Studies of the impact of living donor kidney function on graft outcomes

Enthusiasm for living kidney donation has grown considerably over the past two decades as an ever-expanding waiting list demand has outstripped organ supply, while the number of living kidney donations in the USA has more than doubled during that time to nearly 6000 in 2011 [1], this growth is largely attributable to an increase in older donors (those aged 54 and above), who tend, on average, to have lower kidney function. Therefore, the implications of lower predonation kidney function on graft outcomes are increasingly relevant, and require careful scrutiny. Concern over the use of kidneys from donors with low glomerular filtration rate (GFR) was triggered by a seminal study from Norden et al. [2], which showed that the hazard ratio (HR) for graft loss was more than double when predonation GFR, as measured by Crom EDTA, was <80 mL/min/1.73 m. Despite the small number of patients studied (26 recipients with donor GFR <80 mL/min/1.73 m,), this study became, in part, the basis for requiring a predonation GFR of >80 mL/min/ 1.73 m. This threshold was subsequently adopted by most transplant centers and many guidelines [3–5]. However, a retrospective study examining 2057 living kidney transplantations by Young et al. [6], reported in this issue, has yielded different results. These investigators found that the HR’s for graft loss and patient death after 6 years of follow-up were no different between individuals who received donor kidneys with an eGFR above or below 80 mL/min/1.73 m. Furthermore, they were unable to detect an association between increasing eGFR and improved outcomes when they stratified donor eGFR in 10 mL/min/1.73 m increments (from < 80 to >110 mL/min/ 1.73 m). These findings raise questions about current consensus-based predonation GFR recommendations. Studies of the association between predonation measured GFR (mGFR) and graft outcomes have yielded inconsistent results, likely due to variation in study design, GFR measurement, follow-up duration and outcome ascertainment. Norden et al. [2] observed worse long-term (>5 years) graft survival when predonation mGFR was lower, while Lezaic et al. [7] failed to demonstrate such a difference (Table 1). The studies varied somewhat in their treatment of predonation mGFR: the former used a cutoff of 80 mL/min/1.73 m [2], while the latter used 50 mL/min/1.73 m, albeit in a single kidney [7]. Four other studies examined the effect of GFR on subsequent allograft function [using eGFR or creatinine clearance (CrCl)]. Three showed an association between low predonation kidney function and worse later graft function [8–10], while one did not [11]. Thus, the balance of the historical evidence has suggested that predonation kidney function influences allograft function and, ultimately, graft loss. The GFR in living kidney donors is most accurately measured by clearance of exogenous markers such as inulin or iothalamate. However, due to the cost and complexity of measuring GFR, many centers forego the direct approach and simply estimate living donor GFR. Common approaches include calculating GFR by the Modification in Diet of Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology (CKD-EPI) equations, calculating CrCl by the Cockroft–Gault (CG) equation and measuring CrCl in a 24-h urine collection. Efforts to validate these approaches in living donors have been attempted. In a study of 253 living donors, Tent et al. [12] compared the performance of the MDRD, CKD-EPI and CG equations against mGFR; the three equations underestimated predonation mGFR by 15, 4 and 11 mL/min/1.73 m, respectively. Notably, the discrepancy between eGFR and mGFR grew as mGFR increased. Similar findings were reported by Rule et al. [13], who demonstrated significant underestimation of mGFR by eGFR derived from the MDRD equations in a cohort of 365 living donors. Correlation between the measured and calculated GFR was poor (relative risk [RR] = 0.26). Conversely, Issa et al. [14] showed that a 24-hurine collection for creatinine clearance overestimated mGFR IN F O C U S