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American Journal of Kidney Diseases

CKD in Recipients of Nonkidney Solid Organ Transplants: A Review

  • Alexander C. Wiseman
    Correspondence
    Address for Correspondence: Alexander C. Wiseman, MD, Executive Director, Kidney Transplant, Centura Transplant, 2525 S Downing St, Suite 380, Denver, CO 80220.
    Affiliations
    Centura Transplant, Denver, Colorado
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Published:December 31, 2021DOI:https://doi.org/10.1053/j.ajkd.2021.10.014
      Chronic kidney disease (CKD) after solid organ transplant is a common clinical presentation, affecting 10% to 20% of liver, heart, and lung transplant recipients and accounting for approximately 5% of the kidney transplant waiting list. The causes of CKD are different for different types of transplants and are not all, or even predominantly, due to calcineurin inhibitor toxicity, with significant heterogeneity particularly in liver transplant recipients. Many solid organ transplant recipients with advanced CKD benefit from kidney transplantation but have a higher rate of death while waitlisted and higher mortality after transplant than the general kidney failure population. Recent organ allocation policies and proposals have attempted to address the appropriate identification and prioritization of candidates in need of a kidney transplant, either simultaneous with or after nonkidney transplant. Future research should focus on predictive factors for individuals identified as being at high risk for progression to kidney failure and death and on strategies to preserve kidney function and minimize the CKD burden in this unique patient population.

      Index Words

      Liver, heart, and lung transplantation have expanded over recent decades, resulting in a substantial number of patients with multiple comorbidities surviving longer with a successful nonkidney solid organ transplant (NKSOT). Many of these comorbidities have a direct impact on kidney function, creating a growing cohort of patients with chronic kidney disease (CKD). There are important differences in the pathophysiology and pathology of CKD in the NKSOT population compared to the CKD general population that influence clinical management. Strategies to minimize CKD in this population begin before NKSOT by using allocation policy to provide kidney transplants in selected patients at high risk of CKD, and continue after transplant by addressing the traditional risk factors and immunosuppression. Increasingly, consideration is required of kidney replacement therapy, including later kidney transplant. This review highlights the evolving epidemiology of CKD in NKSOT, discusses the kidney-specific pathophysiological and histological processes prevalent in this population, and describes current management strategies, both preventative and therapeutic, for CKD in NKSOT recipients.

      Epidemiology

      As the survival of patients with lung, liver, and heart transplants improves and as baseline clinical characteristics evolve, so too does the increased risk of CKD. A landmark registry study demonstrated the prevalence of CKD (defined as a glomerular filtration rate [GFR] < 30 mL/min) in NKSOT recipients as approaching and exceeding 25% at 10 years.
      • Ojo A.O.
      • Held P.J.
      • Port F.K.
      • et al.
      Chronic renal failure after transplantation of a nonrenal organ.
      The overall incidence of CKD was 16.5%, ranging from 6.9% in heart-lung transplants to as high as 21.3% in intestine transplants with a median follow-up of 36 months. Not surprisingly, CKD in this patient population was associated with increased mortality risk, with a relative risk of death of 4.55 (95% CI, 4.38-4.74; P < 0.001) compared to those without CKD.
      Although there has not been another formal analysis performed that is as comprehensive as the registry study, it is likely that rates of CKD after NKSOT have increased due to increased prevalence of comorbidities such as obesity and diabetes in liver transplant candidates and risk profiles such as pretransplant acute kidney injury (AKI) in heart transplant candidates, given the expanded use of ventricular assist devices for cardiomyopathy as a bridge to transplant.
      • Valapour M.
      • Lehr C.J.
      • Skeans M.A.
      • et al.
      OPTN/SRTR 2018 annual data report: lung.
      ,
      • Colvin M.
      • Smith J.M.
      • Hadley N.
      • et al.
      OPTN/SRTR 2018 annual data report: heart.
      After NKSOT, the incidence of kidney failure and subsequent kidney transplant eligibility is rising. In a registry analysis of liver transplant recipients in 1995-2010, the incidence of kidney failure with replacement therapy within 5 years of transplant increased more than 2.5-fold to >55 per 1,000 patient-years.
      • Israni A.K.
      • Xiong H.
      • Liu J.
      • et al.
      Predicting end-stage renal disease after liver transplant.
      This trend has contributed to an increase in the number of prior NKSOT recipients who become candidates for kidney transplant. During 1995-2008, listing for subsequent kidney transplant increased by 330% among liver recipients, 307% among heart recipients, and 635% among lung recipients, accounting for 3.3% of the kidney transplant waiting list.
      • Srinivas T.R.
      • Stephany B.R.
      • Budev M.
      • et al.
      An emerging population: kidney transplant candidates who are placed on the waiting list after liver, heart, and lung transplantation.

      Pathophysiology

      A number of factors contribute to the high prevalence of CKD after NKSOT. Important risk factors include pre-existing CKD, glomerulonephritis (particularly in liver transplant candidates), which in some cases is due to hepatitis B and C virus (HBV and HCV) infection, and comorbidities such as diabetes and hypertension. NKSOT transplant candidates with a high illness acuity may experience repeated AKI, which also drives the development of CKD. Importantly, the organ allocation schema for liver transplant heavily favors candidates with kidney dysfunction, which leads to a higher prevalence of NKSOT recipients with CKD after liver transplant. Finally while perhaps not the sole or primary contributor to CKD, calcineurin inhibitor (CNI) use is often implicated in progressive CKD in NKSOT recipients.

      Peritransplant AKI

      As reviewed by Rossi and Vella,
      • Rossi A.P.
      • Vella J.P.
      Acute kidney disease after liver and heart transplantation.
      AKI is a frequent complication of NKSOT, with a reported incidence ranging from 16.9% to 46% (the incidence of AKI treated with dialysis ranges from 4.6% to 8%). Although pretransplant AKI may be expected to be reversible, its contribution to future CKD in NKSOT recipients is exacerbated due to peri/posttransplant insults that include but are not limited to CNI use.

      Calcineurin Inhibitors

      CNIs are implicated in chronic vascular injury to native kidneys when used for treatment of chronic glomerular diseases and in solid organ transplant (SOT) recipients.
      • Naesens M.
      • Kuypers D.R.
      • Sarwal M.
      Calcineurin inhibitor nephrotoxicity.
      Lesions associated with CNI use include focal hyalinosis of small renal arteries and arterioles, with progressive uniform vascular hyalinosis and obliteration, increasingly associated with global or segmental glomerulosclerosis, tubular atrophy, and striped interstitial fibrosis.
      • Myers B.D.
      • Newton L.
      Cyclosporine-induced chronic nephropathy: an obliterative microvascular renal injury.
      ,
      • Sis B.
      • Dadras F.
      • Khoshjou F.
      • Cockfield S.
      • Mihatsch M.J.
      • Solez K.
      Reproducibility studies on arteriolar hyaline thickening scoring in calcineurin inhibitor-treated renal allograft recipients.
      The mechanisms of this arteriolar disease suggest endothelial damage, perhaps related to promotion of transforming growth factor β (TGF-β) through a variety of mechanisms.
      • Shihab F.S.
      • Yi H.
      • Bennett W.M.
      • Andoh T.F.
      Effect of nitric oxide modulation on TGF-beta1 and matrix proteins in chronic cyclosporine nephrotoxicity.
      As I will describe shortly, these lesions are not uniformly identified in NKSOT recipients with reduced GFR.

      Traditional Risk Factors

      Traditional risk factors associated with CKD such as hypertension (seen in up to 70% of liver transplant recipients and 90% of heart transplant recipients) and diabetes (present in ∼30% of all NKSOT recipients) play an important role in progressive CKD after NKSOT.
      • Colvin M.
      • Smith J.M.
      • Hadley N.
      • et al.
      OPTN/SRTR 2018 annual data report: heart.
      ,
      • Khush K.K.
      • Cherikh W.S.
      • Chambers D.C.
      • et al.
      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report—2018; focus theme: multiorgan transplantation.
      Blood pressure at 1 year was recently described as an independent risk factor for GFR decline between 1 and 5 years after liver and heart transplant.
      • Morath C.
      • Opelz G.
      • Döhler B.
      • Zeier M.
      • Süsal C.
      Influence of blood pressure and calcineurin inhibitors on kidney function after heart or liver transplantation.
      This analysis of 2,534 heart transplant recipients and 1,822 liver transplant recipients found an association between increasing systolic blood pressure at year 1 and higher odds of poor kidney function at year 5 after transplant (odd ratios per 20 mm Hg increment of 1.25 for heart transplant recipients [P < 0.001] and 1.35 for liver transplant recipients [P < 0.001]). Another large single-center study of 1,151 liver transplant recipients identified independent associations of CKD stage at 1 year, pretransplant diabetes, urinary tract infections in the first year, and hypercholesterolemia in the first year with CKD stage progression at 3, 5, and 10 years.
      • Lamattina J.C.
      • Foley D.P.
      • Mezrich J.D.
      • et al.
      Chronic kidney disease stage progression in liver transplant recipients.
      In heart transplant recipients, factors of age, female sex, pretransplant/early posttransplant reduced kidney function, diabetes, and hypertension were associated with the risk of CKD after transplantation.
      • Lachance K.
      • White M.
      • de Denus S.
      Risk factors for chronic renal insufficiency following cardiac transplantation.
      Unfortunately, modifiable risk factors are often ineffectively managed, as demonstrated by a recent analysis from a tertiary care center in which <30% of 602 liver transplant recipients were treated to a blood pressure < 140/90 mm Hg at 1 year. Blood pressure control was associated with a substantial reduction in risk of mortality (hazard ratio [HR], 0.48 [95% CI, 0.39-0.87]) and of cardiovascular events (HR, 0.65 [95% CI, 0.43-0.97]).
      • VanWagner L.B.
      • Holl J.L.
      • Montag S.
      • et al.
      Blood pressure control according to clinical practice guidelines is associated with decreased mortality and cardiovascular events among liver transplant recipients.

      Chronic Viral Infection

      Viral infections such as with HBV and HCV have historically been significant contributors to the risk of CKD in liver transplant in particular. However, with the introduction of successful suppressive (for HBV) and curative (for HCV) antiviral therapies,
      • Lok A.S.
      • McMahon B.J.
      • Brown Jr., R.S.
      • et al.
      Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis.
      • Shah A.S.
      • Amarapurkar D.N.
      Spectrum of hepatitis B and renal involvement.
      • Baumert T.F.
      • Berg T.
      • Lim J.K.
      • Nelson D.R.
      Status of direct-acting antiviral therapy for hepatitis C virus infection and remaining challenges.
      • Pol S.
      • Parlati L.
      • Jadoul M.
      Hepatitis C virus and the kidney.
      the contribution of viral infection to posttransplant kidney disease has diminished. This has been replaced by metabolic factors including obesity and diabetes inherent to the rapidly growing postliver transplant population with nonalcoholic fatty liver disease as the cause of liver failure. Although BK virus reactivation is common in kidney transplant recipients, this has not manifested as a significant risk in NKSOT recipients, with only case reports supporting any role and screening studies demonstrating a low rate of BK reactivation.
      • Viswesh V.
      • Yost S.E.
      • Kaplan B.
      The prevalence and implications of BK virus replication in non-renal solid organ transplant recipients: a systematic review.

      Kidney Pathology in SOT CKD

      In the largest kidney biopsy series to date, among a diverse population of NKSOT recipients, histologic assessment among lung (30 biopsies in 28 patients), heart (20 biopsies in 20 patients), and liver (41 biopsies and 39 patients) transplant recipients demonstrated differences in pathologies between SOT types (Table 1).
      • Schwarz A.
      • Haller H.
      • Schmitt R.
      • et al.
      Biopsy-diagnosed renal disease in patients after transplantation of other organs and tissues.
      Arteriolar hyalinosis was much more prevalent in lung and heart transplant recipients than in liver transplant recipients whereas primary glomerular disease (in particular, IgA nephropathy) was more common in liver transplant patients. Further evidence of non–CNI-related renal toxicity in the liver transplant patient population was provided by a series of 81 biopsies performed a mean of 4.8 years after liver transplant in patients with a mean estimated GFR (calculated using the Modification of Diet in Renal Disease [MDRD] Study equation) of 38.7 mL/min and 24-hour urine protein of 1.37 g/d.
      • Kim J.Y.
      • Akalin E.
      • Dikman S.
      • et al.
      The variable pathology of kidney disease after liver transplantation.
      Primary glomerular diseases (focal segmental glomerulosclerosis, membranous nephropathy, and membranoproliferative glomerulonephritis) were identified in 43% of the 81 biopsies, and glomerulosclerosis and arterionephrosclerosis were found universally. However, nodular hyalinosis (typically associated with CNI nephrotoxicity) was uncommon, only identified in 15% of biopsies. These findings (and a lack of isolated CNI nephrotoxicity) were similar in other biopsy series as well.
      • Tsapenko M.
      • El-Zoghby Z.M.
      • Sethi S.
      Renal histological lesions and outcome in liver transplant recipients.
      ,
      • Pinney S.P.
      • Balakrishnan R.
      • Dikman S.
      • et al.
      Histopathology of renal failure after heart transplantation: a diverse spectrum.
      Overall, these biopsy series highlight the fact that diagnoses other than CNI nephrotoxicity are common and are different among the various types of organ transplant, with many features similar to native CKD. Caveats to these findings include selection bias, given the variability in inclusion criteria for biopsy from each single center; era effect, in that treatment for HBV and HCV in the direct-acting antiviral agent era may mitigate the preponderance of glomerular abnormalities; and evolving pathologic criteria for CNI nephrotoxicity, such that the sensitivity and sensitivity for identifying CNI toxicity as a cause of CKD in NKSOT are unknown.
      Table 1Biopsy-Diagnosed Kidney Disease in Patients After Transplantation of Other Organs and Tissues
      Liver (n = 41)Lung (n = 30)Heart (n = 20)
      Clinical characteristics
       Hypertension62%86%90%
       Diabetes36%39%35%
       Time after transplant, mo351966
       eGFR at biopsy, mL/min37.628.125.1
       Cyclosporine-based75%33%55%
       Tacrolimus-based23%33%10%
       CNI plus mTOR inhibitor5%33%35%
      Histologic findings
       Acute tubular injury49%75%70%
       Interstitial fibrosis/tubular atrophy > 20%51%64%35%
       Arteriolar hyalinosis13%64%35%
       Benign nephrosclerosis41%54%40%
       Global glomerulosclerosis18%18%30%
       Nephrocalcinosis13%05%
       Primary glomerular disease26%
      IgA nephropathy: n = 6; minimal change disease: n = 1; membranoproliferative glomerulonephritis: n = 2.
      015%
      IgA nephropathy: n = 2; membranoproliferative glomerulonephritis: n = 1.
      Adapted from Schwarz et al,
      • Schwarz A.
      • Haller H.
      • Schmitt R.
      • et al.
      Biopsy-diagnosed renal disease in patients after transplantation of other organs and tissues.
      with permission of the copyright holder (John Wiley and Sons). Abbreviations: CNI, calcineurin inhibitor; eGFR, estimated glomerular filtration rate; mTOR, mammalian target of rapamycin.
      a IgA nephropathy: n = 6; minimal change disease: n = 1; membranoproliferative glomerulonephritis: n = 2.
      b IgA nephropathy: n = 2; membranoproliferative glomerulonephritis: n = 1.

      Clinical Management

      Assessment of GFR

      GFR estimates, while potentially varying in accuracy across different populations, are likely acceptably applied for the NKSOT population with caveats. Assessment of GFR estimating equations in NKSOT patients was assessed by a systematic review in which the authors identified 26 equations used to estimate GFR in 3,622 individuals (53% kidney, 35% liver, and 12% other SOT recipients).
      • Shaffi K.
      • Uhlig K.
      • Perrone R.D.
      • et al.
      Performance of creatinine-based GFR estimating equations in solid-organ transplant recipients.
      The performance of the CKD Epidemiology Collaboration (CKD-EPI) equation was superior to or comparable with alternative equations, and the CKD-EPI and MDRD Study equations were found to be as accurate in NKSOT populations as they are in other clinical populations, justifying their use in NKSOT recipients. The caveats that must be considered include the overestimation of GFR overall by these equations in the setting of reduced muscle mass, which is common in NKSOT recipients.
      • Kolsrud O.
      • Ricksten S.E.
      • Holmberg E.
      • et al.
      Measured and not estimated glomerular filtration rate should be used to assess renal function in heart transplant recipients.
      • Wagner D.
      • Kniepeiss D.
      • Stiegler P.
      • et al.
      The assessment of GFR after orthotopic liver transplantation using cystatin C and creatinine-based equations.
      • Allen A.M.
      • Kim W.R.
      • Larson J.J.
      • Colby C.
      • Therneau T.M.
      • Rule A.D.
      Serum cystatin C as an indicator of renal function and mortality in liver transplant recipients.
      • Gonwa T.A.
      • Jennings L.
      • Mai M.L.
      • Stark P.C.
      • Levey A.S.
      • Klintmalm G.B.
      Estimation of glomerular filtration rates before and after orthotopic liver transplantation: evaluation of current equations.
      For example, in lung transplant recipients the CKD-EPI creatinine equation appears to be adequate but is inaccurate in the setting of cystic fibrosis, low arm muscle mass, and low body mass index, in which case cystatin C–based equations may be more accurate.
      • Degen D.A.
      • Janardan J.
      • Barraclough K.A.
      • et al.
      Predictive performance of different kidney function estimation equations in lung transplant patients.
      From a practical standpoint, the CKD-EPI creatinine equation, followed by the MDRD Study equation, may be considered the most appropriate estimates of GFR in NKSOT. Clinicians should consider using the CKD-EPI cystatin C equation as a confirmatory test when clinically indicated, such as in cases where muscle mass is poorly represented by weight.

      General Principles

      Because there are few formal data pertaining to CKD management that are specific to NKSOT recipients, their management must rely upon extrapolations from best nephrology practices in the native and kidney transplant CKD patient populations. As described previously, given the variable and unpredictable kidney histology in NKSOT recipients with kidney dysfunction, kidney biopsy is likely underused in the NKSOT population. As in the general population,
      • Wieliczko M.
      • Ołdakowska-Jedynak U.
      • Andrian T.
      • Małyszko J.
      Kidney biopsy in patients after liver transplantation: an underutilized, but clinically important procedure.
      a kidney biopsy should be considered under circumstances of rapid or unexplained decline in kidney function, active urine sediment, and/or increasing or nephrotic-range proteinuria.
      KDIGO clinical practice guideline recommendations that pertain most specifically to the solid organ transplant patient population are summarized in Box 1.
      • Cheung A.K.
      • Chang T.I.
      • Cushman W.C.
      • et al.
      Executive summary of the KDIGO 2021 clinical practice guideline for the management of blood pressure in chronic kidney disease.
      • De Boer I.H.
      • Caramori M.L.
      • Chan J.C.N.
      • et al.
      Executive summary of the 2020 KDIGO diabetes management in CKD guideline: evidence-based advances in monitoring and treatment.
      Blood pressure goals should be less than or equal to 140/90 mm Hg in general; if CKD (eGFR < 60 mL/min), proteinuria, or diabetes is present, the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are considered first-line therapies with an adjusted blood pressure target of less than or equal to 130/80 mm Hg. Despite recent data in the native CKD population that intensive blood pressure lowering to goal <120/80 mm Hg (when measured in a standardized manner in the office setting) prevents the decline of GFR,
      • Cheung A.K.
      • Rahman M.
      • Reboussin D.M.
      • et al.
      Effects of intensive BP control in CKD.
      no studies to date have demonstrated a protective effect with more aggressive blood pressure goals or specific agents in the NKSOT population.
      Relevant Recommendations From KDIGO in Solid Organ Transplant Recipients
      For Hypertension and/or Albuminuria
      • UAE <30 mg/d and BP >140/90: treat to ≤140/90 (grade 1B)
      • UAE ≥30 mg/d and BP >130/80: treat to ≤130/80 (grade 2D)
      • UAE ≥300 mg/d: use ACEI or ARB (grade 1B)
      • DM and UAE 30-300 mg/d: use ACEI or ARB (grade 2D)
      For CKD (eGFR < 60 mL/min)
      • Dietary salt: Reduce intake to < 90 mmol (<2 g) per day of sodium (corresponding to 5 g of sodium chloride). (Grade 1C)
      • Acidosis: Bicarbonate supplementation can be given for patients with bicarbonate concentrations < 22 mmol/L. (Sodium bicarbonate is typically given in a daily dose of 0.5 to 1 mEq/kg daily; 1 tablet of sodium bicarbonate has 7.7 mEq, so typical dose is 1-2 tablets 3 times per day.) (Grade 2B)
      Nephrology Referral (Grade 1B)
      • AKI or abrupt sustained fall in GFR
      • GFR <30 mL/min/1.73 m2
      • Consistent significant albuminuria (UACR ≥ 300 mg/g [≥30 mg/mmol] or albumin excretion rate ≥300 mg/d, equivalent to UPCR ≥ 500 mg/g [≥50 mg/mmol] or protein excretion rate ≥ 500 mg/d)
      • Progression of CKD (drop in eGFR from baseline by 25% or a sustained decline in eGFR of >5 mL/min/1.73 m2 per year)
      • Urinary red cell casts or >20 RBCs per high-power field that is sustained and not readily explained
      • CKD and hypertension refractory to treatment with 4 or more antihypertensive agents
      • Persistent abnormalities of serum potassium
      • Recurrent or extensive nephrolithiasis
      • Hereditary kidney disease
      Based on KDIGO clinical practice guidelines.
      • Di Iorio B.R.
      • Bellasi A.
      • Raphael K.L.
      • et al.
      Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study.
      • Levitsky J.
      • O’Leary J.G.
      • Asrani S.
      • et al.
      Protecting the kidney in liver transplant recipients: practice-based recommendations from the American Society of Transplantation Liver and Intestine Community of Practice.
      Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; BP, blood pressure; CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; RBC, red blood cell; UACR, urinary albumin-creatinine ratio; UAE, urinary albumin excretion; UPCR, urinary protein-creatinine ratio.
      Sodium/glucose cotransporter 2 (SGLT2) inhibitors have been shown to slow CKD progression in both the diabetic and nondiabetic CKD populations
      • De Boer I.H.
      • Caramori M.L.
      • Chan J.C.N.
      • et al.
      Executive summary of the 2020 KDIGO diabetes management in CKD guideline: evidence-based advances in monitoring and treatment.
      but have not been studied extensively in the NKSOT population (or those with a kidney transplant); their effectiveness among NKSOT recipients might be reduced due to differences in infection risk and metabolic/hemodynamic concerns due to attendant CNI use. Additional recommendations with reasonable supporting evidence include a low-salt diet (less than 2 g/d of sodium) and treatment of metabolic acidosis
      • Cheung A.K.
      • Chang T.I.
      • Cushman W.C.
      • et al.
      Executive summary of the KDIGO 2021 clinical practice guideline for the management of blood pressure in chronic kidney disease.
      • De Boer I.H.
      • Caramori M.L.
      • Chan J.C.N.
      • et al.
      Executive summary of the 2020 KDIGO diabetes management in CKD guideline: evidence-based advances in monitoring and treatment.
      • Cheung A.K.
      • Rahman M.
      • Reboussin D.M.
      • et al.
      Effects of intensive BP control in CKD.
      • Dobre M.
      • Yang W.
      • Chen J.
      • et al.
      Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) study.
      • Di Iorio B.R.
      • Bellasi A.
      • Raphael K.L.
      • et al.
      Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study.
      • Park S.
      • Kang E.
      • Park S.
      • et al.
      Metabolic acidosis and long-term clinical outcomes in kidney transplant recipients.
      • Levitsky J.
      • O’Leary J.G.
      • Asrani S.
      • et al.
      Protecting the kidney in liver transplant recipients: practice-based recommendations from the American Society of Transplantation Liver and Intestine Community of Practice.
      • Raphael K.L.
      • Wei G.
      • Baird B.C.
      • Greene T.
      • Beddhu S.
      Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans.
      for patients with bicarbonate concentrations less than 22 mmol/L.

      Immunosuppression Modifications

      For transplant clinicians, it is tempting to try to modify immunosuppression (eg, reduce or eliminate CNIs) in the setting of CKD in NKSOT recipients to attempt to slow progression. Potential strategies include introduction of mTOR inhibitors (sirolimus, everolimus), introduction of mycophenolate mofetil (MMF) with CNI minimization or withdrawal, or CNI conversion to belatacept-based therapy. Unfortunately, there is no strong evidence that reduction or elimination of CNI therapy improves kidney function when performed greater than 1 year after NKSOT, with modest evidence supporting modifications within the first posttransplant year. Table 2 summarizes the key clinical trials that form current perspectives on immunosuppression modifications to preserve kidney function, and further detailed discussion follows.
      Table 2Key Clinical Trials Evaluating Immunosuppression Modifications to Preserve Kidney Function in Recipients of Nonkidney Solid Organ Transplants
      StudyOrganTiming After TransplantNKey Finding
      Fischer et al
      • Fischer L.
      • Saliba F.
      • Kaiser G.M.
      • et al.
      Three-year outcomes in de novo liver transplant patients receiving everolimus with reduced tacrolimus: follow-up results from a randomized, multicenter study.
      (randomized prospective)
      Liver1 mo719CNI minimization with mTORi was associated with improved GFR and reduced risk of rejection vs standard CNI; CNI elimination with mTORi was associated with excessively high rejection rate.
      Teperman et al
      • Teperman L.
      • Moonka D.
      • Sebastian A.
      • et al.
      Calcineurin inhibitor-free mycophenolate mofetil/sirolimus maintenance in liver transplantation: the Randomized Spare-The-Nephron Trial.
      (randomized prospective)
      Liver1-3 mo293SRL converson from CNI was associated with higher GFR but higher rejection rates and medication discontinuation rates.
      Abdelmalek et al
      • Abdelmalek M.F.
      • Humar A.
      • Stickel F.
      • et al.
      Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial.
      (randomized prospective)
      Liver6-144 mo607Conversion from CNI to SRL did not improve GFR and was associated with higher rejection rates.
      De Simone et al
      • De Simone P.
      • Metselaar H.J.
      • Fischer L.
      • et al.
      Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: a prospective, randomized, multicenter trial.
      (randomized prospective)
      Liver12-60 mo145CNI minimization or elimination with mTORi was not associated with improvement in GFR.
      Beckebaum et al
      • Beckebaum S.
      • Klein C.G.
      • Sotiropoulos G.C.
      • et al.
      Combined mycophenolate mofetil and minimal dose calcineurin inhibitor therapy in liver transplant patients: clinical results of a prospective randomized study.
      (randomized prospective)
      Liver12 mo90CNI minimization with addition of MMF was associated with higher GFR and no increase in acute rejection.
      Gustafsson et al
      • Gustafsson F.
      • Andreassen A.K.
      • Andersson B.
      • et al.
      Everolimus initiation with early calcineurin inhibitor withdrawal in de novo heart transplant recipients: long-term follow-up from the randomized SCHEDULE Study.
      (randomized prospective)
      Heart7-11 wk115CNI conversion to SRL was associated with increased acute rejection but reduced chronic allograft vasculopathy and higher GFR; findings persisted with 5-7 year follow-up.
      Asleh et al
      • Asleh R.
      • Alnsasra H.
      • Lerman A.
      • et al.
      Effects of mTOR inhibitor-related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients.
      (single-center retrospective)
      Heart>3 mo402
      137 with proteinuria assessment at time 0 and 1 year after conversion.
      CNI conversion to SRL was associated with reduced chronic allograft vasculopathy and mortality in overall cohort, and less CAV attenuation and higher all-cause mortality in those with proteinuria.
      Zuckerman et al
      • Zuckermann A.
      • Eisen H.
      • See Tai S.
      • Li H.
      • Hahn C.
      • Crespo-Leiro M.G.
      Sirolimus conversion after heart transplant: risk factors for acute rejection and predictors of renal function response.
      (randomized prospective)
      Heart1-8 y116CNI conversion to SRL was associated with modest improvement in GFR, higher rejection rates, and high (33%) SRL discontinuation rate.
      Gullestad et al
      • Gullestad L.
      • Eiskjaer H.
      • Gustafsson F.
      • et al.
      Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial.
      (randomized prospective)
      Heart/Lung>12 mo282Addition of mTORi to 3-drug regimen with CNI minimization was associated with stabilization of GFR over 5 years, higher infection incidence.
      Glanville et al
      • Glanville A.R.
      • Aboyoun C.
      • Klepetko W.
      • et al.
      Three-year results of an investigator-driven multicenter, international, randomized open-label de novo trial to prevent BOS after lung transplantation.
      (randomized prospective)
      Lung<3 mo165CNI minimization combined with mTORi did not improve GFR and was associated with higher incidence of acute rejection.
      Search used for compilation of studies included all articles from 2005-2021 with the following terms: sirolimus and/or mTOR inhibitor and/or mycophenolate and/or belatacept; and liver transplant and/or lung transplant and/or heart transplant; and/or GFR and/or glomerular filtration rate and/or chronic kidney disease and/or kidney disease; and/or conversion. Priority was given for randomized trials and multicenter trials for final selection. Abbreviations: CAV, cardiac allograft vasculopathy; CNI, calcineurin inhibitor; (e)GFR, (estimated) glomerular filtration rate; MMF, mycophenolate mofetil; mTORi, mammalian target of rapamycin inhibitor; SRL, sirolimus.
      a 137 with proteinuria assessment at time 0 and 1 year after conversion.

      CNI Withdrawal

      The impact of CNI conversion to sirolimus is highlighted by a large multicenter trial of 607 liver transplant recipients randomized to sirolimus conversion or continuation of CNI maintenance therapy (mean of 4.0 ± 2.9 years from transplant).
      • Abdelmalek M.F.
      • Humar A.
      • Stickel F.
      • et al.
      Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial.
      An on-therapy analysis demonstrated a decline in creatinine clearance (estimated by the Cockcroft-Gault formula) that was greater in the sirolimus arm (−4.45 mL/min over 12 months) versus CNI maintenance (−3.07 mL/min), and transition was associated with higher acute rejection rates and with a high rate of sirolimus discontinuation compared with CNI continuation (36% vs 11%, P < 0.001). Further evidence of a lack of improvement with CNI conversion to mTOR inhibitors is summarized in a meta-analysis of randomized controlled trials in liver transplantation (10 trials with a total of 1,927 patients).
      • Glover T.E.
      • Watson C.J.
      • Gibbs P.
      • Bradley J.A.
      • Ntzani E.E.
      • Kosmoliaptsis V.
      Conversion from calcineurin to mammalian target of rapamycin inhibitors in liver transplantation: a meta-analysis of randomized controlled trials.
      Overall, a higher eGFR 1 year after randomization to mTOR inhibitor was reported (by 7.5 [95% CI, 3.2-11.8] mL/min/1.73 m2), but this improvement was demonstrated only in studies with early conversion within 1 year after transplant. Conversion was also associated with a higher acute rejection rate (relative risk, 1.8 [95% CI, 1.3-2.3]) and a higher mTOR inhibitor discontinuation rate compared with CNI continuation (relative risk of discontinuation, 2.2 [95% CI, 1.4-3.4]). Although data are less robust in heart transplantation, conversion from CNI to mTOR inhibitor (sirolimus) in a prospective trial of 116 patients showed similar findings of modest improvements in GFR (+3.0 vs −1.4 mL/min/1.73 m2; P = 0.004), coupled with higher rejection rates and a high rate of mTOR inhibitor discontinuation specifically due to adverse events (33.3% vs 0; P < 0001).
      • Zuckermann A.
      • Keogh A.
      • Crespo-Leiro M.G.
      • et al.
      Randomized controlled trial of sirolimus conversion in cardiac transplant recipients with renal insufficiency.
      ,
      • Goralczyk A.D.
      • Bari N.
      • Abu-Ajaj W.
      • et al.
      Calcineurin inhibitor sparing with mycophenolate mofetil in liver transplantion: a systematic review of randomized controlled trials.

      CNI Minimization

      Minimizing CNI (rather than eliminating) may be safer and better tolerated but also has a more modest effect on kidney protection. In liver transplant, a systematic review of randomized trials identified 4 trials in which MMF was introduced and CNI minimized more than 5 years from transplant, with stable or improved GFR and no increase in risk of rejection.
      • Goralczyk A.D.
      • Bari N.
      • Abu-Ajaj W.
      • et al.
      Calcineurin inhibitor sparing with mycophenolate mofetil in liver transplantion: a systematic review of randomized controlled trials.
      In heart and lung transplants, a randomized trial of 282 recipients more than 1 year from transplant minimized CNI (cyclosporine <75 ng/mL or tacrolimus <4 ng/mL) while adding the mTOR inhibitor everolimus to a 3-drug regimen (CNI, azathioprine or mycophenolate, and prednisone).
      • Gullestad L.
      • Eiskjaer H.
      • Gustafsson F.
      • et al.
      Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial.
      The 5-year follow-up demonstrated that measured GFR remained stable in the CNI minimization group (changing from 51.3 to 51.4 mL/min) but decreased in the controls (from 50.5 to 45.3 mL/min) (P = 0.004) with similar rates of rejection, death, and major cardiac events but higher pneumonia rates in the 4-drug/CNI minimization arm. In a 3-year multicenter randomized trial of 165 lung transplant recipients, conversion from MMF to everolimus with CNI dose reduction demonstrated no differences in kidney function with higher rates of side effects and biopsy-proven acute cellular rejection in the mTOR inhibitor arm.
      • Glanville A.R.
      • Aboyoun C.
      • Klepetko W.
      • et al.
      Three-year results of an investigator-driven multicenter, international, randomized open-label de novo trial to prevent BOS after lung transplantation.
      In a minority of patients mTOR inhibitors have been associated with progressive proteinuria and may synergize with CNI to exacerbate CNI nephrotoxic effects.
      • Letavernier E.
      • Legendre C.
      mToR inhibitors-induced proteinuria: mechanisms, significance, and management.
      ,
      • Podder H.
      • Stepkowski S.M.
      • Napoli K.L.
      • et al.
      Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations.
      A recent study in heart transplantation found that the presence of proteinuria in patients converted to mTOR inhibitors was associated with higher all-cause mortality.
      • Asleh R.
      • Alnsasra H.
      • Lerman A.
      • et al.
      Effects of mTOR inhibitor-related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients.
      For this reason mTOR inhibitors are discouraged from use for those patients with an estimated or measured GFR <40 mL/min/1.73 m2 or proteinuria.

      Belatacept Conversion

      The costimulation inhibitor belatacept is approved in kidney transplantation as a result of landmark trials demonstrating improved GFR and better patient and graft survival, despite higher acute rejection rates compared with cyclosporine.
      • Vincenti F.
      • Charpentier B.
      • Vanrenterghem Y.
      • et al.
      A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study).
      ,
      • Vincenti F.
      • Rostaing L.
      • Grinyo J.
      • et al.
      Belatacept and long-term outcomes in kidney transplantation.
      It is currently not approved for use as a de novo immunosuppressive agent in liver, lung, or heart transplant recipients. It carries a black box warning in liver transplant as a result of a multicenter study demonstrating an increase in graft loss and death compared with standard immunosuppression.
      • Klintmalm G.B.
      • Feng S.
      • Lake J.R.
      • et al.
      Belatacept-based immunosuppression in de novo liver transplant recipients:1-year experience from a phase II randomized study.
      A number of small case series have been published describing conversion to belatacept in liver, lung, and heart transplant recipients (summarized in Perez et al
      • Perez C.P.
      • Patel N.
      • Mardis C.R.
      • Meadows H.B.
      • Taber D.J.
      • Pilch N.A.
      Belatacept in solid organ transplant: review of current literature across transplant types.
      and Chandrashekaran et al
      • Chandrashekaran S.
      • Crow Pharm S.A.
      • Shah S.Z.
      • Arendt Pharm C.J.
      • Kennedy C.C.
      Immunosuppression for lung transplantation: current and future.
      ). Although the outcomes in these reports were generally favorable, including stabilization of kidney function when conversion was used for renoprotection, safety is not well understood in these populations, and these findings are best considered exploratory at this point.
      In summary, there are mixed data supporting CNI minimization or withdrawal with mTOR inhibitors during the first year after transplant to preserve GFR. After the first year after transplant, CNI minimization with MMF adjunctive therapy may improve GFR in the setting of mild CKD in liver transplant, with little evidence to support mTOR inhibitor use to preserve kidney function after the first year in liver, heart, or lung transplant recipients and only modest experience with belatacept in these settings.

      Outcomes of Subsequent Kidney Transplant in the NKSOT Population

      The NKSOT population forms a rapidly growing cohort of patients on the kidney transplant waiting list, raising concerns regarding equity and access to kidney transplant for the native CKD population. A 2010 registry analysis compared outcomes of patients with prior NKSOT (lung, heart, or liver) to primary kidney transplant candidates and to repeat kidney transplant candidates.
      • Cassuto J.R.
      • Reese P.P.
      • Sonnad S.
      • et al.
      Wait list death and survival benefit of kidney transplantation among nonrenal transplant recipients.
      Pertinent findings include (1) waiting list mortality was 2- to 4-fold higher for patients with prior heart, liver, lung transplant; (2) kidney transplant provided a significant survival advantage for NKSOT recipients compared to their waitlisted NKSOT counterparts, comparable to the survival benefit in kidney retransplant recipients yet still inferior to primary kidney transplant recipients; and (3) the kidney after lung transplant population had a significantly higher mortality risk than other cohorts, both in the waitlist and posttransplant phase of care. These findings have been corroborated by more recent analyses (Fig 1).
      • Lonze B.E.
      • Warren D.S.
      • Stewart Z.A.
      • et al.
      Kidney transplantation in previous heart or lung recipients.
      ,
      • El-Husseini A.
      • Aghil A.
      • Ramirez J.
      • et al.
      Outcome of kidney transplant in primary, repeat, and kidney-after-nonrenal solid-organ transplantation:15-year analysis of recent UNOS database.
      Figure thumbnail gr1
      Figure 1(A) Patient survival (Kaplan-Meier curves) after primary kidney transplant (n = 178,947), repeat kidney transplant (n = 17,819), and kidney-after-SOT (n = 2,365) from 2000-2014. (B) Hazard ratio of kidney graft loss and mortality after kidney transplant, comparing primary kidney, repeat kidney, and kidney-after-SOT recipient outcomes. Those with previous SOT, particularly those with prior lung transplant had inferior patient and kidney allograft survival when compared to primary or repeat kidney transplant due to posttransplant mortality rather than death-censored kidney graft loss (B). Panel A ©2017 John Wiley and Sons, reproduced from El-Husseini et al
      • El-Husseini A.
      • Aghil A.
      • Ramirez J.
      • et al.
      Outcome of kidney transplant in primary, repeat, and kidney-after-nonrenal solid-organ transplantation:15-year analysis of recent UNOS database.
      with permission of the copyright holder.
      Given the increase in the last decade in the age and comorbidities of the NKSOT population, a pertinent question is how the elderly NKSOT recipient with advanced CKD fares after kidney transplant.
      • Haugen C.E.
      • Luo X.
      • Holscher C.M.
      • et al.
      Outcomes in older kidney transplant recipients after prior nonkidney transplants.
      Of 5,023 prior NKSOT recipients over the age of 65 on the kidney transplant waiting list in 1995-2016, there were 863 candidates who ultimately received a kidney transplant. Kidney transplant conferred a survival benefit, with a greater than 50% reduction in mortality for prior lung, liver, and heart transplant recipients (overall adjusted HR, 0.47 [95% CI, 0.42-0.54]; P < 0.001). Death-censored graft loss was similar to older kidney transplant recipients but mortality was higher (5-year patient survival of 36% vs 28%; adjusted HR, 1.40 [95% CI, 1.28-1.54]; P <0.001). These findings underscore the importance of timely referral of SOT recipients, including elderly patients, for kidney transplant.
      • Cassuto J.R.
      • Reese P.P.
      • Sonnad S.
      • et al.
      Wait list death and survival benefit of kidney transplantation among nonrenal transplant recipients.
      ,
      • Osho A.A.
      • Hirji S.A.
      • Castleberry A.W.
      • et al.
      Long-term survival following kidney transplantation in previous lung transplant recipients: an analysis of the UNOS registry.

      Early Identification and Management of NKSOT Candidates and Recipients at Risk of CKD

      Ultimately, improved predictors and proactive interventions to optimize kidney function and prevent progressive CKD after NKSOT are needed (Box 2). In the pretransplant period, improvements in the management of AKI (eg, hepatorenal syndrome
      • Thomson M.J.
      • Taylor A.
      • Sharma P.
      • Lok A.S.
      • Tapper E.B.
      Limited progress in hepatorenal syndrome (HRS) reversal and survival 2002-2018: a systematic review and meta-analysis.
      ) are necessary, as are better tools to determine the degree of chronic kidney injury before transplant, beyond creatinine-based determinations.
      • Wadei H.M.
      • Heckman M.G.
      • Rawal B.
      • et al.
      Renal outcomes of liver transplant recipients who had pretransplant kidney biopsy.
      ,
      • Labban B.
      • Arora N.
      • Restaino S.
      • Markowitz G.
      • Valeri A.
      • Radhakrishnan J.
      The role of kidney biopsy in heart transplant candidates with kidney disease.
      In an effort to mitigate the risks of prior/ongoing kidney injury on posttransplant outcomes, careful assessments of NKSOT candidates’ kidney function and appropriate allocation of simultaneous kidney-SOT have been prioritized. In August 2017, a new allocation system for simultaneous liver-kidney (SLK) transplantation was implemented (Box 3).
      Organ Procurement and Transplantation Network
      OPTN policies.
      • Wilk A.R.
      • Booker S.E.
      • Stewart D.E.
      • et al.
      Developing simultaneous liver-kidney transplant medical eligibility criteria while providing a safety net: a 2-year review of the OPTN’s allocation policy.
      • Formica R.N.
      • Aeder M.
      • Boyle G.
      • et al.
      Simultaneous liver-kidney allocation policy: a proposal to optimize appropriate utilization of scarce resources.
      • Merola J.
      • Formica R.N.
      • Mulligan D.C.
      Changes in United Network for Organ Sharing policy for simultaneous liver-kidney allocation.
      This policy provides clear definitions of eligibility for combined organ transplant, either on the basis of the degree of CKD (GFR <30 mL/min with a history of GFR <60 mL/min for more than 3 months) or the duration of AKI (GFR <25 mL/min and/or receipt of dialysis for more than 6 weeks). For circumstances in which liver transplant recipients did not receive a simultaneous kidney transplant but had persistent kidney failure, a safety net plan was implemented in which liver transplant recipients with GFR <20 mL/min beginning 2 to 12 months after liver transplant become eligible for subsequent kidney transplant, with substantial allocation priority. Efforts to implement a similar policy for simultaneous heart-kidney transplant are underway, with consensus recommendations modeled after the United Network for Organ Sharing (UNOS) SLK policy.
      • Cheng X.S.
      • Khush K.K.
      • Wiseman A.
      • Teuteberg J.
      • Tan J.C.
      To kidney or not to kidney: applying lessons learned from the simultaneous liver-kidney transplant policy to simultaneous heart-kidney transplantation.
      ,
      • Kobashigawa J.
      • Dadhania D.M.
      • Farr M.
      • et al.
      Consensus Conference Participants. Consensus conference on heart-kidney transplantation.
      Future Research Needs in the Prevention and Management of CKD in NKSOT
      Pre/Peritransplant
      • Role of kidney biopsy in determining etiology/severity of pretransplant kidney injury and relationship to posttransplant kidney function
      • Biomarkers to predict kidney recovery in AKI immediately after transplant
      • Interventions to preserve kidney function intra/postoperatively
      • Perioperative immunosuppression strategies to promote renal recovery
      Posttransplant
      • Role of SGLT2 inhibition in NKSOT recipients with CKD
      • Appropriate blood pressure goal in NKSOT recipients
      • Role of kidney biopsy in the management of CKD after NKSOT
      • Immunosuppression strategies to slow progression of CKD
      • Noninvasive biomarkers in predicting CKD progression in NKSOT
      Risk-benefit analyses of nephrotoxic immunosuppressive medication use (eg, calcineurin inhibitors, mTOR inhibitors), comparing their proposed benefits upon NKSOT graft outcomes and patient complications versus kidney complications. Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; mTOR, mammalian target of rapamycin; NKSOT, nonkidney solid organ transplant; SGLT2, sodium/glucose cotransporter 2.
      Eligibility Criteria for Simultaneous Liver-Kidney Transplantation
      Per OPTN/UNOS criteria for eligibility for simultaneous liver-kidney transplant, candidates must meet at least 1 of the following conditions:
      • 1.
        CKD with GFR <60 mL/min for >90 days with:
        • a.
          Kidney failure treated by maintenance KRT, or
        • b.
          GFR <30 mL/min at time of listing for kidney
      • 2.
        Sustained AKI with:
        • a.
          6 Consecutive weeks of KRT, or
        • b.
          GFR <25 mL/min for 6 consecutive weeks, or
        • c.
          Combination of 2a and 2b for 6 consecutive weeks
      • 3.
        Metabolic disease (hyperoxaluria, aHUS, familial non-neuropathic systemic amyloidosis, or methylmalonic aciduria)a
      “Safety net” provision for kidney after liver transplant: Liver transplant recipients who continue to receive dialysis or who have GFR ≤20 mL/min in the period 2-12 months after liver transplant will receive priority for kidney allocation for kidneys with KDPI >20%.
      These criteria were adopted in August 2017
      Organ Procurement and Transplantation Network
      OPTN policies.
      (pp 147-148 and 215-217) in response to annual increases in SLK transplants since 2012 and a lack of consistency in selection of candidates; there was a subsequent decrease in SLK transplants and an increase in kidney after liver transplants.
      • Wilk A.R.
      • Booker S.E.
      • Stewart D.E.
      • et al.
      Developing simultaneous liver-kidney transplant medical eligibility criteria while providing a safety net: a 2-year review of the OPTN’s allocation policy.
      Abbreviations: aHUS, atypical hemolytic uremic syndrome; AKI, acute kidney injury; CKD, chronic kidney disease; GFR, glomerular filtration rate; KDPI, kidney donor profile index; KRT, kidney replacement therapy; OPTN/UNOS, Organ Procurement and Transplantation Network/United Network for Organ Sharing; SLK, simultaneous liver-kidney transplant.
      aCandidates with these primary diseases are eligible for SLK transplant regardless of GFR or CKD status.
      Beyond allocation policy, a number of emerging approaches to the prevention and treatment of CKD after SOT deserve further study. Clinical risk tools are available to predict those liver transplant candidates at most risk of kidney failure 5 years after transplant, which could be used for further risk stratification.
      • Israni A.K.
      • Xiong H.
      • Liu J.
      • et al.
      Predicting end-stage renal disease after liver transplant.
      ,
      • Sharma P.
      • Goodrich N.P.
      • Schaubel D.E.
      • Guidinger M.K.
      • Merion R.M.
      Patient-specific prediction of ESRD after liver transplantation.
      Patient education programs and clinical pathways can better streamline care for individuals at risk and those with established disease.
      • Park J.M.
      • Koerschner C.
      • Mawby J.
      • et al.
      Knowledge of chronic kidney disease among liver transplant recipients.
      ,
      • Leek R.B.
      • Park J.M.
      • Koerschner C.
      • et al.
      Novel educational and goal-setting tool to improve knowledge of chronic kidney disease among liver transplant recipients: a pilot study.
      Involvement of the general nephrologist earlier in posttransplant management may be valuable because even mild CKD in the first year after liver transplant has been associated with increase in mortality (Table 3).
      • VanWagner L.B.
      • Montag S.
      • Zhao L.
      • et al.
      Cardiovascular disease outcomes related to early stage renal impairment after liver transplantation.
      Table 3Management Considerations of Kidney Disease in the Nonkidney Organ Transplant Candidate/Recipient, With Proposed Clinical Provider Roles and Responsibilities
      Clinical PresentationAssessmentNephrology-specific InterventionsTransplant CenterTransplant NephrologyGeneral Nephrology
      Pretransplant
      Progressive CKD and progressive end-stage organ diseaseKidney function assessment (eg, renal ultrasound, urinalysis, urine protein, eGFR/mGFR)HTN and volume status management, CKD education and management (Box 1)
      Acute exacerbation of organ disease and kidney functionEvaluation for intercurrent kidney injuries; renal preservation strategiesAvoidance of nephrotoxic insults, medication review, imaging modality review, management of hemodynamic status
      Imminent transplantDetermination of eligibility for simultaneous organ/kidney transplantFormal consultation, review of criteria for kidney transplant
      Management of AKIAssessment for transplant eligibility, management of short-term dialysis
      Posttransplant: 0-2 Months
      Reduced kidney function/recoveryManagement of AKIAssessment for nephrotoxic insults, management of short-term dialysis
      ImmunosuppressionAssessment for/implementation of kidney-protective strategies
      Posttransplant: 2-12 Months
      CKDCKD management; assessment of GFRHTN and volume status management, CKD education and management (Box 1)
      ImmunosuppressionAssessment for/implementation of kidney-protective strategies
      Eligibility for kidney transplantLiving kidney donor education, “safety net” eligibility assessment
      Posttransplant: > 12 Months
      CKDCKD management; assessment of GFRHTN and volume status management, CKD education and management (Box 1), consideration of kidney biopsy, dialysis modality planning
      ImmunosuppressionAssessment for/implementation of kidney-protective strategies
      Determination of eligibility for kidney transplantTransplant referral and assessment, living kidney donor education
      This template will vary according to the individual transplant center’s resources and personnel but forms a basis for collaborative care across the transplant continuum. Checkmark indicates roles and responsibilities are established; focus should be on strategies to increase collaboration and encourage ongoing management of CKD. Star denotes roles and responsibilities are less established; focus should be on appropriate transitions of care and follow-up after treatment interventions. Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; (e)GFR, (estimated) glomerular filtration rate; HTN, hypertension; mGFR, measured glomerular filtration rate.
      Biomarkers of injury also should be further explored. For example, urinary neutrophil gelatinase-associated lipocalin (NGAL) when measured at 24 hours after reperfusion has been shown to be independently associated with CKD at 5 years after liver transplant.
      • Cullaro G.
      • Pisa J.F.
      • Brown Jr., R.S.
      • Wagener G.
      • Verna E.C.
      Early postoperative neutrophil gelatinase-associated lipocalin predicts the development of chronic kidney disease after liver transplantation.
      Kidney injury–sparing immunosuppressive strategies should be further developed and may include delayed CNI introduction to promote renal recovery for those with postoperative reduced kidney function
      • Lange N.W.
      • Salerno D.M.
      • Sammons C.M.
      • Jesudian A.B.
      • Verna E.C.
      • Brown Jr., R.S.
      Delayed calcineurin inhibitor introduction and renal outcomes in liver transplant recipients receiving basiliximab induction.
      ,
      • Sharma P.
      • Sun Y.
      • Neal J.
      • et al.
      Renal outcomes of liver transplantation recipients receiving standard immunosuppression and early renal sparing immunosuppression: a retrospective single center study.
      and later CNI conversion with novel immunosuppressive agents such as belatacept. Ideally, future studies may test interventions based upon these preliminary findings (Box 2).

      Conclusion

      In NKSOT recipients, the etiology of CKD is often multifactorial. Judicious use of simultaneous kidney-SOT and management of perioperative AKI are important interventions for NKSOT patients at risk for advanced CKD. Subsequently, blood pressure control and diabetes control are primary considerations, while immunosuppression manipulation should be considered a secondary intervention with unproven benefit particularly after the first year of transplant. Once NKSOT recipients have progressed to late-stage CKD and kidney failure, consideration of kidney transplant is important as the SOT population enjoys survival benefits compared with remaining on the waiting list. However, survival of SOT recipients after kidney transplant (particularly the lung transplant population) remains inferior to the primary kidney transplant population. Collaborative care between transplant clinicians and nephrology practitioners is likely to be valuable in the SOT patient population to attenuate kidney function decline, appropriately manage late-stage CKD, and reduce the increasing burden upon the kidney transplant waiting list.

      Article Information

      Support

      None.

      Financial Disclosure

      Dr Wiseman serves as a consultant for Veloxis (the manufacturer of Envarsus) and has received research support from Novartis (the manufacturer of Zortress [everolimus]), Astellas (the manufacturer of Prograf [tacrolimus]), and Bristol Myers Squibb (the manufacturer of belatacept).

      Peer Review

      Received January 27, 2021, in response to an invitation from the journal. Evaluated by 3 external peer reviewers, with direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form October 25, 2021.

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