Kidney function and non-kidney solid organ transplantation

INTRODUCTION — As outcomes following non-kidney solid organ transplantation have improved, chronic kidney disease (CKD) has become an increasingly prevalent complication in this population [1-3]. CKD occurs despite advancements in immunosuppression and perioperative management, as well as attention to cardiovascular risk factors and infectious complications [4].

The development of CKD is associated with enhanced morbidity and mortality [5].

Issues relating to kidney function following non-kidney solid organ transplantation, including the evaluation of kidney function prior to non-kidney organ transplantation, are presented in this topic review. A review of calcineurin inhibitor nephrotoxicity is presented separately. (See "Cyclosporine and tacrolimus nephrotoxicity".)

EVALUATION OF KIDNEY FUNCTION PRIOR TO NON-KIDNEY ORGAN TRANSPLANT — As a general rule, the preoperative evaluation of kidney function in candidates for non-kidney solid organ transplantation should focus on an assessment of prior kidney injury and function impairment (including duration and prior reversibility), the current level of kidney function, and the likelihood and rate of progression after solid organ transplantation. Patients who are likely to have stage 4 or stage 5 chronic kidney disease (CKD) early after non-kidney organ transplant or those with established primary kidney disease that is likely to progress rapidly (thereby requiring chronic kidney replacement therapy or kidney transplant listing shortly after transplant) should be listed for combined organ transplant. In an era of ever-increasing organ shortage and longer waiting times for kidneys, combined non-kidney and kidney organ transplantation should be considered very judiciously. Until recently, the absence of standardized medical criteria has largely resulted in transplant centers arbitrarily deciding on the indication for kidney transplantation in conjunction with a non-kidney organ.

In 2016, the United Network for Organ Sharing (UNOS) approved a new policy that formalized the allocation of simultaneous liver-kidney (SLK) transplants, which went into effect in August 2017 [6]. Similar formal criteria have not yet been established for combined heart-kidney or lung-kidney transplantation. (See 'Approach in liver transplant candidates' below.)

The vast majority of patients with normal or mild impairment in kidney function should receive a non-kidney solid organ transplant alone.

Initial evaluation — The initial evaluation of kidney function in non-kidney solid organ transplant candidates typically includes the following [7]:

●Assessment of prior kidney function over at least the past 90 days

●Measurement of current kidney function

●Urinalysis with microscopy

●Urinary electrolytes and osmolality

●24-hour urine collection for protein and creatinine

●Imaging studies of the kidneys

Based upon findings from this initial evaluation, a kidney biopsy may be required. (See 'Kidney biopsy' below.)

Assessment of prior kidney function — The level of kidney function and duration of kidney disease prior to organ transplantation is an important risk factor for posttransplant CKD. We determine the baseline serum creatinine concentration and the presence or absence of proteinuria in at least the three months prior to the current evaluation. Acute kidney injury (AKI) may be primarily due to deterioration in underlying heart, lung, or liver disease and is frequently compromised by poor effective circulating volume (eg, cardiorenal syndrome or hepatorenal syndrome). In these situations, kidney function may improve after replacement of the non-kidney failing organ.

Measurement of current kidney function — We routinely evaluate current kidney function through the use of the four-variable Modification of Diet in Renal Disease (MDRD) formula to estimate GFR. However, an alternative option is measurement of 24 hour urine creatinine clearance.

In general, methods of estimating GFR through the use of creatinine-based formulas lack precision, but they may provide a better assessment than serum creatinine alone in this patient population. The serum creatinine level may overestimate GFR, especially in patients with advanced liver disease or advanced heart failure, who frequently have poor nutritional status, low muscle mass, weight loss, and edema [8,9]. Since the pretransplant level of kidney function is one of the main predictors of kidney function following non-kidney solid organ transplantation, failure to accurately estimate GFR by the use of serum creatinine alone may result in unrealistic expectations of what kidney function will be after the transplant. The MDRD and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations have been shown to perform better than other creatinine-based estimating equations in solid organ transplant recipients [10]. More accurate methods of estimating GFR that rely on the renal clearance of various radionuclide markers (eg, 125I-labeled iothalamate) are limited by availability, cost, and radiation exposure [11]. (See "Assessment of kidney function".)

Limitations of the methods available to estimate GFR among transplant candidates are illustrated by the following studies [8,12,13]:

●In a large study of 1447 liver transplant candidates, serum creatinine-based GFR estimation equations (MDRD, Cockroft-Gault, and Nankivell formulas) were compared with 125I-labeled iothalamate GFR measurements performed before and after transplantation [8]. The mean pretransplant creatinine was 1.15 mg/dL, and the mean iothalamate GFR was 91 mL/min. Of the formulas, the MDRD estimates correlated best with GFR, although only 66 percent of estimates were within 30 percent of the measured GFR. When patients were divided into two groups according to GFR greater or less than 40 mL/min, all the formulas overestimated GFR in the patients with poor function (GFR <40 mL/min), while the formulas underestimated GFR in patients with better function (GFR >40 mL/min). (See "Assessment of kidney function".)

●In a study of 300 liver transplant candidates, serum creatinine-based GFR estimation equations (four- and six-variable MDRD, CKD-EPI) were compared with iohexol clearance as the gold-standard measure of GFR [13]. The six-variable MDRD formula had superior accuracy compared with the four-variable MDRD formula as well as with the CKD-EPI equations in identifying patients with GFR <30 mL/min. However, the six-variable MDRD underestimated kidney function in patients with GFR >30 mL/min.

A 24-hour collection for creatinine clearance is also likely to overestimate GFR in patients with kidney disease as the contribution of tubular secretion of creatinine to total clearance is increased in this subset of patients. This was best shown in a systematic review and meta-analysis of seven studies of 193 patients with liver cirrhosis in which the measured creatinine clearance was compared with true GFR (as assessed by inulin clearance) [14]. Overall, the measured creatinine clearance overestimated inulin clearance by a mean of 13 mL/min per 1.73 m², with the overestimation being highest in those with the lowest true GFRs. Among those with inulin clearance of less than 30 mL/min per 1.73 m² (stage 4 and 5 CKD), the measured creatinine clearance correctly classified 64 percent of patients, incorrectly classified 23 percent of patients as having GFRs between 30 to 59 mL/min per 1.73 m², and incorrectly classified 14 percent as having GFRs ≥60 mL/min per 1.73 m².

Some, but not all, studies suggest that cystatin C level measurement (where available) is a more sensitive indicator of kidney function than the serum creatinine concentration in patients with liver or heart disease [15-19]. As examples:

●In a study of 65 cirrhotic patients comparing cystatin C-based formulas with creatinine-based equations, using 51Cr-labeled EDTA-measured GFR as the reference, cystatin C-based formulas were no better than creatinine-based equations at estimating GFR [18].

●In a study of 202 liver transplant candidates, the Chronic CKD-EPI equation (CKD-Epi-CystC) performed better with less bias and more precision than all the creatinine-based equations, although the study was limited by a small number of patients with GFR <60 mL/min per 1.73 m² and Model for End-Stage Liver Disease (MELD) scores >15 [19].

Urine studies — The following urine studies should be performed:

●Urinalysis – A urinalysis should be performed to assess the presence of microscopic hematuria and proteinuria. (See "Urinalysis in the diagnosis of kidney disease".)

●Urine electrolytes and osmolality - Urine electrolytes are useful for assessing the effective volume status of patients and renal concentrating ability of patients with abnormal kidney function. We obtain urinary sodium or fractional excretion of sodium, which may also provide important diagnostic information for hepatorenal syndrome in patients awaiting liver transplantation, or for cardiorenal syndrome in heart transplant candidates. Such conditions represent situations in which the renal hemodynamic state usually improves with appropriate organ transplantation and where kidney function may be expected to likewise undergo some degree of recovery. (See "Fractional excretion of sodium, urea, and other molecules in acute kidney injury" and "Hepatorenal syndrome".)

●Twenty-four-hour urine collection – A 24-hour urine collection should be obtained for quantification of proteinuria. The presence of significant proteinuria (>500 mg/24 hours) should prompt a full evaluation to elucidate the nature and the prognosis of the kidney disease. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)

Kidney imaging — An imaging study (computed tomography [CT] scan, magnetic resonance imaging [MRI], or ultrasound) of the kidneys should be performed to exclude obstruction, stone disease, or cysts, as well as to evaluate kidney size and cortical thickness [20]. A kidney ultrasound can also provide information regarding echogenicity. Echogenic kidneys less than 10 cm in length usually indicate irreversible.

Kidney biopsy — Kidney biopsy may be considered when urinary abnormalities such as microscopic hematuria, proteinuria, and red blood cell casts are detected, or where the etiology of kidney dysfunction is not apparent from routine clinical data [21,22]. As an example, a kidney biopsy may help to differentiate intrinsic kidney disease from renal hypoperfusion.

Biopsy may be performed percutaneously under ultrasound or CT guidance if the patient condition allows, but it may be complicated by bleeding. In a retrospective series in which 44 liver transplant candidates with abnormal kidney function of undetermined etiology for less than eight weeks duration underwent percutaneous kidney biopsy, bleeding complications requiring at least one unit of blood occurred in 30 percent of patients [23]. More than half of the complications were major, defined by the requirement for two or more units of blood and/or intervention. By multivariable analysis, only International Normalized Ratio (INR) at the time of biopsy was an independent predictor of complication. A transjugular kidney biopsy should therefore be considered in patients with severe coagulopathy or on mechanical ventilation in whom a percutaneous approach may not be feasible or safe [24-26] (see "The kidney biopsy"). In a series of 30 heart transplant candidates that underwent kidney biopsy for an eGFR <40 mL/min per 1.73 m² or proteinuria >500 mg/day, only one patient had bleeding to the point of needing a blood transfusion or intervention to stop the bleeding [27].

Glomerulonephritis may be clinically silent in liver transplant candidates, especially those with hepatitis C infection. A single-center study, for example, reported the kidney histology and kidney outcomes of 30 liver transplant patients with hepatitis C virus (HCV) infection who underwent liver transplantation alone and had a kidney biopsy at the time of transplantation [28]. Immune-complex glomerulonephritis was noted in 25 patients, 12 with membranoproliferative glomerulonephritis, seven with IgA nephropathy, and six with mesangial glomerulonephritis; only one patient had a normal kidney biopsy. Of this cohort, 10 patients had normal serum creatinine levels, normal urinalysis results, and normal quantitative proteinuria. For five others, the only kidney abnormality was an increased serum creatinine level. No patient had cryoglobulins in the blood or kidney. This study, together with others [23,27], highlights the lack of correlation between clinical parameters and kidney histology in patients with decompensated liver or heart disease.

Whether post-liver or -heart transplant CKD progression is better predicted prior to surgery by kidney histological damage, kidney function, or clinical judgment, taking into account the entire clinical picture, has not been established.

Approach in liver transplant candidates — Since the introduction in 2002 of the MELD scoring system, which takes creatinine into account in prioritizing patients for liver transplantation, the proportion of liver recipients with impaired kidney function at the time of transplant has increased [29]. In parallel, the proportion of all liver transplants done as simultaneous liver-kidney transplants (SLK) has expanded from 2.2 percent in 1999 to almost 9.3 percent in 2016 [30]. This has led to concerns that some liver transplant recipients who may have reversible kidney injury are prematurely receiving kidney transplants [20].

The introduction of the new kidney allocation system in 2014 further unmasked concerns about the use of kidneys allocated as an SLK rather than as a kidney-alone transplant to ESKD patients. Because multi-organ allocation occurs before kidney-alone allocation, highly sensitized ESKD patients (with high priority in the new kidney-alone allocation system) lose the opportunity for potential kidney offers. In addition, approximately 50 percent of kidneys allocated for SLK are organs that, under kidney-alone allocation, would typically be prioritized for pediatric transplant candidates or young adults with the longest expected posttransplant survival [6]. Thus, an important goal in the evaluation of a liver transplant candidate with impaired kidney function is to determine if the patient should or should not be considered for SLK.

Eligibility criteria for SLK — From a clinical standpoint, the most important determinant of the need for SLK in patients with end-stage liver disease and kidney dysfunction is the ability to understand the nature and the anticipated course of the kidney disease after transplant. However, even though conditions such as hepatorenal syndrome and cardiorenal syndrome are usually associated with posttransplant improvement in kidney function, this is not always possible to predict. It is well recognized that protracted or recurrent episodes of AKI can cause progressive interstitial fibrosis and tubular atrophy, resulting in partial or complete non-recovery of kidney function [31], which may be potentiated in the peri- and posttransplant period by additional insults including hemodynamic stress and calcineurin inhibitor use.

As a result, until recently, the absence of standardized medical criteria has largely resulted in transplant centers arbitrarily deciding on the indication for kidney transplantation in conjunction with a non-kidney organ.

However, in 2016, the United States Organ Procurement and Transplant Network (OPTN) and United Network for Organ Sharing (UNOS) approved a new policy that formalized the allocation of SLK transplants, which went into effect in August 2017 [6]. In accordance with the new UNOS policy, liver transplant candidates who meet one of the following criteria are eligible for SLK allocation:

●Diagnosis of CKD with a measured or calculated GFR of ≤60 mL/min for more than 90 consecutive days and at least one of the following at the time of waiting list registration:

•ESKD on dialysis

•Measured or calculated creatinine clearance or GFR ≤30 mL/min

●Diagnosis of sustained AKI and at least one of the following, for the last six weeks:

•Dialysis at least once every seven days

•Measured or calculated creatinine clearance or GFR of ≤25 mL/min documented at least once every seven days

●Diagnosis of metabolic disease, with an additional diagnosis of at least one of the following:

•Hyperoxaluria

•Atypical hemolytic uremic syndrome from mutations in factor H or factor I

•Familial non-neuropathic systemic amyloidosis

•Methylmalonic aciduria

In addition to the above criteria defining eligibility for SLK, the new policy also includes a safety-net component to ensure that a liver transplant patient who is not initially offered SLK but who remains dialysis dependent after liver transplantation would be highly prioritized for subsequent kidney-alone offers, if both of the following conditions are met:

●The candidate is registered on the kidney waiting list between 60 and 365 days after liver transplantation.

●The candidate is either on chronic dialysis or has a measured or calculated creatinine clearance or GFR of ≤20 mL/min.

Role of pretransplant kidney biopsy — The role of pretransplant kidney biopsy in liver transplant candidates is uncertain. Kidney biopsy findings are not included in the 2016 OPTN/UNOS criteria for selection of patients for SLK. Some experts propose a pre-liver transplant kidney biopsy to help make this determination.

In addition to establishing the cause of impaired kidney function, other potential benefits of kidney biopsy include the ability to determine chronicity, treatability, and likelihood of future progression or reversibility. Some have therefore suggested using the extent of glomerulosclerosis (>40 percent) and interstitial fibrosis (>30 percent) to guide selection of patients for SLK [21,32,33]. Although this may represent useful information regarding chronicity of kidney injury, there are few data supporting the prognostic value of kidney histology or its advantage over kidney function studies alone.

In one retrospective study, kidney biopsies were performed in 59 patients undergoing evaluation for SLK; all patients had a measured creatinine clearance of <50 mL/min and/or proteinuria of >500 mg/day [33]. Patients with >40 percent glomerulosclerosis and/or >30 percent interstitial fibrosis, or those on hemodialysis for more than two months, were recommended for SLK. Based upon these biopsy criteria, only 11 of 36 patients listed for transplant were listed for SLK, and allocation of a kidney could be avoided in 70 percent of liver transplant candidates with kidney dysfunction. Among patients who underwent liver transplantation alone, the extent of glomerulosclerosis, but not interstitial fibrosis, predicted eGFR over the first 12 months posttransplant. However, the predictive ability of kidney biopsy decreased with greater time lapse between the biopsy and liver transplant. In another retrospective study, 22 percent of liver recipients whose pretransplant kidney biopsies were deemed to show reversible histology met criteria for kidney transplantation by 12 months post-liver transplant [34]. Further studies are required to determine whether pretransplant kidney biopsies can predict long-term kidney outcomes after liver transplantation.

Approach in heart transplant candidates — Up to one-third of all patients with New York Heart Association stage 3 or 4 end-stage heart failure have evidence of CKD [35]. Despite this, the rate of combined heart-kidney transplantation is far lower than that of simultaneous liver-kidney transplantation, with 637 combined heart-kidney transplants in the US between 2000 and 2012 [36]. Over this period, the rate of combined heart-kidney transplantation as a proportion of all heart transplants performed has increased from approximately 1.25 percent in 2000 to over 3 percent in 2011 [37]. Registry data indicate that patients receiving double-organ transplantation are more likely to be African American, diabetic, older, and have worse kidney function at the time of transplantation than patients receiving heart transplant alone [37].

Overall, the data on the evaluation of kidney function prior to orthotopic heart transplant are less well defined than in liver transplant candidates, and no formal guidelines exist. However, the following general principles may help guide the evaluation process:

●Given that the combination of kidney dysfunction and severe heart failure is common, the nature of the kidney disease, in terms of chronicity and reversibility, must be determined. Patients with a predominant picture of hemodynamically mediated AKI (cardiorenal syndrome type 1) and without obvious intrinsic kidney disease (as determined by the lack of proteinuria, normal kidney size on ultrasonography, and the absence of severe histopathology in kidney biopsy specimen) can recover sufficient native kidney function after restoration of kidney perfusion to not need subsequent kidney replacement therapy for several years. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology" and "Cardiorenal syndrome: Prognosis and treatment".)

●For heart transplant candidates with kidney dysfunction that appears to be due to irreversible kidney disease, especially those that have been dialysis dependent for a period of time (cardiorenal syndrome type 2), combined heart-kidney transplantation may be a viable option. Pretransplant kidney biopsy may be useful in determining chronicity of kidney injury, although the prognostic value of these findings, or the superiority of this approach over clinical judgment alone, is not established [27]. (See "Heart transplantation in adults: Prognosis", section on 'Heart-kidney transplantation'.)

A separate issue is kidney after heart transplantation when kidney failure develops after heart transplantation. (See 'Cardiac transplantation' below.)

CHRONIC KIDNEY DISEASE AFTER NON-KIDNEY ORGAN TRANSPLANTATION — The degree of kidney function impairment posttransplant and the rate of progression of chronic kidney disease (CKD) depend to a large degree on the extent of pretransplant kidney function impairment, the nature of the organ transplanted, the intra- and early postoperative course, and the immunosuppressive regimen and individual clinical features that determine susceptibility to kidney injury. Since more than one of these factors is usually present in any given patient, some degree of CKD is present in most long-term organ recipients.

Overview — Calcineurin inhibitor (cyclosporine and tacrolimus) therapy remains the cornerstone of immunosuppression in most organ recipients and has been implicated as a principal cause of posttransplantation CKD [38-57]. The histopathologic characteristic of calcineurin inhibitor nephrotoxicity is similar among patients with kidney and non-kidney organ recipients. These include vascular obliteration, focal hyalinosis of small renal arteries and arterioles, global or segmental glomerulosclerosis, tubular atrophy, and striped interstitial fibrosis [58-61].A retrospective report of 105 kidney biopsies performed in a cohort of 101 bone marrow, liver, lung, and heart recipients for acute and chronic indications demonstrated histological findings of primary glomerulonephritis in 17 percent and thrombotic microangiopathy in 10 percent of patients, respectively, in addition to nonspecific chronic changes, hypertension-related damage, and calcineurin inhibitor toxicity [62]. Patients in whom either acute tubular injury or thrombotic microangiopathy predominated had the worst postbiopsy kidney outcomes. A review of calcineurin inhibitor nephrotoxicity is available in a separate topic review. (See "Cyclosporine and tacrolimus nephrotoxicity".)

Besides calcineurin inhibitor nephrotoxicity, a number of other factors predispose to decreased kidney function post-non-kidney solid organ transplant. Among the most common of these is pre-existing protracted/recurrent acute kidney injury (AKI) and/or chronic kidney damage that antedates the transplant, frequently underappreciated in the setting of organ failure pretransplant, where serum creatinine correlates poorly with actual kidney function, as discussed above (hepatorenal syndrome type 2 and cardiorenal syndrome type 2). (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology" and "Cardiorenal syndrome: Prognosis and treatment".)

Additional posttransplant factors that contribute include specific immunosuppressive regimen (especially those containing calcineurin inhibitors or target of rapamycin [TOR] inhibitors), comorbid conditions (particularly diabetes, hypertension, and hepatitis C virus [HCV] infection), older age, type of organ transplanted (rates are higher in intestine transplant than heart transplant recipients), and surgical issues and complications including recurrent episodes of posttransplant AKI [5]. Nephropathy resulting from BK virus infection has also been reported in non-kidney organ recipients, although it is uncommon [63-66]. (See "Kidney transplantation in adults: BK polyomavirus-associated nephropathy".)

The best general data on underlying, independent pathogenic factors and overall incidence of CKD in non-kidney solid organ transplantation patients come from a study that described a population-based cohort of 69,321 persons who received non-kidney transplants (heart, lung, liver, and intestine) in the United States between 1990 and 2000 [5]. Cyclosporine and tacrolimus were given to 60 and 28 percent, respectively. In this report, 11,426 patients (16.5 percent) developed stage 4 or 5 CKD (defined as a glomerular filtration rate [GFR] of 29 mL per minute per 1.73 m² of body surface area or less) during a median follow-up of 36 months. Maintenance dialysis or kidney transplantation was required in 29 percent of those who developed stage 4 or 5 CKD.

The cumulative incidence of stage 4 or 5 CKD at five years ranged from 6.9 percent among recipients of heart-lung transplants to 21.3 percent among recipients of intestine transplants. Among patients who had received liver transplants, the excess risk of CKD associated with the use of a calcineurin inhibitor was greater with cyclosporine than with tacrolimus therapy. This association was not statistically significant in recipients of heart, heart-lung, or lung transplants.

Liver transplantation — Although immunosuppressive therapy with calcineurin inhibitors has dramatically improved patient and graft survival after orthotopic liver transplantation, the nephrotoxic effects of calcineurin inhibitors are well recognized [67,68]. Many studies have described a gradual decline in kidney function following orthotopic liver transplantation [53,55,68-71]:

●Using the Kidney Disease Outcomes Quality Initiative (K/DOQI) classification system, one single-center study examined the risk of CKD by stage among 230 liver recipients followed for a mean period of approximately six years [4]. Overall prevalences of CKD at 10 years were 2 percent with stage 5, 6 percent with stage 4, 57 percent with stage 3, 24 percent with stage 2, and the rest with minimal or no kidney function deficit.

●A single-center, retrospective study of 883 consecutive adult patients receiving a first liver transplant reported that 8 percent of 10-year survivors of orthotopic liver transplants had developed severe CKD (defined in this study as creatinine greater than 2.8 mg/dL [248 micromol/L]), with 50 percent of these developing end-stage kidney disease (ESKD) [55].

The presence of kidney dysfunction prior to liver transplantation is associated with decreased patient survival posttransplantation [29,72]:

●A group of investigators used the United Network for Organ Sharing (UNOS) database to determine the impact of pretransplant kidney function on graft and patient survival rates after liver transplantation [72]. Up to 33 percent of patients undergoing liver transplantation had some degree of kidney injury, with even mild levels of impairment (GFR of 40 to 70 mL/min) being associated with increased 30-day and two-year mortality. Creatinine clearance was the sole variable retaining posttransplant mortality predictive power in liver transplant recipients.

●The impact of preoperative kidney function on outcome after liver transplant alone was assessed using the UNOS/Organ Procurement and Transplant Network (OPTN) database for the period 1999 to 2004 [29]. Compared with those with a preoperative serum creatinine concentration less than 1.0 mg/dL (88.4 micromol/L), the relative risk of death was 1.11, 1.48, 1.77, and 1.44 for those with levels between 1.0 and 2.0 mg/dL (88.4 to 176.8 micromol/L), those with levels ≥2.0 mg/dL (176.8 micromol/L), patients requiring kidney replacement therapy, and those who received a liver/kidney transplant, respectively.

Not surprisingly, the presence of impaired kidney function prior to surgery, particularly the diagnosis of hepatorenal syndrome, is a significant risk factor for posttransplantation kidney dysfunction [69,73-78]:

●One study retrospectively examined 724 orthotopic liver transplant recipients and identified preoperative serum creatinine greater than 1.9 mg/dL, preoperative blood urea nitrogen greater than 27 mg/dL, intensive care unit (ICU) stay more than three days, and Model for End-Stage Liver Disease (MELD) score greater than 21 as important predictors of the need for kidney replacement therapy postoperatively [73].

●In the study previously discussed [69], patients who developed severe kidney failure post-liver transplant had a greater likelihood of having had hepatorenal syndrome preoperatively, when compared with those who maintained normal kidney function.

●In another study, the incidence of ESKD after liver transplantation in patients who had preoperative hepatorenal syndrome was 7 percent, compared with 2 percent in those without the syndrome [74].

On average, approximately 10 percent of patients who have hepatorenal syndrome preoperatively eventually develop ESKD [69,74,75].

Risk factors for ESKD following liver transplantation were identified using data for 43,514 recipients of deceased-donor liver transplants that were linked from the Scientific Registry of Transplant Recipients (SRTR) and the Centers for Medicare and Medicaid Services (CMS) ESKD program [79]. Donor risk factors associated with increased risk of posttransplantation ESKD included age 50 to 59 years (versus reference age 18 to 39 years) (hazard ratio [HR] 1.17, 95% CI 1.03-1.34); age 60 to 69 years (HR 1.29, 95% CI 1.10-1.51); age ≥70 years (HR 1.31, 95% CI 1.06-1.62); and donation after cardiac death (HR 1.45, 95% CI 1.17-1.80). Each hour of cold ischemia was associated with higher risk of ESKD (HR 1.02, 95% CI 1.01-1.06).

Using this data set, the following model for calculating a renal risk index (RRI) was developed:

RRI = exp [(0.00688 x recipient age-53) + (0.4292 if African American) + (-0.3725 if cholestatic) + (0.2711 if HCV) + (0.7111 if diabetes is present) + (0.2450 if BMI ≥35) + (1.2522 x ln (creatinine) if not on dialysis) + (-0.1525 x ln bilirubin/3.5) + (-0.3851 x ln (albumin/2.9) + (-0.3706 if sodium <134) + (-0.2671 if status-1) + (0.4359 if previous LT) + (0.3129 if TIPSS) + (1.9097 if on dialysis)]

The calculated RRI is the risk of ESKD compared with a reference patient who is 53 years old; is not African American; does not have cholestatic disease; is hepatitis C negative; has a body mass index (BMI) <35 kg/m²; does not have diabetes; has serum creatinine 1.0 mg/dL, serum albumin 2.9 g/dL, serum bilirubin 3.5 mg/dL, and serum sodium ≥134 mEq/L; is not status-1; has had no previous transplantation or transjugular intrahepatic portosystemic shunt (TIPS) procedure; and is not on dialysis.

Using 10 random cross-sections of a validation cohort, this model predicted the order of outcome among pairs of subjects approximately 75 percent of the time.

A historical analysis of the UNOS data revealed that the five-year survival in patients with a serum creatinine concentration >2.0 mg/dL (177 micromol/L) was 62 and 50 percent in patients who received a combined liver-kidney transplant and liver transplant alone, respectively [75]. Additional analysis from the UNOS database suggests that kidney allograft half-life is superior with combined liver-kidney transplantation versus that associated with kidney after liver transplantation [80]. However, the findings from both of these retrospective studies were derived from registry data and, therefore, need to be cautiously interpreted. Analysis of the margin of benefit offered from combined kidney and liver transplantation must be tested in properly designed studies. Similarly, it remains to be determined whether the recently implemented simultaneous liver-kidney (SLK) allocation policy will result in improved liver transplant outcomes or what the effect will be on utilization of deceased-donor kidneys.

Pancreas transplantation — Data on kidney function following pancreas transplantation alone, performed for diabetes mellitus, are scant. In this setting, posttransplant kidney function is principally influenced by two competing factors:

●Beneficial effects of sustained normoglycemia

●Nephrotoxic effects associated with transplantation, particularly those resulting from calcineurin inhibitors

It had been previously noted that normoglycemia following pancreas transplantation alone that persisted for five years failed to ameliorate kidney dysfunction or glomerular lesions in type 1 diabetic patients with their own kidneys [81]. The absence of observed benefit with normoglycemia was attributed to the adverse effects of cyclosporine.

Subsequently, the relationship of cyclosporine dose and blood levels to changes in kidney function was examined in type 1 diabetic patients who underwent pancreas transplantation alone [82]. In this study, creatinine clearance decreased from 108 mL/min at baseline to 74 mL/min at five years posttransplantation in those who received pancreas transplantation, while kidney function did not change appreciably in diabetic controls. The decrement in creatinine clearance correlated with cyclosporine blood levels and dose. The investigators concluded that, among patients with type 1 diabetes mellitus who do not have kidney dysfunction and have not received a kidney transplant, pancreas transplantation does not improve kidney function. In addition, it may contribute to a significant decrement in creatinine clearance within five years after transplantation.

It was postulated that the relatively short follow-up in this study may have prevented the renoprotective effects of normoglycemia, if present, from emerging. To address this limitation, the same investigators conducted a longer, 10-year study to discern the quantitative relevance of the competing factors of normoglycemia and cyclosporine nephrotoxicity [83]. The creatinine clearance in recipients of pancreas transplants significantly declined at five years, but stabilized thereafter. Ultrastructural examination of kidney tissue from these patients revealed that the thickness of the glomerular and tubular basement membranes was similar at five years and at baseline, but had decreased by 10 years. It was concluded that pancreas transplantation can reverse the lesions of diabetic nephropathy, but reversal requires more than five years of normoglycemia [83,84].

The natural history of kidney function following pancreas transplantation alone is characterized by an initial decline in kidney function, due most likely to the untoward effect of calcineurin inhibitors. However, kidney function later stabilizes so that, when compared with a cohort of nontransplant patients with diabetes mellitus type 1, those who received a pancreas transplant have a higher creatinine clearance and less albuminuria at 10 years of follow-up.

Practically all patients listed for pancreas transplantation alone have normal or near-normal kidney function. The majority of patients with diabetes mellitus type 1 and CKD are considered for either kidney transplant alone or combined kidney and pancreas transplantation either simultaneously or sequentially. Some have proposed a calcineurin inhibitor challenge test administered pretransplant to pancreas-alone candidates to determine the degree of kidney injury induced by the immunosuppressant when deciding whether to proceed with pancreas alone, simultaneous kidney-pancreas, or kidney transplant alone, followed by subsequent pancreas transplantation [85].

Issues surrounding simultaneous kidney-pancreas transplantation, kidney followed by pancreas transplantation, and pancreas transplantation alone are presented separately.

●(See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications".)

●(See "Pancreas-kidney transplantation in diabetes mellitus: Patient selection and pretransplant evaluation".)

●(See "Pancreas and islet transplantation in diabetes mellitus".)

Cardiac transplantation — The majority of cardiac transplant recipients will develop CKD within the first year after transplant. Cardiac transplant recipients usually suffer an initial, rapid decline in kidney function in the first two years posttransplant, which is followed by a less pronounced decline afterwards [45,48,86-97]. In one study, 200 patients were followed for up to nine years post-heart transplant [86]. The average loss of GFR in the first year posttransplant was 14 mL/min, while the average loss of GFR in the subsequent eight years was 14 mL/min. Severe kidney dysfunction (GFR <20 mL/min per 1.73 m²) developed in 20 percent of the patients, which was predicted by the recipient age at time of transplantation plus the GFR one year after transplantation.

The natural history of kidney function following orthotopic heart transplant was also evaluated in another report [98]. To assess the effect of heart transplantation and exposure of cyclosporine on long-term kidney function, statistical analysis was restricted to patients who survived the first year posttransplantation. Heart transplant survivors beyond the first year posttransplant have a significant decrease in kidney function over time:

●The cumulative incidence of chronic kidney failure, as defined by a GFR ≤29 mL/min per 1.73 m², at 5, 10, and 15 years was 4.2, 10.4, and 12.5 percent, respectively.

●The cumulative incidence of severe chronic kidney failure, as defined by a GFR ≤15 mL/min per 1.73 m², at 5, 10, and 15 years was 2.1, 8.3 and 8.3 percent, respectively.

Age, pretransplantation estimated GFR (eGFR), pretransplantation diabetes, and pretransplantation hypertension were risk factors associated with a ≥10 mL/min per 1.73 m² decrement in eGFR.

Pooled weighted average serum creatinine concentrations (mg/dL) derived from published studies describing kidney function in heart transplant recipients receiving cyclosporine-based immunosuppressive therapy reveal a biphasic pattern [45,86,89-94]. During the first two years following heart transplantation, there is a steep decline in kidney function, followed by a less pronounced decline afterwards (figure 1).

The mechanism for this biphasic pattern appears to be due to the renal response to early versus late effects. The GFR rapidly declines in the first few months after transplant, mainly as a result of exposure to perioperative and postoperative insults plus exposure to calcineurin inhibitors. Kidney function later stabilizes. In general, the GFR at one year is a better reflection of kidney functional reserve, which is also predictive of long-term kidney outcome and mortality [98]. Most studies examining calcineurin inhibitor-mediated nephrotoxicity in heart transplant patients were performed in the cyclosporine era and may not necessarily apply to tacrolimus, the calcineurin inhibitor of choice. Regardless, randomized controlled trials have demonstrated that heart recipients randomized to tacrolimus have better kidney function at 12 months posttransplant, compared with cyclosporine-treated patients [99].

Kidney replacement therapy — In a report from the International Society for Heart and Lung Transplantation (ISHLT) registry, 4.4 percent of heart transplant recipients were on chronic dialysis, and 0.9 percent of patients received a kidney transplant within eight years after heart transplant [100]. Survival in patients receiving kidney transplant after heart transplant was significantly lower than for heart-only recipients at the same time points after heart transplant.

Findings related to ESKD post-heart transplantation were also reported in a study from the Canadian Organ Replacement registry [101]. The incidence of dialysis after heart transplantation was 4 percent, with survival on dialysis being significantly worse than a matched dialysis cohort. By comparison, survival was similar in those who received a kidney transplant after heart transplantation versus those in the matched dialysis cohort who had received a kidney transplant.

Similar findings as those noted from the Canadian registry were reported in a study from France. Survival among heart transplant patients who initiated dialysis was significantly lower than nonheart transplant dialysis patients [102].

Among those who require kidney replacement therapy, survival with a kidney transplant is superior to those who continue dialysis [103,104]. In a study using UNOS data, for example, the risk of death was decreased by 43 percent in patients who received a kidney transplant, compared with heart recipients maintained on dialysis [103]. Another analysis of UNOS data demonstrated that the annual number of kidney-after-heart transplants has quadrupled over the past decade [105]. Increasing dialysis duration was associated with worse outcomes after the kidney transplant, with patient death accounting for over 75 percent of kidneys that were lost. The fact that kidney quality (living versus deceased donors; standard criteria versus expanded criteria) was not a determinant of survival suggests that use of nonstandard kidneys should be readily considered in this population, rather than spending more time on the list waiting for a standard-criteria kidney.

Lung transplantation — CKD is common following lung transplant [47,54,57,71,106-111]. The decline in kidney function is usually biphasic, with a steep decline in the first year posttransplant and a slower decline afterwards [57].

●The largest study examined kidney function in 219 patients who underwent lung or heart-lung transplantation and survived the first six months posttransplant [111]. Over one-half of the patients who survived the first posttransplant year had developed stage 3 CKD by that time [112]. During a median follow-up of 44 months, 7.3 percent of patients had developed ESKD. The cumulative incidence of doubling of the serum creatinine concentration was 34, 43, and 53 percent at one, two, and five years. However, these incidences were from basic descriptive statistics and not survival-analysis statistics, which would account for patient death. Thus, the true incidences of ESKD are much greater. Elevated diastolic blood pressure and elevated serum creatinine at one month posttransplantation were associated with poor kidney function.

In this report, significantly less nephrotoxicity was observed with tacrolimus versus cyclosporine [111]. The use of tacrolimus during the first six months after transplantation was associated with a significant decrease in the risk for time to doubling of serum creatinine concentration and a lower rate of acute rejection. However, these results are somewhat difficult to interpret as cyclosporine was used in an earlier era of lung transplantation, when overall results were not as good. Additional analysis of these patients found that predictors of a shorter time to doubling of the serum creatinine concentration included older age, lower GFR at one month posttransplant, and cyclosporine use during the first one-half year posttransplant [112].

●A second study also illustrated the initial steep decline in kidney function, which is followed by a less vigorous decline. In this report of 124 patients, the serum creatinine concentration at baseline, one year, and five years posttransplant was 0.8, 1.6, and 1.9 mg/dL, respectively [57].

As observed with other solid organ transplants, the tapering and withdrawal of calcineurin inhibitors can be associated with improved kidney function [113].

Among those who require kidney replacement therapy, survival with a kidney transplant is superior to those who continue dialysis. In a study from the UNOS, for example, the risk of death was decreased by 54 percent in patients who received a kidney transplant, compared with lung recipients maintained on dialysis [103].

Islet cell transplantation — A paucity of data exists concerning the posttransplant effect on the kidney function of islet cell transplantation alone in patients with normal or near-normal function [114-116]:

●In an early report on seven patients with diabetes type 1 and normal kidney function who underwent islet transplantation with an average follow-up period of 10 months, the serum creatinine was not found to be significantly different than pretransplant serum creatinine with an average follow-up period of 10 months (1.2 and 1.3 mg/dL, respectively) [114].

●A subsequent report elaborated on the experience with 47 patients who had diabetes type 1 and underwent islet cell transplant [115]. After an average follow-up of five years, the serum creatinine was mildly but significantly elevated when compared with pretransplant serum creatinine (1.1 and 0.9 mg/dL, respectively). Creatinine clearance nonsignificantly decreased over the course of the study period (108 to 84 mL/min at the end of follow-up). In addition, increasing proteinuria appeared to occur, with 45 percent of patients with pretransplant moderately increased albuminuria (formerly called "microalbuminuria") progressing to overt proteinuria, and 10 percent of those with no pretransplant moderately increased albuminuria progressing to overt proteinuria. In this study, patients were induced with daclizumab and subsequently maintained on sirolimus and tacrolimus. Proteinuria in patients with clinical islet cell transplantation has been attributed to the use of sirolimus as the discontinuation of sirolimus has led to the resolution of proteinuria [117]. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors".)

While studies on whole pancreas transplantation have shown that metabolic control in recipients with normal kidney function resulted in stabilization and reversal of diabetic lesions in the native kidney, limited data suggest that successful islet transplant may have a similar, positive impact on diabetic kidney lesions.

As an example, the effect of islet transplantation on the kidney function of 36 patients with type 1 diabetes mellitus, kidney transplants, and some degree of kidney allograft dysfunction was reported [118]. The study compared parameters of kidney function in patients with successful islet transplantation versus those who had an unsuccessful islet transplant (success was defined as fasting C-peptide levels of >0.5 ng/mL for more than one year). Patients with successful islet transplant had better kidney graft survival rates at seven years when compared with those with unsuccessful islet transplant (83 versus 51 percent, respectively). Moderately increased albuminuria increased significantly in patients with an unsuccessful transplant, but did not change appreciably in those with successful islet transplant. Thus, islet transplantation, probably by partially restoring pancreatic endocrine function, not only improves the metabolic control of diabetes mellitus, but also is associated with improvements in kidney function and kidney graft life span.

Heart-lung transplantation — Heart-lung transplantation is now an uncommon procedure that should be reserved for patients who cannot be treated by lung transplantation alone [100]. Suitable candidates include patients with severe, irreversible disease of the lung parenchyma or vasculature who also have severely compromised left ventricular function or other cardiac diseases that would preclude a successful outcome with lung transplantation alone. (See "Heart-lung transplantation in adults".)

The 2005 report from the ISHLT included data on kidney function after heart-lung transplantation [100]. Within one year after transplantation, 17.8 percent of recipients developed some degree of kidney dysfunction, 3.6 percent required maintenance dialysis, and 0.4 percent received a kidney transplant [100]. Within five years, approximately 25 percent developed severe CKD, which was defined in the registry as a serum creatinine concentration >2.5 mg/dL (221 micromol/L), requirement for dialysis, or a kidney transplant.

The incidence of and risk factors associated with CKD post-heart-lung transplant were also assessed in the previously cited population-based cohort study of 69,321 patients who received non-kidney transplants in the United States between 1990 and 2000, of whom 576 received a heart-lung transplant [119]. The cumulative incidence of CKD in recipients of heart-lung transplant, as defined by GFR of less than 29 mL/min per 1.73 m², was 1.7, 4.2, and 6.9 percent at one, three, and five years, respectively.

Because these findings were nearly identical between heart transplant patients and heart-lung transplant patients, the investigators used a combined regression model for both patient groups [119]. In this model, the presence of pretransplantation kidney disease, postoperative acute kidney failure (ARF), a positive serologic test for hepatitis C prior to transplant, pretransplant diabetes, and pretransplant hypertension were all associated with increased risk of chronic kidney failure after the transplant.

Intestinal transplantation — Although data are minimal, studies suggest that kidney function deteriorates among intestinal transplant patients [120-123]. This was best shown in a report of 10 patients (8 adults) in whom the GFR was assessed at baseline, three months posttransplantation, and yearly thereafter using chromium ethylenediaminetetraacetic acid (EDTA) clearance [123]. Among all adults, the median GFR decreased by approximately 50 percent at three months posttransplant. In addition, among the five adults with greater than one-year follow-up, the median GFR decreased by nearly 75 percent, compared with baseline levels.

PREVENTION AND TREATMENT STRATEGIES

Overview — Attenuation of the risk of nephrotoxicity posttransplantation should focus on modifiable risk factors that are common to all patients at risk of chronic kidney disease (CKD) and those that are specific to the transplant setting. As examples:

●Attempts should be made to minimize perioperative and postoperative hypotension.

●Outside of immunosuppression by clinical indication, the use of nephrotoxic agents should be avoided. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity" and "NSAIDs: Acute kidney injury".)

●It is generally advisable to achieve good control of blood pressure. In the absence of specific guidelines, general guidelines for treatment in kidney transplant recipients should be followed for non-kidney transplant recipients (see "Hypertension after kidney transplantation" and "Liver transplantation in adults: Long-term management of transplant recipients", section on 'Hypertension').

●The use of therapeutic modalities to attenuate the degree of proteinuria may help delay the progression of kidney failure. This includes the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) as extrapolated from evidence related to nontransplant as well as kidney transplant patients with kidney dysfunction. These agents reduce the incidence and degree of proteinuria, with potential to slow the progression of kidney function impairment [124-128].

The effectiveness of ACE inhibitors or ARBs in protecting kidney function among non-kidney organ transplant recipients with CKD is yet to be established. Until such data are available, we advise renin-angiotensin-aldosterone system (RAAS) blockade in non-kidney organ recipients who have a cardiac indication for use of these agents or in those with proteinuria. In both settings, kidney function and serum potassium levels should be carefully monitored after drug initiation and with any subsequent dose uptitration.

●Tight control of diabetes and hyperlipidemia are important. (See "Heart transplantation: Hyperlipidemia after transplantation" and "Liver transplantation in adults: Long-term management of transplant recipients", section on 'Diabetes mellitus'.)

●Some investigators have also suggested the use of calcium channel antagonists to counteract the hemodynamic effects of cyclosporine on the afferent arteriole and its effect on the glomerular filtration rate (GFR) [129-131]. Others have suggested the use of ACE inhibitors [132]. In the absence of high-quality evidence in this population to guide this decision, we advise using an ACE inhibitor (or ARB) rather than a calcium channel antagonist in patients with a cardiac indication for use of an ACE inhibitor (or ARB) and in those with proteinuria.

Choice of calcineurin inhibitor and calcineurin-inhibitor sparing regimens — The choice of immunosuppression regimen, including calcineurin inhibitor, is made by the primary transplant team and is usually based on assessment of efficacy and toxicity. Cyclosporine-induced nephrotoxicity may be attenuated by dose reduction coupled with the addition of mycophenolate mofetil, resulting in long-term kidney function improvement [133]. From a purely kidney function standpoint, there are now single-center case series, registry analyses, and multicenter studies demonstrating the benefit of tacrolimus over cyclosporine in both conversion and de novo settings in heart [99,134] and liver recipients [5,135,136]. Tacrolimus appears to cause less renal vasoconstriction than cyclosporine, which may in part explain the typical, short-term decrease in creatinine observed with conversion from cyclosporine [137,138].

Consistent with this notion, the vast majority of non-kidney organ recipients in the United States receive an immunosuppression regimen comprising tacrolimus, mycophenolic acid, and prednisone at the time of transplant [139]. According to the annual report of the Organ Procurement and Transplant Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR), the majority of patients remain on a tacrolimus-based regimen at one year after transplant.

A common strategy in non-kidney organ recipients has involved utilization of regimens that reduce, delay, or eliminate calcineurin inhibition. The target of rapamycin (TOR) inhibitors, sirolimus and everolimus, in particular, have been used in this setting. In some non-kidney organ recipients, while the elimination or minimization of calcineurin inhibitors has been associated with a mild improvement in kidney function, this has often come at the expense of compromised immunosuppressive efficacy and worse patient outcomes [140,141]. TOR inhibitors should also be avoided in patients with estimated GFR (eGFR) <40 or proteinuria as this has been shown to be associated with an accelerated progression of kidney dysfunction. Moreover, the TOR inhibitors also have significant adverse effects that have to be considered in their use (see "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors"). Overall, the results of the many studies in this area have been inconsistent because of tremendous variability in study design and endpoints, patient selection, as well as duration of follow-up. There are no data on costimulation blockade for renal-sparing purposes in non-kidney organ recipients.

Ultimately, the choice of immunosuppression regimen has to be individualized to balance the overall risks and benefits of one therapy versus another.

Kidney transplantation for prior solid organ transplant recipients — For non-kidney transplant recipients who develop end-stage kidney disease (ESKD), kidney transplantation results in superior survival than dialysis. This was demonstrated in one study of kidney transplant recipients who had a prior non-kidney transplant [142]:

●At 141 days, the relative risk of death in patients who received a kidney transplant was the same as those on the waiting list.

●Beyond 141 days, the relative risk of death was decreased and maintained until the end of the study duration (five years).

In one study, the 10-year patient survival after kidney transplantation was 22 and 27 percent lower for recipients of a prior heart and liver transplant, respectively, compared with recipients of a kidney transplant alone [142]. The risk of death was highest among kidney transplant recipients who had received a prior lung transplant (hazard ratio 4.3, 95% CI 2.8-6.6). At five years post-kidney transplant, death with a functioning kidney allograft accounted for most graft loss in patients who had received a prior non-kidney organ transplant.

The combination of improved transplant outcomes coupled with a high prevalence of advanced CKD has led to rapid growth in the rate of being waitlisted for a subsequent kidney among prior non-kidney organ recipients deemed suitable candidates. From 1995 to 2007, the number of such patients listed for a sequential kidney following a prior non-kidney transplant increased from 72 to 975 [142].

By prior organ transplant, listing for subsequent kidney transplant increased by 330 percent among liver recipients, 307 percent among heart recipients, and 635 percent among lung recipients. This compares with 74 percent waiting-list growth for primary kidney recipients and 70 percent growth for prior kidney recipients over the same time period [3]. Because of an increased risk of death on the kidney waiting list for prior non-kidney organ recipients with advanced CKD, timely referral of medically appropriate non-kidney transplant recipients for kidney transplantation is essential [142]. Since non-kidney organ recipients fare poorly on dialysis and most will have very limited priority under the new kidney allocation system, living donation represents the best hope of transplantation for many of these patients. For this reason, we refer patients for transplant when the eGFR is between 20 to 25 mL/min per 1.73 m² in the hopes of identifying a potential donor and proceeding with preemptive kidney transplantation before their health has deteriorated to the point that they are no longer suitable kidney transplant candidates.

SUMMARY AND RECOMMENDATIONS

●Chronic kidney disease (CKD) following non-kidney solid organ transplantation is very common. Approximately 15 percent of these patients eventually develop stage 4 or 5 CKD posttransplantation. (See 'Introduction' above and 'Overview' above.)

●The preoperative evaluation of kidney function in non-kidney solid organ transplantation candidates should focus on establishing the probability of reversibility and the chance of progression to end-stage kidney disease (ESKD). The evaluation of kidney function begins with a complete history and physical examination, an accurate measure of kidney function, a urinalysis, and kidney ultrasonography. Although kidney biopsy may be clinically indicated on occasion, there is no evidence that kidney histology is more predictive of posttransplant kidney outcomes than serum creatinine alone. Further options depend upon the particular clinical scenario and the particular non-kidney solid organ that is failing. (See 'Evaluation of kidney function prior to non-kidney organ transplant' above.)

●Calcineurin inhibitor therapy has been implicated as an important cause of posttransplantation CKD in non-kidney solid organ transplant recipients. An increased risk of CKD in this population is also associated with pretransplant acute kidney injury (AKI), increasing age at transplant, African-American race, female sex, pretransplantation hypertension and diabetes mellitus, type of organ transplanted, surgical issues, and/or hepatitis C infection. (See 'Chronic kidney disease after non-kidney organ transplantation' above.)

●The cumulative incidence of ESKD requiring some form of kidney replacement therapy in non-kidney solid organ transplantation ranges from 3 to 10 percent in liver transplant patients, 0 to 20 percent in heart transplant patients, 5 to 15 percent in lung transplant patients, and 3 percent in heart-lung transplant patients. There are limited data concerning islet cell and intestinal transplantation. (See 'Chronic kidney disease after non-kidney organ transplantation' above.)

●Attenuation of the risk of nephrotoxicity posttransplantation should focus on modifiable risk factors that are common to all patients at risk of CKD and those that are specific to the transplant setting. (See 'Prevention and treatment strategies' above.)

●For non-kidney solid organ transplant recipients with advanced CKD deemed healthy enough to potentially receive a subsequent kidney transplant, the risk of dying or being delisted while awaiting a kidney is markedly elevated. We recommend the timely referral of medically appropriate patients for kidney transplantation, early discussion about live-donor kidney transplantation, and low threshold to recommend use of nonstandard-criteria deceased-donor kidneys. (See 'Overview' above.)