A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy.

BACKGROUND: A proliferation-inducing ligand (APRIL) is implicated in the pathogenesis of IgA nephropathy. Sibeprenlimab is a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL. METHODS: In this phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned adults with biopsy-confirmed IgA nephropathy who were at high risk for disease progression, despite having received standard-care treatment, in a 1:1:1:1 ratio to receive intravenous sibeprenlimab at a dose of 2, 4, or 8 mg per kilogram of body weight or placebo once monthly for 12 months. The primary end point was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio at month 12. Secondary end points included the change from baseline in the estimated glomerular filtration rate (eGFR) at month 12. Safety was also assessed. RESULTS: Among 155 patients who underwent randomization, 38 received sibeprenlimab at a dose of 2 mg per kilogram, 41 received sibeprenlimab at a dose of 4 mg per kilogram, 38 received sibeprenlimab at a dose of 8 mg per kilogram, and 38 received placebo. At 12 months, the geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. At 12 months, the least-squares mean (±SE) change from baseline in eGFR was -2.7±1.8, 0.2±1.7, -1.5±1.8, and -7.4±1.8 ml per minute per 1.73 m2 in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. The incidence of adverse events that occurred after the start of administration of sibeprenlimab or placebo was 78.6% in the pooled sibeprenlimab groups and 71.1% in the placebo group. CONCLUSIONS: In patients with IgA nephropathy, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo. (Funded by Visterra; ENVISION ClinicalTrials.gov number, NCT04287985; EudraCT number, 2019-002531-29.).

A Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of murine IgA nephropathy.

IgA nephropathy (IgAN) is the most prevalent primary chronic glomerular disease for which no safe disease-specific therapies currently exist. IgAN is an autoimmune disease involving the production of autoantigenic, aberrantly O-glycosylated IgA1 and ensuing deposition of nephritogenic immune complexes in the kidney. A Proliferation Inducing Ligand (APRIL) has emerged as a key B-cell-modulating factor in this pathogenesis. Using a mouse anti-APRIL monoclonal antibody (4540), we confirm both the pathogenic role of APRIL in IgAN and the therapeutic efficacy of antibody-directed neutralization of APRIL in the grouped mouse ddY disease model. Treatment with 4540 directly translated to a reduction in relevant pathogenic mechanisms including suppressed serum IgA levels, reduced circulating immune complexes, significantly lower kidney deposits of IgA, IgG and C3, and suppression of proteinuria compared to mice receiving vehicle or isotype control antibodies. Furthermore, we translated these findings to the pharmacological characterization of VIS649, a highly potent, humanized IgG2κ antibody targeting and neutralizing human APRIL through unique epitope engagement, leading to inhibition of APRIL-mediated B-cell activities. VIS649 treatment of non-human primates showed dose-dependent reduction of serum IgA levels of up to 70%. A reduction of IgA+, IgM+, and IgG+ B cells was noted in the gut-associated mucosa of VIS649-treated animals. Population-based modeling predicted a favorable therapeutic dosing profile for subcutaneous administration of VIS649 in the clinical setting. Thus, our data highlight the potential therapeutic benefit of VIS649 for the treatment of IgAN.

State-of-Art Therapeutics in IgA Nephropathy.

Immunoglobulin-A nephropathy (IgAN) is the most common primary glomerulonephritis in the world, with up to 40% of patients progressing to end-stage kidney disease (ESKD) within 30 years of diagnosis. IgAN is characterized by elevated serum levels of galactose-deficient IgA1 (Gd-IgA1), which leads to immune complex formation and deposition in the glomerular mesangium, causing kidney injury. A diverse disease course and the long-term follow-up required for clinically relevant endpoints (e.g., ESKD) have been barriers to the development of novel therapies in IgAN. Disease management has focused on supportive care with inhibitors of the renin-angiotensin system and, more recently, sodium-glucose transporter inhibitors to control proteinuria. The recent acceptance of proteinuria as a surrogate endpoint by regulatory bodies and a better understanding of disease pathology have helped to initiate the development of several novel treatments. Subsequently, a targeted-release formulation of budesonide and a dual endothelin/angiotensin inhibitor (sparsentan) have received accelerated approval for patients with IgAN. However, additional therapies are needed to target the different pathogenic mechanisms and individualize patient care. Several compounds currently under investigation target various effectors of pathology. There are promising clinical results from emerging compounds that target the generation of Gd-IgA1 by B cells, including inhibitors of A PRoliferation-Inducing Ligand (APRIL) and dual inhibitors of APRIL and B-cell activating factor (BAFF). Other investigational therapies target the complement cascade by inhibiting proteins of the lectin or alternative pathways. As the therapeutic landscape evolves, it will be important to revise treatment guidelines and develop updated standards of care.

Factors affecting response and tolerability to ferumoxytol in nondialysis chronic kidney disease patients.

BACKGROUND: Ferumoxytol is a unique intravenous (i.v.) iron therapy. This report examines factors affecting hemoglobin response to i.v. ferumoxytol, and the relationship between hematologic parameters, concomitant erythropoiesis-stimulating agents (ESA), and adverse events (AEs) in nondialysis CKD patients. METHODS: A series of post-hoc efficacy and safety analyses were performed using pooled data from two identically designed Phase III studies in 608 nondialysis CKD patients randomized to receive two 510 mg i.v. injections of ferumoxytol within 5 ± 3 days versus oral iron. RESULTS: Ferumoxytol resulted in a significant increase in hemoglobin in the presence and absence of ESA, and across a range of baseline hemoglobin, transferrin saturation, ferritin, and reticulocyte hemoglobin content levels. Adverse event rates with ferumoxytol were similar across quartiles of change in hemoglobin; there were no trends suggesting an increased rate of cardiovascular AEs with higher maximum achieved hemoglobin or faster rate of hemoglobin rise. There was no meaningful difference in the rate of AEs, serious AEs, and cardiovascular AEs between patients receiving or not receiving ESA. CONCLUSIONS: These analyses add to the knowledge of predictors of response and safety outcomes associated with i.v. iron therapy in nondialysis CKD patients.

Mitochondrial DNA injury and mortality in hemodialysis patients.

The role of mitochondrial injury in the pathogenesis of complications of uremia is incompletely defined, although diminished bioenergetic capacity and the accumulation of mitochondrial DNA (mtDNA) mutations have been reported. This study was undertaken to evaluate the prevalence of mtDNA injury in 180 patients who had ESRD and were enrolled into the baseline phase of the HEMO study and to relate these markers to all-cause mortality. The mitochondrial injury markers studied in peripheral blood mononuclear cells were the mtDNA copy number per cell, measured by quantitative PCR, and the presence of the mtDNA(4977) mutation. After frequency-matching healthy control subjects for age, mtDNA copy number was lower among older dialysis patients compared with older healthy subjects (P = 0.01). A one-log increase in mtDNA copy number was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.64; 95% confidence interval 0.46 to 0.89). The mtDNA(4977) deletion was present in 48 (31%) patients and was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.33; 95% confidence interval 0.19 to 0.56). In summary, the mtDNA(4977) seems to predict survival in ESRD, but a reduced mitochondrial copy number seems to predict a poor outcome. Although further exploration of these associations is needed, evaluation of mitochondrial DNA copy number and somatic mtDNA mutations may provide simple genomic biomarkers to predict clinical outcomes among patients with ESRD.

Ferumoxytol for treating iron deficiency anemia in CKD.

Iron deficiency is an important cause of anemia in patients with chronic kidney disease (CKD), but intravenous iron is infrequently used among patients who are not on dialysis. Ferumoxytol is a novel intravenous iron product that can be administered as a rapid injection. This Phase III trial randomly assigned 304 patients with CKD in a 3:1 ratio to two 510-mg doses of intravenous ferumoxytol within 5 +/- 3 d or 200 mg of elemental oral iron daily for 21 d. The increase in hemoglobin at day 35, the primary efficacy end point, was 0.82 +/- 1.24 g/dl with ferumoxytol and 0.16 +/- 1.02 g/dl with oral iron (P < 0.0001). Among patients who were not receiving erythropoiesis-stimulating agents, hemoglobin increased 0.62 +/- 1.02 g/dl with ferumoxytol and 0.13 +/- 0.93 g/dl with oral iron. Among patients who were receiving erythropoiesis-stimulating agents, hemoglobin increased 1.16 +/- 1.49 g/dl with ferumoxytol and 0.19 +/- 1.14 g/dl with oral iron. Treatment-related adverse events occurred in 10.6% of patients who were treated with ferumoxytol and 24.0% of those who were treated with oral iron; none was serious. In summary, a regimen of two doses of 510 mg of intravenous ferumoxytol administered rapidly within 5 +/- 3 d was well tolerated and had the intended therapeutic effect. This regimen may offer a new, efficient option to treat iron deficiency anemia in patients with CKD.

KDOQI US commentary on the KDIGO clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in CKD.

KDIGO (Kidney Disease: Improving Global Outcomes) is an international initiative with a key mission of developing clinical practice guidelines in the area of chronic kidney disease (CKD). KDIGO recently published evidence-based clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C virus infection in individuals with CKD. The process of adaptation of international guidelines is an important task that, although guided by general principles, needs to be individualized for each region and country. Therefore, the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI) convened a multidisciplinary group to comment on the application and implementation of the KDIGO guidelines for patients with CKD in the United States. This commentary summarizes the process undertaken by this group in considering the guidelines in the context of health care delivery in the United States. Guideline statements are presented, followed by a succinct discussion and annotation of the rationale for the statements. Research recommendations that are of particular interest to the United States are then summarized to highlight future areas of inquiry that would enable updating of the guidelines.

Role of prohepcidin, inflammatory markers and iron status in resistance to rhEPO therapy in hemodialysis patients.

The aim of our study was to assess possible relations between prohepcidin, iron status and inflammatory markers in hemodialysis (HD) patients, as well as its association with resistance to recombinant human erythropoietin (rhEPO) therapy. Fifty HD patients and 25 healthy controls were enrolled in the study. Among HD patients, 25 were non-responders and 25 were responders to rhEPO therapy. Complete blood cell count, reticulocyte count, and circulating levels of ferritin, iron, transferrin saturation, C-reactive protein (CRP), soluble interleukin (IL)-2 receptor (s-IL2R), soluble transferrin receptor (s-TfR), IL-6 and prohepcidin were measured in all patients and controls. HD patients showed higher circulating levels of ferritin, s-TfR, CRP, IL-6, s-IL2R and prohepcidin, and lower levels of transferrin compared to healthy controls. Higher levels of s-TfR, CRP and lower levels prohepcidin were observed among non-responders compared to responders. Prohepcidin levels correlated negatively with s-TfR and reticulocyte count. The weekly rhEPO/kg dose was found to be positively correlated with CRP, hemoglobin and s-TfR. In conclusion, our data show that a close interaction exists between inflammation, iron status and prohepcidin serum levels that ultimately regulate intracellular iron availability. Prohepcidin and s-TfR, together with CRP, may prove to be good markers of resistance to rhEPO therapy in HD patients.

Plasma adiponectin levels and clinical outcomes among haemodialysis patients.

BACKGROUND: Adiponectin (ADPN) levels are consistently elevated among patients with advanced chronic kidney disease, but its relationship with cardiovascular outcomes in this population remains controversial. METHODS: We measured baseline and yearly plasma ADPN in 182 prevalent haemodialysis patients recruited to the Haemodialysis (HEMO) Study from two Boston centres. Plasma ADPN at baseline and during follow-up was studied in relation to prevalent cardiovascular disease (CVD) and cardiovascular and all-cause mortality. RESULTS: Baseline plasma ADPN levels were found to be approximately twofold higher than in the general population and correlated inversely with (log-transformed) CRP levels and (log-transformed) body mass index (BMI). Levels measured over time showed a gradual increase (0.95 microg/mL, 95% CI = 0.12-1.78 microg/mL; P = 0.03) by year, although this difference became non-significant after adjustment for covariates. Baseline ADPN levels were lower among patients with pre-existing CVD (adjusted OR of 0.67; P = 0.03). They also predicted all-cause mortality (P < 0.01) and the composite outcome of 'cardiovascular events/cardiovascular mortality' (P < 0.01); levels measured over time predicted the composite outcome of 'cardiovascular events and all-cause mortality' (P < 0.01). These relationships were non-linear (quadratic) with the hazard for each outcome increasing in the lower and upper ranges of the distribution of ADPN, and strengthened after adjustment for baseline covariates including serum albumin, CVD and the flux and dialysis dose categorization of the HEMO study. CONCLUSIONS: In summary, low plasma levels of ADPN were associated with inflammation and pre-existing CVD; ADPN levels predicted cardiovascular and mortality outcomes, the relationship being extensively confounded by multiple patient-related factors.

Protective effect of intravenous levocarnitine on subsequent-month hospitalization among prevalent hemodialysis patients, 1998 to 2003.

BACKGROUND: Levocarnitine deficiency in hemodialysis patients is common. Although the effect of intravenous levocarnitine therapy was studied in small trials, the effect on global outcomes in larger populations is unclear. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: Centers for Medicare & Medicaid Services data; prevalent hemodialysis patients, 1998 to 2003. PREDICTOR: Intravenous levocarnitine use, clinical characteristics, comorbid conditions. OUTCOMES & MEASUREMENTS: Effect of 1 g or greater per dialysis session of levocarnitine for 10 or more sessions during a month on subsequent hospitalization days. Repeated-measures and marginal structural models were fit, the latter to account for time-dependent confounding. RESULTS: Of the study population, 3% to 7% received levocarnitine for 1 month per year or more. Treated patients were older with more severe comorbidity and larger erythropoietin doses than untreated patients. In repeated-measures model analysis adjusted for demographic characteristics and disease severity, 1 g or greater per dialysis session of levocarnitine for 10 or more sessions during a month was associated with a 10.8% (95% confidence interval, 9.7 to 11.9; P < 0.01) subsequent-month decrease in hospitalization days. In marginal structural model analysis, levocarnitine therapy was associated with a 21.7% (95% confidence interval, 18.4 to 24.9; P < 0.01) decrease in hospitalization days. LIMITATIONS: Algorithm for identifying comorbid conditions from claims validated only for diabetes; biochemical marker levels unavailable in Medicare claims; levocarnitine therapy quantified only while patients were not hospitalized. CONCLUSION: Because hemodialysis patients are hospitalized about 15 days yearly, the association of monthly levocarnitine regimen with lower hospitalization rate is clinically significant. The causality of this association must be confirmed by randomized clinical trials.

Dose requirements among hemodialysis patients treated with darbepoetin-alpha or epoetin-beta.

BACKGROUND/AIMS: In a cohort of hemodialysis patients, we evaluated the hypothesis that weekly administration of intravenous (IV) darbepoetin-alpha (DA) was associated with lower total erythropoiesis-stimulating agent (ESA) requirements as compared to a regimen of multiple subcutaneous (SC) doses per week of epoetin-beta (EB). METHODS: We studied 1,159 hemodialysis patients who were treated exclusively with either IV DA or SC EB across a network of Portuguese clinics during 2004. Linear regression was used to assess the adjusted relationship between the ESA regimen and weekly ESA requirements over the period of observation. Generalized estimating equations were applied in order to model the population average effects of the correlated mean weekly ESA dose for each individual. We also calculated propensity scores for the receipt of DA and assessed the relationship between ESA type and dose requirement within each quintile of the score. RESULTS: The adjusted dose of IV DA, when expressed as a proportion of the dose used in EB-treated patients, did not differ from the dose administered to EB recipients (0.961, 95% CI 0.904, 1.021). A similar relationship was observed within each propensity score quintile. CONCLUSIONS: Hemodialysis patients who received IV DA had dose requirements that were similar to their counterparts who were treated with SC EB. A once-weekly dosing regimen and avoidance of SC administration enhance the attractiveness of DA as an alternative to traditional ESAs. The potential for unmeasured confounding, restriction to a population that was treated with a single ESA preparation and application of a 200 IU:1 mug EB:DA dose conversion are important limitations of this study.

Rationale--Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data. STUDY DESIGN: The Trial to Reduce Cardiovascular Events with Aranesp (Amgen Inc, Thousand Oaks, Calif) (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hb > or =9 g/dL or darbepoetin alfa for Hb <9 g/dL until Hb is again Hb > or =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.

Intractable anemia among hemodialysis patients: a sign of suboptimal management or a marker of disease?

BACKGROUND: Most incident hemodialysis (HD) patients who initiate dialysis therapy with anemia usually can achieve a hemoglobin (Hb) level of 11 g/dL or greater (> or =110 g/L) within a few months of the initiation of recombinant human erythropoietin (EPO) therapy. However, patients unable to achieve this level may be at greater risk for adverse outcomes. Whether intractable anemia is a modifiable problem or a marker for other conditions is unclear. This question was addressed in a cohort of 130,544 incident HD patients from 1996 to 2000 who were administered EPO regularly. METHODS: Medicare claims data were used to determine demographic characteristics, comorbidities, hospitalizations, and related events. Patients who did not achieve an Hb level of 11 g/dL or greater (> or =110 g/L; n = 19,096; 14.6%) during months 4 to 9 after dialysis therapy initiation were compared with those who did. RESULTS: Patients unable to achieve an Hb level of 11 g/dL (110 g/L) were younger and more often of nonwhite race. In addition, these patients had more comorbid conditions; experienced more hospitalizations with longer stays, more infectious hospitalizations, and more catheter insertions; and were administered more blood transfusions. EPO was administered in higher and increasing doses during the years of study among patients with intractable anemia compared with those with an Hb level of 11 g/dL or greater (> or =110 g/L), likely denoting increasing attempts to correct anemia over the years. CONCLUSION: It is apparent that incident HD patients unable to achieve an Hb level of 11 g/dL or greater (> or =110 g/L) have a greater disease burden. The independent association of intractable anemia with such future outcomes as cardiovascular events and hospitalizations remains to be determined.

Effect of comorbidity on the increased mortality associated with early initiation of dialysis.

BACKGROUND: Current recommendations for initiating dialysis therapy are based on level of kidney function and clinical evidence of uremia. Several studies reported no benefit in patient survival from initiating dialysis therapy with a greater glomerular filtration rate (GFR). Whether this is explained by a greater comorbidity burden or detrimental effect of early initiation remains unclear. We thus undertook an evaluation of the impact of comorbidity on the association between GFR at initiation and death. METHODS: Data from the Center for Medicare & Medicaid Services were used to derive 3 incident dialysis populations: (1) general population aged 18+ years, (2) older patients aged 67+ years, and (3) a "low-risk" subgroup without diabetes, heart failure, or atherosclerotic heart disease. A Cox proportional hazard regression technique was used. RESULTS: Greater GFR at initiation of dialysis therapy was associated with a greater risk for death in all populations, and sequential adjustment for additional covariates attenuated the effect. Patients in the general dialysis population who initiated dialysis therapy at a GFR greater than 10 mL/min/1.73 m2 (>0.17 mL/s) had a 42% increased risk for death compared with patients with a GFR less than 5 mL/min/1.73 m2 (<0.08 mL/s) at initiation of dialysis therapy after adjusting for all covariates. In the older and healthier populations, adjusted increased risks were 25% and 39%, respectively. CONCLUSION: Patients initiating dialysis therapy at greater GFRs have an increased risk for death not fully explained by comorbidity. Additional research is required to determine the reasons for poor survival in patients who start dialysis therapy with significant residual renal function.

Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients.

BACKGROUND: Interleukin-6 (IL-6) is a mediator and marker of the chronic inflammatory process that is responsible for much of the morbidity and mortality seen in hemodialysis (HD) patients. This study evaluated circulating plasma IL-6 as a predictor of all-cause mortality and cardiovascular mortality and studied its relationship to prevalent comorbidity and hypoalbuminemia, in a cohort of stable HD patients enrolled in the HEMO study. METHODS: Clinical data included demographic, medical, and routine laboratory parameters. Comorbidities were graded using the Index of Co-Existing Diseases (ICED). Outcomes of interest were all-cause mortality and cardiovascular mortality. Blood samples were drawn at enrollment and annually, and plasma IL-6 levels measured with high-sensitivity enzyme-linked immunosorbent assay. RESULTS: Median plasma IL-6 level in 206 patients was 7.9 pg/mL (range, 0.1 to 90.3 pg/mL) and was higher in patients with vascular disease ( P = 0.03), higher ICED scores ( P = 0.01), and lower Karnofsky indices ( P < 0.01). Serum albumin was inversely related to plasma IL-6 levels ( P = 0.03, r = -0.16). Unadjusted median survival time was 1,209 days in the lowest quartile of plasma IL-6 and 806 days in the highest ( P = 0.02, log rank test). A 1-log increase in plasma IL-6 was associated with a 1.19-fold higher adjusted risk for all-cause mortality ( P = 0.04; 95% confidence interval, 1.01 to 1.40) and a 1.43-fold higher adjusted risk of cardiovascular mortality ( P = 0.02; 95% confidence interval, 1.06 to 1.92). Hazard ratio estimates were higher when IL-6 levels over time were incorporated as a time-dependent covariate. CONCLUSION: Plasma IL-6 levels are strongly associated with comorbidity in HD patients and are a powerful predictor of cardiovascular and all-cause mortality.

Relationship of urine output to dialysis initiation and mortality in acute renal failure.

BACKGROUND: A non-oliguric state is considered a good prognostic indicator in acute renal failure (ARF), and may lead to withholding renal replacement therapy in anticipation of recovery. The present study explores the relationship between urine volume and the start of dialysis and hospital mortality in patients with ARF. METHODS: In a non-concurrent cohort of patients with ARF treated exclusively with intermittent hemodialysis (IHD), demographic, clinical and laboratory characteristics were collected at the time of the first nephrology consultation and at the start of dialysis. Multiple linear and logistic regression analyses were used to identify factors associated with the time to initiation of dialysis and hospital mortality, respectively. RESULTS: Urine volume correlated with the time from admission to start of dialysis (r = 0.60; p < 0.001). Higher urine volume, lower serum creatinine and lower APACHE II score were independently associated with increased time from admission to start of dialysis. Hospital mortality was independently associated with a higher urine volume (odds ratio, OR 3.8, 95% confidence interval, CI, 1.1-12.8, p = 0.03), a higher MOF score (OR 4.9, 95% CI 1.1-21.6, p = 0.03) and a higher number of dialysis treatments performed in the 1st week (OR 3.7, 95% CI 1.2-11.3, p = 0.03). CONCLUSIONS: Among patients with ARF requiring IHD, increased urine output is associated with higher mortality. This observation may reflect physician bias toward later initiation of dialysis in non-oliguric ARF. Further research is needed to help identify patients with non-oliguric ARF who require early dialytic support.

Death in the first year after kidney transplantation: implications for patients on the transplant waiting list.

BACKGROUND: As the kidney transplant waiting list continues to expand, maintaining the medical fitness of transplant candidates will become increasingly difficult. METHODS: To identify patients who are at greatest risk during the wait-list period, we performed a Cox regression analysis to determine risk factors for mortality in the first posttransplantation year among 23,546 adult first kidney transplant recipients recorded in the United States Renal Data System between January 1995 and September 1997. RESULTS: In this study population, 4.6% of the patients died in the first posttransplantation year, and cardiac causes were the leading cause (27%) of death. Patients with diabetes (hazard ratio [HR]=1.58; 95% confidence interval [CI], 1.39-1.80), peripheral vascular disease (HR=1.41; 95% CI, 1.11-1.80), or angina (HR=1.38; 95% CI, 1.15-1.65), and patients with a longer duration of end-stage renal disease (HR=1.06 per year; 95% CI, 1.04-1.09) had a higher risk for mortality. Additionally, patients with early acute rejection (HR=1.47; 95% CI, 1.23-1.76), delayed graft function (HR=1.46; 95% CI, 1.25-1.71), and a lower glomerular filtration rate after transplantation were also at increased risk for death within the first posttransplantation year. CONCLUSIONS: Patients with comorbid disease, patients with a long duration of end-stage renal disease, and potential recipients of organs at high risk for graft dysfunction should be carefully screened for medical complications before transplantation to achieve the most favorable outcomes. Alternate organ allocation strategies that facilitate patient assessment close to the time of transplantation or that prioritize high-risk patients may also improve outcomes.

Why do preemptive kidney transplant recipients have an allograft survival advantage?

BACKGROUND: Preemptive kidney transplantation is associated with an allograft survival advantage and is promoted in part because of this association. The basis for the allograft survival advantage in preemptive recipients is unclear. Possibilities include a lead time bias due to the earlier transplantation of patients with preserved native kidney function, less rapid loss of kidney function after transplantation, or the longer patient survival of preemptive recipients. METHODS: We compared the glomerular filtration rate (GFR) six months after transplantation and the subsequent rate of loss of kidney function as defined by the annualized change in GFR (mL/min/1.73 m2/year) in 5,966 preemptive and 34,997 non-preemptive recipients. Linear regression methods were applied to serial GFR estimates after transplantation to determine the annualized change in GFR. Multiple regression was used to determine the independent effect of preemptive transplantation upon the annualized change in GFR. RESULTS: The mean GFR six months after transplantation was similar among preemptive (49.5+/-15.7 mL/min/1.73 m2) and non-preemptive (49.2+/-14.7 mL/min/1.73 m2) recipients (P=0.37). In multivariate analysis, preemptive recipients had a slower decline in GFR (0.28 mL/min/year/1.73 m2; 95% confidence interval 0.11, 0.46; P=0.002). However, this difference was of modest clinical significance and would not explain the allograft survival advantage of preemptive transplantation. CONCLUSIONS: Neither the preservation of native kidney function nor differences in the rate of loss of kidney function explain the superior allograft survival of preemptive recipients. By exclusion, the allograft survival advantage associated with preemptive transplantation may be due to the longer survival of preemptive recipients.

Hospitalization during advancing chronic kidney disease.

BACKGROUND: The care of patients with end-stage renal disease (ESRD) is associated with substantial costs to society, much of which is accounted for by a high rate of hospitalization. However, the influence of declining kidney function on hospitalization as ESRD approaches is not well understood. METHODS: We performed a retrospective cohort study of national data to evaluate the frequency of hospitalizations among patients with chronic kidney disease (CKD) who reached ESRD and had at least 2 years of Medicare eligibility before initiation of dialysis therapy. The study period for each patient extended from 2 years before to 6 months after the initiation of dialysis therapy. RESULTS: The study cohort was composed of 109,321 patients with a mean age of 75 years, all of whom initiated long-term dialysis therapy between 1995 and 1998. Mean hospitalization rate was 134 hospitalizations/1,000 patient-months at risk (PMAR). Hospitalization rates gradually increased as ESRD approached, peaking in the 3 months immediately after the initiation of dialysis therapy at 487 hospitalizations/1,000 PMAR. Cause-specific hospitalization rates mirrored this trend and were greatest for placement of vascular access and diagnoses related to cardiovascular (CVD) and infectious disease. CONCLUSION: Hospitalizations during CKD become more frequent with the approach of ESRD. The majority of these hospitalizations, both before and after the initiation of dialysis therapy, are caused by comorbidity related to CKD. These hospitalizations may be favorably impacted on by heightened attention to the prevention and management of CVD and timely placement of vascular access during CKD.

Chronic kidney disease in the United States: an underrecognized problem.

The continued growth of the population with end-stage renal disease (ESRD) is partially related to the underrecognition of earlier stages of chronic kidney disease (CKD) and risk factors for the development of CKD. There are several published estimates of the prevalence of CKD in the United States. From Third National Health and Nutrition Examination Survey data it has been estimated that there are 6.2 million individuals with serum creatinine levels at or above 1.5 mg/dL, or 8.3 million individuals with decreased glomerular filtration rate (<60 mL/min/1.73 m (2)). Estimates of prevalence from a health maintenance organization study suggest that there are 4.2 million Americans with persistently elevated serum creatinine levels. In addition to the high prevalence, several studies have shown that CKD is associated with increased risk for cardiovascular disease, hospitalizations, and mortality. To promote earlier detection of CKD, The National Kidney Foundation Guidelines for CKD: Evaluation, Classification and Stratification, recommended screening individuals at increased risk for CKD, such as patients with diabetes, high blood pressure, and family history of kidney disease. Therapeutic interventions to delay progression and reduce comorbidity, such as cardiovascular disease, are more likely to be effective if they are implemented early in the course of CKD.