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• W2015164579 abstract "There is a paucity of high quality clinical trials in glomerular disease, particularly in non-diabetic kidney disease. The aims of this review include quantifying the extent of this problem and exploring reasons for the scarcity of such trials in primary glomerular disease, with an emphasis on immunoglobulin A nephropathy, minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy in comparison with the more common diseases of diabetic nephropathy and lupus nephritis. Reasons for the dearth of high quality clinical trials in primary glomerular disease include (1) low prevalence of disease; (2) variability in clinical presentation; (3) variability in treatment response; (4) lack of consensus in definitions; (5) difficulty in recruiting patients; (6) high costs of randomized controlled trials; and (7) lack of collaborative efforts. To facilitate greater numbers of high quality clinical trials in glomerular disease, practice guidelines should establish common classification systems of disease and common clinical end points, industry and non-industry sponsored research should find common ground and work together toward advancing science, and national registries should be created to encourage collaborations across institutions and across nations. There is a paucity of high quality clinical trials in glomerular disease, particularly in non-diabetic kidney disease. The aims of this review include quantifying the extent of this problem and exploring reasons for the scarcity of such trials in primary glomerular disease, with an emphasis on immunoglobulin A nephropathy, minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy in comparison with the more common diseases of diabetic nephropathy and lupus nephritis. Reasons for the dearth of high quality clinical trials in primary glomerular disease include (1) low prevalence of disease; (2) variability in clinical presentation; (3) variability in treatment response; (4) lack of consensus in definitions; (5) difficulty in recruiting patients; (6) high costs of randomized controlled trials; and (7) lack of collaborative efforts. To facilitate greater numbers of high quality clinical trials in glomerular disease, practice guidelines should establish common classification systems of disease and common clinical end points, industry and non-industry sponsored research should find common ground and work together toward advancing science, and national registries should be created to encourage collaborations across institutions and across nations. Glomerular disease is an important cause of morbidity and mortality;1.Remuzzi G. Schieppat A. Ruggenenti P. Nephropathy in patients with type 2 diabetes.N Engl J Med. 2002; 346: 1145-1151Crossref PubMed Scopus (486) , 2.Marx B.E. Marx M. Prognosis of idiopathic membranous nephropathy: a methodologic meta-analysis.Kidney Int. 1997; 51: 873-879Abstract Full Text PDF PubMed Scopus (35) Google Scholar however, with the exception of diabetic nephropathy (DN) there has been a paucity of high quality randomized controlled trials (RCTs) in this area. The aims of this review include quantifying the extent of this problem and exploring reasons for the scarcity of such trials in glomerular disease. As all etiologies of glomerular disease could not be reviewed, the following major glomerular disease entities were chosen as representative: DN, lupus nephritis (LN), immunoglobulin A nephropathy (IgAN), minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN). Medline and the Cochrane Database were searched for articles written in English and published between 1990 and 2009 using the following keywords: (1) diabetic nephropathy; diabetic kidney disease; (2) lupus nephritis; lupus nephropathy; lupus glomerulonephritis; (3) Immunoglobulin A nephropathy; immunoglobulin A nephritis; immunoglobulin A glomerulonephritis; immunoglobulin A nephropathy; (4) minimal change disease; minimal change nephrotic syndrome; lipoid nephrosis; (5) focal segmental glomerulosclerosis; (6) membranous nephropathy; membranous glomerular nephropathy; membranous glomerulonephritis. Additional criteria used to select articles included the following: (1) articles must have been RCTs or meta-analyses; (2) post-hoc analyses of RCTs were only included if they evaluated different end points than the original study; (3) only studies involving human subjects were included; and (4) studies which included patients with heterogeneous etiologies of kidney disease were counted under each individual category, assuming that the category included a sample size of at least 10 patients. Among the studies in which the total enrollment was fewer than 10 patients, designation was attributed solely to the category with the greatest number of patients. Using the above criteria, the number of RCTs and meta-analyses investigating DN, LN, IgAN, MCD, FSGS, and MN were determined (Figure 1; Supplementary Information for complete list of studies). As shown, many RCTs and meta-analyses have been published regarding DN, however, there is a dearth of studies evaluating non-diabetic glomerular disease. Download .pdf (.8 MB) Help with pdf files Supplementary Information Table 1 shows the total number of patients enrolled and the mean duration of follow-up (not including washout or run-in periods) for each of the RCTs. The average number of subjects enrolled in trials of DN far outweighs the number enrolled in trials of the other glomerular diseases. The average duration of follow-up is comparable across all six diseases represented.Table 1Number of subjects enrolled (n) and duration of follow-up (weeks) for RCTs, and incidence (cases/100,000/year)46.Cervera R. Khamashta M.A. Font J. et al.Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1000 patients.Medicine (Baltimore). 2003; 82: 299-308Crossref PubMed Scopus (909) Google Scholar, 47.Esmatjes E. De Alvaro F. ‘Estudio Diamante’ Investigators Incidence of diabetic nephropathy in Type 1 diabetic patients in Spain: ‘Estudio Diamante.Diabetes Res Clin Pract. 2002; 57: 35-43Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 48.Haas M. Meehan S.M. Karrison T.G. et al.Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976 to 1979 and 1995 to 1997.Am J Kidney Dis. 1997; 30: 621-631Abstract Full Text PDF PubMed Scopus (368) Google Scholar, 49.Llach F. Thromboembolic complications in nephrotic syndrome. Coagulation abnormalities, renal vein thrombosis, and other conditions.Postgrad Med. 1984; 76: 111-123PubMed Google Scholar, 50.Uramoto K.M. Michet Jr, C.J. Thumboo J. et al.Trends in the incidence and mortality of systemic lupus erythematosus, 1950–1992.Arthritis Rheum. 1999; 42: 46-50Crossref PubMed Scopus (367) Google Scholar of renal diseasenFollow-up (weeks)Estimated incidence (cases/100,000/year)Overall104.2±13.479.9±5.7NADiabetic nephropathy (DN)127.6±19.370.0±6.154Lupus nephritis (LN)68.7±12.2106.2±17.32.8IgA nephropathy (IgAN)51.9±4.7113.3±16.71.4Minimal change disease (MCD)34.7±5.283.1±25.00.5Focal segmental glomerulosclerosis (FSGS)34.9±5.262.7±18.81.1Membranous nephropathy (MN)49.4±6.0123.8±29.80.7Abbreviations: NA, not applicable; RCT, randomized controlled trial.Values indicate mean±s.e.m. Open table in a new tab Abbreviations: NA, not applicable; RCT, randomized controlled trial. Values indicate mean±s.e.m. In addition to the relatively small sample sizes and general shortage of RCTs evaluating non-diabetic glomerular disease, the quality of many of these trials was poor. For example, a meta-analysis of 10 RCTs investigating treatments for IgAN found that none adequately described appropriate randomization methods, only 2 of 10 had blinding of both participants and investigators, 5 of 10 reported intention-to-treat analysis, and 6 of 10 had relevant number of patients lost at follow-up.3.Strippoli G.F.M. Manno C. Schena F.P. An ‘evidence-based’ survey of therapeutic options for IgA nephropathy: assessment and criticism.Am J Kidney Dis. 2003; 41: 1129-1139Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Furthermore, pertinent data was often missing from methods and statistical sections. Similarly, in a meta-analysis of 18 RCTs investigating immunosuppressive treatment for idiopathic MN, few of the conducted trials included information on the method of randomization, reported on blinding of both investigators and participants, used intention-to-treat analysis, or provided information regarding completeness of follow-up.4.Perna A. Schieppati A. Zamora J. et al.Immunosuppressive treatment for idiopathic membranous nephropathy: a systematic review.Am J Kidney Dis. 2004; 44: 385-401Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar One obvious explanation for the scarcity of RCTs in non-diabetic glomerular disease relates to their infrequent occurrence. Table 1 shows estimates of the incidence of DN, LN, IgAN, MCD, FSGS, and MN. The incidence of DN is approximately 20-fold the incidence of LN and over 40-fold the incidence of the primary glomerular diseases. Studies of non-diabetic renal disease limited to a single center or few centers would be unlikely to recruit adequate number of patients in any reasonable time period. However, rarity alone does not fully explain the scarcity of RCTs in glomerular disease. By comparison, Huntington's disease and Guillain–Barre syndrome are the two rare neurological disorders with estimated incidences of 0.3 and 1.3 per 100,000 people per year, respectively, which is similar to the incidence of the primary glomerular diseases.5.Kokmen E. Ozekmekci F.S. Beard C.M. et al.Incidence and prevalence of Huntington's disease in Olmstead County, Minnesota (1950 through 1989).Arch Neurol. 1994; 51: 696-698Crossref PubMed Scopus (40) Google Scholar, 6.Matias-Guiu J. Martin R. Blanquer J. et al.Incidence of Guillain-Barre syndrome and ganglioside intake in Alcoi, Spain.Neuroepidemiology. 1993; 12: 58-60Crossref PubMed Scopus (19) Google Scholar However, the number of RCTs performed in the last two decades, evaluating these two disorders, is 40 and 30, respectively, which is substantially greater than the corresponding number of trials evaluating the primary glomerular diseases (with the exception of IgAN). Accordingly, alternative explanations for the scarcity of RCTs addressing glomerular disease must be sought. Many primary glomerular diseases are heterogeneous in their clinical presentation. Some patients present with a gradual asymptomatic increase in proteinuria, while other patients present with the sudden onset of massive edema and overt nephrotic syndrome. Even among patients with the same type of glomerular histopathology, the degree of proteinuria may vary and the threshold for starting immunosuppressive therapy is often controversial. In MN, for example, rates of spontaneous remission are very high and many patients may receive unnecessary treatment. One prospective study of 100 patients with idiopathic MN, who received symptomatic therapy only (i.e. no glucocorticoid or immunosuppressive drugs), found an 88% estimated probability of retaining adequate kidney function at 5 years, and 65% of patients had complete or partial remission of proteinuria.7.Schieppati A. Mosconi L. Perna A. et al.Prognosis of untreated patients with idiopathic membranous nephropathy.N Engl J Med. 1993; 329: 85-89Crossref PubMed Scopus (319) Google Scholar In contrast, other investigators recommend a wait-and-see policy in idiopathic MN only for low-risk patients.8.Geddes C.C. Cattran D.C. The treatment of idiopathic membranous nephropathy.Semin Nephrol. 2000; 20: 299-308PubMed Google Scholar, 9.Du Buf-Vereijken P.W. Branten A.J. Wetzels J.F. Idiopathic membranous nephropathy: outline and rationale of a treatment strategy.Am J Kidney Dis. 2005; 46: 1012-1029Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Even in these studies, the indication for immunosuppressive therapy differs between persistent proteinuria8.Geddes C.C. Cattran D.C. The treatment of idiopathic membranous nephropathy.Semin Nephrol. 2000; 20: 299-308PubMed Google Scholar and risk-stratifying patients based on the renal function and urinary excretion of β2-microglobulin.9.Du Buf-Vereijken P.W. Branten A.J. Wetzels J.F. Idiopathic membranous nephropathy: outline and rationale of a treatment strategy.Am J Kidney Dis. 2005; 46: 1012-1029Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Similarly, controversy exists regarding the optimal timing of renal biopsy. In IgAN, for example, some experts advocate for early biopsy in patients with persistent microhematuria and low-grade proteinuria, whereas others advocate an initial trial of angiotensin converting enzyme inhibitor therapy, limiting renal biopsy only to those patients with a non-satisfactory antiproteinuric response. Such heterogeneity of disease activity and the difference in opinion of when to perform biopsy and when to initiate specific therapy present a challenge to investigators. An additional challenge to investigators studying glomerular disease is heterogeneity of response to the treatment. IgAN, for example, may have a variable response to treatment depending on the ethnicity and inclusion criteria of study participants. Although a recent meta-analysis concluded that the current available evidence does not support the routine use of mycophenolate mofetil (MMF) in patients with IgAN,10.Xu G. Tu W. Jiang D. et al.Mycophenolate mofetil treatment for IgA nephropathy: a meta-analysis.Am J Nephrol. 2009; 29: 362-367Crossref PubMed Scopus (40) Google Scholar this finding was based on only four RCTs. Among these four RCTs, the two which included predominantly the Asian patients11.Tang S. Leung J.C.K. Chan L.Y.Y. et al.Mycophenolate mofetil alleviates persistent proteinuria in IgA nephropathy.Kidney Int. 2005; 68: 802-812Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 12.Chen X. Chen P. Cai G. et al.A randomized control trial of mycophenolate mofetil treatment in severe IgA nephropathy (in Chinese).Zhonghua Yi Xue Za Zhi. 2002; 82: 796-801PubMed Google Scholar found a significant reduction in proteinuria with MMF, whereas the two that included caucasian13.Frisch G. Lin J. Rosenstock J. et al.Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial.Nephrol Dial Transplant. 2005; 20: 2139-2145Crossref PubMed Scopus (166) Google Scholar and north European patients14.Maes B.D. Oyen R. Claes K. et al.Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study.Kidney Int. 2004; 65: 1842-1849Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar found no reduction in proteinuria compared with controls. Similarly, although a meta-analysis3.Strippoli G.F.M. Manno C. Schena F.P. An ‘evidence-based’ survey of therapeutic options for IgA nephropathy: assessment and criticism.Am J Kidney Dis. 2003; 41: 1129-1139Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar concluded that cytotoxic agents (cyclophosphamide and azathioprine) are beneficial in IgAN, this finding was driven almost entirely by a single positive study15.Ballardie F. Roberts I.S.D. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy.J Am Soc Nephrol. 2002; 3: 142-148Google Scholar in which the inclusion criteria differed significantly from other studies that have explored this treatment modality. Specifically, the patients in Ballardie's study were older, had higher levels of serum creatinine, and had more severe renal lesions on biopsy, as compared with other trials of cytotoxic agents on patients with IgAN.16.Walker R.G. Yu S.H. Owen J.E. et al.The treatment of mesangial IgA nephropathy with cyclophosphamide, dipyridamole and warfarin: a two-year prospective trial.Clin Nephrol. 1990; 34: 103-107PubMed Google Scholar, 17.Woo K.T. Edmondson R.P.S. Yap H.K. et al.Effects of triple therapy on the progression of mesangial proliferative glomerulonephritis.Clin Nephrol. 1987; 27: 56-64PubMed Google Scholar, 18.Yoshikawa N. Ito H. Sakai T. et al.A controlled trial of combined therapy for newly diagnosed severe childhood IgA nephropathy. The Japanese Pediatric IgA Nephropathy Treatment Study Group.J Am Soc Nephrol. 1999; 10: 101-109PubMed Google Scholar Not only are both clinical presentation and response to treatment highly variable in many glomerular diseases but the spectrum of histopathology on renal biopsy may also be diverse. Disagreement regarding histopathological classification within a given disease entity is not uncommon. This concept is well-exemplified by FSGS, in which a classification system of five distinct variants has been proposed and widely accepted.19.D'Agati V.D. Fogo A.B. Bruijn J.A. et al.Pathologic classification of focal segmental glomerulosclerosis: a working proposal.Am J Kidney Dis. 2004; 43: 368Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar However, as noted by Meyrier,20.Meyrier A. E pluribus unum: the riddle of focal segmental glomerulosclerosis.Semin Nephrol. 2003; 23: 135-140Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 21.Meyrier A. Nephrotic focal segmental glomerulosclerosis in 2004: an update.Nephrol Dial Transplant. 2004; 19: 2437-2444Crossref PubMed Scopus (43) Google Scholar this system is not without limitations as one renal biopsy may reveal multiple variants simultaneously or, alternatively, may indicate a different histological variant due to sampling error. Others have proposed that the classification of primary nephrotic diseases should incorporate specific pathophysiological mechanisms.22.Barisoni L. Schnaper H.W. Kopp J.B. A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases.Clin J Am Soc Nephrol. 2007; 2: 529-542Crossref PubMed Scopus (183) Google Scholar Further disagreement regarding disease categorization centers around lumping and splitting. For example, some investigators23.Howie A.J. Pankhurst T. Sarioglu S. et al.Evolution of nephrotic-associated focal segmental glomerulosclerosis and relation to the glomerular tip lesion.Kidney Int. 2005; 67: 987-1001Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar favor grouping tip variant FSGS as being merely a variant of MCD. Other investigators have suggested that MCD itself encompasses a heterogeneous group of disorders and can be split into three distinct categories on the basis of the presence or absence of hypoalbuminemia, overt edema, and hypovolemia.24.Vande Walle J.G. Donckerwolcke R.A. van Isselt J.W. et al.Volume regulation in children with early relapse of minimal-change nephrosis with or without hypovolaemic symptoms.Lancet. 1995; 346: 148-152Abstract PubMed Scopus (0) Google Scholar This problem is further complicated in children with nephrotic syndrome, wherein a renal biopsy is typically not performed before initiating corticosteroids. Moreover, in some diseases, such as MN, the ability of the renal histopathology to predict disease progression and response to therapy is still debated. The recognition of problems associated with the lack of uniform and widely accepted histopathological classification systems has been addressed by collaborative formulations in a number of glomerular diseases, including LN,25.Weening J.J. D'Agati V.D. Schwartz M.M. et al.The classification of glomerulonephritis in systemic lupus erythematosus revisited.J Am Soc Nephrol. 2004; 15: 241-250Crossref PubMed Scopus (1324) Google Scholar FSGS,19.D'Agati V.D. Fogo A.B. Bruijn J.A. et al.Pathologic classification of focal segmental glomerulosclerosis: a working proposal.Am J Kidney Dis. 2004; 43: 368Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar and, most recently, IgAN. Specifically, with regard to IgAN, lack of consensus regarding its pathological classification was addressed by the Working Group of the International Nephropathy Network and the Renal Pathology Society.26.Working Group of the International IgA Nephropathy Network and the Renal Pathology Society The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.Kidney Int. 2009; 76: 534-545Abstract Full Text Full Text PDF PubMed Scopus (789) Google Scholar Renal biopsies from 265 adults and children with IgAN were examined, and four specific pathological features were identified as having an independent value in predicting the renal outcome. In LN and FSGS, validation of these classifications has been made in other populations. This remains to be done in IgAN. It should be emphasized, however, that one of the unique characteristics of the IgAN classification scheme is that the pathological features identified had significant predictive value even after accounting for all clinical indicators available at baseline, thereby potentially becoming relevant factors in future study designs. Hopefully, greater consensus in definition, including agreement on classification systems as well as important clinical end points, will encourage more robust collaborative efforts (see below) and will allow for greater number of high quality clinical trials. Many clinical trials investigating primary glomerular disease use medications with narrow therapeutic indexes and relatively high rates of toxicity, such as immunosuppressant and immunomodulatory agents. Thus, it is likely that patients may have greater reluctance to participate in such trials as compared with trials of milder interventions, such as angiotensin converting enzyme inhibitors in DN. Furthermore, patients may be especially reluctant to participate in trials, such as those studying primary glomerular disease, in which the response to treatment is highly variable. This notion is especially true for diseases, such as IgAN and MN, which often have a slow progressive course. In addition, many patients as well as their physicians may feel it is better for an individual patient not to enter a controlled trial but rather to wait and see the results of such studies in other patients. Finally, those patients who are most likely to progress in any given disease will be reluctant to accept a placebo arm to any study given the wide array of potential immune modulating agents available, which are Food and Drug Administration (FDA) approved (albeit for other indications). Another major barrier to patient recruitment relates to late diagnosis and late referral to a nephrologist. Earlier referral of patients by general practitioners would greatly increase the pool of potential subjects for enrollment in prospective clinical trials. Moreover, there is increasing evidence that early referral to a nephrologist, defined by some as greater than a year before the initiation of dialysis, results in improved patient survival.27.Kessler M. Frimat L. Panescu V. et al.Impact of nephrology referral on early and midterm outcomes in ESRD: EPidémiologie de l'Insuffisance REnale chronique terminale en Lorraine (EPIREL): results of a 2-year, prospective, community-based study.Am J Kidney Dis. 2003; 42: 474-485Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 28.Kazmi W.H. Obrador G.T. Khan S.S. et al.Late nephrology referral and mortality among patients with end-stage renal disease: a propensity score analysis.Nephrol Dial Transplant. 2004; 19: 1808-1814Crossref PubMed Scopus (121) Google Scholar For this reason, many have advocated for more intensified education of non-nephrologist physicians regarding the importance of early referral to a specialist.29.Huisman R.M. The deadly risk of late referral.Nephrol Dial Transplant. 2004; 19: 2175-2180Crossref PubMed Scopus (71) Google Scholar Although these studies predominantly involved referrals for end-stage renal disease evaluation among predialysis patients, it is not unreasonable to extrapolate these findings to glomerular disease and to expect improved outcomes with earlier referral here as well. The increasing costs associated with performing RCTs is, without a doubt, a major barrier. According to one report,30Clinical operations: accelerating trials, allocating resources and measuring performance. http://www.cuttingedgeinfo.com/clinical-trials/ accessed 13 January 2010Google Scholar the cost per patient for performing Phase 1, 2, and 3 clinical trials in 2006 was $15,700, $19,300, and over $26,000, respectively, and these costs continue to increase. For example, the European clinical trials market in 2008 was calculated to have a value of $32 billion, and is projected to reach a value of $47 billion by 2012.31Applied clinical trials online. http://appliedclinicaltrialsonline.findpharma.com/ accessed 13 January 2010Google Scholar Reasons for the increasing costs associated with RCTs are numerous and include expenditures related to: (1) salaries of research staff, including study coordinators, research pharmacists, and administrators; (2) complex statistical methodology requiring expensive data management systems and highly-trained statisticians (often at the PhD level); (3) increased documentation requirements; (4) independent data safety and monitoring committees; (5) institutional review boards; and (6) compliance with federal regulations, such as the Health Insurance Portability and Accountability Act, making the sharing of data both complex and expensive.32.Erdmann J. Researchers facing increasing costs for clinical research, with few solutions.J Natl Cancer Inst. 2005; 97: 1492-1494Crossref PubMed Scopus (5) Google Scholar Although these costs and the problems associated with them are not unique to nephrology, they are particularly challenging to our field because of the limited funding of our national granting agencies as compared with certain other fields. Such prohibitive costs are one reason that large RCTs can sometimes only be supported by pharmaceutical companies or governmental funding agencies such as the NIH (National Institutes of Health). Clearly the aim of industry-sponsored trials is to bring a new drug to market or to broaden the indication of an existing drug. For example, the ‘gold standard’ medication for the treatment of LN for years was intravenous cyclophosphamide, supported by data derived from NIH ‘in-house’ studies. This medication never received an FDA indication as therapy for LN. Thus, to get the FDA approval for a new medication for LN, the new drug requires evidence of superiority, not equivalency, to intravenous cyclophosphamide. Pharmaceutical studies, designed to obtain the FDA approval, must therefore adjust recruitment and duration for the end point of superiority rather than the easier aim of equivalency. Hence, the pharmaceutical-sponsored aspreva lupus management study trial of MMF versus intravenous cyclophosphamide needed to recruit 370 patients to attempt to establish the superiority of the former over the latter regimen, and thereby broaden the indication of MMF.33.Appel G.B. Contreras G. Dooley M.A. et al.Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.J Am Soc Nephrol. 2009; 20: 1103-1112Crossref PubMed Scopus (690) Google Scholar In contrast, the Euro–Lupus group, funded by a non-industry source (the European League Against Rheumatism), was able to show equivalency of two different regimens of cyclophosphamide with only 90 patients.34.Houssiau F.A. Vasconcelos C. D'Cruz D. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.Arthritis Rheum. 2002; 46: 2121-2131Crossref PubMed Scopus (737) Google Scholar For generic drugs, funding a large study essentially means that, with rare exceptions, a governmental agency has to provide the funding, as pharmaceutical companies have little incentive to study and fine-tune optimal dosages for medications, which are inexpensive and have already been FDA-approved. An example is the FSGS clinical trial, which compares generic cyclosporine with MMF and steroids in patients with steroid-refractory FSGS.35National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Focal segmental glomerulosclerosis clinical trial. ClinicalTrials.gov. National Library of Medicine (US): Bethesda, MD,. 2000-[cited 18 January 2010]. Available athttp://clinicaltrials.gov/ct2/show/NCT00135811?term=fsgs&rank=15 NLM Identifier: NCT00135811Google Scholar Finally, among diseases as rare as the primary glomerulopathies, recruiting adequate number of subjects for high quality RCTs is nearly impossible without robust collaborative efforts. Nonetheless, these efforts are lacking. Among the RCTs that evaluated MCD, for example, only 3/11 (27.3%) were multi-center studies (2/9 in children and 1/2 in adults). Consequently, among the six glomerular diseases studied in this review, MCD represents the category with the fewest number of enrolled subjects (Table 1). Furthermore, in cases where single-center designs are used, lengthy recruitment periods are often required and concepts of ideal management may change during this time. Large, multi-center trials with relatively short recruitment periods are much less likely be affected by this problem. The European Vasculitis Study Group,36European Vasculitis Study Group. http://www.vasculitis.org/ accessed 27 September 2009Google Scholar a partnership of clinicians and researchers interested in clinical trials of vasculitis, represents an ideal model of collaborative efforts spanning across multiple nations. The group has been successful in carrying out several, large RCTs evaluating antineutrophil cytoplasmic-antibodies associated vasculitis, including a study establishing the safety of azathioprine substitution for cyclophosphamide after remission (n=155)37.Jayne D. Rasmussen N. Andrassy K. et al.A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.N Engl J Med. 2003; 349: 36-44Crossref PubMed Scopus (1084) Google Scholar and a study establishing the efficacy of plasma exchange in improving rates of renal recovery (n=100).38.Jayne D.R. Gaskin G. Rasmussen N. et al.Randomized trial of plasma exchange or high-dose methylprednisolone as adjunctive therapy for severe renal vasculitis.J Am Soc Nephrol. 2007; 18: 2180-2188Crossref PubMed Scopus (732) Google Scholar Collaborative efforts such as these should be enthusiastically echoed by similar efforts in the investigation of glomerular disease. Such efforts have been made in treating LN by combined efforts of rheumatology and nephrology recruitment,33.Appel G.B. Contreras G. Dooley M.A. et al.Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.J Am Soc Nephrol. 2009; 20: 1103-1112Crossref PubMed Scopus (690) Google Scholar, 39.Ginzler E.M. Dooley M.A. Aranow C. et al.Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.N Engl J Med. 2005; 353: 2219-2228Crossref PubMed Scopus (829) Google Scholar, 40LUNAR Study. A study to evaluate the efficacy and safety of Rituximab in subjects with ISN/RPS Class III or IV lupus nephritis (LUNAR). http://clinicaltrials.gov/ct2/show/NCT00282347?term=lunar&rank=3/ accessed 27 September 2009Google Scholar however, they are lacking in other areas of glomerular disease. The most obvious reason for the shortage of meta-analyses among the primary glomerular diseases is the shortage of corresponding RCTs. However, a second factor is also a likely contributor: heterogeneity of clinical end points. Meta-analyses depend on common end points to answer specific clinical questions. When common clinical end points cannot be found, meta-analyses are either not performed or performed using a distribution-based approach, such as Cohen's standardized effect size, which is simply the mean change divided by the s.d.41.Cohen J. Statistical Power Analysis for the Behavioural Sciences. Lawrence Earlbaum, New Jersey1988Google Scholar However, this approach has several limitations.42.Leaf D.E. Goldfarb D.S. Interpretation and review of health-related quality of life data in CKD patients receiving treatment for anemia.Kidney Int. 2009; 75: 15-24Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Some investigators have suggested that effect sizes may underestimate clinically important differences.43.Lydick E. Epstein R.S. Interpretation of quality of life changes.Qual Life Res. 1993; 2: 221-226Crossref PubMed Scopus (396) Google Scholar Furthermore, effect sizes cannot be used to interpret individual-based differences over time.44.Osoba D. King M. Interpreting QOL in individuals and groups: meaningful differences.in: Fayers P. Hays R. Assessing Quality of Life in Clinical Trials: Methods and Practice. 2nd edn. Oxford University Press, Oxford, UK2005: 243-257Google Scholar Table 2 shows the wide heterogeneity among clinical end points used in RCTs of glomerular disease. Even among the end points of which significance is universally agreed upon, such as proteinuria in the progression of kidney disease, there is variability among studies regarding methods of quantification and thresholds of clinical relevance. Despite the heterogeneity of clinical end points, the focus of clinical trials in glomerular disease often centers largely on proteinuria and/or serum creatinine. End points such as quality of life have been slow to be embraced, especially as compared with other nephrology subspecialties such as anemia of chronic kidney disease where an abundance of literature exists on quality of life.42.Leaf D.E. Goldfarb D.S. Interpretation and review of health-related quality of life data in CKD patients receiving treatment for anemia.Kidney Int. 2009; 75: 15-24Abstract Full Text Full Text PDF PubMed Scopus (102) Google ScholarTable 2Heterogeneity of clinical end points used in RCTs of renal diseaseComposite outcomes Progression to CKD or death; doubling of baseline serum creatinine or progression to CKD stage IV or V or ESRDReduction in GFR Serum creatinine, eGFR (MDRD, Cockgraft–Gault, iothalamate clearance, creatinine clearance), or (99 m) Tc-diethylenetriamine penta-acetic renogramProteinuria Spot microalbuminuria, spot urine protein/creatinine; 24 h urine protein collectionRemission Complete/partial: improvement in proteinuria, improvement/stabilization of renal function, and improvement/stabilization of systemic features.Blood pressure (BP) control Ambulatory BP, office BP, nocturnal BP, orthostatic hypotension, number of antihypertensive medicationsGlycemic control Fasting blood glucose, hemoglobin A1c, and serum insulin and C-peptide concentrationsLipid profile Low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TGs), and cholesterolBiomarkers/serology Serum TNF-α, IGF-1, N-acetyl-β-glucosaminidase, type IV collagen, von Willebrand factor, anti-double-stranded (ds) DNA antibodies; urinary prostaglandin E2, urinary TGF-βHistological/Pathological Mesangial fractional volume (Mes/glom), nephrin expression, and urinary podocytesHealth-related quality of life SF-36, visual analog scale (VAS), and lupus symptom checklistAbbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filteration rate; ESRD, end-stage renal disease; GFR, glomerular filteration rate; IGF-1, insulin-like growth factor 1; MDRD, modification of diet in renal disease; RCT, randomized controlled trial; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α. Open table in a new tab Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filteration rate; ESRD, end-stage renal disease; GFR, glomerular filteration rate; IGF-1, insulin-like growth factor 1; MDRD, modification of diet in renal disease; RCT, randomized controlled trial; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α. (1)To facilitate greater numbers of high quality clinical trials in glomerular disease, investigators and clinicians should be encouraged to agree on common classification systems of disease and common clinical end points. To this point, a global non-profit foundation known as Kidney Disease: Improving Global Outcomes is currently conducting an evidence-based review process to establish clinical practice guidelines for glomerulonephritis.45Kidney Disease: Improving Global Outcomes (KDIGO) Available at http://www.kdigo.org/ accessed 27 September 2009Google Scholar The guidelines are anticipated to be published in 2011 and will include disease classification definitions and recommendations for future research.(2)To reconcile the contrasting aims and resources of studies funded by pharmaceutical and non-industry sources, collaboration between these two entities is to be strongly encouraged. The funding provided by the industry would ensure high quality research, with high numbers of enrolled patients and adequate follow-up, whereas peer-review agencies would lend credibility and aid in the recruitment of patients through their connections with national registries (see #3 below).(3)Finally, given the small number of patients enrolled in most studies of glomerular disease, national registries should be created to facilitate collaborations across institutions and across nations, as modeled by the European Vasculitis Study Group. Such an endeavor would have a greater chance of success if physicians feel a greater obligation to register such patients in a central databank, perhaps with the supervision and monitoring by a governmental agency, thereby emulating various cancer registry models. In conclusion, until there is greater agreement on classification systems of disease and greater collaboration among investigators, it is unlikely that the fruit on the tree of glomerular knowledge will germinate to its full potential. Supplementary material is linked to the online version of the paper at http://www.nature.com/ki" @default.
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