Measuring and Estimating GFR and Treatment Effect in ADPKD Patients: Results and Implications of a Longitudinal Cohort Study

Abstract

Trials failed to demonstrate protective effects of investigational treatments on glomerular filtration rate (GFR) reduction in Autosomal Dominant Polycystic Kidney Disease (ADPKD). To assess whether above findings were explained by unreliable GFR estimates, in this academic study we compared GFR values centrally measured by iohexol plasma clearance with corresponding values estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas in ADPKD patients retrieved from four clinical trials run by a Clinical Research Center and five Nephrology Units in Italy. Measured baseline GFRs and one-year GFR changes averaged 78.6±26.7 and 8.4±10.3 mL/min/1.73 m2 in 111 and 71 ADPKD patients, respectively. CKD-Epi significantly overestimated and aMDRD underestimated baseline GFRs. Less than half estimates deviated by <10% from measured values. One-year estimated GFR changes did not detect measured changes. Both formulas underestimated GFR changes by 50%. Less than 9% of estimates deviated <10% from measured changes. Extent of deviations even exceeded that of measured one-year GFR changes. In ADPKD, prediction formulas unreliably estimate actual GFR values and fail to detect their changes over time. Direct kidney function measurements by appropriate techniques are needed to adequately evaluate treatment effects in clinics and research.

Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4

“…A core study primarily aimed to assess whether 12-month treatment with sirolimus added on to conventional treatment significantly reduced measured GFR decline (12,13) versus conventional treatment alone and was safe. Evidence that sirolimus may safely slow GFR decline would have provided the background for an extension phase to evaluate treatment effect on kidney and cystic growth and progression to ESRD over an additional 2-year follow-up.…”

“…GFR was measured every 6 months by iohexol plasma clearance (12,13). Computed tomography images were acquired and analyzed at baseline and 12 months as previously reported (15,16) (Supplemental Appendix 2).…”

“…Failure to detect significant associations between sirolimus levels and considered outcomes was most likely explained by the relatively small sample size, the wide data fluctuations (particularly in sirolimus levels), and the confounding effect of changes introduced in sirolimus dosing to target therapeutic range and limit side effects. Direct measurement of GFR by a gold standard technique (12) was a major strength that allowed powerful analyses and avoided the limitations of estimation equations (13). In the context of the prospective, randomized, open label, blind end point design, the assessors of outcome variables were blinded to treatment.…”

Serum Uric Acid Levels and Endothelial Dysfunction in Patients with Autosomal Dominant Polycystic Kidney Disease

“…Additionally, the oxidant-antioxidant balance was likely reliably reflected by ADMA. Because it has been reported that prediction formulas unreliably estimate actual GFR values and fail to detect their changes over time in ADPKD, another possible limitation of this study is the method that used eGFR instead of direct kidney measurements [48]. …”

Should We Still Believe in Randomized Controlled Trials in Nephrology?

“…Thus, in the ALADIN trial, the clinically relevant renoprotective effect of Octreotide-LAR would have been missed if GFR had not been measured, but just estimated with equations. In the same vein, the prediction formulas CKD Epidemiology Collaboration and aMDRD unreliably estimated actual GFR values, and failed to predict GFR changes over time in a cohort of adult patients with ADPKD, independent of their kidney function [29] . Similarly, evidence is available that questions the use of any GFR estimation formula to monitor renal disease progression and response to treatment in type 2 diabetics with normo-or microalbuminuria [30] .…”