Editorial

Does the porcine model give us insight as tohow can we improve renal transplantationfrom large donors to small recipients?

The last 40 yr have shown marked improvementin the outcomes in pediatric renal transplanta-tion, largely because of surgical techniques,donor selection and organ allocation procedures,prevention, identification and treatment of acuterejection episodes, management of post-trans-plant complications, and better knowledge ofimmunosuppressive drug doses and metabolism(1–3). Thus, transplantation now provides betterpatient survival than prolonged dialysis therapy,making renal transplantation the preferred ther-apy for pediatric renal failure (4).As we have attempted to expand the donor

pool for pediatric renal transplantation, we haverealized that the crux of using large donor kidneysfor small recipients is ischemic injury. A longitu-dinal analysis out of Stanford in 2007 (5) eluci-dated the pivotal role of the size of the recipientfor non-immune injury after transplantation ofan adult-sized kidney into a small recipient. Theyfound that adult-sized donor kidneys showedmore interstitial fibrosis, tubular atrophy, andtubular microcalcification in the earliest phaseafter transplantation into a small recipient. Inaddition, the small recipients receiving an adult-sized kidney had an absolute glomerular filtrationrate (GFR) early after transplantation similar tothe normal expected GFR if they had two nativekidneys, but importantly, the adult-sized kidneystransplanted into small recipients lack the in-crease in absolute GFR that would be expectedwith growth of the child, as is seen in olderchildren. The study also importantly noted thatthe initial ‘‘functional’’ adaptation of the adult-sized kidney to the small recipient size (decreasein renal blood flow [6, 7], decrease in kidneyvolume [7], and decrease in absolute GFR [6, 8]) isnot only a reversible autoregulatory response torenal hypoperfusion (9), but associated with

irreversible damage to the tubulointerstitial com-partment of the kidney. Despite the pristinecondition of the transplanted kidneys and theabsence of both cellular and antibody-mediatedrejection episodes in the cohort of patientsreceiving a large kidney to recipient size, therewas an important increase in tubular atrophy andinterstitial fibrosis in the first year after trans-plantation. Because this is a clear problem forattempting to expand the donor pool with adult-sized kidneys, it was commendable of Ravio et al.to explore the area of physiologic renal injuryfrom large donors to small versus size-matchedrecipients in order to better understand thepathophysiology in this cohort of patients.In this issue of Pediatric Transplantation,

Ravio et al. report on renal transplantation fromlarge donors to small and size-matched recipientsusing a porcine model in order to shed light onthe physiologic mechanism of injury in trans-planting a large donor kidney into a smallrecipient. The study focused on the first 10 hfollowing transplantation by studying GFR,renal plasma perfusion (RPP), and markers ofkidney injury. By focusing on these areas, thestudy was able to conclude that improvement inearly graft perfusion may be a goal to improveshort- and long-term GFR and avoid graftthrombosis in pediatric recipients.GFR, measured with constant infusion clear-

ance technique using 51Cr-EDTA as a referencesubstance and timed urine samples, was found tobe decreased (p = 0.0008) in the first 60 minfollowing transplantation in the small recipientsand did not increase as much in the smallrecipients over the 10 h as compared with thesize-matched controls. RPP, as measured byMRI, decreased by nine h in the cortical regionand by three h in the medullary region.

Pediatr Transplantation 2012 � 2012 John Wiley & Sons A/S.

Pediatric TransplantationDOI: 10.1111/j.1399-3046.2012.01724.x

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Urinary levels of neutrophil gelatinase-associ-ated lipocalin (NGAL) may be useful in deter-mining the suitability of a potential deceasedkidney donor (10). This study used NGAL as abiomarker of renal injury and found no signif-icant difference in urinary NGAL between thesmall recipients and size-matched control group.Donor renal tissue levels of HO-1 were studied

using qPCR and Western blotting of renal tissuecollected immediately after removal of the kid-ney. HO-1 was chosen as studies have shown thatselective up-regulation of HO-1 gene attenuatesoxidative stress caused by angiotensin II inprimary cultured cells of the thick ascendingloop of Henle (TALH). The TALH segment ofthe nephron is highly susceptible to ischemicinjury because of its location in the oxygen-poormedulla (11). This suggests that the more theHO-1, the more the more oxidative injury. In theporcine model, HO-1 was found to be signifi-cantly higher in the cortex of small recipients, butthere was no significant difference in the medul-lary tissue, suggesting that there is perhaps ananatomical difference in the distribution ofischemic injury.

Normal physiology of the kidney and its relation to theporcine study

Because the RPP showed decreased medullaryflow, but the HO-1 was increased in the cortex, itis important to understand the normal physiol-ogy of the kidney. More than 90% of the bloodflow is directed to the outer cortex, and relativelylittle goes to the renal medulla. The high meta-bolic requirement of the thick ascending loop ofHenle in a hypoxic environment of the medullamakes it especially vulnerable to injury associ-ated with an imbalance in oxygen supply anddemand.Cortical and medullary nephrons have a

unique relationship with their respective vascularbundles in the kidney. Cortical nephrons havetheir thick ascending limbs far from vascularbundles, and medullary nephrons have theirthick ascending limbs adjacent to vascular bun-dles. Therefore, during hypoxia, it is the corticalnephrons that suffer the most. This may be whythe mRNA levels of HO-1 were found to be thehighest in the cortical region of the kidney.When renal blood flow is compromised, a

decrease in GFR seems to be protective becausedecreased urine delivery to the tubules requiresless reabsorptive work of tubules and preventsfurther imbalance in oxygen supply and demand.This is likely why the group found there was adecrease in the GFR within the first 60 min that

was significant in the small recipients but not inthe size-matched recipients—a protective effectby the kidney. This was then followed by asubsequent gradual increase in GFR over thesubsequent 10 h of observation, likely as thekidneys were allowed to recover in function.

Biomarkers in renal injury

An ideal biomarker for renal injury is one that issensitive and found very early in renal injury,before the creatinine has been affected. Theurinary biomarkers identified in this study wereNGAL, Ala-AP, and NAG. Concentrations inurine and serum of NGAL were found torepresent sensitive, specific, and highly predictiveearly (within two h) biomarkers for acute renalinjury after cardiac surgery (11, 12). Ala-AP wasshown to be an early biomarker of renal injury incisplatin-treated rats (13), and NAG was foundto be a valuable biomarker in another study ofacute kidney injury in humans (14). Recently,urinary NGAL was actually found to be asequential predictive biomarker for acute kidneyinjury, correlated with disease severity and clin-ical outcomes after pediatric CPB (15, 16).Therefore, this biomarker, in particular, may beuseful to allow for earlier intervention in acutekidney injury post-transplant. Perhaps it couldbe used to adjust volume replacement to maxi-mize renal perfusion and predict ischemic injuryto the kidney.

Study limitations

The physiologic conclusions of this study arelimited by the non-human conditions, the lack ofcentral pressure monitoring and arbitraryamounts of volume replacement given, the lackof stroke volume data that affects the smallrecipient kidney, and the lack of immunosup-pression. We also do not have a good under-standing of the effects of the particularanesthetics used in this study on renal perfusionwhen transferred to the human context.The lack of immunosuppression in this study

allows for a study of non-immunologic eventsthat contribute to medullary injury. However,this is not the reality in pediatric transplantationwhere patients are treated perioperatively andpostoperatively with immunosuppressive agentsthat affect renal function and potentially urinarybiomarkers and markers such as HO-1. Thus, notonly are the physiologic conclusions limited inthe context of no immunosuppression, but theuse of these urinary biomarkers may be limited inthe clinical setting if immunosuppressive agentswere to affect their levels.

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Conclusion

This study is certainly a contribution to the fieldfrom the physiologic point of view, sheddinglight on a cascade of short-term events followingtransplantation of a large donor into a smallpediatric recipient versus a size-matched recipi-ent. However, it will be important that futurestudy is performed to determine the effects ofhyperhydration on stroke volume and acute renalinjury, immunosuppressive agents on potentialpredictive urinary biomarkers, and the effect ofimmunosuppressive agents on HO-1 mRNAlevels. It is a challenge to make a clinicalcorrelation with the results of this study owingto the porcine model, different anesthetics, lackof immunosuppression, and short time frame.However, it has a value as a basic sciencemanuscript focusing on the short-term physiol-ogy following the transplanted state, whichunderscores the importance of medullary perfu-sion in the immediate postoperative state. Thiscan help us understand reperfusion injury withthe potential to improve future pediatric trans-plantation outcomes.

Amy Hill and Waldo Concepcion

Department of Surgery, Stanford University, Stanford, CA

USA

E-mail: wconcepcion@stanfordmed.org

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