Clinical Relevance of Kidney Biopsy in Patients Qualified for Liver Transplantation and After This Procedure in the Model for End-stage Liver Disease (MELD) Era: Where Are We Today?

Background

Chronic kidney disease (CKD) is the most common kidney problem in the general population, and, in advanced stages, patients need dialysis treatment. CKD is also a huge problem in special patient groups, such as patients with end-stage liver disease (ESLD).

The number of patients with concomitant renal dysfunction qualified for liver transplantation (OLTx) and after this procedure has recently further increased due to the implementation of MELD (Model for End-stage Liver Disease) score-based allograft allocation. About 30–80% of patients develop CKD, with a cumulative risk of ESRD (End-Stage Renal Disease) requiring renal replacement therapy consisting of either maintenance dialysis or renal transplantation [1,2]. Although chronic kidney disease (CKD) is a common problem in these patients, kidney biopsy is rarely performed because of its invasive nature and potential complications, and therapeutic decisions are made solely on the basis of biochemical tests. There is no criterion standard diagnostic assessment used in most transplant centers, and data on histological changes and complications in patients with CKD in ESLD patients are scarce. The prevalence of CKD in patients qualified to OLTx and after this procedure has not been precisely defined, but it is known to affect the long-term results of liver transplant recipients. Several large studies have shown that pretransplant CKD in patients with a stage higher than 1 (especially with elevated creatinine), presence of hepatorenal syndrome before transplantation, or requirement of renal replacement therapy early after transplantation have an increased risk of post-transplant ESRD [3–6]. Chronic renal dysfunction has also been shown to have a significant association with cardiovascular events in clinical analyses [7]. These findings confirm retrospective evidence that the risk of major cardiac events increases with deteriorating renal function in liver recipients. At present, the decision is made on a case-by-case basis and there is no guideline regarding the role of renal biopsy in the setting of kidney injury in liver transplant patients [8].

We conducted a literature review of kidney biopsy performed in patients before and after liver transplantation, including percutaneous and transjugular procedures. We performed a search in Medline, PubMed, and Embase using the keywords: kidney biopsy, kidney impairment, kidney failure, CKD, liver transplantation, ESLD, and liver cirrhosis. We limited our search to adult patients and publications in English and Polish between 1995 and 2020. We found 2306 articles, but only 23 articles were analyzed due to lack of information about histological changes in kidneys, lack of full clinical data, and availability of abstracts only.

Pretransplant Kidney Biopsy and OLTx

Assessment of kidney function before liver transplantation is important because the presence of impaired kidney function before transplantation, particularly the presence of hepatorenal syndrome, is a significant predictor of post-transplant CKD or even requirement for renal replacement therapy [9,10]. Approximately 25% of patients qualified for OLTx have some renal function damage. Cirrhotic patients have specific disturbances that affect the serum creatinine value; therefore, this endogenous marker remains an imperfect parameter of renal function in this clinical setting [11]. In patients with glomerulonephritis, it is particularly important in regard to treatment and outcome, especially when there is co-existing hepatitis B and/or C [12]. Published studies have not established the correlation between kidney disease progression after transplantation and renal histological damage, kidney function, or clinical picture [12–14]. The role of pretransplant kidney biopsy in liver transplant candidates has not been established. Kidney biopsy findings are not included in the 2016 OPTN/UNOS criteria for selection of patients for simultaneous liver-kidney transplantation [15,16], although only kidney biopsy can differentiate the type and severity of kidney injury and provide information about reversibility or irreversibility of renal damage (excluding obvious cases like cystic disease or atrophy). A pre-liver transplant kidney biopsy can help make the decision and establish the cause of kidney disease. In addition, kidney biopsy can be helpful to determine chronicity, treatability, and likelihood of future progression or reversibility. A few published studies on pretransplant kidney biopsy and evaluation for potential simultaneous liver-kidney transplantation suggest performing dual transplantation in a case of glomerulosclerosis exceeding 40% and interstitial fibrosis exceeding 30% [5,6,17], but these studies are limited by the small number of biopsies performed. However, a study reported avoidance of dual transplantation in 70% of patients on the basis of biopsy [6]. In these patients, the extent of glomerulosclerosis was a predictor of eGFR reduction over the first 12 months after liver transplantation [6]. Wadei et al. [18] reported that 22% of liver transplant recipients with pretransplant kidney biopsies showing reversible histology were evaluated for kidney transplantation by 12 months after liver transplant [18]. Therefore, more studies are needed to determine whether pretransplant kidney biopsies can predict long-term kidney outcomes after liver transplantation. A summary of studies on pretransplant kidney biopsy with clinical relevance is presented in Table 1.

Post-Transplant Kidney Biopsy and OLTx

The etiology of CKD after liver transplantation may be multifactorial. The disease may result from treatment (e.g., early renal dysfunction after LT has been associated with the use of the calcineurin inhibitors [CNI] approved to prevent liver graft rejection in all immunosuppression regimens), with complications after transplantation (e.g., post-transplant diabetes or hypertension), may appear de novo, or can be an unrecognized pre-LTx disease [19]. Beyond the evaluation of CKD, a biopsy can reveal additional, sometimes unsuspected, pathology, as several studies have reported frequent glomerular abnormalities [12,20]. The best approach to a more appropriate diagnosis of kidney disease and thus reversibility of renal dysfunction, especially in patients after LTx, is performing native kidney biopsy in these patients. Modification of treatment without histological confirmation can harm the patient, and the existence of concurrent specific renal disease and the chance to administer specific treatment options to preserve or improve of renal function may be missed. Kidney biopsy is very useful, and, in the general population, is the standard procedure for diagnosis of kidney disease and is often necessary to make the right therapeutic decision. It is performed in native and transplanted kidneys and is generally considered a safe procedure. The most common indications for kidney biopsy are: proteinuria (especially nephrotic range), nephritic syndrome, and unknown acute kidney injury with rapid deterioration of kidney function. Figure 1 provides indications for kidney biopsy after liver transplantation and a short algorithm. The procedure is usually performed with a percutaneous access with the use of real-time ultrasound and automated needles, and over 99% of biopsies are diagnostic. A summary of studies on post-transplant kidney biopsy with clinical relevance is presented in Table 2. In special cases, such as in patients with a high risk of bleeding or with extreme obesity, transjugular access or computed tomography, respectively, are also used. A summary of studies on post-transplant transjugular kidney biopsy with clinical relevance is presented in Table 3. The success of the procedure is defined by the ability to obtain adequate tissue for diagnosis and, equally important, by the safety profile. The most frequent complications after percutaneous kidney biopsy are hematuria, hematoma around the kidney, arteriovenous fistula, and pain, and are usually not dangerous. Major complications, including death and the need for nephrectomy, are extremely rare. Life-threatening complications occur in <0.1% of biopsies and appear during the first 24 h after the procedure in most cases. The standard of care after kidney biopsy has included bed rest with 24-h observation [21]. Biopsy risk in the OLTx patient population is definitely higher and several studies have shown lower bleeding risk when the transjugular approach to kidney biopsy is used in the presence of cirrhosis [22,23]. Unfortunately, the availability of transjugular kidney biopsy is lower than that of percutaneous biopsy. The correct diagnosis of kidney disease is the key to optimal treatment in all such patients, especially in cases where all potential causes are likely to exist. The etiological spectrum of kidney disease in patients after liver transplantation is very broad, ranging from diseases that can damage both the liver and kidneys, to those with procedure- and treatment-related complications, from mild and stable CKD, to rapid deterioration of renal function [24,25]. At present, kidney biopsy is the most reliable examination for diagnosing kidney disease. Although many liver recipients have some signs of potential kidney disease that may be important for kidney and liver function, kidney biopsy is performed too rarely and data about histological changes and complications in patients with CKD after liver transplantation are scarce [6,26–28]. Our histological results showed the discordance between clinical, laboratory, and ultrasound information. In 1 case, histological findings demonstrated typical changes for end-stage disease, even though the deterioration of kidney function was acute and suggested acute kidney injury. In other cases, kidney biopsy has prevented unnecessary modifications of immunosuppression [29]. Percutaneous kidney biopsy is a very good method for sampling the kidney tissue and is associated with bleeding risk in 3–13% of cases, with 6.4% of complications requiring intervention and/or blood transfusion in the general population [21]. Similar native kidney biopsy studies documented a 2.3-fold increased risk of bleeding after kidney biopsy in patients with a low eGFR [21, 30]. Wadei et al. [14,18] found a 30% rate of kidney biopsy complications in patients with renal failure qualified for liver transplantation, with major complications occurring in 18% and INR (international normalized ratio) ≥1.5 was the single predictor of post-biopsy bleeding. In the study by Welker et al. [31], 4/14 patients (29%) had peri-renal hematoma, all without subsequent interventions. In our study, kidney biopsy complications were documented in all our patients (4/4), but the patients had slightly higher creatinine concentration at the time of the study (2.39 vs. 1.83 mg/dl) [29]. This group was too small for statistical analysis, but our study also showed that complications in this group are not life-threatening and do not cause hemodynamic changes. Our results, similar to other studies, highlight the discordance between clinical information and histological findings, and suggest that percutaneous kidney biopsy is safe and helpful in avoiding unnecessary immunosuppression treatment modifications [30,31]. Histopathological analysis may have diagnostic and prognostic implications, allowing individualized management protocols aimed at renal protection among liver transplant recipients. Transjugular kidney biopsy is an alternative method for sampling kidney tissue, especially in patients with advanced liver disease. Complications after this procedure are rare (about 4%), but up to 30% of patients do not provide adequate diagnostic samples and some of these patients need a repeat biopsy. We do not have experience with transjugular kidney biopsy, but this is certainly an interesting diagnostic option for patients with high bleeding risk, such as patients with liver diseases.

Conclusions

Kidney biopsy is very useful in diagnosing kidney damage and assessing prognosis in liver transplant recipients. The procedure is safe, but is rarely performed. The data on pre- and post-transplant kidney biopsy are very scarce. Kidney damage occurring in approximately 25% of patients qualified for OLTx is often irreversible, and predicting renal recovery after OLTx, without knowledge of histological changes in the kidneys, is imperfect and challenging. In some studies, the incidence of kidney biopsies was about 1–2% [32]. It would be helpful to know if a patient has a chance to improve kidney function after OLTx or should be qualified for simultaneous transplantation (SLKT). On the other hand, immunosuppressive treatment after OLTx with a CNI reduction can improve kidney function, but studies show that CNI toxicity accounts for only a small percentage of complications. Performing a kidney biopsy in such a situation may reduce unnecessary discontinuation of immunosuppression. We suggest that kidney biopsy in patients qualified for OLTx and after transplantation should be done more often, as it can help in the treatment and prognosis of CKD in this vulnerable population.