Kidney Disease in Non-kidney Solid Organ Transplantation Ⅱ

KIDNEY DISEASE AFTER LIVER TRANSPLANTATION

Kidney disease is common for patients with liver failure, due to hemodynamic changes associated with portal hypertension as well as disease processes impacting both organs e.g., viral hepatitis, hepatorenal syndrome, secondary immunoglobulin A nephropathy, oxalosis[2,3]. Although hepatitis C as a primary diagnosis of liver failure is declining, as described by the Organ Procurement Transplant Network/SRTR (OPTN/SRTR) 2019 annual data report, it still constitutes 12.6% of liver registrations [25]. In addition to its association with glomerulonephritis, hepatitis C has been shown to increase the risk of developing diabetes mellitus[3]. As previously mentioned, CKD is often underreported in this group of NKSOT recipients due to liver failure-mediated sarcopenia and malnutrition[26]. Here we will explore recent studies describing kidney function after liver transplantation. Ojo et al[2] utilizing SRTR data, observed that in 36849 liver transplant recipients at 1-year follow-up, 8% had advanced CKD (CKD stage IV or V) and at 60 mo, 18.1% did. Key risk factors associated with chronic renal failure (CRF) after liver transplantation were pre-transplant GFR, particularly that of ≤ 29 mL/min/1.73 m2 [relative risk (RR) = 3.78], postoperative renal failure (RR = 2.11), pre-transplant dialysis (RR = 1.45), hepatitis C (RR = 1.22), and pre-transplant diabetes mellitus (RR = 1.39). 

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Given the dilemmas associated with creatinine/eGFR interpretation in liver disease, several groups have attempted to evaluate kidney function after liver transplantation by serially following mGFR as summarized below. Cohen et al[27] looked at 353 liver transplant recipients with pre- and post-transplant mGFR via iothalamate clearance. The mean age at transplant was 50.3 years, with a mean follow-up of 6.8 years. 41% of their liver transplant recipients were transplanted due to cholestatic liver disease. Tacrolimus (51.7%) was the most common CNI used. At 3 years and 5 years in both the entire group (n = 353) and intensive follow-up group (n = 191), mean mGFR was > 50 mL/min/body surface area at 3 (56.5 and 56.4) and 5 years (56.6 and 53.9). Although mGFR at listing did not correlate well with 3-year mGFR in the intensive follow-up group (correlation coefficient, r = 0.35). 1-year mGFR correlated relatively well with 3-year mGFR (r = 0.72). The authors reported a near doubling of transplant recipients with mGFR < 40 at 3 years post-transplant (39/191, 20.4%) vs pre-transplant (10/191, 10.5%). In the entire cohort of 353 orthotopic liver transplant (OLT) recipients, 15 patients (4.2%) developed ESKD. The mean time to ESKD was 7.5 years after transplant (range = 2.5-11.3 years). In Kaplan-Meier analysis, the incidence of ESKD within 10 years was 10% ± 3%, 95%CI: 3%-15%.

In their study of 152 OLT recipients at least 5 years post-liver transplant, Herlenius et al[28] set out to describe the prevalence of CKD by linking early mGFR to late mGFR and to determine risk factors leading to CKD after liver transplant. At 5 years, 8 (5%) of the patients were on dialysis. GFR decreased by 36% at 5 years and 42% at 10 years. The authors observed that baseline mGFR had a weak correlation with 5-year mGFR (Pearson correlation coefficient, R 2 = 0.27). A stronger correlation was observed between 3 mo and 5-year mGFR [0.67 and R 2 = 0.46 (2-tailed P < 0.001) and 1-year and 5-year mGFR (0.72 and R 2 = 0.52 (2-tailed P < 0.001)]. They also conducted a multivariate logistic regression analysis on risk factors for developing advanced kidney disease (CKD IV, V) at 5 years post-liver transplant and found that only mGFR 3 mo post-liver transplant below 30 mL/min/1.73 m2 was predictive (P = 0.03).

The following studies describe kidney disease after liver transplantation using eGFR: Wilkinson and Pham[29] reported the following rates in terms of incidence and mortality rate from AKI and CKD: 17%- 95% rate of AKI with a mortality rate of 25%-74% in those on RRT vs 52% not requiring RRT; 10%-20% incidence of CKD, 2%-8% rate of ESRD with a mortality rate between 25%-50%. AKI risk factors included delayed graft function, poor liver allograft function, body mass index, use of cyclosporine-A, and pre-transplant AKI. CKD risk factors included the following: AKI, need for hemodialysis, hepatorenal syndrome, CNI use, diabetes mellitus, hepatitis C, and age. Gonwa et al[30] inspected 834 liver transplant recipients which they stratified into 3 groups: Controls (n = 748), CRF [defined as sustained SCr > 2.5 mg/dL, (n = 41)], and ESRD (n = 45). They observed an incidence of “severe renal dysfunction”, CRF + ESRD in 18.1% of OLT recipients after 13 years of follow-up. In multivariate stepwise logistic regression analysis, increased creatinine by 1 mg/dL above the average of the group conferred the following risk for CRF or ESRD: Creatinine at 4 wk (odds ratio (OR) = 1.598, 95%CI: 1.076- 2.372), creatinine at 3 mo (OR = 2.254, 95%CI: 1.262-4.025), and 1-year creatinine (OR = 2.582, 95%CI: 1.633-4.083). Survival was markedly decreased at year 13 in the ESRD group (28.2%) compared to the control group without significant kidney disease (54.6%). The authors also noted decreased survival after ESRD onset for those who did not receive a subsequent kidney transplant: 6 years after the onset of ESRD, patients receiving HD without a transplant had a survival of only 27% compared with 71.4% in the kidney transplant group (P = 0.04). O’Riordan et al[26], in their study of 230 OLT recipients, observed that at 5 years post-liver transplant, 71% had CKD with GFR < 60 mL/min. Pre-transplant factors associated with progression to ESRD included age, female gender, liver transplant from cytomegalovirus (CMV) positive donor to CMV positive recipient, and pre-liver transplant diabetes in univariate analysis (all P < 0.05). Though pre-OLT proteinuria was missing in 53% of patients, more than 40% of those with measurements had > 150 mg/L/d. Mean pre-transplant proteinuria = 0.21 ± 0.29 g/L (range = 0.00-2.09) and was significantly associated with CKD progression (OR = 5.36, 95%CI: 1.41- 20.45, P = 0.01). In multivariate analysis for factors impacting CKD progression to stage 5 disease, pre-OLT total urinary protein (OR = 7.48, 95%CI: 1.04-53.97) and female gender (OR = 7.84, 95%CI: 2.04- 30.08, P < 0.005) were the most predictive. In multivariate Cox regression analysis, GFR < 30 mL/min (HR = 3.05, 95%CI: 1.21-7.70, P = 0.02) was meaningfully associated with reduced patient survival. Similarly, survival was significantly decreased for those with GFR < 30 mL/min compared to those with GFR > 30 mL/min in Kaplan-Meier analysis (log-rank P = 0.04). Wyatt and Arons[31] observed significant mortality in 358 liver transplant recipients who sustained AKI, irrespective of whether they required RRT or not: AKI without RRT [adjusted OR (aOR) = 8.69, 95%CI: 3.25-23.19, P < 0.0001]; AKI requiring RRT (aOR = 12.07, 95%CI: 3.90-37.32, P < 0.0001). Bahirwani et al[32] retrospectively reviewed 40 OLT recipients with CKD prior to transplant, which they defined as SCr ≥ 2 mg/dL for 90 d. Notable demographics included median eGFR of 24 mL/min (range 16-33), mean age of 56.5 years [interquartile range (IQR) = 52-60.5], 21 (53%) of the group had liver failure from hepatitis C, median Model of End Stage Liver Disease (MELD) of 26 (range = 22-31) and 19 (48%) of the recipients had pre-transplant diabetes. Interestingly, they observed the following median eGFR at 1, 2, and 3 years post-transplant 35 mL/min (IQR = 27-47), 34 mL/min (IQR = 20-51), and 37 mL/min (IQR = 22-55). 53% of recipients developed CKD stage 4 at 3 years. At a median follow-up of 1.21 years post-transplant, 12 (30%) of recipients were on RRT. On univariate analysis, pre-transplant diabetes (HR = 4.23, 95%CI: 1.12-15.93, P = 0.03) and African American race (HR = 3.44, 95%CI: 1.04-11.35, P = 0.04) significantly predicted post-transplant RRT. This association was not significant on multivariate analysis. Interestingly, hypertension, hepatitis C, pre-transplant RRT, MELD score, and pre-transplant eGFR were not predictive of post-transplant RRT on univariate analysis (all P > 0.05). Cabezuelo et al[33] analyzed 184 OLTs for both early postoperative acute renal failure (> 50% increase in SCr within 1 wk of transplant) and late postoperative acute renal failure (similar increase in creatinine two to four weeks post-transplant). 12% of the cohort required RRT. Predictors of early acute renal failure were pre-transplant acute renal failure (OR = 10.2, P = 0.025), serum albumin (OR = 0.3, P = 0.001), duration of dopamine treatment (OR = 1.6, P = 0.001), and grade II-IV dysfunction of the liver graft (OR = 5.6, P = 0.002). Late postoperative risk factors were: Re-operation (OR = 3.1, P = 0.013) and bacterial infection (OR = 2.9, P = 0.017). Pham et al [34] in their review of AKI in NKSOT refer to a study whereby renal recovery after liver transplantation in recipients who were on dialysis at transplant was related to pre-transplant dialysis vintage: The percentage of renal function recovery for those who were on dialysis for ≤ 30 d 31-60 d, and 61-90 d were 71%, 56%, and 24%. They also note that in an analysis of the Canadian Organ Replacement.

Register database by Al Riyami et al[35], despite a low incidence of ESRD (2.9%) in their cohort, the unadjusted mortality rate for those with AKI requiring dialysis compared to those who did not was 49.2% vs 26.8%, respectively (P < 0.001)[34,35]. 

A particularly interesting study by Kollmann et al[36] investigated whether donor type [donation after circulatory death (DCD) (n = 57) vs donation after brain death (DBD) (n = 446) or living donor liver transplantation (LDLT) (n = 178)] impacted AKI rates. They observed that perioperative AKI (defined as AKI within the first 7 postoperative days) was observed more often in the DCD group (61%; DBD, 40%; and LDLT, 44%; P = 0.01) and was associated with significantly higher peak aspartate aminotransferase levels (P < 0.001). DCD patients also had a significantly higher peak SCr (P < 0.001) and a trend toward higher rates of AKI stage 3 per Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease criteria (DCD, 33%; DBD, 21%; LDLT, 21%; P = 0.11). AKI recovery (DCD, 77%; DBD, 72%; LDLT, 78%; P = 0.45) and progression to CKD (DCD, 33%; DBD, 32%; LDLT, 32%; P = 0.99) were similar across groups. Patient survival was significantly lower in OLT recipients who received DCD or DBD organs and required perioperative RRT in multivariate analysis (HR = 7.90; 95%CI: 4.51-13.83; P < 0.001).

While a plethora of studies examining kidney function after liver transplantation exist, this appears to be representative of the body of work, including both studies using measured and eGFR to assess kidney function. As is the case of longitudinal studies, impaired kidney function definitions and immunosuppression eras have changed over time, rendering comparison difficult. Clearly, AKI and CKD are adverse outcomes that lead to adverse outcomes including ESKD and patient mortality. While some risk factors are unmodifiable (age, sex, ethnicity), potentially modifiable risk factors, such as diabetes, hypoalbuminemia, proteinuria, and donor type were observed in these studies. Perhaps these modifiable risk factors can be diagnosed and managed as part of pre-transplant care to optimize before transplantation, especially in those with lower baseline kidney function. Moreover, these studies support the use of mGFR in select candidates and recipients both in the pre- and post-transplant contexts to identify kidney disease better. These studies are abbreviated in Table 2. 

KIDNEY DISEASE AFTER HEART TRANSPLANTATION 

With kidney and heart functions intricately related, disease in one organ precipitates disease in the other; the same comorbidities (hyperlipidemia, hypertension, diabetes, metabolic syndrome, etc) lead to kidney and heart disease[2,10,37]. While heart failure can arise from kidney-sparing, acute conditions, de novo heart failure in CKD is a common occurrence, with rates cited between 17%-21%[38]. Estimating pre-heart transplant kidney disease can be challenging in waitlisted heart transplant candidates due to underestimated eGFR stemming from cardiac cachexia/poor nutrition. Moreover, thoracic transplantations (heart and lung) are complex, high-risk surgeries with high rates of AKI due to aortic cross-clamping, cardiopulmonary bypass, aggressive diuresis, and fluid shifts[3]. The following studies describe kidney disease after heart transplantation: Ojo et al[2] described a perioperative acute renal failure rate of 20%-30% of heart transplant recipients with a 10.9% CKD IV/V rate at 60 mo post-transplant. In addition to shared mechanisms, they noted systemic atherosclerosis, and renal hypoperfusion from cardiorenal disease as organ-specific risk factors leading to kidney dysfunction[10]. 

In their retrospective cohort study of 233 orthotopic heart transplant (OHT) recipients, Cantarovich et al[39] observed that early renal dysfunction predicts poor long-term kidney function: A 30% decline in CrCl between 1 mo and 3 mo independently predicted the need for chronic dialysis (P = 0.04) and time to first CrCl < 30 mL/min at > 1 year after transplant (P = 0.01). Rubel et al[40] studied 370 OHT recipients with up to 10 year of follow-up up looking for early GFR decline and ESKD. They found mean eGFR fell 24% at year one, 23% of patients developed a 50% reduction in GFR by year 3, and that 20% of the cohort developed ESRD at 10 years post-transplant. Significant predictors of post-transplant ESRD in Cox multivariate analysis included the following: GFR < 50 mL/min (HR = 3.69, P = 0.024); high mean cyclosporine trough in the first 6 mo (HR = 5.10, P = 0.0059); and presence of diabetes (HR = 3.53, P = 0.021). Lindelöw et al[37] investigated kidney outcomes in 151 of their OHT recipients with 9-year follow-up. The average preoperative GFR (66 ± 17 mL/min per 1.73 m2 ) declined to 52 ± 19 (P < 0.0001) at 1 year. From 2 years to 9 years after heart transplantation, overall kidney function remained fairly stable (all P > 0.05). There was no significant correlation between the preoperative GFR and postoperative renal function or survival. Recipient age predicted post-heart transplant renal function. Boyle et al[14] set out to determine risks and consequences of post-heart transplant AKI in their study of 756 OHT recipients. They observed an AKI rate of 5.8% (44 of 756). Significant AKI risk factors were insulin-dependent diabetes (P = 0.019) and prior cardiac surgery (P = 0.014). OHTs with AKI had higher preoperative SCr, lower preoperative GFR, lower preoperative albumin, lower preoperative hematocrit, increased cardiopulmonary bypass time, and increased blood transfusion needs compared to those without AKI (all P < 0.01). They observed a 50% (22/44) mortality rate in OHTs with AKI requiring dialysis compared to those who did not have AKI (1.4%, 10/712). 

In their analysis of CKD risk factors after heart transplantation, Hamour et al[8] evaluated 352 OHT recipients. They found that the cumulative probability of eGFR < 45 mL/min/1.73 m2 over time was the following: 45% at year 1, 71% at year 5 and 83% at year 10. In their multivariable logistic regression model for the decrease in eGFR to < 45 mL/min/1.73 m2 at 3 years, they found the following significant risk factors: Post-operative RRT for AKI, P < 0.001; pre-transplant diabetes (P = 0.005); increasing recipient age, (P < 0.001); female recipient (P = 0.029) and female donor (P = 0.04). Interestingly cyclosporine regimen was not significantly associated with CKD development progression. In their analysis of the Planning and Research Cooperative database, which included 141 OHTs, Wyatt and Arons[31] observed that postoperative AKI, especially that requiring RRT, was associated with increased mortality (aOR = 8.96, 95%CI: 1.75-45.80, P = 0.008).

As previously described, progressive CKD is common after heart transplantation. Similar to other NKSOT, perioperative/early AKI incites CKD and increased mortality. Modifiable risk factors exist in addition to those inherent to heart failure and subsequent transplantation. Though studies have mixed results, recipient age (as modified by selection/organ allocation), pre-transplant diabetes, as well as elevated CNI levels are potentially modifiable. Moreover, several of the risk factors described by Boyle et al[14] such as low pre-transplant albumin, lower preoperative hematocrit are perhaps biomarkers of frailty, and malnutrition and may suggest a role for “pre-habilitation” to bolster nutrition, frailty, and anemia preoperatively in hopes of abating AKI and future adverse renal and patient outcomes in heart transplantation. These studies are abridged in Table 3. 

KIDNEY DISEASE AFTER LUNG TRANSPLANTATION

Lung transplantation shares many parallels with heart transplantation in terms of kidney disease. For one, end-stage lung disease is a debilitating, profound state of illness rendering GFR estimations difficult due to the toll chronic lung disease exerts. As described previously, characteristics inherent to thoracic transplantation predispose lung transplant recipients to AKI[3]. Below are studies chronicling kidney disease after lung transplantation. 

In their examination of SRTR, Ojo et al[2] observed a 2.9% incidence of CKD IV/V at 12 mo and 15.8% incidence of GFR < 30 mL/min/1.73 m2 at 5 years post lung transplant. Rocha et al[41] examined 296 lung transplant recipients whereby they observed an overall AKI rate of 56% (n = 166). 8% of those with AKI required RRT (n = 23). AKI predictors included the following in multivariate analysis: Baseline GFR (OR = 0.98, 95%CI: 0.96-0.99, P = 0.012), pulmonary diagnosis other than chronic obstructive pulmonary disease (OR = 6.80, 95%CI: 1.5-30.89, P = 0.013), mechanical ventilation > 1 d (OR = 6.16, 95%CI: 1.70- 22.24, P = 0.006) and parenteral amphotericin B use (OR = 3.04, 95%CI: 1.03-8.98, P = 0.045). Patient survival was significantly impacted both by AKI and AKI requiring RRT with one-year patient survival of 92.3%, 81.8% and 21.7% in the no AKI, AKI sans RRT and AKI requiring RRT subgroups, respectively (P < 0.0001). This relationship was observed at 5 (61%, 58% and 13%) and 10 years (59%, 55% and 13%) as well. Single lung transplant (HR = 1.78, 95%CI: 1.24-2.55, P = 0.0018) and AKI requiring RRT (HR = 6.77, 95%CI: 4.00-11.44, P < 0.0001) were independent variables associated with increased mortality in multivariate Cox proportional-hazards regression. In their prospective trial examining mGFRs in lung transplant recipients, Broekroelofs et al[42] identified an association between pulmonary diagnosis and GFR loss. A nearly 50% decrease in mGFR at 36 mo post-transplantation (100 mL/min pre-transplant vs 51 mL/min at 36 mo post-transplant) was observed in lung transplant recipients. The highest median loss of GFR occurred in cystic fibrosis (CF) recipients (-10 mL/min/year, range -14 to -6 mL/min/year), compared to those who were transplanted for emphysema (-6 mL/min/year, range -27 to +12 mL/min/year) and pulmonary hypertension (-1 mL/min/year, range -6 to +7 mL/min/year). This is a relatively consistent finding as described in other studies with CF lung transplant recipients having more severe kidney complications than lung transplant recipients with lung failure from pulmonary hypertension[34,43].

Mason et al[44] retrospectively reviewed their 425 lung transplant recipients to describe dialysis after transplantation. In examining the need for dialysis, they determined a prevalence 0.6%, 4%, 9%, 13%, 16% and 19%, at 30 d and 1, 3, 5, 7 and 9 years post-transplant. Significant risk factors associated with dialysis were the following: Lower creatinine clearance (P = 0.03) and greater recipient height (P = 0.0002). Notably, donor blood type O (P = 0.001) and head trauma as donor cause of death (P = 0.01) decreased risk for dialysis needs. Mortality risk after ESRD was 100%, 17% and 3.1% per year at 3 mo, 1 year and 3 years, respectively. Median survival after starting dialysis was 5 mo. In their single-center retrospective study, Canales et al[45] examined 186 lung transplant recipients (plus 33 heart-lung transplant recipients), looking for predictors of time to doubling SCr and ESKD. A major takeaway observed from their trial was the prevalence of CKD, particularly advanced CKD at 1 and 7 years compared to the NHANES III cohort. At 1 and 7 years, the prevalence of CKD IV (81 and 95 times) and V (10 and 20 times) were substantially higher in the lung, and heart-lung transplant recipients than the general population as described by NHANES III. In their multivariate step model, older age, lower 1 mo GFR and CSA use in the first 6 mo were associated with a faster doubling of SCr (all P < 0.05). AKI episodes (RR = 1.6, 95%CI: 1.2-2.0, P < 0.001), and older age at transplant (RR = 1.02, 95%CI: 1.008-1.04), P = 0.004) were significant predictors of death. Ishani et al[9] in their study of the lung, heart-lung transplant recipients found that diastolic blood pressure greater than 90 mmHg (RR = 1.30, 95%CI: 1.05-1.60, P = 0.02), 1 mo post-transplant creatinine (RR = 1.28, 95%CI: 1.02-1.70, P =0.03) were associated with increased risk to time to doubling baseline SCr. Cause of lung failure, age at transplant, or rejection were significantly associated. Tacrolimus use in the first 6 mo after transplant was associated with a decrease in the risk for doubling time of SCr (RR = 0.38, 95%CI: 0.19-0.79, P = 0.0009). Paradela de la Morena et al[46] retrospectively evaluated 161 lung transplant recipients at their centers. They found that 68.6% of the cohort developed CKD. On multivariate analysis, older age (OR = 2.0; P < 0.001) and CMV infection (OR = 2.2; P = 0.045) were associated with CKD development. CKD at 1 year was associated with increased mortality compared to those without CKD (P = 0.001).

Kidney disease, both in terms of AKI and CKD, is common in lung transplant recipients. There appear to be certain risk factors associated with CKD development, namely lower pre- and early post-transplant creatinine, AKI, end-stage lung disease from CF, and older recipient age. There appears to be a subset of lung transplant recipients at higher risk for progressive CKD. Early transplant nephrology referral may be of benefit for these patients. Despite CKD commonly manifesting post-lung transplant, modifiable/preventable risk factors including diastolic blood pressure and CMV infection are potential targets in terms of blood pressure optimization and prophylaxis strategies to mitigate CKD development. In summary, early multidisciplinary care and co-management from transplant pulmonology and nephrology is vital for appropriate patient selection and continued management of kidney disease in lung transplant recipients. These studies are summarized in Table 4. 

KIDNEY DISEASE AFTER INTESTINAL TRANSPLANTATION 

Kidney disease after IT is understudied due to the rarity of IT. As described in the OPTN/SRTR annual report, 104 ITs were performed in 2018[47]. We will highlight pertinent studies in the field of intestinal transplantation discussing kidney disease. Huard et al[48] in their evaluation of SRTR data of 843 IT recipients, assessed incidence, risk factors, and impact on survival of severe CKD, which they defined as GFR < 30 mL/min/1.73 m2 in IT recipients. They observed a cumulative incidence of severe CKD of 3.2%, 25.1%, and 54.1% 1, 5 and 10 years after IT, respectively. Female sex (HR = 1.34), older age (HR = 1.38/10 year increment), catheter-related sepsis (HR = 1.58), steroid maintenance immunosuppression (HR = 1.50), graft failure (HR = 1.76), acute cellular rejection (HR = 1.64), prolonged requirement for IV fluids (HR = 2.12) or total parenteral nutrition (HR = 1.94), and diabetes (HR = 1.54) were associated with severe CKD. Individuals with higher GFR at the time of IT (HR = 0.92 for each 10 mL/min/1.73 m2 increment), and those receiving induction therapies (HR = 0.47) or tacrolimus (HR = 0.52) showed lower hazards of severe CKD. In adjusted analysis, severe CKD was associated with a significantly higher hazard of death (HR = 6.20). Herlenius et al[28] studied 10 patients after IT via serial measurements of GFR. They performed measurements at baseline, 3 mo post-transplantation, and yearly thereafter. The median follow-up time for the cohort was 1.5 years (0.5-7.8 years). Tacrolimus was discontinued in four patients because of impaired renal function. These four patients were switched to sirolimus at 11, 18, 24, and 40 mo post transplantation. Median baseline GFR was 67 (22-114) mL/min/1.73 m2 (22-114). In the adult patients, GFR 3 mo post transplantation had decreased to 50% of the baseline. At 1 year, median GFR in the adult patients was reduced by 72% (n = 5). Two patients developed renal failure within the first year and required hemodialysis. Notably, eGFR via the MDRD formula consistently overestimated GFR by approximately 30% compared with the mGFR. Ueno et al[49] examined 24 adult IT recipients with at least 2 years of survival in the tacrolimus-based era. They measured kidney function via 6 mo averages of SCr along with calculating creatinine clearance per the Cockcroft-Gault formula. Post-transplant mean CrCl was significantly lower at 2 years compared to baseline (49.6 mL/min/1.73 m2 vs 114 mL/min/1.73 m2 , P < 0.0001). The authors also evaluated the role of tacrolimus by cumulative level, which they defined as the sum of weekly average tacrolimus levels (ng∙day/mL). They found that recipients with cumulative tacrolimus levels > 4500 ng ng∙day/mL had significantly decreased CrCl at 2 years compared to those with cumulative tacrolimus levels less than 4500 ng ng∙day/mL (P = 0.006).

Kidney disease after IT is understudied. Even so, there are key takeaways that can be derived from the data to date. In this moribund population, perhaps mGFR and/or cystatin C could be used adjunctively with typical estimating equations to better characterize kidney function and guide nephrology referral/management. One can surmise that a subset of patients i.e., older, diabetic IT recipients, with persistent IV fluid needs could benefit from early transplant nephrology care. These results are described in Table 5. 

DIAGNOSIS AND MANAGEMENT OF CKD POST-NON-KIDNEY SOT 

Uncertainty regarding kidney function is an overarching theme surrounding kidney disease in NKSOT. While mGFR would be the ideal, most accurate/precise test of function, it is impractical, expensive, and not widely available. As previously described, CKD-EPI and MDRD in some contexts appear to be acceptable eGFR equations that can aid in screening for and diagnosis of CKD. Bloom et al[3] endorse using MDRD, acknowledging that it is conservative i.e., would be sensitive in that it has better capture of SOT recipients with permissible false-positivity. As with any test, patient selection is of utmost importance, in both a macro and micro sense i.e., a test primarily based on clearance of a muscle waste product will be flawed in those with significant malnutrition, or sarcopenia. 

Nephrologists are aptly suited to manage kidney disease in NKSOT as the modifiable risk factors leading to progressive CKD are shared across SOT recipients and the general public alike. As is well described in Bloom et al’s seminal work, CKD management after NKSOT is founded on the same tenets of CKD management generally[3]. Fundamentally, CKD after NKSOT is CKD management + CNI considerations. In other words, the same disease processes that effect native kidney function remain relevant after SOT. The literature/guidelines describing CKD management are well described and summarizing them is beyond the scope of this review[1,12,50]. The impact of therapies and management strategies for risk factors leading to CKD in NKSOT is understudied. In the following sections, we will highlight salient points on CKD management. 

Proteinuria 

Renin-angiotensin-aldosterone system (RAAS) blockade for proteinuria management in transplant recipients is extrapolated from the non-transplant CKD literature with limited direct evidence. Most research in this domain has occurred in kidney transplants. Knoll et al[51] attempted to answer this question in the context of kidney transplant with a randomized controlled trial. However, as is aptly put by Toto[52] in his comment from Nature Reviews Nephrology, this study did not “settle the controversy surrounding the use of RAAS blockade in the renal transplant population”. Though proteinuria management in non-kidney SOT is understudied, RAAS blockade appears to be a reasonable approach not only for treating proteinuria but also for those with significant risk factors for heart disease given their cardioprotective benefit[53,54].

CNI use/minimization strategies 

With CNIs as possible potentiators of CKD, CNI-sparing/minimizing maintenance immunosuppression regimens have been proposed as a renoprotective management strategy. There is a large body of evidence examining CNI minimization in NKSOT, which we will discuss below. With the advent of tacrolimus and the results of ELITE-SYMPHONY, tacrolimus has ousted cyclosporine CNI-wise, as tacrolimus appears to have a less nephrotoxic profile[55]. Mechanistically, this may be due to less renal vasoconstriction as has been demonstrated in both in vivo and in vitro studies[3,56,57]. Pancreas transplant-wise, limited evidence exists supporting CNI minimization or sparing. While Kandula et al [58] compared the tacrolimus-sirolimus-based regimen to the tacrolimus-mycophenolate immunosuppression in PTA recipients, mean tacrolimus levels were similar across groups at all time points. 

In the context of liver transplantation, there is an expansive body of literature supporting the use of CNI-sparing or minimization therapy with sirolimus and mycophenolate[59-64]. For heart transplant recipients, CNI minimization/sparing has been shown as a viable immunosuppression approach. Cornu et al[65] in their systematic review and meta-analysis of eight studies on CNI minimization showed that creatinine clearance was preserved in individuals with impaired renal function, which they defined as eGFR < 60 mL/min, at 6 mo [+12.23 (+5.26, +18.82) mL∙min−1, P = 0.0003). Although longer-term benefit was not shown in this study, CNI minimization strategies were not associated with increased rejection, mortality or adverse events compared to the standard CNI regimen approach (all P > 0.05). As is aptly described by Zuckermann et al[66], the use of induction in OHT recipients has “provided immunosuppressive cover” to allow for the following approaches: CNI minimization and delayed CNI introduction whilst kidney function is recovering post-heart transplantation[66-70]. 

In lung transplant recipients, evidence exists supporting the use of CNI-sparing/minimization regimens. Högerle et al[71] in their recent review describe the following approaches including basiliximab induction, which showed favorable short-term renal outcomes. They also noted CNI minimization approaches with tacrolimus/mammalian target of rapamycin (mTOR) inhibitor combinations which showed improved renal function with comparable allograft/patient survival. Notably, mTOR use was associated with increased wound complications, proteinuria, hypertension, post-transplant diabetes, and dyslipidemia. They also highlighted CNI minimization approaches with mTOR use instead of anti-metabolite immunosuppression. Strueber et al[72] examined 190 lung transplant recipients randomized to everolimus or mycophenolate mofetil 1 mo post-transplant. Though results were limited due to lack of completion of the study protocol, rejection, and infectious complications were lower in the everolimus group of whom 20%-28% of recipients were also on reduced CNI doses. In a 3-year multicenter randomized prospective study, Glanville et al[73] did not show significant differences in creatinine at 3 years comparing lung transplant recipients on mycophenolate sodium vs everolimus. While the authors stated that they utilized reduced 2-h post-dose CSA levels in the everolimus group and that “most levels measured were within pre-specified target ranges”, granular data describing CNI levels in these cohorts is lacking. Further in support of CNI minimization/sparing is a study by Stephany et al[74], who observed improved GFR durable out to 18 mo for lung transplant recipients converted to sirolimus-based immunosuppression, with the greatest benefit incurred to lung transplant recipients without proteinuria.

In IT recipients, the benefit of CNI minimization/sparing strategies appears to be limited in terms of preserving renal function. Rutter et al[75] in their single-center study demonstrated a significant decline in renal function irrespective of tacrolimus exposure. Herlenius et al[76], in their study of 10 IT recipients, noted that 4 patients were switched from CNI to sirolimus-based regimen. Of these, one developed renal failure leading to hemodialysis, one died due to hemorrhage with CKD IV at the time of death, and the other 2 had “stable GFR” at 2 and 3 years post-conversion without developing rejection or intestinal allograft failure. Based on the initial successes of the BENEFIT and BENEFIT-EXT trials comparing belatacept to cyclosporine in kidney transplant recipients, belatacept in lieu of CNI or with CNI minimization has been proposed as a novel immunosuppression strategy for NKSOT[77,78]. There is mounting research describing CNI-minimizing or sparing approaches using belatacept in OHT recipients[79], lung transplant recipients[80], and PTA recipients[81,82]. More robust studies e.g., randomized control trials with longer follow-ups are needed to better understand outcomes related to belatacept in NKSOT as these early studies are limited in design (case-series, retrospective studies) and follow-up.

An important caveat to belatacept use is that of liver transplantation. As demonstrated by Klintmalm et al[83] in their phase II trial and Schwarz et al[84], concerns exist regarding allograft function and safety with belatacept. Though results from a study conducted by LaMattina et al[85] were more favorable, these are limited due to small numbers as well as the patients being converted back to a CNI-based regimen. Thus, belatacept use in liver transplantation is at most controversial. Additional studies sufficiently powered are needed to determine the efficacy and safety of belatacept in liver transplant recipients. 

Approaches to minimize CNI use via induction/maintenance immunosuppression appear promising in terms of preserving renal function. While these often incur adverse effects related to specific therapies e.g., mTOR inhibitors, in several instances, they have not led to decreased allograft or patient survival. Appropriate, sufficient CNI minimizing immunosuppression tailored to preserve renal function while also staving off rejection is achievable via multidisciplinary collaboration and dialogue between transplant experts across nonrenal organ systems and transplant nephrology.

Hypoalbuminemia 

Low serum albumin appears to impact kidney function in NKSOT recipients. As described in their review, Kim et al[86] note that hypoalbuminemia may indicate a poor nutritional state, impact pharmacokinetics/pharmacodynamics, and/or represent an increased inflammatory state. As a relatively inexpensive, trackable biomarker, perhaps albumin and goal albumin e.g., greater than 3.0 g/dL could be a pre-transplant goal for the multi-disciplinary team including nutritionists/dieticians to help patients with pre-transplant CKD with high risk for progression. 

Nephrology referral/management considerations

The integration of nephrology care into dedicated NKSOT care throughout various stages of pre-, peri-, and post-transplantation is critical for the diagnosis and management of kidney disease. Wiseman[12], in his recent review, provides substantive recommendations on the timing/appropriateness of nephrology referral, based on KDIGO guidelines, and management considerations across transplant time points in tabular form. As has been described throughout this study, SOT recipients are a unique subset of patients with CKD that often progress to ESKD necessitating RRT. This has led to the growing demand for kidney transplantation (KT) after solid organ transplantation which will be discussed subsequently.

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