Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis.

OBJECTIVE: To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN). METHODS: In a multicenter, randomized, open-label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group), or treated with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients' peripheral blood were analyzed by flow cytometry. RESULTS: Treatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/µl in the RCB group versus 11 cells/µl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with the observed impaired maturation of naive B cells and enhanced censoring of autoreactive B cells. CONCLUSION: The addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN.

Treatment of acute kidney injury with cast nephropathy.

Nearly 50% of patients with multiple myeloma develop renal disease; acute kidney injury (AKI) from cast nephropathy, or "myeloma kidney" is the most common type. Development of AKI is associated with worse 1-year survival and reduces the therapeutic options available to patients. Therefore, there is a great need to develop more effective therapies. Cast nephropathy is due to the interaction and aggregation of filtered free light chains (FLCs) and Tamm- Horsfall protein (THP) causing intratubular obstruction and damage. The key to treating cast nephropathy is rapid lowering of FLCs as this correlates with renal recovery. Newer chemotherapy agents lower FLCs and have been referred to as "renoprotective". However there remains great interest in using various extracorporeal therapies to remove serum FLCs. Initially, therapeutic plasma exchange (TPE) was thought to improve renal outcomes in cast nephropathy based on small trials. The largest randomized trial of TPE, however, failed to show any benefit. A newer technique is extended high cut-off hemodialysis (HCO-HD). This modality uses a high molecular weight cut-off filter to remove FLCs. To date, trials with HCO-HD in patients with cast nephropathy have been encouraging. However, there are no randomized trials demonstrating the benefit of HCOHD when used in addition to newer chemotherapeutic regimens. Until these studies are available, HCO-HD cannot be recommended as standard of care.

Summary of clinical practice guidelines for acute kidney injury.

Clinical practice guidelines are intended to standardize the diagnosis and treatment of diseases in order to improve both patient outcomes and resource utilization, using evidence-based criteria. As recently as a decade ago, there was no agreed upon definition of acute kidney injury (AKI), making it difficult to conduct proper clinical studies on the epidemiology and treatment of the disorder. Following the advent of the Risk, Injury, Failure, Loss, and End-stage (RIFLE) criteria for defining AKI, several guidelines for the diagnosis and management of AKI have been developed. In our review, we present a narrative description and comparison of the major published guidelines. Overall, there has been significant agreement among the various guidelines, and each seems well-reasoned and clinically useful. Perhaps the most striking conclusion upon review of the various guidelines is the limited scope of knowledge about optimal management of patients with AKI.

Incidence and outcome of early acute kidney injury in critically-ill trauma patients.

OBJECTIVE: To determine the incidence and effect on mortality of early acute kidney injury in severely injured trauma patients using the Acute Kidney Injury Network creatinine criteria. DESIGN: A retrospective cohort study of severely injured trauma patients admitted to the shock trauma intensive care unit. SETTING: Texas Trauma Institute, a state designated level I trauma unit certified by the American College of Surgeons Committee on Trauma. PATIENTS: 901 severely injured trauma patients admitted over a 15 month period to the shock trauma intensive care unit. INTERVENTIONS: Retrospective analysis of prospectively collected data abstracted from an electronic trauma database. MEASUREMENTS AND MAIN RESULTS: Of 901 eligible patients admitted to the shock trauma intensive care unit after traumatic injury, 54 patients (6%) developed acute kidney injury, of whom 10 (19%) required renal replacement therapy. The 30-day mortality rate for the entire cohort was 83/901 (9.2%). Patients with early acute kidney injury had a mortality rate of 16/54 (29.6%). When corrected for multiple covariates including injury severity scores, the development of early acute kidney injury was associated with a significantly higher risk of death at 30 days with an OR of 3.4 (95% CI 1.6-7.4). CONCLUSIONS: Applying the Acute Kidney Injury Network creatinine criteria in severely injured trauma patients, the incidence of early acute kidney injury was 6%. After correction for injury severity, development of early acute kidney injury was independently associated with significantly higher 30-day mortality.

Myoglobin removal using high-volume high-flux hemofiltration in patients with oliguric acute kidney injury.

BACKGROUND: Rhabdomyolysis can cause acute kidney injury (AKI). It remains controversial whether or not myoglobin can be removed from the circulation with extracorporeal therapy and decrease the incidence of AKI. Therefore, we examined myoglobin removal in a series of 11 patients with oliguric AKI treated with high-volume hemofiltration. METHODS: Patients received prefilter hemofiltration using a polysulphone filter with a molecular size cutoff of 65 kDa and a surface area of 1.7 m(2). Sieving coefficients and myoglobin clearances were calculated at 6, 12, and 24 h after the start of hemofiltration. RESULTS: The mean sieving coefficient was 0.158, and the mean myoglobin clearance was 8.7 ml/min. CONCLUSION: Despite the use of high-volume hemofiltration, the removal of myoglobin was negligible. In patients with normal renal function, the anticipated amount of extracorporeal removal would not significantly impact renal exposure to myoglobin.

Liver support systems--a review.

Liver failure is associated with a high morbidity and mortality rate and is the seventh leading cause of death worldwide. Orthotopic liver transplantation remains the definitive treatment; however, because of the limited number of available organs many patients expire while on the transplant list. Currently, there are no established means for providing liver support as a means of bridging patients to transplantation or allowing for recovery from liver injury. Analogous to the clinical situation of renal failure, there is great interest in developing liver support systems that replace the metabolic and waste removal functions of the liver. These support systems are of two general types: artificial and bioartificial livers. In this review, based on a presentation from the 57th American Society of Artificial Internal Organs Annual Meeting (Washington, D.C., June 2011), we review the current status of liver support systems.

Prevalence of chronic kidney disease and progression of disease over time among patients enrolled in the Houston West Nile virus cohort.

INTRODUCTION: In experimental models of West Nile virus (WNV) infection, animals develop chronic kidney infection with histopathological changes in the kidney up to 8-months post-infection. However, the long term pathologic effects of acute infection in humans are largely unknown. The purpose of this study was to assess renal outcomes following WNV infection, specifically the development of chronic kidney disease (CKD). METHODS: In a cohort of 139 study participants with a previous diagnosis of WNV infection, we investigated the prevalence of CKD using the Kidney Disease Outcomes Quality Initiative (KDOQI) criteria based on the Modification of Diet in Renal Disease (MDRD) formula and urinary abnormalities, and assessed various risk factors and biomarkers. RESULTS: Study participants were primarily male (60%) and non-Hispanic white (86%) with a mean age of 57 years. Most (83%) were four to nine years post-infection at the time of this study. Based on the KDOQI definition, 40% of participants had evidence of CKD, with 10% having Stage III or greater and 30% having Stage I-II. By urinary dipstick testing, 26% of patients had proteinuria and 23% had hematuria. Plasma NGAL levels were elevated in 14% of participants while MCP-1 levels were increased in 12%. Over 1.5 years, the average change in eGFR was -3.71 mL/min/1.73 m(2). Only a history of Neuroinvasive WNV disease was independently associated with CKD following multivariate analysis. DISCUSSION: We found a high prevalence of CKD after long term follow-up in a cohort of participants previously infected with WNV. The majority of those with CKD are in Stage I-II indicating early stages of renal disease. Traditional risk factors were not associated with the presence of CKD in this population. Therefore, clinicians should regularly evaluate all patients with a history of WNV for evidence of CKD.

Evidence-based practice in nephrology: critical appraisal of nephrology clinical research: were the correct statistical tests used?

Nephrologists rely on valid clinical studies to inform their health care decisions. Knowledge of simple statistical principles equips the prudent nephrologist with the skills that allow him or her to critically evaluate clinical studies and to determine the validity of the results. Important in this process is knowing when certain statistical tests are used appropriately and if their application in interpreting research data will most likely lead to the most robust or valid conclusions. The research team bears the responsibility for determining the statistical analysis during the design phase of the study and subsequently for carrying out the appropriate analysis. This will ensure that bias is minimized and "valid" results are reported. We have summarized the important caveats and components in correctly choosing a statistical test with a series of tables. With this format, we wish to provide a tool for the nephrologist/researcher that he or she can use when required to decide if an appropriate statistical analysis plan was implemented for any particular study. We have included in these tables the types of statistical tests that might be used best for analysis of different types of comparisons on small and on larger patient samples.

Complications of continuous renal replacement therapy.

Continuous renal replacement therapy (CRRT) is commonly used in critically ill patients with acute kidney injury. Many studies show that compared with intermittent hemodialysis, continuous therapy has superior hemodynamic stability, metabolic clearance, and volume control. Despite these benefits, no survival advantage can be demonstrated with its use. Although study design explains much of this paradox, it is also quite plausible that the complications associated with CRRT negate its potential benefits in the critically ill patient. We summarize the common complications associated with the use of CRRT.

Hospital-acquired acute kidney injury.

Acute kidney injury (AKI) is a common clinical syndrome in hospitalized patients associated with high morbidity and mortality rates. Despite several years of improvement in the medical care of the severely ill, there has been little improvement in outcome. Furthermore, effective means of preventing and treating AKI have remained elusive. Although dialysis has been the mainstay of treating AKI for > 40 years, several questions regarding its application remain unsettled, including method (continuous vs intermittent), timing, and dose. The purpose of this review is to summarize recent advances in the epidemiology and treatment of AKI in hospitalized patients.