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LiveDonorRenalAnatomicAsymmetryandPosttransplantRenalFunction

ARTICLEinTRANSPLANTATION·FEBRUARY2015

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OriginalClinicalScience

Live Donor Renal Anatomic Asymmetryand Posttransplant Renal FunctionBekir Tanriover,1 Sonalis Fernandez,2 Eric S. Campenot,3 Jeffrey H. Newhouse,4 Irina Oyfe,4 Prince Mohan,2

Burhaneddin Sandikci,5 Jai Radhakrishnan,2 Jennifer J. Wexler,6 Maureen A. Carroll,6 Sairah Sharif,2

David J. Cohen,2 Lloyd E. Ratner,7 and Mark A. Hardy7

Background. Relationship between live donor renal anatomic asymmetry and posttransplant recipient function has not beenstudied extensively. Methods.We analyzed 96 live kidney donors, who had anatomical asymmetry (>10% renal length and/orvolume difference calculated from computerized tomography angiograms) and their matching recipients. Split function differences(SFD) were quantified with technetium-dimercaptosuccinic acid renography. Implantation biopsies at time 0 were semiquantita-tively scored. A comprehensive model using donor renal volume adjusted to recipient weight (Vol/Wgt), SFD, and biopsy scorewas used to predict recipient estimated glomerular filtration rate (eGFR) at 1 year. Primary analysis consisted of a logistic regressionmodel of outcome (odds of developing eGFR>60 mL/min/1.73 m2 at 1 year), a linear regression model of outcome (predicting re-cipient eGFR at one-year, using the chronic kidney disease-epidemiology collaboration formula), and a Monte Carlo simula-tion based on the linear regression model (N=10,000 iterations). Results. In the study cohort, the mean Vol/Wgt and eGFR at1 year were 2.04 mL/kg and 60.4 mL/min/1.73 m2, respectively. Volume and split ratios between 2 donor kidneys were stronglycorrelated (r = 0.79, P < 0.001). The biopsy scores among SFD categories (<5%, 5%–10%, >10%) were not different (P = 0.190).On multivariate models, only Vol/Wgt was significantly associated with higher odds of having eGFR > 60 mL/min/1.73 m2 (oddsratio, 8.94, 95% CI 2.47–32.25, P = 0.001) and had a strong discriminatory power in predicting the risk of eGFR less than60 mL/min/1.73 m2 at 1 year [receiver operating curve (ROC curve), 0.78, 95% CI, 0.68–0.89].Conclusions. In the presenceof donor renal anatomic asymmetry, Vol/Wgt appears to be a major determinant of recipient renal function at 1 year aftertransplantation. Renography can be replaced with CT volume calculation in estimating split renal function.

(Transplantation 2015;00: 00–00)

L iving donor kidney transplantation is the treatment ofchoice for advanced renal failure.1 It offers survival ben-

efit and better quality of life when compared to either de-ceased donor renal transplantation (DDRT) or to dialysis.2

Despite significant improvement in 1-year renal allograftsurvival, most likely due to the use of more potent immu-nosuppressive drugs, half-lives for grafts originating fromliving donors have not changed significantly (11.4 years in1989 to 11.9 years in 2005).3 Although many factors

Received 28 May 2014. Revision requested 22 June 2014.

Accepted 10 November 2014.1 Division of Nephrology, UT Southwestern Medical Center, Dallas, TX.2 Division of Nephrology, Columbia University College of Physicians and Surgeons,New York, NY.

3 Department of Pathology, Columbia University College of Physicians and Sur-geons, New York, NY.

4 Department of Radiology, Columbia University College of Physicians and Sur-geons, New York, NY.

5 Booth School of Business, University of Chicago, Chicago, IL.6 Renal Transplantation, New York Presbyterian Hospital, New York, NY.7 Renal and Pancreatic Transplantation, Department of Surgery, Columbia UniversityCollege of Physicians and Surgeons, New York, NY.

Supported, in part, by NIH T32HL007854-19 (MAH).

The authors declare no conflicts of interest.

B.T. participated in research design, writing of the paper, and data analysis. S.F.participated in the performance of research. E.S.C. participated in the performance

Transplantation ■ Month 2015 ■ Volume 00 ■ Number 00

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influence late graft attrition, nonimmunologic causes, partic-ularly donor kidney volume (as a surrogate marker oftransplanted nephron mass), are therefore areas of great in-terest.4-8 This is particularly true because donated renal vol-ume has been previously demonstrated to be an importantfactor in subsequent allograft outcomes.9-13

Volumetric imaging based on 3-dimensional postprocessingdata obtained from magnetic resonance or computerized to-mography (CT) angiograms is a sensitive method for assess-ment of renal volume due to complex renal anatomy and

of research and writing of the paper. J.H.N. participated in the performance ofresearch and writing of the paper. I.O. participated in the performance of research.P.M. participated in the performance of research. B.S. participated in researchdesign, writing of the paper, and data analysis. J.R. participated in research designand writing of the paper. J.J.W. participated in the performance of research. M.A.C.participated in the performance of research. S.S. participated in the performance ofresearch. D.J.C. participated in research design. L.E.R. participated in researchdesign. M.A.H. participated in research design, writing of the paper, and data analysis.

Correspondence: Bekir Tanriover, MD, MPH, Division of Nephrology, UTSouthwestern Medical Center, 5939 Harry Hines Blvd., Dallas, TX 75390-9258.(bekir.tanriover@utsouthwestern.edu)

Supplemental digital content (SDC) is available for this article. Direct URL citationsappear in the printed text, and links to the digital files are provided in the HTML textof this article on the journal’s Web site (www.transplantjournal.com).

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ISSN: 0041-1337/15/0000-00

DOI: 10.1097/TP.0000000000000599

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shape (see Figure S1, SDC, http://links.lww.com/TP/B111).14,15

A volume variation between right and left kidneys has beenfound to be common (mostly left > right, mean difference10–15ml).15 A significant difference in renal size (asymmetryin length >2 cm and/or volume difference >10%) between thekidneys has previously suggested that a split renal functiontest (renography as a functional assessment of anatomicalasymmetry) should be performed.16 In routine clinical prac-tice therefore, additional testing with split renal functionhas not been unusual and has been indicated in up to 34%of donor evaluations as a guide to selection of 1 of 2 kidneysfor donor nephrectomy.17,18 In the case of significant asymme-try, this assessment ensures that the better functioning kidneyremains in the donor and that the donated kidney providesadequate function for the recipient's metabolic needs.

Most transplant centers arbitrarily consider anatomicaland functional asymmetry of less than 10% as clinically in-significant (either one of donor kidneys can be removed)and greater than /20% as a relative contraindication for do-nation due to the concern that chronic histological changes(tubular atrophy, interstitial fibrosis and arteriolosclerosis)may be present in the smaller kidney. However, little isknown about the effect of degree of asymmetry in donor kid-neys on recipient's renal function and histological changesafter transplantation.

To study this issue, we designed a retrospective cohortstudy using living donors at our institution between 2009and 2013 and subsequently performed a theoretical simula-tion analysis based on our preliminary findings. In the co-hort, we analyzed only living donors who had anatomicalasymmetry defined as greater than 10% renal length and/orgreater than 10% difference in volume calculated from CTangiograms. The analysis included the donated renal volumeadjusted to recipient weight (Vol/Wgt), split function differ-ence (SFD), and semiquantitative scores of postimplantationrenal biopsies. Our goal was to evaluate the impact of renalasymmetry on recipient estimated glomerular filtration rate(eGFR) at 1 year. Because our study was limited by a rela-tively small sample size, lack of power, and risk of type 2error, we developed a simulation model to determine howchanges in predictors (mainly donor eGFR, donated renalvolume, SFD, and renal biopsy score) affect recipient eGFRat 1 year after transplantation (1-way sensitivity analysis).

MATERIALS AND METHODS

Study Cohort

An approval from the Institutional Review Board at theColumbia University College of Physicians and Surgeonswas obtained before the research. In our institution,we annu-ally perform approximately 250 renal transplants, of which50% result from living-related donation. This is a retro-spective cohort study using living donors with asymmetricalkidneys and their matching recipients who underwent stan-dard evaluation and follow-up care based on our institu-tional protocol between January 2009 and January 2013.Out of 521 living related donor-recipient pairs, 96 donors(~18%) met the inclusion criteria (living kidney donors withmore than 10% renal length and/or volume mismatch be-tween two kidneys on CT angiogram). All these potentialdonors underwent renal split function test [technetium-dimercaptosuccinic acid (99mTc-DMSA) radionuclide

Copyright © 2015 Wolters Kluwer Health, Inc. Unau

scintigraphy] to assess functional asymmetry; this was notperformed in those donors without asymmetry. The donorselection criteria excluded the donors with significant comor-bidities, such as hypertension, diabetes, body mass indexgreater than 40, or significant social and psychiatric problems.All donors underwent laparoscopic nephrectomy during thestudy period without major complications, and no conversionto open nephrectomy. In the case of significant asymmetry,better functioning kidney is left for the live donor. An implan-tation (time 0) renal biopsy was routinely performed after do-nor kidney reperfusion in all recipients as a part of our center-specific protocol. The baseline donor-recipient characteristics,laboratory results, and radiological data were collected bychart review. The primary outcome measure was recipient'seGFR at 1 year after transplantation, which is thought to bepredictive of long-termoutcome of an allograft.19 Pediatric pa-tients were excluded from the study. In our institution, we useantithymocyte globulin induction therapy (6 mg/kg) with anearly steroid withdrawal (a total Solumedrol dose of1000 mg tapered intravenously over 4 consecutive days anddiscontinued on day 5) followed with maintenance immuno-suppression consisting of tacrolimus (0.05 mg/kg twice daily)andmycophenolic acid (720mg twice daily). Tacrolimus levelsare maintained in the range of 10 to 12 ng/mL for the first3 months, 8 to 10 ng/mL in 3 to 6 months, and 6 to 8 ng/mLthereafter. At 1-year follow-up, 80% of the patients werestill on steroid-free regimen, and more than 90% were main-tained on a tacrolimus-based regimen.

Predonor Nephrectomy Kidney Function Assessment

We assessed GFR for all potential living kidney donors in2 steps: (1) initial screening with the chronic kidney disease-epidemiology collaboration formula (CKD-EPI) equationtargeting 100 mL/min/1.73 m2 or above; (2) 125I-iothalamateplasma clearance (Glofil) if the chronic kidney disease-epidemiology collaboration formula (CKD-EPI) was less than100 mL/min/1.73 m2.20 Subjects who underwent the Glofiltest received 35 millicurries of 125I-iothalamate intravenouslyinto the upper arm. Blood was sampled at 15, 30, 60, 90,120, and 180 minutes to measure GFR based on plasmadisappearance rate of 125I-iothalamate. Our renal functioncutoff for donation is a clearance above 80 mL/min/1.73 m2.

Renal Volume Measurement by CT VolumetricTechnique

Potential donors were evaluated with a 64-row multide-tector CT scanner (LightSpeed VCT XT; GE Health Care,Milwaukee, WI) with 2.5-mm slice thickness and 0.625 col-limation. Triphasic kidney images (unenhanced, arterialphase, and excretory phase) were obtained. All patients re-ceived 100 mL contrast agent with 350 mg/mL (Iohexol,Omnipaque 350; GE Healthcare, Princeton, NJ). A 3-dimensional advanced postprocessing (Vitrea software, VitalImages Inc., Minnetonka, MN) was performed on an inde-pendent workstation by a 3 dimensional technologist usingvolume rendering techniques to better evaluate anatomyand calculate renal volumes based on topographic surfacearea. Left (L) and right (R) kidney volume percentages werecalculated as [L / (L + R)] � 100 or vice versa.

Radionuclide Scintigraphy

All subjects with renal asymmetry underwent a radio-nuclide scintigraphy (99mTc-DMSA) to assess functional

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© 2015 Wolters Kluwer Tanriover et al 3

asymmetry and to guide laterality for donor nephrectomyprocedure. The patients were hydrated during the procedureby drinking 1000 mL of fluids. They lay supine on a SPECT/CT.ecoline single head E camera (Siemens, Germany) with aparallel hole collimator interfaced with a digital computerunderneath. After intravenous administration of 5 millicuriesof 99mTc-DMSA, anterior and posterior planar imaging wasperformed over both kidneys. Subtraction technique betweenpreinjection and postinjection was used to calculate net activ-ity. The relative renal uptake was calculated from the follow-ing formula: relative right renal uptake (%) = absolute rightrenal uptake � 100 / (the absolute right + left renal uptake)or vice versa.

TABLE 1.

Characteristics of the study cohort and outcomes based on split

N=96

N (%)Donor factorsAge, yRace (AA), %Sex (female), %BMI, kg/m2

BSA, m2

Serum creatinine, mg/dLeGFR (CKD-EPI), mL/min/1.73 m2

Urine albumin/creatinine, μg/mgKidney length difference (|L-R|), %Kidney volume difference (|L-R|), %Kidney split function difference (|L-R|), %

Recipient factorsAge, yRace (AA), %Sex (female), %BMI, kg/m2

BSA m2

Peak PRA, %Retransplant, %Cause of ESRD (diabetes), %

Transplant factorsHLA mismatchUnadjusted donated renal volume, mLDonated kidney volume/recipient weight, mL/kgPost-perfusion biopsy GS score (0-3)Post-perfusion biopsy IFTA score (0-3)Post-perfusion biopsy AS score (0-3)Post-perfusion biopsy total score (0-9)

Transplant outcomesDelayed allograft function, %Rejection, %Tacrolimus level at 1 year, ng/mLBK viremia, %Allograft survival at 1 year, %Patient survival at 1 year, %Recipient serum creatinine at 12 months (CKD-EPI), mL/min/1.73 m2

Recipient eGFR at 12 months (CKD-EPI), mL/min/1.73 m2

Recipient eGFR <60 ml/min/1.73 m2 at 12 mo, %

AA, african american; BSA, body surface area; ESRD, end stage renal disease; CKD-EPI, chronic kidney d

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Implantation Biopsies

Light microscopy sections from implantation biopsies ofrenal transplants were selectively reviewed by a renal pa-thologist (E.S.C.). A pathological scoring system was usedsimilar to those described by the Banff 97 working classifica-tion group and Rule et al.21,22 The percentage of globallysclerotic glomeruli, the percentage of tubular atrophy andof interstitial fibrosis (if any), and the degree of arteriosclero-sis and/or arteriolosclerosis (if any) were recorded andscored as follows: % of globally sclerotic glomeruli: 0 (0),1 (1%–10%), 2 (11%–25%), 3 (26%–50%); % of tubularatrophy and interstitial fibrosis: 0 (0), 1 (1%–10%), 2(11%–25%), 3 (26%–50%); degree of arteriosclerosis and

function difference

Split function difference (%)

<5% 5%–10% >10% P

47 (49%) 32 (33%) 17(18%)

41.6 ± 11.5 46.9 ± 13.5 45.3 ± 8.7 0.11312.8 12.5 11.8 0.99453.2 56.3 70.6 0.457

25.4 ± 4.7 26.7 ± 4.6 25.3 ± 3.6 0.3681.84 ± 0.23 1.88 ± 0.28 1.80 ± 0.19 0.6510.83 ± 0.16 0.83 ± 0.17 0.82 ± 0.16 0.982101 ± 16 96 ± 17 99 ± 18 0.3666.6 ± 9.3 5.6 ± 3.8 6.6 ± 5.7 0.9525.1 ± 3.0 5.9 ± 4.2 5.8 ± 2.9 0.7246.0 ± 2.8 6.1 ± 2.9 10.6 ± 6.5 0.0172.6 ± 1.6 7.0 ± 1.2 15.8 ± 5.1 0.001

42.2 ± 13.6 49.4 ± 15.0 48.9 ± 14.2 0.04910.6 21.9 6.3 0.23036.2 31.3 31.3 0.879

26.7 ± 5.5 27.5 ± 5.1 28.7 ± 5.5 0.4151.9 ± 0.3 2.0 ± 0.2 2.0 ± 0.2 0.47023 ± 26 26 ± 31 18 ± 24 0.6502.2 12.9 6.3 0.16323.4 34.4 25.0 0.547

3.6 ± 2.0 3.6 ± 1.9 3.9 ± 1.8 0.918149.0 ± 32.8 156.9 ± 38.2 147.2 ± 28.4 0.5162.2 ± 0.7 2.0 ± 0.6 1.7 ± 0.4 0.0330.6 ± 0.7 1.1 ± 0.7 0.9 ± 0.9 0.0480.5 ± 0.5 0.5 ± 0.5 0.7 ± 0.5 0.3240.8 ± 0.5 0.6 ± 0.5 1.0 ± 0.6 0.0901.9 ± 1.2 2.1 ± 1.1 2.6 ± 1.3 0.190

2.2 0.0 6.3 0.37517.0 12.9 20.0 0.806

7.3 ± 2.5 6.9 ± 2.2 6.7 ± 1.9 0.43715.9 14.3 26.7 0.56097.9 96.9 100 0.85097.9 100 100 0.932

1.37 ± 0.39 1.46 ± 0.40 1.54 ± 0.40 0.24263.8 ± 19.2 57.9 ± 20.1 54.6 ± 18.8 0.182

52.3 64.3 71.4 0.360

isease-epidemiology collaboration.

horized reproduction of this article is prohibited.

FIGURE 1. Scatter plot demonstrating relationship between split re-nal function and renal volume ratios, (L/R).

FIGURE 2. (A) Area under ROC curve for Vol/Wgt to predict risk ofrecipient eGFR less than 60 mL/min/1.73 m2 at 1 year based onthe study cohort. (B) Area under ROC for SFD to predict risk of re-cipient eGFR less than 60 mL/min/1.73 m2 at 1 year based on thestudy cohort.

4 Transplantation ■ Month 2015 ■ Volume 00 ■ Number 00 www.transplantjournal.com

arteriolosclerosis: 0 (0), 1 (mild, intimal fibrosis or hyalinosisinvolving up to 25% of luminal area), 2 (moderate, intimalfibrosis or hyalinosis involving 26%–50% of luminal area),3 (severe, intimal fibrosis or hyalinosis involving greater than50% of luminal area). Total biopsy score was calculated asthe sum of these 3 categories.

Statistical Analysis

Donor and recipient characteristics were described usingmean and standard deviation or frequencies as needed. Com-parisons between groups were made using t test, Kruskal-Wallis, or χ2 test, as appropriate. Pearson and Rankcorrelation coefficients were used to examine correlationamong predictors of recipient's GFR at 12 months. Univari-ate and multivariable linear and logistic regression modelswere fitted to estimate recipient's GFR and to predict riskof developing eGFR less than 60 mL/min/1.73 m2 at12 months. P value less than 0.05 is considered statisticallysignificant, respectively. Statistical analyses were performedwith Stata 13/MP4 (Stata Corp., College Station, TX).

Monte Carlo Simulation

Simulation refers to a method whereby the distribution ofpossible outcome (dependent variable) is generated by a com-puter using different randomly selected sets of values fromthe probability distributions of predictors (independent vari-ables) through a formula (a linear regression model in ourstudy). In other words, the computer is trying all valid com-binations of the values of predictors to simulate possibleoutcome. It encompasses 3 steps: (1) developing a model, de-fining relationshipwith dependent and independent variables(the linear regression model); (2) identifying uncertainty,specifying plausible values of independent variables withprobability distributions; and (3) analyzing the model withsimulation to determine the range and probabilities of allpossible outcomes. A sensitivity analysis is carried out with3 different analytical techniques: change in outcome statistic,regression analysis and rank correlation calculation. The re-sults of a sensitivity analysis can be displayed as a “tornado”type chart, with longer bars at the top representing the mostsignificant predictors of outcome.

A probabilistic model was developed to simulate the out-come (recipient's eGFR at 1 year) of a hypothetical groupof potential living donor (with asymmetrical kidneys >10%

Copyright © 2015 Wolters Kluwer Health, Inc. Unau

renal size difference between 2 kidneys)-recipient pairs(n =10,000 iterations) based on the study cohort. MonteCarlo simulation was used to determine how variations inpredictors affect the outcome of a transplanted kidney. Thepredictors were chosen from clinically and/or statistically sig-nificant variables found in the univariate andmultivariate re-gression analysis. The main predictors were Vol/Wgt, donoreGFR, renal biopsy score, and split renal function difference.Primary outcome consisted of recipient's eGFR at 1 year aftertransplantation. We initially defined the distribution of eachpredictor variable and the correlations among predictorsfrom the study cohort. The final model was fitted based onthe coefficients from the multivariable linear regression andadjusted for the correlations among predictors in the model.We used @Risk 6.2 software (Palisade Corporation, Ithaca,NY) for simulation task.

RESULTS

Characteristics of the Study Cohort

Table 1 lists characteristics of both the 96 donors withrenal size asymmetry greater than 10% and those of thematching recipients, and their transplant outcomes basedon SFD categories (<5%, 5%–10%, >15%). In our cen-ter, approximately 20% of the donors (96 of 521) who

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© 2015 Wolters Kluwer Tanriover et al 5

underwent donor nephrectomy between 2009 and 2013 hadgreater than 10% anatomical asymmetry. More than halfof the donors in all categories were women. The mean per-cent of Vol/Wgt and SFD (|L-R|) were significantly differentamong the 3 SFD categories. Compared to their correspond-ing donors, recipients were older, heavier, and more likely tobe male. There was a downward trend in Vol/Wgt withhigher SFD categories. The higher SFD categories were alsoassociated with slightly higher total biopsy scores, but thatdid not reach statistical significance. Recipients in the lowestSFD category had the highest eGFR at 1 year and lowest oddsof having eGFR less than 60 mL/min/1.73 m2. Approxi-mately 60% of 96 patients had eGFR less than 60 mL/min/1.73m2 at 1 year in our study cohort. There was a strong cor-relation(r=0.79, P value < 0.001) between volume and splitratios (L/R) of 2 donor kidneys shown in Figure 1. Discrimi-natory power of Vol/Wgt (ROC curve, 0.78; 95% CI, 0.68–0.89; a positive predictive value of 74% at the optimalcutpoint of 1.99 mL/kg) to predict risk of eGFR less than60 mL/min/1.73 m2 at 1 year was higher compared withSFD (ROC curve, 0.61; 95% CI, 0.49–0.73), as shown inFigure 2A and B. The Vol/Wgt (r=0.59, P < 0.001), the donoreGFR (r=0.35, P < 0.001), and the biopsy score (−0.27, P =0.018) were significantly correlated with recipient eGFR at1 year; the SFD (r=−0.19, P = 0.079) did not correlate withthe above findings (data not shown).

Multivariable Regression Models in the Study Cohort

In a multivariable linear and logistic regression, only Vol/Wgt was significantly associated with higher recipient eGFR(1 mL/kg increase in adjusted renal volume, resulting in16.815 mL/min/1.73 m2 rise in eGFR, P < 0.001) and higherodds of having recipient eGFR greater than 60 mL/min/1.73 m2 at 1 year (odds ratio, 8.94; 95% CI, 2.47–32.25;P = 0.001) (Table 2). On the other hand, the 3 categories ofSFD and renal biopsy scores did not predict the outcomesin either model.

TABLE 2.

Multivariable regression models for predicting recipient's eGFR1.73 m2 (logistic) at 1 y in the study cohort (the models only incluthe ones causing multicollinearity)

Linear model Coefficient

Donor eGFR, mL/min/1.73 m2 0.1734Weight adjusted donor renal volume, mL/kg 16.815Delta split function, % −0.203Biopsy score −2.945Constant 16.759

Logistic Model Odds Ratio

Donor eGFR, mL/min/1.73 m2 1.001Weight adjusted donor renal volume, mL/kg 8.938Delta split function0%–5% 15%–10% 0.775>10% 1.247Biopsy score 0.603Constant 0.019VIF for the modela 1.15

a VIF<10 shows no significant multicollinearity.VIF, variance inflation factor.

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Simulation Analysis

The probabilistic model was designed to simulate the out-come (recipient eGFR at 1 year) in a hypothetical group ofpotential living donor (with asymmetric kidneys)-recipientpairs (N=10,000 iterations). Distributions and correlationsamong the predictors (Vol/Wgt, SDF, biopsy score ,and do-nor eGFR) for the model are summarized in Tables S1 andS2 (SDC, http://links.lww.com/TP/B111). The model basedon coefficients used in the multivariable linear model isshown in Table 2. The mean recipient eGFR at 1 year was60.6 ± 11.9 mL/min/1.73 m2 for the simulation cohort (seeFigure S2, SDC, http://links.lww.com/TP/B111). The effectof each predictor ranked by its impact on the outcome(1-way sensitivity analysis, Tornado chart) is illustratedin Figure S3 (SDC, http://links.lww.com/TP/B111). TheVol/Wgt had the largest impact on the outcome (range,44.9–82.8 mL/min/1.73 m2); whereas variation in SFD be-tween 0% and 30% causedmodest change in recipient eGFR(range, 52.4-67.5 mL/min/1.73 m2). An incremental dose-effect response was observed between the Vol/Wgt and theeventual outcome (Figure 3A). There was mild inverse rela-tionship between higher levels of SFD and the outcome(Figure 3B). The Vol/Wgt of 2.03 mL/kg and SFD of 6.3%were associated with recipient eGFR of 60.5±12.0 mL/min/1.73 m2 at 1 year (Figure 3A and B). When the simula-tion model was restricted to the recipients of kidneys withVol/Wgt greater than 2 mL/kg (generally considered as ade-quate renal volume), the recipients in the SFD categoriesgreater than 5% were less likely to achieve eGFR greaterthan 60 mL/min/1.73 m2 at 1 year (see Table S3, SDC,http://links.lww.com/TP/B111).

DISCUSSION

Relationship between living donor renal anatomic asym-metry and post transplant recipient function has not beenstudied extensively. This study shows that transplanted renal

(linear) and odds of having eGFR greater than 60 mL/min/de the significant variables from univariate analysis and avoid

Standard Error P 95% CI

0.113 0.130 −0.05 to 0.3993.208 <0.001 10.41–23.210.340 0.552 −0.88 to 0.471.564 0.064 −6.06 to 0.1712.064 0.169 −7.29 to 40.81

Standard Error P 95% CI

0.176 0.916 0.96–1.035.853 0.001 2.47–32.25

0.489 0.687 0.22–2.670.972 0.777 0.27–5.750.161 0.060 0.35–1.020.038 0.050 0.00–0.99

horized reproduction of this article is prohibited.

FIGURE 3. (A) Scatter plot for weight adjusted renal volume (mL/kg) versus recipient's eGFR at 1 year based on the Monte Carlo simulation.(B) Scatter plot for split renal function difference versus recipient’s eGFR at one-year based on the Monte Carlo simulation.

6 Transplantation ■ Month 2015 ■ Volume 00 ■ Number 00 www.transplantjournal.com

volume (as a surrogate marker for nephron mass), in the set-ting of anatomical and functional asymmetry between thetwo donor kidneys, has the highest impact on allograft func-tion compared with other predictors.11,12,23,24 The simula-tion data suggest that transplantation of Vol/Wgt greaterthan 2 to 2.5 mL/kg generally achieves target recipient eGFRat 1 year less than 60 mL/min/1.73 m2 which is the expectedrenal function of 1 healthy kidney. Our study also demon-strates that when SFD is greater than 10%, the smaller do-nated kidneys with lesser function is significantly associatedwith neither lower recipient eGFR at 1 year nor with in-creased chronic histological changes (tubular atrophy, inter-stitial fibrosis, or arteriolosclerosis) in the implantationrenal biopsies. However, these findings must be interpretedwith caution because 80% of the donors in our study cohorthad functional asymmetry of less than 10%.

It is important to focus this discussion on important prac-tical issues and uncertainties in living donor evaluation andmedical decision-making. We summarize our views below.

Nonuniform Total and Split Renal Function Evaluation

The Amsterdam Forum laid down internationally acceptedguidelines in the evaluation of potential kidney donors.25,26

However, these guidelines lack specific recommendations

Copyright © 2015 Wolters Kluwer Health, Inc. Unau

regarding methods for GFR estimation and split functionassessment. Thus, current practices of pretransplant livingdonor evaluations vary considerably among countries andeven among transplant centers.27 Halleck et al28 conducteda survey among all Eurotransplant centers (7 countries and61 centers) in 2012. They found that majority of the centersuse creatinine clearance (64%) in estimating GFR and radio-isotopic techniques (82%) in assessing SFD. All Germantransplant centers (39)measured split functionwith radioiso-topic methods, whereas all Dutch centers (7) used CT-basedvolumetric methods. It appears that CT-based volumemeasure-ment is becoming the more promising single session methodfor assessment of donor renal anatomy and function.16,29-31

DoWeNeed Split Function Test to Decide on Lateralityor can CT Volumetric Measurements ReplaceRenography for that Purpose?

Significant correlation (r, ~0.6-0.9) has been reported be-tween CT- and renography-based measures of split func-tion.16,29-31 Halleck et al28 reported a strong correlation(r = 0.93, P < 0.001) between MAG3-based radioisotopicsplit function estimates andCT-based split renal volumemea-surements in their center specific cohort of 144 consecutiveliving donors. They also reported that moderate correlation

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TABLE

3.

List

ofthe

artic

lesfocu

sedontherelatio

nbetwee

ndona

tedrena

lsizean

dallograftoutco

me

Referenceandsamplesize

Studycohortanddesign

Follow-up,

mo

Imagingtechnique

Donatedrenalsizeto

achieve

target

GFRof

≥60mL/min

GFRmeasurement

method

Allograft

survival

benefit

Donatedkidney

volume,mL

Sikoraetal13n=125

Livingdonors,prospective

12CT,volum

etric

2.13

mL/kg

CKD-EPI

Notdefined

Poggioetal12n=119

Livingdonors,prospective

24CT,prolateellipsoidformula

69.4mL/m2

MDR

DNotdefined

Tanrioveretal(currentstudy)n=96

(forM

Csim

ulationn=

10,000)

Livingdonorsandretrospective;

andMCsim

ulation

12CT,volum

etric

2.04

ml/kgforstudy

cohort;2.02

ml/kg

forthe

MonteCarlo

simulationcohort

CKD-EPI

Notdefined

Hugenetal35n=114

Livingdonors,retrospective

12CT,volum

etric

72mL/m2(foraverage

patient'seGFR

of>55

mL/min/1.73m2 )

Serumcreatinine

(target<1.5ml/dL)

Notdefined

Donatedkidney

weight,g

Ohetal21n=195

Livingdonors,prospective

1N/A

2gm

/kg(form

eanCrCl≥55

mL/min)

24hurinecollection

Notdefined

Seun

Kimetal34n=259

Livingdonors,retrospective

36N/A

3g/kg

(form

eanCrCl≥55)m

l/min)

24hurinecollection

Nobenefit

Giraletal11

n=914

Deceased

donor,prospective

48N/A

2-4g/kg

CrCl

Nobenefit

CrCl,Creatinineclearance;M

C,MonteCarlo

simulation;MDR

D,Modificationofdietinrenaldisease;N/A,notapplicable.

© 2015 Wolters Kluwer Tanriover et al 7

existed between percentage of both split function estimates(MAG3-based split function: r = 0.45, P < 0.001; CT-measured split cortex volume: r = 0.43, P < 0.001) and theposttransplant eGFR (calculated by using Cockcroft-Gaultequation) in the recipient. In our study, we showed thatvolume and split function ratios between 2 donor kidneys(r = 0.79, P < 0.001) were strongly correlated. The Vol/Wgtpredicted eGFR at 1 year (r = 0.59, P < 0.001) reasonablywell. These findings support the possibility of eliminatingthe use of split renal function testing in potential living do-nors with renal asymmetry since renal donor volume esti-mated by CT-based calculation appears to be an adequatesurrogate. Single CT evaluation substituting radioisotopicassessment of split renal function potentially minimizes costand radiation exposure and is also more convenient forthe donors.

Relationship Between Donated Renal Volume andPosttransplant Recipient eGFR

Several studies have previously demonstrated the impactof donated kidney volume on recipient's short-term out-comes, specifically on GFR. Sikora et al12 described a livingdonor-recipient transplant cohort (N=125 recipients) wherethe mean donated renal volume of 2.13 ± 0.62 mL/kg (mea-sured by volumetric technique) led in the recipients to a meaneGFR of 63.6 mL/min/1.73 m2 at one year after transplanta-tion. In the same cohort, a donor volume greater than2.5 mL/kg was associated with the lowest risk of havingeGFR less than 60 mL/min/1.73 m2. Another study usingCT-based prolate ellipsoid formula concluded that atransplanted kidney volume greater than 69.4 mL/m2 pre-dicts a higher eGFR (>60 mL/min/1.73 m2) at 2-year aftertransplantation.11 Overall, a minimumweight adjusted renalvolume less than 2 to 2.5 mL/kg seems to achieve ideal allo-graft function in all transplant recipients, as Brenner correctlypointed out 2 decades ago.13 A list of recent references on thesubject of the relation of donated renal size and recipient's re-nal function is provided in Table 3.

Role of Implantation Biopsy in Living KidneyTransplantation

Chronic histological changes, mostly mild, are commonlydetected in renal allografts biopsies obtained intraopera-tively at the time of implantation.21,32-34 Cosio et al35 havedemonstrated graft interstitial fibrosis (7%), tubular atrophy(25%), and arterial hyalinosis (10%) in biopsies taken fromliving donor kidneys. They reported that interstitial fibrosiscorrelated well with both function and eventual graft sur-vival. In our study, we observed higher histological scores(2–2.5/9) inkidneysobtainedonly fromolder donors (>40years),but not in those which had higher SFDs (>10%), (data notshown). Overall, these findings would support the elimina-tion of routine practice of potentially morbid implantationbiopsies in living renal transplantation (LRT) because the bi-opsy findings are mostly benign and variations in biopsyscore causes small changes in recipient eGFR at 1 year(52.3–68.9 mL/min/1.73 m2).

ToProceedWith LRT in Case of ExtremeSFD or toWaitfor DDRT?

Based on the results from the simulation model, we con-clude that when adequate Vol/Wgt (>2 mL/kg) is trans-planted, higher SFD categories were associated with only a

Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

8 Transplantation ■ Month 2015 ■ Volume 00 ■ Number 00 www.transplantjournal.com

small incremental risk of developing eGFR less than 60 mL/min/1.73 m2 at 1 year (an increase from 0%-5% to 25%–30% in SFD categories led to a decrease in eGFR from63.9±11.6 mL/min/1.73 m2 to 48.4±9.3 mL/min/1.73 m2).In a situation where there is only 1 living donor availablewho has extreme SFD/lower eGFR and when preemptivetransplantation is a feasible option, the question that needsto be answered is whether to proceed with LRT or wait fora DDRT. In our opinion, the risk of receiving a preemptiveLRT with lower eGFR outweighs the benefit of waiting forDDRT with higher eGFR. The reason for this is that pre-emptive kidney transplantation offers lower mortality (therelative risk, 0.69; 95% CI, 0.56–0.85) and lower allograftfailure risk (relative risk, 0.73; 95% CI, 0.64–0.83) ascompared with patients who receive a transplant whileon dialysis.36-38

Strength and Limitation of This Study

We have comprehensively evaluated in this study the con-cept of using asymmetrical living donor kidneys and relatedone year outcomes in the recipients by assessing volumetricrenal size measurement, radionuclide renography, and im-plantation biopsy results as major evaluation criteria. Weempowered our findings with a Monte Carlo simulationmodel using a large hypothetical cohort of patients to over-come our study's limitation of small sample size, lack ofpower and risk of causing type 2 errors. We were also ableto account for correlations among predictors in the simula-tion model ((Risk RiskCorrmat function) (see Table S2,SDC, http://links.lww.com/TP/B111). Along with thesestrengths, our study has several limitations. First, the accu-racy of split function measurement with radionuclide renog-raphy is subject to variations due to operator dependence,patient habitus, kidney position, and depth.16 Second, thefollow-up period was limited to 12 months despite the factthat GFR at 1 year predicts long-term allograft survival.19

Third, only a small number of living donors had higher func-tional asymmetry (SFD>10%; selection bias). Finally, we rec-ognize that assessing renal function with a creatinine-basedformula has its limitations due to variability in creatinine gen-eration and its tubular excretion rate.20

CONCLUSIONS

Our study supports that the Vol/Wgt estimate seems to bethe major determinant of recipient's renal function at 1 yearin the presence of renal asymmetry in donor's kidney andmay successfully replace split function testing. A large multi-center study is required to include donors in the higher SFDcategories and such a study would more accurately assessthe effects of true functional asymmetry in living donorsand subsequent recipient renal function.

ACKNOWLEDGMENTSThe authors thank Dr. Robert D. Toto for his critical reviewof the manuscript.

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