Chronic Kidney Disease after Nonrenal Solid-Organ Transplantation
Roy D. Bloom and
Peter P. Reese
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Correspondence: Dr. Roy D. Bloom, Department of Medicine, Renal-Electrolyte and Hypertension Division, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104. Phone: 215-662-2638; Fax: 215-615-0349; E-mail: rdbloom{at}mail.med.upenn.edu
Chronic kidney disease (CKD) is a common complication afternonrenal solid-organ transplantation. The risk for CKD is influencedby many factors, some of which have a direct impact on how suchpatients are treated in the pre-, peri-, and posttransplantationsettings. This review describes hazards for acute and chronickidney injury, with particular emphasis on calcineurin inhibitor–mediatednephrotoxicity. Rather than a detailed description of managementissues that are common to the general CKD population, highlightedare aspects that are more specific to nonrenal solid-organ transplantrecipients with a focus on liver, heart, and lung recipients.Strategies to minimize nephrotoxic insults and retard progressiverenal injury are discussed, as are issues that are pertinentto dialysis and transplantation. Finally, future approachesto prevent and treat CKD without compromising function of thetransplanted organ are addressed.
Chronic kidney disease (CKD) develops frequently after nonrenalsolid-organ transplantation and is associated with substantiallyincreased morbidity and mortality.1 Multiple factors contributeto CKD risk in this patient group, including level of pretransplantationrenal function, recipient demographics and comorbidity, acutekidney injury (AKI) during the perioperative period, and longerterm calcineurin inhibitor (CNI) exposure. Many facets of renalpathophysiology and treatment in nonrenal organ recipients parallelthose seen among the general CKD population.
Improved outcomes among solid-organ transplant recipients havecontributed to the growth in the absolute number of patientswith CKD in this group. Although advances in immunosuppressionand perioperative management, as well as attention to cardiovascularrisk factors and infectious complications, largely account forthe decreased mortality rates among organ recipients, most areleft with CKD.2 During the first 6 posttransplantation months,renal function typically deteriorates most quickly, with a slowerdecline thereafter.3,4
PREVALENCE OF CKD AFTER NONRENAL ORGAN TRANSPLANTATION
Historically, CKD prevalence rates in nonrenal organ recipientshave ranged from 10 to 90%.1,5–8 This wide range is partlyexplained by a lack of consensus criteria as to what constitutesCKD in these populations and by shortcomings of estimating equationsthat depend on serum creatinine.9 Transplant candidates andrecipients often have lower muscle mass and less creatininegeneration than the populations in which these equations weredeveloped, limiting the accuracy of the equations.10,11 Thisproblem is exemplified in a large cohort study in which I125iothalamate GFR measurements were performed in 1447 liver transplantcandidates before and sequentially after transplantation. Comparisonof this "gold standard" measurement was made to GFR estimatesthat were based on serum creatinine, using the Modificationof Diet in Renal Disease (MDRD) Study, Cockcroft-Gault, andNankivell formulas. The mean pretransplantation, serum creatininewas 1.15 mg/dl, and the mean iothalamate GFR was 90.7 ml/min.Of all formulas, the six-variable MDRD fared best, althoughit lacked precision and underestimated renal function in patientsbeyond the first posttransplantation year.9 Recent studies suggestthat the formulas are similarly limited in estimating kidneyfunction in lung and heart recipients as well.12,13
The largest and most comprehensive study of CKD prevalence aftersolid-organ transplantation used a definition of GFR of <30ml/min per 1.73 m2 body surface area, calculated with the four-variableMDRD equation. Applying this definition to a data set from theScientific Registry of Transplant Recipients (SRTR), Ojo etal.1 reported a CKD prevalence at 5 yr after transplantationof 21.3% among intestine recipients, 18.1% among liver recipients,15.8% among lung recipients, 10.9% among heart recipients, and6.9% among heart-lung recipients. More expansive definitionsof CKD, such as GFR <60 ml/min or presence of albuminuria,would have led to higher prevalence estimates.
More recently, using the Kidney Disease Outcomes Quality Initiative(KDOQI) classification system, O'Riordan et al.8 examined therisk for CKD by stage among 230 liver recipients who were followedfor a mean of approximately 6 yr. Overall point prevalencesof CKD among survivors at 10 yr was 2.26% with stage 5, 6.11%with stage 4, 56.77% with stage 3, 23.71% with stage 2, andthe rest with minimal or no renal function deficit. In datafrom the SRTR, among nonrenal organ recipients who survivedthe first 3 posttransplantation months, 4% required maintenancedialysis within a median of 3 yr after transplantation.1 Inthe future, in concert with improving survival, it is probablethat ESRD rates will proportionately increase in this population.
Renal Function before Transplantation
The level of kidney function before organ transplantation isan important risk factor for posttransplantation CKD. Relianceon serum creatinine alone typically leads to an overestimationof renal function in patients before transplantation, particularlyin those with poor nutritional status, low muscle mass, weightloss, and edema.5,14 Kidney function in patients who are awaitingnonrenal transplantation is frequently compromised by poor effectivecirculating volume (e.g., low cardiac output in advanced heartfailure, hepatorenal syndrome in liver candidates) that is notalways reversible after successful placement of a functioningorgan (Figure 1).2,15 For instance, in a retrospective cohortstudy of heart recipients, more than one third of patients hadstage 3 or worse CKD before transplantation. Preoperative renaldisease was a strong risk factor for perioperative AKI requiringdialysis.16
Figure 1. Relationship between acute kidney injury (AKI) and chronic kidney disease (CKD) in the nontransplantation population (A) and after nonrenal solid-organ transplantation (B). Many factors contribute to CKD risk in nonrenal organ recipients, including unrecognized preexisting CKD with superimposed AKI, pretransplantation insults leading to AKI, and exposures peri- and postoperatively. Whereas near complete recovery from AKI is the rule for patients without end-stage organ failure (A), the multitude of risk factors in nonrenal organ recipients leads to CKD in the majority of patients after transplantation (B). CNIs, calcineurin inhibitors; CO, cardiac output; DM, diabetes; HCV, hepatitis C virus; HRS, hepatorenal syndrome; HTN, hypertension; txp, transplant.
The utility of pretransplantation kidney biopsy for assessingcause and severity of kidney injury is not established. In manycases, impaired kidney function is hemodynamically mediated,and biopsy may have limited diagnostic value. Even when thecause is unclear, consideration of renal biopsy is often temperedby a heightened procedural risk as a result of coagulopathy,hemodynamic instability, or respiratory compromise.17
Demographic and Comorbid Factors
Baseline recipient demographics and comorbidities also relateto CKD risk after organ transplantation. Several studies haveshown that both advancing age and female gender confer greaterrisk for development of CKD, likely as a result of overestimationof pretransplantation renal function in the context of lowermuscle mass.1,18,19 Diabetes and hypertension, common comorbiditiesamong liver and heart transplant candidates, increase risk forrenal disease. Preexisting kidney disease may be masked in thesecases if serum creatinine is used as the renal function marker.1,5,15,19
Hepatitis C virus (HCV) infection has also been recognized asan important risk factor for CKD in liver and heart transplantpatients. HCV-related cirrhosis is the major indication forliver transplantation, with 41% of liver recipients in 2004infected with this virus.1,20 The CKD risk in liver recipientswith HCV infection is primarily due to glomerulonephritis (GN).McGuire et al.21 recently described 30 HCV-infected patientswho had cirrhosis and underwent kidney biopsy at the time ofliver transplantation. The median serum creatinine level was1.4 mg/dl; 13 patients had normal serum creatinine and urinalysis.Renal biopsies demonstrated immune complex GN in >80% ofpatients, most commonly membranoproliferative GN, followed byIgA nephropathy and mesangial GN. The clinical significanceof such histologic abnormalities in liver and other nonrenalorgan recipients with normal renal laboratory parameters, however,is unknown. The importance of recognizing pretransplantationrenal function deficits is underscored by the observation thatCKD before transplantation portends poor posttransplant survival.10,15,22,23
Perioperative Renal Insults
AKI during the peritransplantation period creates additionalrisk for posttransplantation CKD (Figure 1). Mechanisms duringand after surgery that may precipitate AKI include hypotensionand hypoperfusion, administration of nephrotoxic agents suchas radiocontrast, sepsis, and aggressive diuresis. With heartand/or lung transplantation, AKI may also be triggered by aorticcross-clamp, ventricular dysfunction with poor cardiac output,or atheroembolism.2 Acute dialytic requirement bodes particularlypoorly for both patient and kidney outcomes.24,25
Dysfunction of the transplanted organ may also be associatedwith renal decompensation. Rocha et al.22 published a retrospectivestudy of lung recipients, 56% of whom had AKI defined as a doublingof serum creatinine within 2 wk postoperatively, and 7.7% requireddialysis. Requirement for mechanical ventilation for >1 dwas associated with a greater than six-fold higher risk forAKI. Impaired kidney function in the setting of effective volumecontraction has been observed early after both liver and hearttransplantation.5,17,26
Polyomavirus BK Infection
Although polyomavirus nephropathy (PVN) is an increasingly importantcause of renal injury in kidney recipients, the virus's rolein contributing to CKD in nonrenal organ transplant patientsis poorly defined.27 Prevalence rates of BK viruria rangingfrom 7 to 32% have been reported in nonrenal recipients, butviremia is observed less frequently.28–30 Cases of biopsy-provenPVN have been described in heart transplant patients.31,32 Largerscale observational studies incorporating serial BK viremiascreening are required to determine whether PVN is an unrecognizedand clinically important risk factor for CKD among nonrenalorgan recipients.
CNIs cause renal vasoconstriction that predisposes patientsto AKI and chronic kidney injury, particularly when other insultsare present. CNI nephrotoxicity has been studied most extensivelywith cyclosporin A (CsA), although the general mechanisms likelyapply to tacrolimus as well. In organ recipients during theCsA era, the steepest decline in kidney function was shown tooccur within the first 6 mo after transplantation. CNI-associatedchronic nephrotoxicity increases with duration of exposure andhas limited potential for reversibility.
Acute Effects on the Kidney
Acutely, CNIs induce reversible vasoconstriction of afferentand efferent glomerular arterioles that is maximal several hoursafter peak serum concentrations and declines as serum concentrationgradually reach the trough.33 The net effects of these acutechanges are reversible, concentration-related reductions inGFR and increases in renovascular resistance. Vasoconstrictionseems to be mediated by nitric oxide inhibition, by increasedangiotensin II and thromboxane levels, and by augmented endothelinactivity.34–36 These abnormal responses may be potentiatedin the presence of other inhibitors of autoregulation, suchas renin-angiotensin-aldosterone-system (RAAS)-blocking agentsor nonsteroidal anti-inflammatory drugs.
Chronic Nephrotoxicity
Chronic CNI nephropathy has been extensively studied but remainsincompletely understood. The typical clinical picture of chronicCNI nephropathy is characterized by a lack of symptoms, a blandurine sediment, and gradual decline in renal function. Albuminuriais common, although nephrotic-range proteinuria is a rare findingthat should precipitate suspicion for other causes of renaldisease.35 Renal biopsy studies among nonrenal organ recipientswith CKD have shown that CNI-related injury is a common finding.7,14,37Histopathologic findings include interstitial fibrosis witha "striped" appearance, nodular arteriolar hyalinosis, and,later, tubular atrophy with glomerulosclerosis and arteriosclerosis.14,38Renal hemodynamic studies in CsA-treated patients have revealeddecreased GFR in association with reduced blood flow, elevatedmean arterial pressure, increasing renal vascular resistance,and albumin excretion.7 Over time, these perturbations resultin progressive arteriolopathy and glomerular ischemic collapse.Hyperfiltration injury occurs in remaining nephrons, sometimesleading to ESRD.7
Direct and indirect mechanisms of chronic CNI-mediated renalinjury have been proposed. Direct mechanisms include that CNIsmay increase oxidative stress, leading to systemic inflammationwith deleterious effects on endothelial function.39,40 CsA inparticular may upregulate genes that are involved in renal fibrogenesisor enhance their activity. Implicated fibrogenic cytokines includeTGF-, matrix metalloproteinase-9, and PDGF.41–43 Otherinvestigators have focused on the pathogenic role of dysregulationof the RAAS. For example, CsA has been shown to increase transcriptionof angiotensin II receptors.44 In liver recipients, the angiotensin-convertingenzyme (ACE) gene D/D phenotype has been associated with increasedrisk for CNI nephropathy.45 In rats with tacrolimus nephrotoxicity,quinapril administration decreased interstitial fibrosis, althoughcreatinine clearance was similar between quinapril-treated andcontrol animals.46
Occasionally, CNIs can cause thrombotic microangiopathy witha spectrum of clinical findings, including impaired kidney function.Some authors have proposed that unrecognized, chronic thromboticmicroangiopathy might be partially responsible for CNI nephropathy.14,47Potential indirect mechanisms of CNI-mediated renal injury include(1) sodium retention and hypertension, more often observed withCsA48; (2) diabetes, a more common tacrolimus-related effect49–51;and (3) dyslipidemia, typically CsA associated and implicatedas a risk factor for worsening kidney disease in the generalCKD population.52
Tacrolimus versus CsA
A growing body of evidence suggests that tacrolimus is lessnephrotoxic than CsA, although a substantial challenge in comparingthese agents is identifying clinically relevant comparable dosagesand blood concentrations.5 An additional important considerationwhen comparing immunosuppressive regimens is the spectrum ofadverse effects and long-term efficacy, such that therapiesshould be tailored to individual recipient needs.
From a purely renal function standpoint, there are now single-and multicenter studies as well as registry analyses demonstratingthe benefit of tacrolimus over CsA in both conversion and denovo settings in heart and liver recipients.1,26,53–57Tacrolimus seems to cause less renal vasoconstriction than CsA,which may explain the short-term decline in creatinine frequentlyobserved after conversion from CsA.58,59In vitro evidence demonstratingmore renal vasoconstriction with CsA was provided by Epsteinet al.,60 who exposed bovine arteries to CsA or tacrolimus.CsA treatment caused sustained vascular smooth muscle contractions,whereas tacrolimus did not.
Improved kidney outcomes among nonrenal organ recipients usingregimens containing tacrolimus may be partly attributable toless nephrotoxicity than that seen with CsA but may also reflectbetter organ transplant function or both. For instance, an intriguingstudy by Peura et al.61 evaluated left ventricular hypertrophyamong 12 stable cardiac recipients who were converted from CsAto tacrolimus. The indications for switching were refractoryCsA-related adverse effects such as hypertension, hyperlipidemia,or gingival hyperplasia. Six months after conversion, patientshad a mean 24% reduction in left ventricular mass. Long-termfollow-up of ongoing trials, coupled with investigations amongrecipients of other nonrenal organs, may help to establish whetherthe apparent lower nephrotoxicity of tacrolimus compared withCsA is due to distinct direct renal effects or differences infunction of the transplanted organ.
CONSEQUENCES OF CKD AFTER SOLID-ORGAN TRANSPLANTATION
The devastating consequences of CKD among solid-organ recipientsresemble the health problems that are endemic in the nontransplantationpopulation with kidney disease. These health concerns includeincreased rates of cardiovascular disease, hypertension, anemia,and bone disease.
Nonrenal solid-organ transplant recipients have a shorter lifespancompared with the general population, but their average survivalis further compromised when CKD develops. Data from the 2005Organ Procurement and Transplantation Network (OPTN)/SRTR AnnualReport indicated that the baseline 5-yr survival ranged from90.6% for pancreas-alone transplant recipients to 40.2% forheart-lung transplant patients. Ojo et al.1 reported that therelative risk for death after development of CKD in nonrenalorgan recipients was 4.55. This elevated mortality risk waspresent even before dependence on renal replacement therapy,although it was highest for recipients who were on dialysis.
Hypertension is a commonly observed posttransplantation complication,occurring in >70% of lung, heart, and liver recipients.62–64CNIs are important contributors to posttransplantation hypertension,often characterized by a low renin and aldosterone state.64Ishani et al.5 demonstrated that diastolic BP elevation is anindependent predictor of progressive kidney disease after lungor heart-lung transplantation. This observation is consistentwith those in nontransplantation patients.
Anemia may also complicate the treatment of solid-organ recipientswith CKD. Besides erythropoietin deficiency, additional factorsthat contribute to anemia include immunotherapies such as azathioprine,mycophenolate acid, and sirolimus, as well as patient comorbidities.65–68Anemia has a negative impact on quality of life and may be ofparticular concern in patients with cardiovascular or pulmonarydisease.
The prevalence of CKD-related bone disease in solid-organ transplantpatients has not been well studied. In addition to derangementsof their mineral metabolism, these patients may develop bonedisease related to corticosteroids.
ORGAN-SPECIFIC CONSIDERATIONS REGARDING KIDNEY DISEASE AFTER TRANSPLANTATION
Liver Transplantation
Before liver transplantation, abnormal renal function is frequent.Manifestations range from limited elevations in serum creatinineto frank hepatorenal syndrome that requires dialysis. Earlypostoperative kidney injury also occurs commonly, often in thesetting of effective volume contraction related to persistenthepatorenal syndrome (especially if there is ongoing liver dysfunction)or hypovolemia. Liver recipients with AKI frequently experienceincomplete recovery of renal function and remain with CKD (Table 1).
Table 1. Organ-specific considerations in CKD after nonrenal solid-organ transplantationa
As noted previously, HCV infection is a risk factor for renaldisease after liver transplantation, usually as a result ofGN.21 In addition, HCV increases the risk for hyperglycemiaafter transplantation.69,70 Liver recipients with preexistingas well as newly acquired diabetes are at higher risk for developingCKD.71
Despite the fact that liver transplant patients generally requireless immunosuppression than recipients of other solid organs,CNI-related CKD occurs commonly. At the same time, a strategyof CNI minimization should be safely achievable in this patientgroup.
Heart and Lung Transplantation
Heart, lung, and heart-lung transplant recipients experiencehigh rates of AKI during the perioperative period, which predisposesto CKD. Heart and lung transplantation are high-risk surgicalprocedures that involve aortic cross-clamping, bypass, largevolume shifts, and aggressive diuresis. Dysfunction of bothleft and right ventricles and difficulty in achieving adequateoxygenation may persist for prolonged periods after surgery.These management issues increase the risk for AKI through renalhypoperfusion and/or tubular injury. The situation is compoundedby the greater risk for rejection in heart and lung recipients,which usually dictates the need for augmented CNI dosing anda higher likelihood of renal damage. In one single-center studyof 756 heart transplant recipients, the incidence of postoperativeAKI that required dialysis was 6%; these patients had 50% mortality,versus 1.4% for patients who did not require dialysis. Riskfactors for dialysis requirement included bypass time, serumalbumin, and diabetes.16 In another single-center study, 12%of heart and lung transplant recipients required dialysis beforedischarge.72
The accelerated cardiovascular disease and sodium retentionthat accompany CKD also pose particular challenges for thesepatients. Optimization of ventricular and/or lung function oftenrequires maintaining patients in a relatively volume-depletedstate, which may lead to chronic ischemic injury to the kidney.In heart recipients, effective volume contraction may occurin the setting of either an underfilled ventricle or ventriculardysfunction. Careful patient assessment has essential therapeuticimplications as far as whether intravenous fluids or diureticsare required; close collaboration with the heart transplantteam is imperative.
DIAGNOSTIC AND TREATMENT APPROACH TO CKD AFTER NONRENAL SOLID-ORGAN TRANSPLANTATION
Measurement of GFR
Acknowledging the previously discussed limitations of estimatingequations on the basis of serum creatinine, we recommend usingthe MDRD formula for assessing GFR in patients after solid-organtransplantation. Although this equation may underestimate therecipient's kidney function, leading to false-positive diagnosesof CKD, we believe that such a conservative approach is warrantedgiven the high morbidity associated with renal disease aftertransplantation. If anything, this approach should result inearlier identification by the trans-plant team of patients withCKD and timely referral to nephrology. Although iothalamateclearance may improve accuracy of GFR measurement, the technologyis not widely available.
Principles of KDOQI
Our approach to treating organ recipients with CKD is guidedby the same principles used in general CKD populations as outlinedby KDOQI (Table 2).73 For the most part, the principles of CKDmanagement described in KDOQI have not been tested and validatedin nonrenal organ recipients. Nonetheless, we believe that themechanisms and consequences of kidney injury are similar tothose in general CKD populations. Therefore, we advocate treatmentof BP according to the Joint National Committee VII guidelines;management of anemia, bone disease, and dyslipidemia accordingto KDOQI; and glycemic regulation using American Diabetes Associationcriteria.74
Table 2. Recommendations to protect residual renal function in nonrenal solid-organ transplant recipients with CKDa
RAAS Blockade
Studies of CKD and proteinuria in nontransplantation patientsdemonstrate that ACE inhibitors and angiotensin receptor blockersexert renoprotective effects independent of BP control.75,76There is a paucity of literature on the renal benefits of RAASblockade in nonrenal solid-organ recipients, although one studydemonstrated that these agents can be safely used in heart transplantpatients for controlling hypertension.77 In retrospective studiesof kidney recipients, RAAS blockade slowed progression of chronicallograft nephropathy and reduced circulating levels of TGF-.78,79Because TGF- mediates CNI-related fibrosis, RAAS blockade mayretard renal injury by disrupting this mechanism. In supportof this notion, kidney biopsies from heart and lung transplantpatients with CsA nephropathy demonstrated less TGF- expressionamong patients who received ACE inhibitors than in those whodid not.42 Recent experimental data also suggest a direct roleof RAAS activation in promoting CKD and kidney fibrogenesisin nonrenal solid-organ recipients.45,46 Besides the renoprotectiveadvantages of RAAS blockade, two other potential benefits inselect nonrenal organ transplant settings are (1) inductionof uricosuria and reduction of uricemia in heart recipientswho are treated with losartan80 and (2) decreased hepatic fibrosisin liver recipients with recurrent HCV infection.81
CNI-Sparing Therapy with Mycophenolate Mofetil or Sirolimus
The presence of CKD in nonrenal organ recipients creates anopportunity for the nephrologist to initiate discussion aboutlowering CNI exposure to the minimum level for effective immunosuppression.We strongly recommend that this decision be made together withthe patient's transplant team, because the potential benefitof protecting kidney function must be weighed against risk tothe transplanted organ. Lowering cumulative CNI exposure hasbeneficial effects on renal function and may lead to improvementsin BP, glucose regulation, volume status, and dyslipidemia.55
CNI-sparing therapy can take the form of either minimizationor withdrawal. Sparing therapy is usually attempted while addingor increasing mycophenolate mofetil (MMF) or sirolimus. Studiesin heart, lung, and liver recipients have shown that serum creatinineand BP can improve when CNI exposure is reduced in concert withMMF addition.82–84 Similarly, in liver recipients in whomimmunosuppression requirements are less stringent, emergingdata suggest that elimination of CNIs and replacement by MMFmay also achieve these goals.85 In contrast, there is growingrecognition that sirolimus is not devoid of nephrotoxicity,as originally hoped. Sirolimus potentiates nephrotoxicity ofCNIs, especially CsA.55,86–88 In the absence of convincingevidence of benefit, we advocate caution if the addition ofsirolimus to a minimized CNI regimen is done for the purposeof attenuating renal injury. In addition, besides an associationwith thrombotic microangiopathy, reports have recently describedincreasing proteinuria in sirolimus-treated kidney and islettransplant patients.89,90 As opposed to a CNI-minimization approach,several retrospective studies in nonrenal organ recipients haveinvestigated conversion to sirolimus as part of a CNI-withdrawalstrategy to protect renal function. Results have generally beenconflicting with both CsA91–94 and tacrolimus.95 Ongoing,prospective clinical trials should establish whether conversionto sirolimus preserves kidney function and whether level ofkidney function at the time of conversion determines the utilityof this strategy.
Dialysis and Sequential Kidney Transplantation
In keeping with KDOQI guidelines, timely preparation for renalreplacement therapy is essential for nonrenal organ transplantpatients with declining kidney function. In light of an SRTRanalysis demonstrating superior long-term outcomes comparedwith dialysis among previous nonrenal organ recipients, sequentialkidney transplantation should be considered the ESRD treatmentof choice for appropriate candidates.1 Early referral to thetransplant center, prompt placement on the waiting listing,and consideration of live donors will likely further enhanceoutcomes for such patients. Given the high mortality observedin patients who are awaiting kidney transplantation, the useof lesser quality deceased donor organs, such as extended-criteriaor cardiac death donors, may be a reasonable consideration toshorten waiting times, although no published data exist on thissubject.
Dialysis has a high mortality rate and exerts substantial burdenson patient quality of life. Most organ recipients who need renalreplacement therapy undergo hemodialysis (HD), although smallseries of transplant recipients undergoing peritoneal dialysis(PD) have been reported. Jayasena et al.96 performed a studyof 17 heart and heart-lung transplant recipients who underwentPD. An increased frequency of peritonitis was observed in thesepatients compared with a control group who were immunosuppressedbecause of either autoimmune disease or recent transplant failure.Another small observational study of cardiac recipients whowere treated with HD or PD reported an increased mortality ratewith PD, although patients with increased volume sensitivitymay have been directed to PD, biasing the results. We believethat HD or PD may be reasonable options to consider for organtransplant patients on a case-by-case basis. Better studiesare needed before firm conclusions may be drawn about the relativebenefits or hazards of PD in these populations.
Simultaneous Solid-Organ Kidney Transplantation
The issue of simultaneous solid-organ kidney transplantationfrequently surfaces when nonrenal organ transplant candidatesundergoing evaluation have concomitant kidney disease (Table 3).In the United States, >2800 multiorgan transplants involvinga simultaneous kidney have been performed. Registry data indicatethat the preponderance of combined transplants has been simultaneousliver-kidney transplantation (SLKT), whereas a smaller proportionare simultaneous heart-kidney transplants; simultaneous transplantationof a kidney with either lung or small bowel is extremely rare.20For logistical reasons, these kidneys invariably derive fromdeceased donors.
Table 3. Renal considerations in the evaluation of patients for simultaneous transplantation of a kidney with another solid organ
Because serum creatinine is a key component of the Model forEnd-Stage Liver Disease scoring system, adopted in 2002 to prioritizepatients for liver transplantation, the number of liver recipientswith kidney dysfunction has grown.97 Concern about the implicationsof impaired kidney function at transplantation has led to asurge in the proportion of SLKT, from 2% in 1999 to just under5% in 2004.20 The rationale underlying this trend is that (1)SLKT recipients may avoid poor postoperative renal functionand its attendant risk for inferior liver transplant outcomes;(2) SLKT may prevent CKD and rapid progression to dialysis dependency;and (3) SLKT provides an immunologic advantage by using thesame donor for both organs, with no requirement for additionalimmunosuppression. This practice change in recent years hasfueled debate in the transplant community as to the optimaltherapeutic approach to such patients. Although a randomized,prospective study could resolve this issue, it is unlikely everto be done. Whereas most agree that SLKT is indicated for patientswith stages 4 to 5 CKD and concomitant end-stage liver disease,there is little consensus regarding patients with preoperativeAKI, because of the limitations of measuring kidney functionand predicting posttransplantation renal recovery.
One philosophy is that SLKT should be routinely performed becausethere is no reliable method to predict which patients will remainwith severe CKD without a concomitant kidney. Alternatively,we and others have asserted that most liver candidates withpretransplantation AKI should not get a simultaneous kidneybecause these patients generally experience sufficient renalrecovery after transplantation to the point that they do notwarrant dialysis or a subsequent kidney for years.98 This approachhas the following benefits: (1) It avoids unnecessary depletionof the limited deceased-donor kidney pool; (2) nonrenal organrecipients who progress to stage 5 CKD can subsequently be preemptivelylisted for sequential deceased donor kidney or undergo live-donorkidney transplantation, thereby minimizing or even avoidingeventual need for dialysis; and (3) purely from a deceased-donororgan use standpoint, kidneys that are placed into kidney-alonerecipients have greater longevity than kidneys that are transplantedsimultaneously with another organ.99,100
The decision for SLKT should be based on multiple factors, includingduration and degree of kidney dysfunction, potential for renalrecovery after liver transplantation alone, and the impact ofdual transplantation on recipient survival.101 By conventionalcriteria, current United Network for Organ Sharing regulationsmandate that patients can be listed for kidney transplantationalone only once their estimated GFR is 20 ml/min, representingadvanced stage 4 CKD. Recognizing that 90% of liver recipientswill have some degree of CKD after transplantation,8 our institutionalpractice has been to restrict SLKT to patients who are projectedto need listing for a kidney within 12 mo after receiving aliver. Our pretransplantation nephrologic assessment entailsa thorough medical record review to (1) establish baseline kidneyfunction, (2) ascertain any evidence of previous reversibility,and (3) determine the duration of kidney injury. Additionalstudies include detailed urinalysis, urine sodium, urine protein/creatinineratio measurement, and ultrasound to assess renal size and morphology.Although some have advocated a pretransplantation kidney biopsy,101we believe that biopsy has a limited ability to predict thedegree of recovery of kidney function or time to ESRD afterliver transplantation. As such, routine renal biopsy shouldbe considered investigational.
Criteria weighted toward SLKT include dialysis duration, thepresence of persistent stages 4 to 5 CKD for >8 to 12 wkimmediately before transplantation, and preexisting diabetes.Both dialysis duration and diabetes were significantly associatedwith serum creatinine and requirement for chronic renal replacementtherapy at 12 mo after liver transplantation.98 Using this approach,our rate of SLKT was 3%, compared with 5% nationally, whereasless than 1% of recipients of a liver alone were on long-termdialysis at the end of the first posttransplantation year.98
Pharmacokinetic Interactions between CKD Medications and Immunosuppressants
Monitoring for drug interactions with immunosuppressants typicallyfalls under the purview of the transplant center. However, severalmedications that commonly are used by nephrologists in CKD managementmay have pharmacokinetic interactions with immunotherapies,with potential for catastrophic consequences for the transplantedorgan. Examples include (1) nondihydropyridine calcium channelblockers, which increase levels of CNIs and sirolimus throughinhibition of the Cyp3A enzyme system; (2) sevelamer, whichreduces MMF exposure102; and (3) statins, which have markedlyincreased exposure and potential for toxicity in the presenceof CsA but not tacrolimus.103 We recommend that changes in themedication regimen of nonrenal organ recipients with CKD bepromptly brought to the attention of the transplant team.
The escalating problem of CKD after nonrenal organ transplantationand the paucity of established therapies call for intense researchefforts to identify strategies to prevent and treat this complication.Such research efforts may require focus on a single organ system,whereas others may be able to pool recipients of different solidorgans.
Innovations in Immunosuppression
Given the impact of CKD on outcomes in this population, a majorresearch objective is the development of effective immunosuppressiveregimens that avoid kidney injury. Novel therapies that mayoffer freedom from CNI-mediated nephrotoxicity are under investigationin renal transplant patients, including belatacept, AEBO71,and CP-690-550. Assuming that safety and efficacy can be establishedin the kidney transplant setting, the investigation of thesetherapies among nonrenal organ transplant patients could representa major advancement.104
Antifibrogenic and Anti-Inflammatory Therapies
Experimentation with antifibrogenic and anti-inflammatory therapiescan also take advantage of the existing mechanistic insightsinto the pathogenesis of CKD after solid-organ transplantation.Even at this time, an urgent need exists for systematic studiesto evaluate the potential benefit of statins and RAAS blockadeon preserving kidney function.
CKD after solid-organ transplantation is a burgeoning problemwith devastating morbidity and mortality. Transplant professionalsshould understand the limitations of serum creatinine and estimatingequations for renal function both in transplant candidates andin recipients. In addition, given strong evidence that AKI isan important risk factor for the development of CKD, every effortmust be made to avoid nephrotoxic insults during the perioperativeperiod of the organ transplant. In the absence of clinical trialsfor the prevention and treatment of CKD specifically among nonrenalsolid-organ transplant recipients, we advocate for aggressivetreatment of risk factors such as BP, as outlined in KDOQI.CNI minimization may also be an important approach to slowingprogression to ESRD, although this decision must be balancedagainst the need to avoid rejection of the transplanted organ.
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Abstract
Introduction
, matrix metalloproteinase-9, and PDGF.41–43 Other investigators have focused on the pathogenic role of dysregulation of the RAAS. For example, CsA has been shown to increase transcription of angiotensin II receptors.44 In liver recipients, the angiotensin-converting enzyme (ACE) gene D/D phenotype has been associated with increased risk for CNI nephropathy.45 In rats with tacrolimus nephrotoxicity, quinapril administration decreased interstitial fibrosis, although creatinine clearance was similar between quinapril-treated and control animals.46 
20 ml/min, representing advanced stage 4 CKD. Recognizing that 90% of liver recipients will have some degree of CKD after transplantation,8 our institutional practice has been to restrict SLKT to patients who are projected to need listing for a kidney within 12 mo after receiving a liver. Our pretransplantation nephrologic assessment entails a thorough medical record review to (1) establish baseline kidney function, (2) ascertain any evidence of previous reversibility, and (3) determine the duration of kidney injury. Additional studies include detailed urinalysis, urine sodium, urine protein/creatinine ratio measurement, and ultrasound to assess renal size and morphology. Although some have advocated a pretransplantation kidney biopsy,101 we believe that biopsy has a limited ability to predict the degree of recovery of kidney function or time to ESRD after liver transplantation. As such, routine renal biopsy should be considered investigational. 
