Kidney transplantation in cirrhotic patients represents an area of some controversy. The high morbidity and mortality associated with major surgery in cirrhotic patients has led many programs to exclude cirrhotic patients from kidney transplantation. In the majority of cases, cirrhotic patients with end-stage renal disease are listed for a combined kidney and liver transplant. With the advent of the MELD system, the number of combined liver/kidney transplants increased by 300% [1]. However, there are a large number of patients who do not have a high enough MELD score to qualify for a liver/kidney offer. These are the cirrhotic patients with normal liver function tests and INR who are on dialysis; they automatically receive a MELD of 21 because of dialysis, but the sad reality is that this score cannot give them a liver offer in most regions. Unfortunately, the mortality of these patients on dialysis is very high, with a median survival of 11 months [2]. This has raised the question of whether these patients would benefit from a kidney transplant alone as opposed to waiting on the list for a combined liver/kidney transplant. Multiple studies have been carried out on kidney transplantation in patients with end-stage liver disease, mainly but not exclusively on hepatitis C–infected patients, and have addressed multiple end points such as patient survival with and without kidney transplantation, graft survival, incidence of liver decompensation, and worsening of hepatitis C. The results, although in some settings controversial and conflicting, suggest that kidney transplantation in cirrhotic patients is justifiable and should be done in certain circumstances and with certain indications.

Chronic liver disease is not uncommon among patients with end-stage renal disease. In the majority of cases the etiology is hepatitis C. Studies on hemodialysis patients have shown that the incidence of chronic hepatitis C infection is higher in this group than in the general population [3]. The number of years on hemodialysis and the number of blood products received seem to correlate with the infection risk. In developed countries, advanced methods of detecting hepatitis C infected products and the increased use of erythropoiesis stimulating factors instead of transfusions have caused a decline in hepatitis C infection in hemodialysis patients, with a prevalence between 3% and 30% [4–8]; however this percentage remains higher in developing countries (6–80%) [9–11]. The incidence of cirrhosis among these patients is quite high, with reports of over 20% [12]. Other etiologies of liver cirrhosis can also be found among ESRD patients but with a much lower incidence than hepatitis C. In particular, Nonalcoholic steatohepatitis, a rapidly emerging etiology of chronic liver disease and cirrhosis in the western population has also been linked with ESRD. Interestingly, this correlation seems to be independent of the metabolic syndrome and traditional common risk factors such as diabetes [13, 14].

Major concerns about kidney transplantation in patients with chronic hepatitis C are the potential acceleration of the hepatitis C infection due to the immunosuppression treatment post transplant and eventual histological progression and decompensation of the liver disease [15, 16]. Some studies have shown a rising viral load after a kidney transplant, especially in patients with significant viremia at the time of transplantation; the hepatitis C-RNA levels after transplant have been shown to increase between 2-fold and 30-fold [17]. However, the impact of this increase on the liver histopathology and function is not clear. Few studies have performed serial liver biopsies after the kidney transplantation [18, 19]. Most of them showed several degrees of histological progression of Hepatitis C disease, especially in patients with worse histopathology pretransplant, but not persistently and without significant worsening of the liver function [20–23].

Regardless of the evolution of the hepatitis C infection and liver fibrosis the most important question is how hepatitis C affects survival after kidney transplantation. There are a large number of studies which evaluated the effects of Hepatitis C on patient and graft survival [12, 15, 24]. Most of the studies have shown that graft survival in hepatitis C positive recipients is lower than the Hepatitis C negative counterparts. Fabrizi et al. conducted a meta-analysis on observational studies and demonstrated a 1.56 Relative Risk of graft loss in Hepatitis C positive patients when compared to hepatitis C negative patients. The same study showed that hepatitis C positivity is an independent risk factor for graft loss [25]. In a more recent review of 18 studies Rostami et al. showed similar results with a Hazard Ratio of 1.5 for graft loss and also demonstrated that hepatitis C infection is an independent predictor of unfavorable graft outcome [26].

The reasons for inferior graft function in hepatitis C positive recipients are not fully understood, but certain mechanisms are possible. These patients can develop a de novo hepatitis C–related glomerulonephritis. This can be a cryoglobulinemic or noncryoglobulinemic membranoproliferative glomerulonephritis (MPGN) or membranous glomerulonephritis (MGN), and the pathogenesis seems to be the deposition of immune complexes containing viral RNA in the glomerulus [27]. Berthoux et al. [17] studied MPGN and MGN in renal transplant recipients and found that hepatitis C positivity was statistically higher in patients who developed these types of glomerulonephritis post transplant. In addition, hepatitis C infection increases the risk of interstitial fibrosis/tubular atrophy (IF/TA). Post-transplant glomerulopathy among hepatitis C recipients has a prevalence of IF/TA of up to 50% [27]. The mechanisms underlying this correlation are not fully understood; however, direct effect of the hepatitis C virus on the glomeruli or higher immunologic risk in hepatitis C patients are very likely. Rejection has also been considered a potential causative factor of graft loss in hepatitis C patients. However, the majority of studies have failed to demonstrate increased rate of rejection in this group. Corell et al. [28] showed a decreased prevalence of rejection in hepatitis C patients, while others have showed increased [29] or similar rates between the two groups [30]. Another possible explanation of the reduced graft survival in hepatitis C patients is the increased incidence of new onset diabetes after transplant (NODAT). It is well known that there is a correlation between hepatitis C infection and diabetes, because of insulin resistance caused by inhibitory actions of the virus on the insulin regulatory pathways of the liver [27, 31]. NODAT can negatively affect graft survival, but it is also an independent risk factor for lower patient survival.

The survival of hepatitis C infected patients after kidney transplantation has been extensively studied. Even though the results are not consistent in all the studies it has been shown that hepatitis C positive patients have lower survival post kidney transplant compared to hepatitis C negative patients [32]. Some studies did not show any difference in survival between the hepatitis C positive and hepatitis C negative groups until after the first 5 years post transplant [33]. In a retrospective study of 835 patients Mathuri et al. [33] found a decrease in patient survival after 10 years post transplant but no difference prior to 10 years. In the two largest metanalyses of Fabrizi and Rostami the hazard ratio of death in the hepatitis C population was 1.79 and 1.69, respectively, vs. nonhepatitis C patients. The majority of deaths were due to cardiovascular causes, infection and liver related complications [15, 26]. It is known that hepatitis C patients have an increased risk of infection post transplant [34]. In many studies, hepatitis C has been shown to be an independent risk factor for blood stream infections. On the other hand, the increased incidence of NODAT in these patients may explain the higher rate of cardiovascular complications and death especially after 10 years. Finally, some increase in PTLD and myeloma has been observed in hepatitis C patients post transplant and may be contributing to the increased mortality [35]. However, despite the decreased survival of hepatitis C patients compared to the nonhepatitis C population, it is important to point out that there is a significant survival advantage within the hepatitis C group [36]. All the studies which compared the survival of hepatitis C patients with end-stage renal disease with and without a kidney transplant showed a significant benefit with transplantation [36, 37]. The mortality of hepatitis C patients on dialysis, especially when they have diabetes [37], is substantial, with a survival of less than 30% at 8 years [38]. Cirrhotic patients on dialysis have a 35% higher death rate than their noncirrhotic counterparts [2]. Roth et al. in a prospective study of 175 hepatitis C–positive patients listed for a kidney transplant showed that the mortality in the transplant group was significantly lower than staying on the waiting list, with a Hazard Ratio for death of 0.3 in favor of transplantation [34, 39]. So despite the lower patient and graft survival that the hepatitis C infected patients demonstrate after kidney transplantation in comparison to hepatitis C–negative patients, these differences are less important than the clear survival benefit in the hepatitis C population from a kidney transplantation vs. staying on dialysis. This survival benefit is comparable with the benefit observed after transplantation in the general population with ESRD [34].

Many researchers have investigated the factors that affect the mortality of patients with hepatitis C who receive a kidney transplant. One of the first studies was by Rao et al. who looked at the effect of liver fibrosis pretransplant on patient and graft survival post-transplant [22]. They demonstrated that the severity of liver histopathology was correlated with worse postransplant outcomes. Their study and other similar studies showed the importance of the liver biopsy in the evaluation of hepatitis C and other chronic liver disease patients who need a kidney transplant. Their suggestion was that advanced stages of fibrosis and histological evidence of cirrhosis should be a contraindication for a kidney transplant alone. More recent studies, however, showed that the severity of the liver histopathology is not the only predictor of post-transplant outcome. Maluf et al. demonstrated that worse liver histopathology (Knodel score > 6) is indeed a predictor of worse outcome after a kidney transplant with a mortality Hazard Ratio of 1.3, but it is not the only risk factor and not the strongest one either. In their multivariate analysis, they showed that apart from liver histology, deceased donor (HR: 17.9), previous kidney transplant (HR: 9.3) and pretransplant diabetes (HR: 4.7), are independent predictors of mortality post transplant [24]. Moreover, Campbel et al. in their cohort of 108 chronic hepatitis C patients with end-stage renal disease (18 of whom had cirrhosis) showed that the degree of liver fibrosis did not affect patient survival post transplant. The hazard ratio of death for cirrhotic patients post kidney transplant was 0.64 (P: 0.38). They also showed that diabetes mellitus was an independent factor of mortality post-transplant [32]. These studies supported that advanced fibrosis and cirrhosis in the pretransplant biopsy should not exclude patients from a kidney transplant, but they should be evaluated in the context of other comorbidities especially diabetes, previous transplantation and advanced age of the recipient. We must emphasize that the cirrhotic patients included in these studies were younger, with no portal hypertension and with well compensated cirrhosis. Any signs of portal hypertension or any decompensating episode such as encephalopathy, ascites or varices/upper GI bleeding were excluding factors. In the same context Paramesh et al. compared the 1 and 3 year patient and graft survival between cirrhotic and noncirrhotic hepatitis C patients who received a kidney transplant. They used HVPG measurements in all the cirrhotic patients and a portal pressure of less than 10 was the cut off for acceptance for transplantation. They found no statistically significant difference between the two groups in their post-transplant outcomes [40]. Advanced age and low albumin were two independent factors which affected negatively the survival in the cirrhotic group. Parsikia et al. in a similar retrospective study showed that when they transplanted hepatitis C well compensated cirrhotic patients with normal (<10) HVPG, normal PLT count, and normal albumin levels, their 1 and 3 year patient and graft survival were similar to their noncirrhotic counterparts [2]. Finally Chan et al. looked at cirrhotic patients with ESRD in the UNOS data base from 1987 to 2012 and demonstrated that well-compensated patients who received kidney transplantation had excellent survival and in some cases better than patients with combined liver/kidney transplants [1].

Separate consideration should be given to the patient population with decompensated liver cirrhosis and renal dysfunction. Up to 20% of hospitalized patients with decompensated liver cirrhosis have some degree of acute renal failure [41]. In these patients the renal failure is part of the extrahepatic manifestations of severe liver disease. The 3-month survival of these patients without a liver transplantation is very low, ranging between 20% and 40% [42]. The only option for these patients is a liver transplantation. As determined by ASTS/UNOS guidelines a kidney should be transplanted simultaneously with the liver in the following cases: (i) end-stage renal disease with cirrhosis and symptomatic portal hypertension or hepatic vein wedge pressure gradient ≥10 mm Hg, (ii) liver failure and chronic kidney disease with GFR ≤30 mL/min, (iii) acute kidney injury or hepatorenal syndrome with creatinine ≥2.0 mg/dL and dialysis ≥8 weeks, (iv) liver failure and chronic kidney disease with kidney biopsy demonstrating >30% glomerulosclerosis or 30% fibrosis [43].

Kidney transplantation in patients with hepatitis C chronic liver disease is justifiable. It may not achieve the excellent patient and graft survival of the nonhepatitis C patients but it offers comparable results; most importantly hepatitis C patients on dialysis have a much higher mortality than the nonhepatitis C counterparts, and within this population kidney transplantation offers a markedly improved survival vs. staying on dialysis. We need to emphasize that all the studies on hepatitis C patients were conducted in the interferon era where a sustained virologic response before or after transplantation was achieved in a small percentage of patients. The new Protease inhibitors and the revolutionary second generation direct acting antivirals (DAAs) have made hepatitis C a curable disease today. Even though the pivotal studies on these medications did not include patients with compromised renal function [44], more and more literature is actively immerging showing that they can be used in that population [45] and even on patients on dialysis [11, 46, 47]. Also other studies have demonstrated the efficacy and safety of those medications in patients after kidney transplantation [48, 49]. A question that sometimes emerges is whether to treat a patient with hepatitis C before or after kidney transplantation. The treatment before may halt the progression of liver disease, but the patient loses the chance of a more expeditious transplantation with a hepatitis C–positive kidney. The treatment after transplantation seems to be a better option, as it is associated with nearly routine and complete eradication of the virus. Even though we do not have enough data at this point, we can safely assume that in hepatitis C patients, patient and graft survival will only improve. Regardless of the etiology of the liver disease, there is a proven correlation between the degree of the liver fibrosis/inflammation pretransplant and the outcomes after kidney transplant. That is why routine liver biopsy should be a part of the pretransplant evaluation of these patients. Patients with advanced fibrosis and fully developed cirrhosis can be candidates for kidney transplantation, under certain conditions. Absence of portal hypertension and liver decompensation (ascites, encephalopathy, esophageal varices, or variceal bleeding) is of paramount importance. An HVPG measured portal pressure of <10 is a prerequisite. Finally, the patients should ideally be free of other comorbidities such as advanced age, previous kidney transplantation, and diabetes. When these conditions are met, kidney transplantation in a cirrhotic patient with end-stage renal disease offers a substantial survival advantage compared to staying on dialysis.