treated with hemodialysis: correlates and outcomes.

The first three decades of the ESRD program were devoted to extending patient survival. Few data have been generated regarding the factors associated with successful patient adjustment. Depression and perception of the effects of illness are important responses to the experience of ESRD and may be associated with differential survival. Perception and extent of social support can moderate these factors. The association of psychosocial factors and assessments of quality of life are incompletely understood and are topics of research interest. The role of variation in socioeconomic status in association with these factors has not been extensively studied. The challenges for the next 30 years include understanding the relationship of psychosocial factors to demographic and medical factors in large ESRD patient populations and the refinement of associations between psychosocial factors and patient outcomes, including adjustment, compliance, morbidity, and mortality.

The nephropathies of HIV infection: pathogenesis and treatment.

Several different renal syndromes have been reported in patients with HIV infection. Patient characteristics and a syndrome approach may help the clinician formulate a tentative diagnosis, but a renal biopsy is necessary to make a firm diagnosis in patients with chronic renal disease in the setting of HIV infection. The pathogenesis of the HIV nephropathies can teach us much about the pathophysiology of common renal problems such as IgA nephropathy, immune complex glomerulonephritis, focal segmental glomerulosclerosis, and diabetic renal disease. HIV-associated renal disease may be the result of the interaction of the expression of specific HIV genes in patients with distinct genetic susceptibilities to disease in particular environments. New treatment approaches have provided hope for patients with classic HIV-associated nephropathy.

Interdialytic weight gain and survival in hemodialysis patients: effects of duration of ESRD and diabetes mellitus.

BACKGROUND: Medical mortality determinants in end-stage renal disease (ESRD) patients treated with hemodialysis (HD) are well known. More recently, associations have been established between the dose of dialysis administered and patient survival. We showed in a prospective study that both dialyzer type and patient compliance with the dialysis prescription were independently associated with survival. Although several parameters of dialytic technique and patient compliance are associated with differential survival in patients with ESRD treated with HD, the association of interdialytic weight gain (IWG) with survival is unclear. No study has assessed the relationship between IWG and mortality in HD patients, controlled for multiple medical risk factors. The aim of our study was to determine whether IWG was associated with survival in patients with ESRD treated with HD, controlling for multiple medical and dialytic risk factors. METHODS: We prospectively conducted an observational, longitudinal, multicenter study of 283 urban HD patients to determine the relationship of IWG with several dialytic parameters and patient survival. Medical risk factors such as demographic indices and comorbid conditions were assessed. We studied Kt/V, the protein catabolic rate (PCR), serum albumin and anthropometric measurements, behavioral compliance indices, dialyzer characteristics, and serum electrolyte concentrations, and correlated these with IWG. In addition, the duration of dialysis was assessed in HD patients with and without diabetes mellitus. Cox proportional hazards models assessed the relative mortality risk of increased IWG, controlling for variations in medical comorbidity and other mortality determinants. RESULTS: The mean (+/- SD) age of our population was 54.6 +/- 14.1 years, and the mean time they were treated with HD was 30.4 +/- 46.9 months. The mean IWG was 1.54 +/- 0.71% dry wt/day. Correlations were found between increased IWG and younger age, and lower midarm circumference, and increased Kt/V, PCR, and serum potassium concentration. The mean follow-up period was 48.9 +/- 10.6 months. An increase in IWG was associated with a significantly increased relative mortality risk in diabetic ESRD patients treated with HD when variations in age, comorbidity, serum albumin concentration, and dialyzer type and site were controlled. There was, however, no association of increased mortality risk with increased IWG in the larger population of patients without diabetes. In further analyses, the increased mortality risk associated with increased IWG was found to be present only in patients with diabetes mellitus who had recently started HD therapy for ESRD. CONCLUSION: IWG is correlated with several nutritional and dialytic variables and with parameters that predict survival in HD patients. Increased IWG is independently associated with decreased survival of diabetic ESRD patients treated with HD, after adjusting for variation in other medical risk factors. The population of incident diabetic HD patients is particularly susceptible to increased risk associated with increased IWG. The mechanisms underlying these results are obscure, but IWG might be associated with poorer survival in this population if it were linked to worsened hypertension, cardiovascular stress, or poorer glycemic control. Interventions to improve compliance with IWG in incident diabetic HD patients are warranted.

Ethical issues in aging and renal disease.

The incidence of elderly patients reaching end-stage renal disease (ESRD) and requiring renal replacement is increasing. Better medical care is helping patients live longer but, at the same time, is raising ethical questions. Treatment decisions for ESRD patients present a forum for the consideration of ethical questions surrounding the issues of scarce health care resource allocation and the withholding or withdrawal of life-sustaining treatment. As background for the consideration of ethical issues in ESRD patients, the quality of life they experience and what they may expect as death approaches also are discussed.

Family structure and patient survival in an African-American end-stage renal disease population: a preliminary investigation.

Few studies have examined the influence of the family on the course of chronic illness in African-Americans. We explore the relationship between family structure, defined as marital status and household composition, and patient survival. Patient gender was examined as a possible moderator in this relationship. Using data from a survey of 476 African-American end-stage renal disease (ESRD) patients, a significant association between household composition and patient survival was found. Results from Cox proportional hazards model, controlling for patient age, indicated that patients who live in 'complex' households (i.e. those with a partner and/or others) are at greater risk for shortened survival as compared to those who live alone or with a spouse/partner (p < 0.05). When we examined whether patient gender moderates this relationship, female patients who live in these households were found to be at 2 times greater risk for shortened survival (p < 0.01) than female patients who live alone or with their spouse/ partner only. Family structure was not significantly associated with survival in male patients. Discussion and implications of findings are addressed.

Secular trends in recombinant erythropoietin therapy among the U.S. hemodialysis population: 1990-1996.

BACKGROUND: Chronic anemia is a major cause of morbidity among the end-stage renal disease (ESRD) population. Recombinant erythropoietin (rHuEPO) has been recognized as a major advance in the treatment of anemia among the ESRD population. This study examines the secular trends in the use of and response to rHuEPO therapy among severely, moderately and mildly anemic hemodialysis patients. METHODS: We designed a cohort analytic study using seven years of claims data. The study population comprised all facility-based adult hemodialysis patients receiving rHuEPO therapy, who were initially reimbursed by Medicare in each of the first quarter of the calendar years 1990 through 1996 (N = 64,957). RESULTS: Between 1990 and 1996, the mean rHuEPO dose increased by 139% for the patient cohorts with a first observed hematocrit < 0.25, 122% for the 0.25 to 0.29 cohorts, and 107% for the > or = 0.30 cohorts, and produced a 0.02 to 0.03 increase in achieved hematocrit (A-Hct) over this time. Dosing of rHuEPO did not appear to be influenced by patient or provider characteristics, although African-Americans, the elderly, non-diabetics and persons receiving dialysis in a non-profit facility had a larger percent change in hematocrit compared to their counterparts (P < 0.001). CONCLUSIONS: The results of the clinical use of rHuEPO seven years after FDA approval found in the general ESRD hemodialysis population have not equaled the results obtained in the initial clinical trials. Overall, our findings suggest that substantial increases in rHuEPO dose provided to anemic patients have resulted in only modest increases in hematocrit in the seven years since rHuEPO's introduction. Resistance to rHuEPO, prior rHuEPO treatment, inadequate use of supplemental iron, and policy and financial incentives may explain this finding.