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Surrogate endpoint and ESRD

Miho Shimizu, Kengo Furuichi, Tadashi Toyama, Tomoaki Funamoto, Shinji Kitajima, Akinori Hara, Daisuke Ogawa, Daisuke Koya, Kenzo Ikeda, Yoshitaka Koshino, Yukie Kurokawa, Hideharu Abe, Kiyoshi Mori, Masaaki Nakayama, Yoshio Konishi, Ken-Ichi Samejima, Masaru Matsui, Hiroyuki Yamauchi, Tomohito Gohda, Kei Fukami, Daisuke Nagata, Hidenori Yamazaki, Yukio Yuzawa, Yoshiki Suzuki, Shouichi Fujimoto, Shoichi Maruyama, Sawako Kato, Takero Naito, Kenichi Yoshimura, Hitoshi Yokoyama, Takashi Wada
BACKGROUND: There is increased interest in surrogate endpoints for clinical trials of chronic kidney disease. METHODS: In this nationwide observational study of 456 patients with type 2 diabetes and clinically suspected diabetic nephropathy followed for a median of 4.2 years, we evaluated the association between estimated glomerular filtration rate (eGFR) and albuminuria at baseline or during follow-up and risk of ESRD. RESULTS: Low eGFR (<60 mL/min/1...
September 9, 2017: Clinical and Experimental Nephrology
Eiichiro Kanda, Tomoko Usui, Naoki Kashihara, Chiho Iseki, Kunitoshi Iseki, Masaomi Nangaku
BACKGROUND: Because of the necessity for extended period and large costs until the event occurs, surrogate endpoints are indispensable for implementation of clinical studies to improve chronic kidney disease (CKD) patients' prognosis. METHODS: Subjects with serum creatinine level for a baseline period over 1-3 years were enrolled (n = 69,238) in this community-based prospective cohort study in Okinawa, Japan, and followed up for 15 years. The endpoint was end-stage renal disease (ESRD)...
September 7, 2017: Clinical and Experimental Nephrology
Kunihiro Matsushita, Jingsha Chen, Yingying Sang, Shoshana H Ballew, Ryutaro Shimazaki, Masafumi Fukagawa, Enyu Imai, Josef Coresh, Akira Hishida
Predominantly based on North American and European studies, 30% to 40% declines in estimated glomerular filtration rate (eGFR) over a few years are strongly associated with the risk of end-stage renal disease (ESRD) and have been proposed as surrogate endpoints of ESRD for clinical research. However, this association has not been systematically quantified in Asian populations. To do this we studied adult Japanese patients with baseline eGFR 10-59 ml/min/1.73m(2). Changes in eGFR from baseline measured by centrally assessed serum creatinine were linked to subsequent ESRD in 2410 patients after one year and in 2079 patients after year 2...
November 2016: Kidney International
Yu Pan, Song Jiang, Dandan Qiu, Jingsong Shi, Minlin Zhou, Yu An, Yongchun Ge, Honglang Xie, Zhihong Liu
AIMS: This study aimed to determine whether eGFRcre-cys and its slope could improve the prediction of the long-term renal outcome in patients with type 2 diabetic nephropathy (DN). METHODS: The cross-sectional and longitudinal analyses included 501 type 2DN patients from 2003 to 2009. GFR was estimated using either eGFRcre-cys or the serum creatinine-based equation (eGFRcre) or the cystatin C-based equation (eGFRcys), and was classified into 3 categories (≥90, 60-90, ≤60ml/min per 1...
November 2016: Journal of Diabetes and its Complications
Bauke Schievink, Peter G M Mol, Hiddo J Lambers Heerspink
PURPOSE OF REVIEW: There is increased interest in developing surrogate endpoints for clinical trials of chronic kidney disease progression, as the established clinically meaningful endpoint end-stage renal disease requires large and lengthy trials to assess drug efficacy. We describe recent developments in the search for novel surrogate endpoints. RECENT FINDINGS: Declines in estimated glomerular filtration rate (eGFR) of 30% or 40% and albuminuria have been proposed as surrogates for end-stage renal disease...
November 2015: Current Opinion in Nephrology and Hypertension
Erum A Hartung
Kidney disease and its related comorbidities impose a large public health burden. Despite this, the number of clinical trials in nephrology lags behind many other fields. An important factor contributing to the relatively slow pace of nephrology trials is that existing clinical endpoints have significant limitations. "Hard" endpoints for chronic kidney disease, such as progression to end-stage renal disease, may not be reached for decades. Traditional biomarkers, such as serum creatinine in acute kidney injury, may lack sensitivity and predictive value...
March 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Hiddo J Lambers Heerspink, Tobias F Kröpelin, Jarno Hoekman, Dick de Zeeuw
Albuminuria has been proposed as a surrogate end point in randomized clinical trials of renal disease progression. Most evidence comes from observational analyses showing that treatment-induced short-term changes in albuminuria correlate with risk change for ESRD. However, such studies are prone to selection bias and residual confounding. To minimize this bias, we performed a meta-analysis of clinical trials to correlate the placebo-corrected drug effect on albuminuria and ESRD to more reliably delineate the association between changes in albuminuria and ESRD...
August 2015: Journal of the American Society of Nephrology: JASN
Bauke Schievink, Hiddo Lambers Heerspink, Hubert Leufkens, Dick De Zeeuw, Jarno Hoekman
AIM: There is discussion whether medicines can be authorized on the market based on evidence from surrogate endpoints. We assessed opinions of different stakeholders on this topic. METHODS: We conducted an online questionnaire that targeted various stakeholder groups (regulatory agencies, pharmaceutical industry, academia, relevant public sector organisations) and medical specialties (cardiology or nephrology vs. other). Participants were enrolled through purposeful sampling...
2014: PloS One
Jean-Michel Halimi, Bénédicte Sautenet, Philippe Gatault, Mélanie Roland, Bruno Giraudeau
Several recent major randomized clinical trials (RCTs) using renal outcomes resulted in conflicting results. We searched MEDLINE via PubMed with the search request '(dialysis OR end-stage renal disease) and creatinine' in six major general journals and two leading journals of nephrology; 123 articles were found; 17/123 were relevant RCTs. Some disagreement among surrogate endpoints in 11/15 articles (missing data in two RCTs) and between surrogate and hard renal endpoints in 10/13; the intervention effects were in the opposite direction in 4/15, mostly in patients with cardiovascular disease, but discrepancies and conflicting results were also found among renal trials...
December 2012: Fundamental & Clinical Pharmacology
Majid Alfadhel, Sandra Sirrs
Fabry disease (FD) is a multisystem, X-linked disorder of glycosphingolipid metabolism caused by enzyme deficiency of α-galactosidase A. Affected patients have symptoms including acroparesthesias, angiokeratomas, and hypohidrosis. More serious manifestations include debilitating pain and gastrointestinal symptoms, proteinuria and gradual deterioration of renal function leading to end-stage renal disease, hypertrophic cardiomyopathy, and stroke. Heterozygous females may have symptoms as severe as males with the classic phenotype...
2011: Therapeutics and Clinical Risk Management
Gianna Fabbri, Giuseppe Di Pasquale, Cristiano Greco, Anna Chiara Musuraca, Luigi Tavazzi
In the last 20 years clinical trials evaluating statins showed the importance of LDL-cholesterol lowering in decreasing the risk of cardiovascular disease. The efficacy of statin therapy has been well documented both in primary and secondary prevention, in patients with subclinical atherosclerosis and in those with average cholesterol levels. However, the so-called "residual risk" remains significant and new strategies are needed for reducing it, such as raising HDL-cholesterol levels. Recently, the JUPITER study demonstrated the efficacy of statins in reducing the risk in healthy subjects with elevated C-reactive protein levels, highlighting the potential protective mechanisms of these drugs...
December 2009: Giornale Italiano di Cardiologia
Lalitha De Silva, Matthew R Weir
PURPOSE OF REVIEW: Microalbuminuria is an indicator of increased cardiovascular disease risk. Herein, we review microalbuminuria as a predictor of the onset and progression of renal disease in people with and without diabetes. We evaluate the data on the use of direct renin inhibitors (DRIs) for treatment of hypertension with microalbuminuria. RECENT FINDINGS: It is known that DRIs have an antiproteinuric effect, whether used alone or with an angiotensin receptor blocker (ARB), independent of its hypotensive effects in patients with type 2 diabetes...
September 2010: Current Opinion in Nephrology and Hypertension
Paolo Verdecchia, Fabio Angeli, Giovanni Mazzotta, Giuseppe Ambrosio, Gianpaolo Reboldi
The combined use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) poses a dilemma to clinicians. On the one hand, indirect evidence from compelling, but still surrogate outcome measures such as blood pressure and proteinuria suggest some merits of this combination. On the other hand, the outcome benefits of the ACEIs+ARBs combination in morbidity/mortality trials remain confined to patients with severe congestive heart failure (CHF) and reduced ejection fraction. Incidentally, most of the benefit offered by the ACEIs+ARBs combination in these patients was not driven by mortality, but by fewer rehospitalizations for CHF...
November 2010: Current Vascular Pharmacology
J-M Halimi, R Asmar, J Ribstein
Results from the ONTARGET trial remind us that acute haemodynamically mediated renal dysfunction, triggered by low arterial pressure or volume depletion, can occur in high-risk cardiovascular patients (who usually have some degree of diseased intrarenal vessels) treated with renin-angiotensin system (RAS) blockers (especially in combination). However, nephroprotection could not be properly assessed in the trial, as the population was at low renal risk. Although albuminuria remains a useful marker in many patients, it can neither predict acute renal dysfunction nor replace end-stage renal disease (ESRD) as the endpoint in clinical trials...
December 2009: Diabetes & Metabolism
Macaulay A Onuigbo
Despite reported renoprotection with angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), and notwithstanding their increased use, we continue to experience an epidemic of acute renal failure (ARF)/chronic kidney disease/end-stage renal disease. Consequently, concerns about iatrogenic renal failure have resurfaced. Different analysis of these trials revealed flaws such as recruitment of relatively younger patients with preserved baseline renal function, common utilization of lower end doses of ACEIs/ARBs, high drug discontinuation rates, excessive use of surrogate endpoints, inadequate reporting of adverse effects, and short duration studies...
2009: Nephron. Clinical Practice
Raymond O Estacio
Cardiovascular (CV) and renal complications associated with diabetes can be attenuated with antihypertensives that work on the renin-angiotensin-aldosterone system (RAAS),particularly angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and possibly direct renin inhibitors (DRIs). Cardioprotective and renoprotective benefits are independent of the blood pressure-lowering effect of the RAAS inhibitor. Given more complete RAAS blockade, evidence has suggested that the use of ACE inhibitor/ARB combination therapy may provide greater target organ protection...
May 2009: Postgraduate Medicine
Christopher T Chan
Cardiovascular mortality remains the leading cause of death in patients with end-stage renal disease. Frequent home hemodialysis in the form of short daily hemodialysis and nocturnal home hemodialysis has been suggested to correct multiple cardiovascular surrogate endpoints in observational and randomized controlled studies. This review discusses recent advances of intensive hemodialysis on important cardiovascular outcomes including blood pressure control and cardiovascular geometry and function. Its impact on calcium-phosphate metabolism and anemia management as they relate to cardiovascular outcomes are highlighted...
May 2009: Advances in Chronic Kidney Disease
Matthew H Liang, Julia F Simard, Karen Costenbader, Benjamin T Dore, Michael Ward, Paul R Fortin, Gabor G Illei, Susan Manzi, Barbara Mittleman, Jill Buyon, Samardeep Gupta, Michal Abrahamowicz
No new drugs have been approved for the treatment of systemic lupus erythematosus (SLE) by the Food and Drug Administration for the last 30 years. One barrier has been the lack of validated biomarkers and surrogate endpoints. Validation of SLE biomarkers in the past have been methodologically flawed. We put forth a conceptual framework and five critical criterion for validating putative biomarkers and bio-surrogates in this heterogeneous multi-system disease with protean manifestations. Using the example of a putative biomarker for end-stage lupus nephritis, we performed computer simulations for planning a biomarker bio-repository to support the validation process...
March 2009: Endocrine, Metabolic & Immune Disorders Drug Targets
Stéphane Laurent, Pierre Boutouyrie
Measurement of arterial stiffness is assuming an increasing role in the clinical assessment of patients. Indeed, arterial stiffness and wave reflections are now well accepted as the most important determinants of increasing systolic and pulse pressure in our aging community, and thus as the cause of cardiovascular (CV) complications and events, including stroke and myocardial infarction. Carotid-femoral pulse wave velocity (PWV), which is a direct measure of arterial stiffness, is the gold standard, since it requires little technical expertise and is supported by the greatest amount of epidemiological evidence...
November 2007: Journal of Nephrology
Kevin V Lemley
Diagnosis and management of chronic kidney disease (CKD) will be characterized in the future by an increasing use of biomarkers-quantitative indicators of biologic or pathologic processes that vary continuously with progression of the process. "Classical" biomarkers of CKD progression include quantitative proteinuria, the percentage of sclerotic glomeruli or fractional interstitial fibrosis. New candidate biomarkers (e.g., urinary proteomic patterns) are being developed based on both mechanistic and "shotgun" approaches...
November 2007: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
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