Editorial

How should we identify early chronic kidneydisease risk in non-kidney transplantrecipients?

It has been well established that there is anincreased risk of chronic kidney disease (CKD)in adult heart and liver transplantation recipients(1); however, among children, this risk has beenless clearly defined. In adults, CKD is associatedwith increased risk of non-kidney allograft fail-ure and death. Risk factors for CKD includeischemic kidney injury with evolving end-stagenon-kidney organ failure pre-transplant, acutekidney injury in the peri- and post-transplantrecovery phase, and ongoing nephrotoxicityassociated with higher-dose calcineurin-inhibitormedications.In children, the risk of kidney damage is

expected to be similar; however, mounting evi-dence suggests that the CKD risk has beenunderestimated. This concern is highlighted byLin et al. in this issue of the Journal (2), whohave identified >50% prevalence of CKD in theirpediatric cardiac transplant population, whenthey employ quantitative assessment of glomeru-lar filtration rate (GFR) using a novel iohexol-based method. This is supported by other studiesreporting quantitative GFR measurement bynuclear medicine scintigraphy. Bharat et al.reported that freedom from CKD drops to 33%within five yr after pediatric heart transplanta-tion (3). A similar analysis of the SPLIT registryidentified 17.6% of pediatric liver transplantrecipients with CKD at a mean of 5.2 yr post-transplant (4). Risk factors for CKD in thesestudies included intensity of calcineurin-inhibitordrug exposure, older age at transplantation, andthe presence of renal insufficiency at transplanta-tion, which are similar to risk factors in adults.Importantly, in both studies, estimated GFR(eGFR) was found to significantly underestimatethe prevalence of CKD in these populations.The age of pediatric recipients at the time of

transplantation is important in considering the

risk of CKD over time. In the cohorts reportedby Bharat et al. and Cambell et al., recipientswere very young at transplantation (3.3 and2.2 yr, respectively), and in both cases, the riskof CKD was most prevalent in older recipients.This may be due in part to lead time bias, asinfants and small children have excess functionalreserve and may only begin to manifest restrictedGFR capacity as they approach adult body mass.In kidney transplant recipients, small childrenreceiving a single kidney achieve above-normalrange GFR in early years post-transplant, whichwanes more rapidly than their older counterpartsand resembles GFR capacity of older recipientsafter 5–10 yr post-transplant (5). If this is thecase for liver and heart transplants, then evenmodest reductions of GFR in smaller childrenrequire careful scrutiny as they may signal risk ofmore substantially reduced functional capacityover time. It also suggests the need for increasedvigilance as these young transplant recipients sur-vive into adolescence, when CKD may manifestas increasing metabolic requirements related tobody size outstrip functional reserve.The importance of measuring kidney function

post-solid organ transplant is well documented,and clinical practice guidelines advocate for rou-tine GFR monitoring with decreasing frequencypost-transplant (6). The optimal clinical standardto assess kidney function is with a measuredGFR by nuclear medicine scintigraphy (99TcDTPA or 51Cr EDTA), adjusted to body surfacearea. The drawback of this type of testing is therequirement for intravenous access and multipleblood draws over many hours and the associatedradiation exposure. It is also costly, depends onthe ready availability of medical isotopes, and isnot available in all centers. The most recentK-DIGO guidelines advocate for the use ofeGFR for regular monitoring of kidney function

661

Pediatr Transplantation 2014: 18: 661–662 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Pediatric TransplantationDOI: 10.1111/petr.12356

in children post-transplant (6), favoring their rel-ative simplicity and cost efficiency over poten-tially more accurate direct measurement.In this issue, Dr. Lin et al. describe an innova-

tive, modified iohexol clearance protocol, whichtakes advantage of the iohexol administered dur-ing cardiac catheterization procedures in pediatriccardiac transplant recipients to concomitantlyobtain measured iohexol GFR (iGFR). Iohexol, anon-ionic low osmolar contrast agent, is emergingas a safer, equally valid alternative to nuclearscintigraphy that can be measured by spectros-copy in serum samples (7). Although blood drawsare still required at three time points over five hpost-iohexol injection, the protocol proposed byLin et al. significantly decreases the inconveniencefor patients as they only need to extend their dayprocedure in hospital by a few hours and affordsthe opportunity for longitudinal monitoring ifcoordinated with regularly scheduled surveillancecatheterization tests. The advantage is certainlydue to increased accuracy of measurement whencompared to estimating equations.These quantitative methods stand in contrast

to the more broadly used GFR estimating equa-tions, which may lack sufficient accuracy. Theirappeal is that they can be applied in the clinic toresults from a simple blood draw. The additionalchallenge, however, with pediatric eGFR is theneed to account for significant differences inbody size between children. The most commonlyused estimating equation for children is the bed-side Schwartz formula 0.413*(height/serum cre-atinine) (7). The validity of such equations isevaluated by the proportion of GFR estimatesthat are within �10% of the measured GFR.When there is more than �30% variation com-pared to the measured GFR, their clinical utilityis more doubtful. For the bedside Schwartz equa-tion, only 37% of estimated results fall within10% of measured GFR, and 21% of estimatedresults are more than 30% different. The mostvalid eGFR equation combines creatinine andcystatin C, yet achieves only a modest improve-ment in eGFR accuracy with 46% of estimateswithin 10% of the measured value (7). It alsorequires the additional measurement of cystatinC (with creatinine), which is not available atmany centers. These limitations are supported byLin et al., who reported that 52% of the “best”GFR estimates fell within 10% of the measurediGFR in their study, meaning that nearly half ofthe GFR estimates fall outside of the morerobust range for accuracy.Processes for early identification of CKD

should ideally be integrated into our routine

post-transplant monitoring protocols. Strate-gies to delay CKD progression in non-trans-plant populations with kidney disease includecontrol of hypertension, anemia, acidosis, andangiotensin-converting enzyme inhibition andshould be similarly applicable to non-kidneytransplant recipients. Early identification andtreatment of CKD-related comorbidities areexpected therefore to improve cardiovascularand bone health outcomes, and quality of life.Measures to delay CKD progression mayimprove non-kidney allograft survival as well.If we do not identify children with milder-stage CKD, these opportunities to interveneearly, reduce comorbidity, and improve out-come will be missed.GFR estimation remains an imperfect clinical

tool. While estimating equations will likely retainutility as screening and monitoring tools, theymay not be relied upon to fully replace measure-ment of GFR to identify those at risk of CKD.Periodic GFR testing is likely necessary for mon-itoring as well, until more accurate non-invasivepredictive testing is available. Ideally, such test-ing will be integrated with routine clinical care,and incorporating GFR testing with surveillancecardiac catheterization is a progressive step inthat direction.

Tom D. Blydt-Hansen and Allison B. Dart

Department of Pediatrics and Child Health (Nephrology),

University of Manitoba, Winnipeg, Manitoba, Canada

E-mail: tblydthansen@HSC.MB.CA

References1. OJO AO, HELD PJ, PORT FK, et al. Chronic renal failure after

transplantation of a nonrenal organ. N Engl J Med 2003: 349:

931–940.2. LIN KY, FURTH SL, SCHWARTZ GJ, SHADDY RE, RUEBNER RL.

Renal function assessment in child and adolescent heart trans-

plant recipients during routine cardiac catheterization. Pediatr

Transplant 2014: 18: 757–763.3. BHARAT W, MANLHIOT C, MCCRINDLE BW, POLLOCK-BARZIV S,

DIPCHAND AI. The profile of renal function over time in a cohort

of pediatric heart transplant recipients. PediatrTransplant 2009:

13: 111–118.4. CAMPBELL K, NG V, MARTIN S, et al. Glomerular filtration rate

following pediatric liver transplantation–the SPLIT experience.

Am J Transplant 2010: 10: 2673–2682.5. NAPRTCS. 2010 Annual Transplant Report. Available at:

https://web.emmes.com/study/ped/annlrept/2010_Report.pdf.

2010 (accessed August 5, 2014).

6. Kidney Disease: Improving Global Outcomes Transplant Work

(KDIGO) Transplant Work Group. KDIGO clinical practice

guideline for the care of kidney transplant recipients. Am J

Transplant 2009; 9(Suppl 3): S1–S155.7. SCHWARTZ GJ, MUNOZ A, SCHNEIDER MF, et al. New equations

to estimate GFR in children with CKD. J Am Soc Nephrol

2009: 20: 629–637.

662

Editorial