Management Of Lupus Nephritis Research Articles

Management of Lupus Nephritis in Constrained Environments

Management of Lupus Nephritis in Constrained Environments

Effects of concomitant hepatitis C virus infection in patients with underlying lupus nephritis on long-term renal outcome

Despite recent advances in the management of lupus nephritis (LN), these unfortunate patients are at a higher risk of developing chronic kidney disease (CKD). Concomitant chronic hepatitis C virus (HCV) infection is associated with adverse outcome in patients with LN and further compounds the risk as some of these patients choose to undergo kidney transplantation in the near future. Objectives. The aim of the present study is to evaluate the long-term impact of chronic HCV infection in patients with underlying Class IV LN on renal function, progression to end-stage renal disease (ESRD) and patient survival. Retrospective analysis of the medical records of 134 nondialysis-dependent patients with biopsy-proven World Health Organization Class IV LN with chronic HCV infection was done from January 1995 to January 2008 at King Khalid University Hospital, Riyadh, Saudi Arabia. Primary and the secondary end points were death or the development of ESRD. The patients were followed over a period of 6.7 ± 3.3 (1-14.4) years. From a total of 134 biopsy-proven Class IV LN patients, 15 (11.2%) patients were HCV positive of which 2 (13.3%) patients were male and 13 (86.7%) patients were female. One hundred and nineteen (88.8%) patients were HCV negative of which 17 (14.3%) were male and 102 (85.7%) were female. The mean age was 32.47 ± 11.8 years. Eight (53.3%) patients in the HCV-positive group versus 19 (22.6%) patients in the HCV-negative group progressed to severe renal impairment with serum creatinine >350 μmol/L (P = 0.024). A total of 8 (53.3%) patients in the HCV-positive group versus 18 (17.3%) in HCV-negative group progressed to ESRD (P = 0.005). The mean creatinine clearance was higher (43.3 ± 33 mL/min) in the HCV-negative LN group at last follow-up than in the HCV-positive patients (25 ± 34.9 mL/min) with a statistically significant P-value of 0.0463. Five patients (33.3%) with HCV-positive LN died in comparison to eight (7.6%) patients who were HCV negative P = 0.03; however, the cause of hospital mortality was mainly cardiovascular disease (CVD) and infection and none of the patients died of chronic liver disease, although there was significant deterioration of the liver function at the end of the study. Kaplan-Meier survival estimates showed a significantly inferior renal function and rapid deterioration to ESRD in LN patients with concomitant HCV infection, with a dialysis free survival of 95 and 80% for the HCV-negative group and 90 and 65% for the HCV-positive groups at the end of 5 and 10 years respectively, with a highly significant P-value of <0.05 at the end of 10 years. The present study highlights that concomitant HCV infection in patients with LN is associated with worse renal outcome, higher rate of progression to ESRD and reduced patient survival.

Novel Therapeutic Approaches to Lupus Glomerulonephritis: Translating Animal Models to Clinical Practice

Systemic lupus erythematosus is a chronic autoimmune disease frequently affecting the kidney. Renal involvement is characterized by glomerular immune complex deposits and proliferative glomerulonephritis progressing to glomerulosclerosis and kidney failure. The development of systemic lupus erythematosus is regulated genetically, and lupus susceptibility genes have been linked to immune hyper-responsiveness and loss of immune regulation. In addition to the systemic immune defects, recent studies in animal models show that susceptibility to lupus nephritis is influenced by intrinsic renal factors. Thus, renal cell responses to immune-mediated glomerular injury determine disease outcome. This supports the idea that future treatments for lupus nephritis need to focus on regulating end-organ responses. The feasibility of this approach has been shown in animal models of kidney disease. For more than 50 years, the emphasis in management of lupus nephritis has been suppression of autoimmune responses and systemic control of inflammation. This review describes recently developed targeted drug delivery technologies and potential targets that can regulate glomerular cell responses, offering a novel therapeutic approach for lupus nephritis.

Brief review: management of lupus nephritis–randomized controlled trials: an update

Lupus nephritis leads to significant morbidity and mortality in patients with systemic lupus erythematous. Immunosuppressive agents are recommended in management of Class III, IV and V lupus nephritis. The goals of therapy are to control the disease and to prevent relapse while minimizing side-effects of therapy. Most of the evidences in managements of Class III and IV lupus nephritis comes from randomized controlled trials using intravenous cyclophosphamides, oral mycophenolate mofetil and oral azathioprine. In Class V lupus nephritis, there are few studies available and they have assessed the use of intravenous cyclophsophamide, oral mycophenolates mofetil and oral cyclosporine. In this review article, we have summarized the major randomized controlled trials in managements of Class III, IV and V lupus nephritis and offer an interpretation of the evidence to date.

Mycophenolate mofetil as maintenance therapy for proliferative lupus nephritis: a long-term observational prospective study

IntroductionWhile the role of mycophenolate mofetil (MMF) in the management of lupus nephritis has been increasingly recognized, limited information is available regarding its efficacy and safety as a long-term maintenance treatment. The aim of the present study was to evaluate the efficacy and safety profile of MMF as maintenance therapy for proliferative lupus nephritis.MethodsThirty-three consecutive patients with proliferative lupus nephritis received induction therapy with five to seven monthly intravenous (iv) pulses of cyclophosphamide (CYC) plus iv steroids followed by oral MMF 2 g/day as maintenance therapy for a median time of 29 months (range 9 to 71 months). Primary end points were the achievement of renal remission, complete renal remission, disease remission - renal and extrarenal -, the occurrence of renal relapse, chronic renal failure and death. Secondary end points were the extrarenal disease activity and drug adverse events. The clinical and laboratory parameters were compared during follow-up by means of nonparametric statistical tests. Time to event analysis was performed according to the Kaplan-Meier method.ResultsA significant improvement of all renal parameters was observed at the end of the induction treatment and at the latest follow-up compared to baseline. The rate of patients achieving renal remission until the end of follow-up was 73%, whereas that of complete renal remission was 58%. The median survival times in the Kaplan-Meier analyses were 7 and 16 months, respectively. Remission was maintained in all but four (12%) patients who relapsed within 19 to 39 months after initial response. At the end of follow-up, 51% of the patients had reached disease remission. The median survival time of disease remission was 18 months. Extrarenal manifestations were well controlled in most of the patients. In one patient receiving MMF, extrarenal activity led to treatment discontinuation. Non life-threatening drug adverse events developed in 18 patients (58%) and included infections, amenorrhea, myelotoxicity, gastrointestinal complications, hypercholesterolemia, alopecia and drug intolerance. None of the patients developed chronic renal insufficiency or died from any cause.ConclusionsMMF appeared to be efficacious and safe as maintenance treatment for proliferative lupus nephritis.

Practical management of lupus nephritis in pregnancy and the puerperium

Pregnancy represents a major challenge in the management of patients with systemic lupus erythematosus, with substantial risks to both mother and baby. Over the past 40 years there have been major improvements in outcomes. This partly relates to the discovery of the antiphospholipid syndrome, which has transformed management of lupus pregnancy, but also due to more effective drugs and better obstetric practice. Despite these advances, significant maternal and fetal morbidity may still occur in patients with lupus nephritis, and there remain ongoing challenges in order to improve outcomes further. In this article we focus on the challenges facing lupus nephritis patients considering pregnancy, and discuss how we approach practical management issues in relation to the current literature.

Place du mycophénolate mofétil dans la néphropathie lupique proliférative de l’enfant

The management of lupus nephritis remains a clinical problem in children as in adults. Corticosteroids, cyclophosphamide and azathioprine have been used with satisfactory response, but the most important problems are their potential toxicities. Therefore, we evaluate the use of mycophenolate mofetil (MMF) as a new agent for treatment of lupus nephritis in children. Five children with biopsy-proven proliferative glomerulonephritis with active lesions received MMF, combined with corticosteroids during the induction phase and alone during the maintenance phase. We retrospectively studied the efficacy and safety of this therapeutic regimen. All patients had proteinuria and renal failure. Four patients from five presented nephrotic syndrome. During the induction phase, three patients achieved complete remission of their nephrotic syndrome with normalization of renal function. One patient achieved partial remission and kept moderate renal failure. One patient died at 50 days by severe sepsis secondary to leucopenia. During the maintenance phase, three patients had complete remission. One patient was kept proteinuria with a creatinine clearance of 55 mL/min/1,73 m 2. The growth of these patients is not affected. In childhood lupus proliferative glomerulonephritis, MMF was well tolerated, and most of the patients achieved remission and improvement of their renal functions.

Lupus nephritis: where are we now?

To consider the challenges in the management of lupus nephritis with respect to diagnosis and optimal therapy for induction and maintenance of response. Despite several large clinical trials in lupus nephritis, no second line drug is licensed for use in induction of remission in lupus nephritis. An important issue is how remission and flare are defined and the role of repeat renal biopsies. On the background of negative trials with mycophenolate mofetil and rituximab, there are recent data demonstrating superiority of mycophenolate mofetil in certain subgroups. New data suggest a role for tacrolimus in the treatment of lupus nephritis. Additionally, dogma is being challenged by data showing very low and even no oral steroids can be used in mycophenolate mofetil and rituximab-based regimes. Despite the negative outcome of recent trials there is growing evidence that there are increasing opportunities in patients with lupus nephritis to offer treatments tailored to the individual needs of the patient based not only on the class and severity of their nephritis but also on their ethnicity, their desire to have children and their predictors of outcome.

Cyclophosphamide and Lupus Nephritis: When, How, For How Long?

Ever since the introduction of cyclophosphamide (CY), the management of lupus nephritis has dramatically changed, and its prognosis has greatly improved. Based on randomized controlled trials and long-term observational studies, pulse therapy with CY in combination with methyl-prednisolone (MP) is the "gold standard" of therapy for severe lupus. The realization of the significant gonadal toxicity intensified the efforts for the development of alternative immunosuppressive agents. In a large, randomized controlled trial, newer agents such as mycophenolate mofetil (MMF) have demonstrated comparable efficacy and less toxicity for moderately severe disease. To date, combinations of monthly pulses of CY with MP remain the gold standard for the induction of remission in severe lupus. For maintenance, less toxic agents such as azathioprine or MMF are equally effective and are routinely used in the current therapy of lupus.

Beyond immunosuppression – challenges in the clinical management of lupus nephritis

Lupus nephritis remains the most common severe manifestation of SLE with increased risk of death and end-stage renal disease. Although, recent research has focused on the choice of immunosuppressive in its treatment, other factors, including the quality and delivery of healthcare, the management of glucocorticoids and co-morbidity are probably of more importance. There has been significant progress in induction regimes with the successful use of mycophenolate mofetil, low dose intravenous cyclophosphamide and development of sequential regimens whereby cyclophosphamide is followed by an alternative immunosuppressive. However, the attention on the day-to-day management of lupus nephritis in the clinic has merited less attention. In this article, we aim to address more widely the major issues which are encountered regularly in the long-term management of these patients. The overall goals are the reduction of mortality and preservation of renal function.

Update on the management of lupus nephritis: let the treatment fit the patient

The introduction of new therapeutic modalities, such as biologic agents, for the treatment of lupus nephritis has re-energized research into this disorder, enabling investigators to formulate evidence-based recommendations. Thus, it is now widely accepted that the management of lupus nephritis involves a period of intensive induction therapy, followed by a longer period of less-intensive maintenance therapy. Risk stratification, based on histologic, demographic, clinical and laboratory characteristics, allows the identification of patients at high risk of renal dysfunction, for whom aggressive therapy is likely to be the most beneficial. New studies and meta-analyses comparing mycophenolate mofetil with cyclophosphamide have confirmed the efficacy of the former for induction and maintenance therapy--particularly induction therapy, owing to its favorable toxicity profile; however, claims of efficacy superior to that of cyclophosphamide require additional documentation. Nonetheless, an increasing number of physicians use mycophenolate mofetil as induction therapy for most cases of proliferative lupus nephritis, while reserving cyclophosphamide for the most severe cases. No evidence yet indicates that mycophenolate mofetil is better than azathioprine for the maintenance of remission. For patients who relapse or who are unable to be treated with these agents, rituximab seems to offer some benefit with an acceptable toxicity profile. This article summarizes the advances in the management of lupus nephritis since our 2005 Review.

Current treatment of lupus nephritis

This review on the management of lupus nephritis is based on the results of randomized clinical trials, and discusses the principles of treatment and the current options for induction and maintenance therapy. The respective place of mycophenolate mofetil and intravenous cyclophosphamide are balanced, taking into account efficacy, safety and patients' perspective. The authors anticipate that, in a few years, when long-term data on lupus nephritis patients induced with mycophenolate mofetil becomes available, it is probably that intravenous cyclophosphamide, which has been for so long the 'standard of care', will be prescribed only in specialized conditions such as documented necrotizing vasculitis.

Interdisziplinärer deutscher Konsensus zum Management der Lupusnephritis in Deutschland

In October 2006 a German ad hoc committee consisting of rheumatologists and nephrologists developed a consensus statement on the current practice in the management of lupus nephritis. The published results are summarized.

Current management of lupus nephritis: popular misconceptions

The management of lupus nephritis is typified by popular misconceptions: that there is a 'standard of care', that treatment has well-defined aims and that the optimum length of treatment is established. In reality, however, uncertainties still exist and the evidence base remains weak. Until recently, initial therapy for class IV lupus nephritis typically involved intravenous cyclophosphamide, yet although cyclophosphamide is superior to azathioprine in improving renal function, it is not superior in terms of mortality. In fact, recent studies show mycophenolate mofetil to be superior to cyclophosphamide in terms of response rate and safety profile and at least as effective as other immunosuppressants. The role of steroids is unclear. Clearly, no standard of care exists in lupus nephritis. The Euro-Lupus Nephritis Trial found that treatment response at six months, in terms of reduced serum creatinine and proteinuria, was the best predictor of long-term renal outcome. Proteinuria, however, can take a long time to reach baseline levels, and normalization of urine is not the same as loss of histological disease activity. Response to treatment thus is not the same as disease remission. Although treatment should aim to reduce the risk of end-stage renal disease and death, control of proteinuria and prevention of flares are also important. Patients who have nephritic flares are almost seven times as likely to progress to end-stage renal disease compared with those who do not. Regimens involving maintenance phases have been developed, but uncertainty remains about the risk of flares and how they can be predicted. The optimum duration of treatment has yet to be determined.

The role of kidney biopsy in the management of lupus nephritis

Purpose of reviewThis review evaluates the role of kidney biopsy as a tool in the diagnosis, prognostication and therapeutic management of lupus nephritis. The renal biopsy is the only method available for diagnosing and classifying lupus nephritis. However, disagreements persist regarding the appro

The role of kidney biopsy in the management of lupus nephritis

This review evaluates the role of kidney biopsy as a tool in the diagnosis, prognostication and therapeutic management of lupus nephritis. The renal biopsy is the only method available for diagnosing and classifying lupus nephritis. However, disagreements persist regarding the appropriate role of a renal biopsy in the management and identification of predictors of short and long-term outcomes. Recent modifications to the classification of lupus nephritis, the emergence of newer scoring indices, and the availability of a variety of therapeutic options predicate a reassessment of the role of the renal biopsy in the management of lupus nephritis, especially for high-risk patients. Despite some controversy, the renal biopsy has been shown to provide information over and above that provided by the clinical variables, and remains a pivotal element in optimizing therapy and the rational management of lupus nephritis.

Cyclophosphamide for severe lupus nephritis: Where are we now?

Renal disease is a major complication of systemic lupus erythematosus. If not managed appropriately, the condition can culminate in renal failure and even death. Despite the use of cyclophosphamide (CYC) in the treatment of severe lupus glomerulonephritis for more than 3 decades, the optimal route of administration, dosage, and duration of therapy remain undefined. This situation is partly related to the lack of well-designed prospective studies comparing different CYC-containing regimens. The paucity of such data also reflects the technical difficulties in organizing clinical trials in lupus nephritis. First, a sizable sample is needed to reveal a small difference between treatment regimens. This is difficult to achieve in areas where lupus nephritis is not very prevalent. Second, in multicenter or multinational trials, it may be difficult to ensure that a treatment/ monitoring protocol is strictly and uniformly followed. Third, because a very long period of observation may be necessary to reveal a difference between treatment arms, investigators often have to invest a considerable amount of time, effort, and perseverance into their studies. A common pitfall of existing treatment trials in lupus nephritis is the protocol design. Because of the difficulty in patient recruitment, only 2–3 treatment regimens are usually tested in a study. Investigators often compare regimens that are frequently prescribed by physicians in their localities. Although conclusions generated from such studies are likely valid, the lack of data regarding the treatment efficacy of a wellestablished protocol in the same group of patients makes it unsound to claim that a certain treatment regimen is “an alternative” to one reported in a different study. An example of the lack of perfection in study design is the pilot randomized trial comparing continuous daily oral CYC with mycophenolate mofetil (MMF) as initial therapy for severe lupus nephritis, conducted by Chan et al (1) in Chinese patients. Although MMF was safe and as effective as oral CYC in this study, it is difficult to convince physicians who have been prescribing the intravenous pulse CYC regimen that MMF is as good as their “routine.” While one may compare the efficacy of treatment regimens by examining data obtained in different studies, interpretation can be confounded by discrepancies in the ethnic composition of the cohorts and the severity of renal disease at study entry. The lack of simultaneously obtained data regarding the treatment efficacy of a widely used protocol in the same study can lead to the impression that a therapeutic regimen, though effective in certain patients, may not necessarily be equally effective in patients of another ethnic group or in a different locality. In choosing a treatment regimen for severe lupus nephritis, the risk-to-benefit ratio has to be considered. There is evidence that a longer course of pulse CYC and the oral route of CYC administration, which often results in a higher cumulative dose, albeit more effective in the intermediate-term, are associated with an increase in frequency of adverse events such as menstrual disturbances, herpes zoster, and cervical carcinoma in-situ (2,3). A major concern regarding the use of CYC in young patients is gonadal toxicity. From the experience of investigators at the National Institutes of Health (NIH) (4) and a previous study at this institution (5), the risk of infertility in women is related to the cumulative dose of CYC. Thus, there is a trend to use regimens that are less toxic. Examples are a shortened course of oral CYC (6–8) or intravenous pulse CYC (9) compared with the NIH protocols (10), as well as use of newer immunosuppressive agents such as MMF for the initial treatment of lupus nephritis (1). However, the lack of long-term data is the major deterrent to the use of these newer regimens in high-risk patients. A recent trend in the management of lupus nephritis is the division of the treatment schedule into an Chi Chiu Mok, MD, FRCP: Tuen Mun Hospital, Hong Kong, China. Address correspondence and reprint requests to Chi Chiu Mok, MD, FRCP, Department of Medicine, Tuen Mun Hospital, Tsing Chung Koon Road, New Territories, Hong Kong, China. E-mail: ccmok2005@yahoo.com. Submitted for publication July 5, 2004; accepted in revised form August 23, 2004.

UPDATE ON CYCLOPHOSPHAMIDE FOR SYSTEMIC LUPUS ERYTHEMATOSUS

Over the past decade cyclophosphamide has come to assume an increasingly prominent role in the management of severe, life-threatening manifestations of SLE. Intermittent, intravenous pulse cyclophosphamide has become the standard of treatment of diffuse proliferative lupus nephritis (WHO Class IV), and there is now substantial clinical literature to suggest an indication for intermittent cyclophosphamide therapy in most other forms of serious lupus affecting major organ systems, in particular lupus vasculitis and acute central nervous system manifestations. This update reviews the use of cyclophosphamide in the management of lupus nephritis, expands on its role in other manifestations of SLE, and discusses potential complications of the drug.

The Value of Electron Microscopy in the Diagnosis and Clinical Management of Lupus Nephritis

The diagnosis and clinical management of patients with lupus nephritis can be a challenge from a clinicopathologic point of view. Although the majority of patients that are biopsied already have either an established clinical diagnosis or a presumptive diagnosis of systemic lupus erythematosus, determination of the immunomorphologic characteristics, pattern, and distribution of renal involvement is important for clinical management. In a clear subset of these patients with lupus nephritis, electron microscopy plays a pivotal role in accurately characterizing the type of renal involvement and determining the degree of activity, providing useful and objective guides for patients' management. Ultrastructural evaluation can also be crucial in the initial diagnosis of patients with lupus who, at the time of biopsy, lack either diagnostic clinical manifestations and/or serologic markers, and are therefore clinically unsuspected. Electron microscopic evaluation also plays a significant role in the evaluation of renal dysfunction in transplant patients with lupus nephritis, helping to determine whether recurrence of the lupus has occurred in the renal allograft. There are some ultrastructural findings that, although not pathognomonic, in the proper clinico-pathologic context are very suggestive or even diagnostic of lupus nephritis. Correlating light, immunofluorescence, and electron microscopic findings within the clinical context of lupus nephritis cases is crucial for appropriate clinical management. In some of these patients, electron microscopy provides key information that cannot be otherwise obtained.

4 Current role of renal biopsy in patients with SLE

All aspects of the role of renal biopsy in systemic lupus erythematosus may not be defined and accepted, but there is increasing agreement as to the information that can be obtained from biopsy. Awareness of the importance of clinical (non-biopsy) predictors has permitted a clearer understanding of the ability of renal biopsy to confirm and to add information to a determination of prognosis based on clinical data. New techniques for scoring the patterns of injury detectable on renal biopsy have provided important insights into prognosis, pathogenesis and treatment of lupus nephritis. Watchful waiting is often an unwise course for the management of lupus nephritis. Thus, renal biopsy is increasingly seen as an important tool in the timely determination of prognosis.