American Journal of Kidney Diseases

Longitudinal Estimated GFR Trajectories in Patients With and Without Type 2 Diabetes and Nephropathy

Published:November 16, 2017DOI:


      In clinical practice and clinical trials, changes in serum creatinine concentrations are used to evaluate changes in kidney function. It has been assumed that these changes follow a linear pattern when serum creatinine concentration is converted to estimated glomerular filtration rate (eGFR). However, the paradigm that kidney function declines linearly over time has been questioned by studies showing either linear or nonlinear patterns. To verify how this impacts on kidney end points in intervention trials, we analyzed eGFR trajectories in multiple clinical trials of patients with and without diabetes.

      Study Design

      Longitudinal observational study.

      Setting & Participants

      6 clinical trials with repeated measurements of serum creatinine.


      Patient demographic and clinical parameters.


      Probability of nonlinear eGFR function trajectory calculated for each patient from a Bayesian model of individual eGFR trajectories.


      The median probability of a nonlinear eGFR decline in all trials was 0.26 (interquartile range, 0.13-0.48). The median probability was 0.28 in diabetes versus 0.09 in nondiabetes trials (P < 0.01). The percentage of patients with a >50% probability of nonlinear eGFR decline was generally low, ranging from 19.3% to 31.7% in the diabetes trials and from 15.1% to 21.2% in the nondiabetes trials. In the pooled data set, multivariable linear regression showed that higher baseline eGFR, male sex, diabetes status, steeper eGFR slope, and non–renin-angiotensin-aldosterone-system antihypertensives were independently associated with a greater probability of a nonlinear eGFR trajectory.


      Relatively short follow-up and no measured GFR.


      In both diabetes and nondiabetes trials, the majority of patients show a more or less linear eGFR decline. These data support the paradigm that in diabetic and nondiabetic kidney disease, eGFR decline progresses linearly over time during a clinical trial period. However, in diabetes, one should take the nonlinearity proportion into account in the design of a clinical trial.

      Index Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Kidney Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Brenner B.M.
        • Cooper M.E.
        • de Zeeuw D.
        • et al.
        The losartan renal protection study–rationale, study design and baseline characteristics of RENAAL (reduction of endpoints in NIDDM with the angiotensin II antagonist losartan).
        J Renin Angiotensin Aldosterone Syst. 2000; 1: 328-335
        • Rodby R.A.
        • Rohde R.D.
        • Clarke W.R.
        • et al.
        The Irbesartan Type II Diabetic Nephropathy Trial: study design and baseline patient characteristics. For the Collaborative Study Group.
        Nephrol Dial Transplant. 2000; 15: 487-497
        • Wright Jr., J.T.
        • Bakris G.
        • Greene T.
        • et al.
        Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.
        JAMA. 2002; 288: 2421-2431
        • Klahr S.
        • Levey A.S.
        • Beck G.J.
        • et al.
        The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group.
        N Engl J Med. 1994; 330: 877-884
        • Barnett A.H.
        • Bain S.C.
        • Bouter P.
        • et al.
        Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy.
        N Engl J Med. 2004; 351: 1952-1961
        • The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia)
        Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy.
        Lancet. 1997; 349: 1857-1863
        • Ruggenenti P.
        • Perna A.
        • Gherardi G.
        • et al.
        Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria.
        Lancet. 1999; 354: 359-364
        • Stevens L.A.
        • Greene T.
        • Levey A.S.
        Surrogate end points for clinical trials of kidney disease progression.
        Clin J Am Soc Nephrol. 2006; 1: 874-884
        • Jones R.H.
        • Hayakawa H.
        • Mackay J.D.
        • Parsons V.
        • Watkins P.J.
        Progression of diabetic nephropathy.
        Lancet. 1979; 1: 1105-1106
        • Li L.
        • Astor B.C.
        • Lewis J.
        • et al.
        Longitudinal progression trajectory of GFR among patients with CKD.
        Am J Kidney Dis. 2012; 59: 504-512
        • Ambrogi V.
        • Thilly N.
        • Boini S.
        • et al.
        Patterns and predictors of kidney function decline in the last year prior to dialysis.
        Nephron Clin Pract. 2009; 111: c95-c101
        • BENEDICT Group
        The BErgamo NEphrologic DIabetes complications trial (BENEDICT): design and baseline characteristics.
        Control Clin Trials. 2003; 24: 442-461
        • Hou F.F.
        • Xie D.
        • Zhang X.
        • et al.
        Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency.
        J Am Soc Nephrol. 2007; 18: 1889-1898
        • Hou F.F.
        • Zhang X.
        • Zhang G.H.
        • et al.
        Efficacy and safety of benazepril for advanced chronic renal insufficiency.
        N Engl J Med. 2006; 354: 131-140
        • Levey A.S.
        • Stevens L.A.
        • Schmid C.H.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Intern Med. 2009; 150: 604-612
        • Mitch W.E.
        • Walser M.
        • Buffington G.A.
        • Lemann Jr., J.
        A simple method of estimating progression of chronic renal failure.
        Lancet. 1976; 2: 1326-1328
        • Mogensen C.E.
        Progression of nephropathy in long-term diabetics with proteinuria and effect of initial anti-hypertensive treatment.
        Scand J Clin Lab Invest. 1976; 36: 383-388
        • Parving H.H.
        • Smidt U.M.
        • Friisberg B.
        • Bonnevie-Nielsen V.
        • Andersen A.R.
        A prospective study of glomerular filtration rate and arterial blood pressure in insulin-dependent diabetics with diabetic nephropathy.
        Diabetologia. 1981; 20: 457-461
        • Viberti G.C.
        • Bilous R.W.
        • Mackintosh D.
        • Keen H.
        Monitoring glomerular function in diabetic nephropathy. A prospective study.
        Am J Med. 1983; 74: 256-264
        • Skupien J.
        • Warram J.H.
        • Smiles A.M.
        • et al.
        The early decline in renal function in patients with type 1 diabetes and proteinuria predicts the risk of end-stage renal disease.
        Kidney Int. 2012; 82: 589-597
        • Boucquemont J.
        • Loubere L.
        • Metzger M.
        • et al.
        Identifying subgroups of renal function trajectories.
        Nephrol Dial Transplant. 2017; 32: ii185-ii193
        • Zhong Y.
        • Munoz A.
        • Schwartz G.J.
        • Warady B.A.
        • Furth S.L.
        • Abraham A.G.
        Nonlinear trajectory of GFR in children before RRT.
        J Am Soc Nephrol. 2014; 25: 913-917
        • Haynes R.
        • Lewis D.
        • Emberson J.
        • et al.
        Effects of lowering LDL cholesterol on progression of kidney disease.
        J Am Soc Nephrol. 2014; 25: 1825-1833
        • James M.T.
        • Grams M.E.
        • Woodward M.
        • et al.
        A meta-analysis of the association of estimated GFR, albuminuria, diabetes mellitus, and hypertension with acute kidney injury.
        Am J Kidney Dis. 2015; 66: 602-612
        • O'Hare A.M.
        • Batten A.
        • Burrows N.R.
        • et al.
        Trajectories of kidney function decline in the 2 years before initiation of long-term dialysis.
        Am J Kidney Dis. 2012; 59: 513-522
        • Levey A.S.
        • Inker L.A.
        • Matsushita K.
        • et al.
        GFR decline as an end point for clinical trials in CKD: A scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration.
        Am J Kidney Dis. 2014; 64: 821-835