Key words : End-stage liver disease, Glomerular filtration rate, Renal function

Introduction

Liver transplant (LTx) has become an established therapy in patients with end-stage liver disease.¹ As a successful life-saving procedure in patients with irreversible liver disease,² some unwanted comp-lications may occur. Renal dysfunction, a common problem after LTx,³ can be related to hepatorenal syndrome or nephrotoxicity caused by immunosup-pressive regimens.¹ Dramatically improved perio-perative management and immunosuppressive therapy in LTx recipients during the past few decades have led to long-term survival, thus increasing the prevalence of late complications such as chronic kidney disease (CKD),⁴ which is associated with higher cardiovascular risk, hospitalization, and mortality in transplant recipients compared with people with preserved kidney function.⁵

Since February 2002, the Model for End-Stage Liver Disease (MELD) score has been implemented as a basis for liver allocation6 with 3 components: serum bilirubin level, serum creatinine level, and international normalized ratio of prothrombin time. Serum creatinine, as a prominent part of this scoring, expands the role of renal function in pretransplant evaluations,7 which prioritizes candidates with impaired renal function because of poor prognosis.⁶

This systematic review aimed to evaluate the prevalence, incidence, stage progression rates, and adjustable (or no) risk factors for CKD after LTx.

Materials and Methods

We evaluated CKD outcomes in LTx recipients under the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2015 statement.⁸

Search strategy
Two independent investigators elicited related studies published in English and Persian from online international databases (the ISI Web of Science, PubMed/Medline, Google Scholar, and Scopus). The searched keywords were “liver transplant” OR “liver transplants” OR “liver transplantation” OR “hepatic transplantation” OR “hepatic transplantations” OR “liver grafts” OR LT OR orthotopic liver transplantation (OLT) OR OLT AND “chronic kidney disease” OR CKD OR “chronic renal failure” OR CRF OR “chronic renal disease” OR CRD NOT “acute kidney injury” OR AKI.

Literature search
Data were collected individually by 2 independent investigators based on titles. We identified 1413 articles through different databases. After removing duplications, we had 356 remaining records and screened 312 articles excluded by title and abstract. We assessed 44 full texts for eligibility (Figure 1). The relevant studies were reviewed, and the references were explored to find more related studies. After reviewing the full texts, we had 23 eligible articles. Some information was extracted from the studies, including title, author names, year of study, the country, population, sample size, and study results (Table 1 and Table 2).

Characteristics of included studies
Of 23 included articles, 15 articles evaluated incidence^{1,6,9,11-14,16,17,19,20,22-24,4,28}; 7 articles examined prevalence^{4,9,10,13,18,21,25}; and 19 articles reported risk factors.^{1,6,9-20,22-24,26,27}

Quality assessment and risk of bias
The authors independently assessed quality assessment and risk of bias using the Cochrane Risk of Bias Tool,²⁹ and disagreements were resolved through the consensus method.

Results

Description of studies
Ramachandran and colleagues⁹ retrospectively studied 130 patients who underwent OLT. According to the Kidney Diseases Outcome Quality Initiative Guidelines, patients were divided into 3 categories for CKD: no or mild CKD (stages 1 and 2), moderate CKD (stage 3), and severe CKD (stages 4 and 5) after 0.6 to 15.5 years of follow-up. Notably, before OLT, 8.5% of patients had severe CKD. The prevalence of severe CKD was 3%, 4%, and 8% at 1, 3, and 5 years post-OLT. Incidence of severe CKD at 2, 4, 5, 6, and 15 years posttransplant were 3.8%, 9.6%, 12.8%, 14.8%, and 14.8%, respectively, and significantly associated with mortality (hazard ratio [HR] = 6.5; P < .001). Cumulative survival of patients with severe CKD was significantly different compared with patients with mild or moderate CKD (P < .001). Some variables were reported to be significant predictors of severe CKD, including post-OLT acute renal failure (ARF) (odds ratio [OR] = 43.8; P = .020), female sex (OR = 29.6%; P = .010), pre-OLT diabetes mellitus (OR = 682.3; P = .010), hepatitis C virus (HCV) infection (OR = 25.3; P = .020), and low 1-year glomerular filtration rate (GFR) (OR = 0.9; 95% CI, 0.8-1.0; P = .040). In addition, type of calcineurin inhibitor and level, and pre-OLT renal dysfunction parameters showed no significant effect on the prediction of post-OLT severe CKD.⁹

In a single-center post-OLT Polish population, the prevalence of CKD, which seemed to be higher in the study group compared with the general population, was 17%, 32%, and 39% before, 12, and 24 months after LTx, respectively. The presence of diabetes and arterial hypertension caused a higher prevalence of CKD during the post-OLT period. On the other hand, among reasons for liver failure that led to LTx, autoimmune diseases caused lower CKD prevalence than ethanol abuse and viral etiology (P < .040). In addition, 12 and 24 months after LTx, blood trough tacrolimus concentration showed a significant negative association with estimated GFR (eGFR) (P = .040).¹⁰

Among patients registered in the Canadian Organ Replacement Register for LTx, 4186 OLT recipients were enrolled in a cohort study by Al Riyami and colleagues.¹¹ In addition, 228 nontransplant patients on chronic dialysis were matched as a control group. During the observation period, 2.9% of OLT recipi-ents required chronic dialysis due to end-stage renal disease (ESRD), whereas the remaining study group did not have ESRD. Among the OLT recipient group, patients dependent on dialysis experienced a higher unadjusted mortality rate compared with those not on dialysis (49.2% vs 26.8%; P < .0001) and also lower survival compared with controls (P = .010). Male sex and age were also significant predisposing characteris-tics for dialysis status in the study group (P < .001).¹¹

Of 502 OLT recipients, 231 patients were enrolled in a US retrospective cohort study by de Boccardo and colleagues.¹² At the end of median 73 months of follow-up, CKD (GFR <60 mL/min/1.73 m²) was diagnosed in 61% of patients (10% with stage 1, 28% with stage 2, 47% with stage 3, 6% with stage 4, 8% with stage 5). Compared with the non-CKD group, CKD patients were significantly older, had higher cholesterol levels, and had higher prevalence of hypertension (P < .003). An association was observed between CKD and uric acid levels >6.0 mg/dL, diabetes, insulin-dependent diabetes mellitus, and hypertension (P < .001).¹²

In a retrospective study of 230 patients who underwent deceased donor OLT, at 10 years post-OLT, the incidence of CKD was 9.6% with stage 0/1, 53.7% with stage 2, 56.8% with stage 3, 6.1% with stage 4, and 2.6% with stage 5. Female sex (OR = 7.84, P < .005), age (OR = 1.08; P = .01), use of tacrolimus (OR = 0.31; P < .05), increase in GFR from first year (OR = 0.90; P < .0005), increase in creatinine from 6 months (OR = 1.05; P = .001), and pre-OLT proteinuria (OR = 7.48; P < .05) significantly influenced prog-ression to ESRD.¹³

In a study by Cantarovich and colleagues,14 significant predictors of stage 4 CKD, need for chronic dialysis, and all-cause mortality at year 1 posttransplant were decreased with eGFR ≥30% between 3 and 12 months posttransplant (OR = 16.1, 14.6, and 2.6; P < .001, respectively) and diabetes mellitus pretransplant (OR = 4.1, 3.8, and 1.9; P < .001, respectively). Other significant variables for stage 4 CKD included HCV, new-onset diabetes mellitus during the first year posttransplant, and total bilirubin levels at month 1; all-cause mortality was associated with positive serology for HCV, total bilirubin, and alkaline phosphatase at 1 year. In patients with eGFR decreases between <30% and ≥30%, the incidence of chronic dialysis post-transplant was 0.5% and 7.1% at 5 years and 4.2% and 7.1% at 10 years.¹⁴

Of LTx recipients studied in Sweden between 1988 and 2001, GFR level was 87.3 ± 25.5 mL/min/1.73 m² pretransplant, which then decreased overall within the first 3 months and then changed at 1, 5, and 10 years post-LTx by 29%, 36%, and 42% from baseline (P < .001). In addition, after the first year, 4% of patients developed CKD stage 4/5. By 5 years, the percentage increased to 12%, and after 10 years, 29% of patients had a GFR <30 mL/min. A GFR level <30 mL/min within 3 months posttransplant was the only potential risk factor for progression to severe CKD 5 years after transplant (P = .03).¹⁵

Data from 1151 adult LTx recipients were studied by Lamattina and colleagues. After 1 year, the CKD incidence was 7%, 34%, 56%, 3%, and 1%, for stage 1, 2, 3, 4, and 5, respectively. CKD stage progression occurred in 28%, 40%, and 53% of patients after 3, 5, and 10 years, respectively. After 1 year, more tended to display CKD stage progression in patients with better renal function (HR = 0.33; P < .0001), and 18% of patients experienced ESRD after 20 years. In a multivariate model of stage progression, pretransplant stage of CKD at year 1, hypercholesterolemia, and urinary tract infection, pretransplant DM, CKD stage at year 1 posttransplant showed significant association with stage progression.¹⁶

Giusto and colleagues¹⁷ investigated elective LTx operations performed at the University of Rome from 2000 to 2011 among patients followed for a median of 63 months’. The incidence of CKD at 1, 3, and 5 years post-LTx was 6%, 30%, and 45%, respectively. The investigators considered eGFR at LTx the only pretransplant variable for CKD progression. Nine patients had ESRD. Survival did not differ between CKD versus non-CKD patients (P = .100). Estimated GFR, severe infection, and hypertension were identified as significant risk factors for CKD onset within each 12-monthinterval.¹⁷

Ninety-seven patients with 5 years or more survival after LTx were investigated by Leithead and colleagues.¹⁸ They reported a mean decline of GFR of 1.1 mL/min/1.73 m² per year. The prevalence of stages 4 and 5 CKD increased overall during the follow-up period. At baseline, 3.1% had stage 3, 1% had stage 4, and 0% had stage 5 disease; thereafter, the proportion for each stage changed to 17.5%, 1%, and 0%, respectively, at 6 months; 23.7%, 3.1%, and 1.0% at 5 years; and 29.9%, 6.2%, and 6.2% at 10 years post-LTx. Higher eGFR at baseline, female sex, dyslipidemia, and hypertension were associated with faster progression to renal dysfunction after LTx.¹⁸

In a study by Narciso and colleagues, before LTx, patients who had eGFR <60 mL/min/1.73 m² developed ESRD in a shorter time than those with high eGFR and also had shorter kidney survival rates compared with patients with higher GFR. Among this group, ESRD occurred in 10% of patients. After adjusting for other factors, the investigators found that low preoperative eGFR showed a 4-fold increased risk of development of ESRD (HR = 4.0; P = .001).¹⁹

Velidedeoglu and colleagues²⁰ reviewed the outcomes of 181 patients who underwent OLT. In the first week after OLT, the incidence of acute renal disease was 39.2% but attenuated over time, with 3.9% at 90 days after OLT. Over the long-term, the incidence of CKD was 6.0%; CKD in 3 of these patients progressed to ESRD. Among the various factors that were evaluated in this study, a creatinine level ≥2 mg/dL in the first week posttransplant (P = .003) and pretransplant diabetes (P < .001) were significantly associated with posttransplant CKD.²⁰

In a single-center study, Kim and colleagues investigated 341 OLT patients to assess their CKD 6 months posttransplant. Only 14% of the patients had normal renal function 6 months after OLT, and 78% demonstrated CKD stages 2 and 3. Also, 8% of patients showed stage 4.²¹

To evaluate the risk factors correlated with progressive renal dysfunction after OLT, Sezer and colleagues22 analyzed 50 OLT recipients. Over the 52-month follow-up, pretransplant eGFR was 84 ± 30.0 mL/min/1.73 m² and altered to 70 ± 16.3 mL/min/1.73 m² at 3 years and to 62 ± 23.8 mL/min/1.73 m² at 5 years. Furthermore, rates of kidney injury at 3 and 5 years were 16% and 28%, respectively. At 3 years after OLT, GFR showed significant positive association with pre-OLT serum albumin and alanine aminotransferase and negative association with microalbuminuria, pre-OLT serum creatinine level, initial Child-Pugh score, MELD score, and renal resistive index. In addition, at 5 years, GFR had significant negative correlation with renal resistive index, smoking, and serum triglyceride levels.²²

Clinical records from 431 adult patients who underwent LTx between 1997 and 2008 and who were followed for 46 ± 31.4 months were analyzed retrospectively. The cumulative incidence of CKD was 17.6% at 1 year, 23.7% at 3 years, and 27.5% at 5 years. The significant risk factors for CKD were old age, cyclosporine, posttransplant ARF, the causes (ischemic acute tubular necrosis and calcineurin inhibitor nephrotoxicity) and severity of ARF after transplant, pretransplant low eGFR, pretransplant hepatorenal syndrome, pretransplant proteinuria, high Child-Pugh score, and high MELD score. During the first 6 months posttransplant, the recipients with pretransplant eGFR ≤29 mL/min/1.73 m² significantly improved, with kidney function subsequently maintained. For patients with eGFR of 30 to 59 mL/min/1.73 m², no significant change occurred; during the first 6 months, a significant reduction occurred in kidney function of patients with pretransplant eGFR ≥60 mL/min/1.73 m². In addition, multivariate Cox regression subgroup analysis showed that, in patients with good pre-operative kidney function (GFR ≥60 mL/min/1.73 m²), pretransplant low hemoglobin level, and non-HBV, as well as the previously described risk factors, can lead to CKD.²³

Guitard and colleagues²⁴ investigated 72 patients who had OLT and were still alive with the same graft 1 year later. In the patient group, 45.8% developed chronic renal failure 1 year after OLT. In multivariate analysis, the significant factors correlated with chronic renal failure development included HCV infection, creatinine clearance <80 mL/min before OLT, female sex, and serum creatinine >130 ?mol/L at 6 months after OLT.²⁴

Intraoperative blood loss >300 mL/kg (HR = 5.38; P = .038) and month 1 post-LTx eGFR <60 mL/min/1.73 m2 (HR = 8.48; P = .041) were considered as independent predictors for posttransplant CKD at 2 years in 63 patients in multivariate analysis from Sato and colleagues.¹ In addition, eGFR changes in the CKD and the non-CKD groups were as follows: no change versus decrease immediately after LTx, increase in both groups at month 1, stable for both groups at month 6, and increase in both groups at year 1. Among the non-CKD group, only 5.3% of patients demonstrated an eGFR <60 mL/min/1.73 m² at 2 years post-OLT.¹

In a multicenter study, Herrero and colleagues investigated 230 patients with GFR ≥60 mL/min/1.73 m². Within month 1 post-OLT, kidney functions rapidly deteriorated. Nonetheless, eGFR increased from 72.3 mL/min/1.73 m² at month 6 post-LTx to 76.5 mL/min/1.73 m² at month 12 and 75.6 mL/min/1.73 m² at month 30 (P < .01). The percentage of recipients with stage 3 CKD decreased from 31.7% at month 6 to 26.4% at month 30.²⁵

Allen and colleagues,⁴ after adjustment for age and sex, found that presence of severe CKD significantly increased the risk of death (2.67 times for GFR 15-29 mL/min/1.73 m² and 5.47 times for GFR <15 mL/min/1.73 m²).⁴

In another study, 413 of 500 people who had living donor LTx were alive after 1 year, with 8% developing CKD. In this study, operative time ≥714 minutes (OR = 37.7) and graft-to-recipient weight ratio ≥0.9 (OR = 0.07) were significant predictors of developing CKD after the first year after LTx.²⁶

In a study to evaluate renal function after LTx in patients with pre-LTx impaired kidney function, there were no significant differences in eGFR measurements at 12, 24, and 36 months after OLT between impaired and normal kidney function. The risk of reaching eGFR <20 mL/min/1.73 m2 was significant and increased in patients with renal impairment duration of >12 weeks (HR = 5.3). Diabetes mellitus and serum creatinine at the time of LTx were significant predictors of eGFR <20 mL/min/1.73 m² after LTx.²⁷

Sanchez and colleagues²⁸ demonstrated that lower initial GFR caused sooner renal failure development and that GFR <60 mL/min/1.73 m² at month 3 caused a higher risk of renal failure.

In a study from Israni and colleagues that determined early versus late risk factors for ESRD during the posttransplant period, ESRD during the first 6 months in the MELD era was higher than in the pre-MELD era (P < .0001). Positive history of diabetes mellitus, dialysis, malignancy, recipient age, creatinine, body mass index, and liver donor risk index at the time of transplant were considered predictors for early onset of ESRD. However, serum creatinine, bilirubin, albumin, recipient race/ethnicity, history of diabetes mellitus, and HCV were reported as predictors of late-onset ESRD.⁶

Discussion

Data from the 2019 Organ Procurement and Transplantation Network report noted continuous growth in the number of new candidates added to transplant wait lists and who received transplants, including living donor transplants. More living donor LTx procedures were performed compared with that reported in 2018 (by 31%).30 Although LTx outcomes have improved remarkably over the past few decades, CKD and ESRD as long-term complications are still common problems that cause significant morbidity and mortality.³¹

Prevalence of posttransplant chronic kidney disease
Different studies (Table 1) have estimated the prevalence of CKD stage through various follow-up periods after transplant. The overall rate for stages 1 and 2 was 47% at 6 months, 50% at 1 year, and 44% at 3 years. Ranges for stage 3 were 17.5% to 31.7% at 6 months, 47% to 48% at 1 year, 26.4% to 52% at 3 years, and 30% to 41% at 10 years. Ranges for stage 4 and 5 were 0.4% to 8% at 6 months, 3% to 8% at 1 year, 0.5% to 4% at 3 years, and 11% to 12.4% at 10 years.

Incidence of posttransplant chronic kidney disease
Previous studies (Table 1) have reported a wide range of incidences of post-LTx CKD. Different criteria to define CKD, methods to measure renal function, follow-up duration, and immunosup-pressive regimens may justify these differences.32 Some studies reported incidence of ESRD6,^{11,13,14,16,19,20,28} of 0.5% at 5 years in patients with eGFR, with decrease of <30% in 3 to 12 months post-LTx14 to 62.2% at 5 years in patients with GFR <60 ml/min/1.73m² at baseline.²⁸ Assessment of renal function by using creatinine-based equations can cause overestimation of renal function in patients with cirrhosis because of lower muscle mass, lower hepatic synthesis of creatinine, and increased renal tubular creatinine secretion, leading to unreliable estimation and making reported rates from various existing studies difficult to compare.⁴ However, Tinti and colleagues33 demonstrated no significant differences in evaluating GFR between different methods (creatinine clearance, Cockcroft-Gault, Modified Diet in Renal Disease [MDRD] 4 and 6, CKD epidemiology formulas).³³

Common stage of posttransplant chronic kidney disease
Our review of 9 studies that evaluated the prevalence of post-LTx CKD stages at different time intervals showed that stage 3 was the most prevalent stage.^4,9,18,21,25

Reason for difference rates
Because only advanced stages of renal failure are considered when describing prevalence, incidence, or risk factors of post-OLT CKD, the existing literature may underestimate the actual burden of CKD after LTx because many LTx patients do not reach end stages throughout the follow-up or need to be assessed for long-term outcomes.¹² The prevalence and incidence of CKD after LTx estimated by GFR are shown in Table 1.

Mortality of posttransplant chronic kidney disease
Severe CKD⁹ and chronic dialysis¹¹ are significantly associated with mortality in LTx recipients; however, Giusto and colleagues reported no significant difference in survival between the group who developed CKD after LTx and the group who did not.17 The risk of death seems to increase as GFR decreases,^9,11,19 which is consistent with Allen and colleagues who reported that GFR <60 mL/min/1.73 m² affected survival.⁴ Additionally, the non-CKD group (eGFR ≥60 mL/min/1.73 m²) had higher rates of kidney survival than patients with eGFR <60 mL/min/1.73 m² according to a study by Narciso and colleagues.¹⁹ However, the study used the creatinine-based eGFR by MDRD equation to show that survival decreased only in patients with GFR <45 mL/min/1.73 m². In other words, eGFR is less sensitive to detecting increased mortality than the measured GFR equation.⁴ Giusto and colleagues reported no significant differences in survival between their CKD group and patients who did not develop CKD posttransplant.¹⁷

For renal function, the MELD score includes serum creatinine in its calculation. Serum creatinine is also an essential variable to estimate morbidity and mortality of LTx candidates and recipients.^1-3 Although creatinine is affected by creatinine production, which is influenced by muscle mass and dietary intake, inulin clearance and radioisotopes are widely regarded as the gold standard for measuring GFR. However, they are expensive, time-consuming techniques that require patient hospitalization. The use of eGFR is common for indicating CKD, as it is an accurate, convenient, and reproducible value for the early detection of this condition. It is calculated from the serum creatinine level, age, sex, and race/ethnicity using the MDRD equation.⁶ However, the MDRD equation was developed based on data from White patients and patients of African descent and is unsuitable for Asian populations. To evaluate the development of renal function in Japanese LTx patients, the MDRD equation modified by a new coefficient can allow for ethnic differences in muscle mass and dietary protein.⁷ The equation was developed using measurements of inulin clearance and estimated a 19% lower GFR in Japanese patients than in White patients with the same serum creatinine level.¹

The decline in GFR after LTx seems to be biphasic.^4,6,28 The first phase with a steep decline occurs during the first months after transplant; in most cases, the decline is attributed to immunosup-pressive agents and their nephrotoxic effects. The second phase tends to be more gradual and persistently progressive, which happens through posttransplant follow-up years.⁴

Renal function before liver transplant
Among LTx recipients, pre-LTx renal dysfunction as one of the most critical predictors is strongly associated with future renal-related outcomes.²⁷ According to a study by Sanchez and colleagues,²⁸ the lower initial GFR causes sooner renal failure development post-LTx. Notably, prolonged wait list times and prolonged pretransplant CKD duration may cause worse outcomes in these patients.⁵ Preoperative renal dysfunction in terms of both degree and course⁵ is associated with considerable development of CKD in the first year posttransplant that the following factors may justify. First, in cases of liver cirrhosis, defined as the development of liver fibrosis histologically as a final pathway in end-stage liver disease due to multiple etiologies,³⁴ various factors including hypoalbuminemia, disturbances of the renin-angiotensin-aldosterone system, renal parenchymal edema, and immune-mediated vasodila-tation can lead to intravascular hypovolemia, with subsequent renal perfusion impairment. Second, there may be a delay in uncovering renal damage by biological markers. Third, there are higher inter-national normalized ratios, encephalopathy, and shock in patients with severe renal impairment compared with those with normal kidney function. In addition, the more prolonged operative time in patients with renal dysfunction can be from frequent hypotensive episodes, clamping, and more need to use norepinephrine and fluids rich in chloride, which are predictors of renal dysfunction at year 1 post-LTx.²⁶

Nonrenal risk factors of posttransplant chronic kidney disease
The cause of CKD in transplants that are nonrenal is multifactorial. Among various risk factors, the pivotal predictors for CKD are hypertension, diabetes mellitus, atherosclerotic cardiovascular disease, aging, female sex, and pre- and posttransplant early renal impairment, HCV, and calcineurin inhibitor-based immunosuppression therapy.^35-38 Assessing risk at the time of LTx may help determine the need to avoid or minimize the use of nephrotoxic agents. Assessing risk associated with the different recipient, donor, and transplant characteristics may help clinicians advise patients about the need to avoid nephrotoxic agents and help clinicians determine how much and what immunosuppressive medication to use.⁶

In our study, one of the most repeated risk factors was the presence of diabetes mellitus before LTx.^{9,10,12,14,16,19,20} Diabetes mellitus is associated with microvascular and macrovascular complications, as previous studies have shown that pretransplant diabetes significantly reduces survival and increases morbidity and mortality in recipients.^39-40 Hepatitis C virus infection is correlated with many extra-hepatic manifestations, including CKD⁴¹; HCV as the underlying cause of LTx can be an underlying factor predisposing recipients to CKD.^9,14,24 Advanced age as a major traditional risk factor for CKD is also an immutable underlying factor that increases the chance of CKD in LTx recipients.^{11,13,23, 42} In our study, we found that female patients were more prone to post LTx CKD than male patients; Al Riyami and colleagues, however, identified male sex as an underlying risk factor.^{9,11,13,18,24}
Conclusions

The outcomes of LTx have improved; therefore, the presence of CKD as a long-term complication has become more commonly seen. Survival is affected by renal function; subsequently, the risk of death seems to increase as GFR decreases. A decline in GFR during the first months after LTx may be attributed to immunosuppressive agents. Later, renal function tends to change more gradually posttransplant. Before LTx, renal dysfunction and some nonrenal etiologies of posttransplant CKD are the risks associated with future renal dysfunction. Measuring risks at the time of transplant could help avoid or minimize CKD occurrence.

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