Blog entry by Meguid El Nahas
After years and even decades of total neglect, the Nephrology community is waking up to the fact that Creatinine Clearance is affected by Tubular Secretion of Creatinine (TSCr)...!!!
A recent article in the September 2013 issue of the Am J Kidney Disease by Sithoven and colleagues in Groningen, Netherlands shows that there is a good agreement in ADPKD between eGFR and measured GFR (mGFR) in individuals with normal renal function highlighting the fact that at normal eGFR range, tubular secretion (TS) Creatinine (TSCr) is relatively small and therefore doesnt confound estimation of kidney function by eGFR (MDRD or CKD EPI). They also argue that such correlation was maintained in a subgroup of patients followed-up for 3 years.
This somehow disagrees with teh observations of Rugennenti and his colleagues in Bergamo who showed poor agreement between eGFR and mGFR in estimating the rate of decline in kidney function in ADPKD and that both MDRD and CKD EPI failed to accurately detect changes in mGFR in those with ADPKD and declining renal function. This, in spite of a comparebale baseline GFR to that of the Groningen group at the onset but a significant rate of decline with time of around 8-10ml/min.
The discrepancy between the two articles highlight the fact well know to Nephrologists for the last century or so that the Tubular secretion of Creatinine is relatively small in normal GFR ranges but increases significantly as GFR declines to reach as mush as 50% of Creatinine Clearance when GFR is <20-30ml/min.
Therefore, eGFR is most likley to be useless in the evaluation of interventions aimed at impacting on the rate of GFR progression as when true GFR declines tubular secretion of creatinine increases confounding the use of serum creatinine as a parameter of progressive CKD. So whilst Spithoven et al are right in their statement that eGFR is accurate in evaluating true measured GFR in ADPKD, the difference between the studies and their resepctive and contradictory assertions may lay in the level of GFR and the rate of decline of kidney function; lower GFR and faster rate of GFR decline leads to increased tubular secretion of creatinine and consequently decreased agreement between measured and calculated GFRs.
This was also reported by Gaspari et al, 2013 in T2DM where formulated GFR underperformed and underestimated the rate of true GFR decline.
This again highlights the fact that TSCr cannot be ignored including in diabetes mellitus where changes in tubular secretion of creatinine have been reported due to the impact of diabetes on proximal tubules transporters of creatinine and changes related to impaired kidney function and metabolic control. Too many confounders for serum creatinine to be an accurate marker of glomerular filtration.
Furthermore, interventions themselves may impact on the tubular handling and secretion of creatinine and consequently making interpretation of the intervention of rate of decline of GFR impossible. Incidentally, this is the case with RAS (renin angiotensin system) inhibition that has been show both experimentally and clinically to improve tubular secretion of creatinine in diabetic nephropathy confounding ANY conclusions on the impact of RAS inhibitors on the decline in eGFR in diabetic nephropathy:
All the studies on the progression of CKD relying on measurements and changes in serum creatinine levels or the changes in formulated/estimated GFR (eGFR) are likely to be inaccurate due to the major confounding effect of Tubular Secretion of Creatinine. Not withstanding the additional confounder of the impact of any given intervention on Tubular Secretion of Creatinine. The BEAM/BEACON studies are tragic reminders of the unreliability of eGFR in interventions with agents that impact on tubular viability and function and consequently impact on serum creatinine/eGFR through mechanisms unrelated to changes in GFR.
Sadly and disappointingly, to date I am not aware of a single intervention study in CKD where GFR was measured serially to asses progression in the entire study population (with the exemption of the MDRD study in 1994 where iothalamate clearance was used throughout the study period).
Reliance on eGFR to test interventions that may slow the progression of CKD is a tragic and often wilful mistake.