Objectives: Liver disease is an important cause of morbidity and mortality among recipients of transplanted organs. In addition to the liver, hepatitis C virus infection has a significant prevalence among recipients of kidney transplant and is related to worse graft and recipient survival as the kidney is an important component of the hepatitis C virus clinical syndrome.
Materials and Methods: This retrospective single center study included 336 patients with end-stage renal disease who received a kidney transplant at the Mansoura Urology and Nephrology Center from January 1992 to December 1995. Of 336 patients, 63 were excluded, and the remaining 273 patients were divided into 3 groups: viremic active (72 patients), viremic inactive (108 patients), and nonviremic (93 patients). Division of patients was based on hepatitis C virus RNA complement level (C3 and/or C4 consumption), circulating cryoglobulins, and rheumatoid factor detection.
Results: Our study showed insignificant differences regarding patient characteristics and demographic data among the study groups but significantly higher incidence of transaminitis in viremic (active and inactive) patients. Nonsignificant differences were found regarding proteinuria among the 3 groups, including among those who had levels in either nephrotic or nonnephrotic ranges. Biopsy-proven acute rejection episodes among the 3 groups of recipients were statistically comparable, with significantly higher frequency of chronic rejection episodes among viremic active patients. Nonviremic recipients had significantly lower serum creatinine levels than viremic (active and inactive) recipients. Patient and graft survival results were comparable among the groups.
Conclusions: Presence of hepatitis C virus immunologic markers does not have a significant effect on patient and graft survival; however, it may be a clue for long-term incidence of chronic rejection.
Key words : Cryoglobulinemia, Graft outcome, HCV, Hypocomplementemia, Renal transplant
Hepatitis C virus (HCV) infection has a significant prevalence among kidney transplant recipients and is related to worse graft and recipient survival.1 In addition to the liver, the musculoskeletal, immune, and hematopoietic systems, and skin, the kidney is an important component of the HCV clinical syndrome. This notorious viral infection imposes itself as a cause of kidney disease and is a major risk factor during dialysis. Hepatitis C virus can cause acute kidney injury in patients with acute or fulminant cryoglobulinemic vasculitis. Chronic HCV infection can be a significant risk factor for acute kidney injury in patients with dehydration, sepsis, or advanced liver injury. In addition, acute kidney injury is a potential risk in several HCV treatment protocols.2
Cryoglobulinemic vasculitis is a systemic disease reported in approximately 5% to 15% of HCV-positive patients. It is rarely associated with ‘‘occult” HCV infection, which can be only shown by nucleic acid testing in liver or bone marrow biopsy. This disease is characterized by multiorgan involvement. The fundamental lesion is an endothelial injury, with small vessel necrosis, perivascular inflammation with lymphocytic and neutrophilic infiltration, and luminal occlusion by cryoglobulins and fibrin thrombi.3 In the kidneys, the mechanism of vascular injury is typically attributed to C1q, the active complement component incorporated within the cryoglobulin complex. This leads to endothelial injury by dual effects, namely, activation of the complement cascade via the classical pathway and binding to endothelial complement receptors, thereby localizing the injury in target capillary beds. Complement activation generates chemotactic factors C3a and C5a, which recruit and activate proinflammatory leucocytes. This occurrence also leads to the formation of C5-9, the membrane attack complex, which may have an important role in endothelial damage. In addition, a direct viral cytopathic effect has been proposed to participate in the pathogenesis of endothelial injury.4 Here, we investigated the HCV-related immunologic markers and how these can affect outcomes of living-donor kidney transplant recipients.
Materials and Methods
The study was approved by the Mansoura Urology and Nephrology Center Ethics Committee. Our analyses included 336 patients with end-stage renal disease who received kidney transplants at the Mansoura Urology and Nephrology Center from January 1992 to December 1995. We excluded 63 patients because of presence of hepatitis B surface antigen (13 patients), death or graft failure within the first 6 months posttransplant from causes other than HCV (15 patients), or lost to follow-up (35 patients).
The remaining 273 patients were divided into 2 groups: viremic (180 patients) and nonviremic (93 patients) according to their HCV RNA polymerase chain reaction status. The viremic group was subdivided into viremic active (72 patients) and viremic inactive (108 patients) based on presence of hypocomplementemia, circulating cryoglobulinemia, or positive rheumatoid factor. The two viremic groups (active and inactive) were retrospectively analyzed after an average 16-year follow-up and compared with the control nonviremic group.
We compared a number of variables between the groups, including recipient age, sex, donor age and relation, duration of hemodialysis, number of blood transfusion episodes and anti-schistosomal treatment pretransplant, posttransplant liver status (judged by ALT level, synthetic functions, and ultrasonographic appearance), frequency of biopsy-proven rejection (acute and chronic, cellular and humoral), mean serum creatinine levels at comparable times, frequency of posttransplant diabetes mellitus, proteinuria, hypertension, and patient survival and graft survival.
Qualitative data were displayed in cross tabulations, and quantitative data were described in terms of mean and standard deviation. Bivariate techniques were used for initial evaluation of contrasts. Analysis of variance was used to compare continuous data between the groups. Categorical data were compared using chi-square test. P < .05 was considered significant. Graft and patient survival rates were assessed using the Kaplan-Meier method. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 16.0, IBM Corporation, Armonk, NY, USA).
In this study, our objective was to identify the
HCV-related immunologic markers and their effects on outcomes of living-donor kidney transplant recipients regarding incidence of graft acute and chronic rejection, mean serum creatinine at certain time points, incidence of proteinuria and its degree, and posttransplant diabetes mellitus as well as its impact on patient and graft survival. Transplant recipients who were seen at the Mansoura Urology and Nephrology Center between 1992 and 1995 were included in this study. Included patients were divided into viremic active (108 patients), viremic inactive (72 patients), and nonviremic groups (93 patients). These 3 groups were followed up and compared retrospectively 16 years posttransplant.
Table 1 shows the patient characteristics and demographic differences between groups of renal allograft recipients at time of transplant. Recipient age, sex, donor age, and donor relation were not significantly different between groups. Hepatitis C virus RNA-positive recipients received more blood units and had longer duration of hemodialysis than recipients who were polymerase chain reaction negative (P = .09). Moreover, a significantly higher percentage of viremic recipients (active and inactive) had a history of anti-schistosomal treatment than nonviremic recipients (P < .001). Liver status posttransplant was evaluated biochemically using alanine aminotransferase as a marker of hepatitis (Table 2), and a significantly higher proportion of viremic patients had evidence of transaminitis (transient and persistent) than patients who were nonviremic (P = .01). Table 3 demonstrates the differentiation of the HCV-active group according to C3/C4 consumption and/or cryoglobulin/rheumatoid factor positivity. When we analyzed frequency of posttransplant complications, no significant differences were shown between the 3 groups (Table 4). The overall frequencies and number of acute rejection episodes and the type of acute (cellular and humoral) rejection among the 3 groups of recipients were statistically comparable, but incidence of chronic rejection was significantly higher in HCV-active group (P = .03; Table 5). Mean serum creatinine levels at comparable time points were statistically significant (Table 6). Regarding last follow-up, no significant differences were shown among the 3 groups regarding patient and graft survival rates (Table 7).
Liver disease is an important cause of morbidity and mortality among recipients of transplanted organs.5 In 1989, HCV was cloned and identified as parenterally transmitted non-A and non-B hepatitis.6 Transplant recipients develop HCV infection after transplant through transfusion of blood products or from infected donor organs.7 To evaluate the effects of HCV immunogenic markers on patient and graft survival after living-donor kidney transplant, we conducted this long-term retrospective study of 273 kidney transplant recipients.
The positive correlation between blood transfusion on hemodialysis and the risk of HCV infection shown here is similar to results reported by others.8,9 Indeed, a longer hemodialysis duration before transplant necessitates multiple blood units for transfusion, resulting in more risk of infection. In addition, the endemicity of HCV in Egypt is mostly attributed to receiving anti-schistosomal treatment through multidose vials and thus also a cofactor to increased risk. Transmission of HCV to sequential patients using the same hemodialysis machine, however, has not been widely reported; therefore, guidelines do not advocate the use of dedicated hemodialysis machines for HCV-positive patients. In a report from Thomson and associates, viral gene sequencing and phylogenetic analyses strongly suggested HCV transmission from a patient with low infectivity to a patient who shared the same hemodialysis machine.10 The patient who was HCV positive developed either transient or persistent transaminitis after transplant. This was significantly higher than that traced in HCV-negative patients (P = .01), confirming the previously reported critical role of HCV infection as a leading cause of liver disease posttransplant.11
Posttransplant diabetes mellitus is a common complication after solid-organ transplant and is associated with adverse outcomes with regard to patient and graft survival. In our study, we found a higher incidence of diabetes mellitus in viremic groups (active and inactive) than in nonviremic patients and in the viremic active group versus the inactive group, although results were not significant (P = .19). These results agree with previous studies.12,13 In addition, Baid-Agrawal and associates14 suggested that impaired peripheral insulin sensitivity is associated with HCV infection irrespective of the transplant status and is the most likely pathogenic mechanism involved in the development of type 2 diabetes mellitus associated with HCV infection.
Chronic HCV infection has also been associated with glomerular disease in native and in transplanted kidneys. In our study, we found no significant differences in incidence and/or quantity of proteinuria between viremic and nonviremic groups. These results are similar to previous reports.15,16 On the other hand, other investigators have documented a higher incidence of proteinuria among viremic than in nonviremic patients.17,18
In this long-term follow-up study, we found no association between the presence of HCV and the number or type of acute rejection. In contrast, other studies have reported significantly higher incidences of acute rejection in recent transplant HCV-positive recipients.19,20 However, we found a significant difference in incidence of biopsy-proven chronic allograft rejection among the 3 groups, which is in agreement with previous results,21 although not all previous results have shown a significant difference.22 These contradictions may be related to either the duration of follow-up, method of detection of HCV (either antibody detection through enzyme-linked immunosorbent assay or nucleic acid testing by polymerase chain reaction), and the number of recipients followed. On the other hand, in renal allograft recipients with and without detectable viremia, significant differences have been shown in mean serum creatinine levels at the most studied time points, with lower levels mainly in nonviremic patients. These findings are in concordance with previous findings.15,17
Our study has some limitations, including deficiency of histopathologic data, lack of graft biopsy when HCV-induced active immunologic markers were detected, and no investigation on the clinical impact on graft function or extrarenal manifestations of cryoglobulinemia.
The presence of HCV immunologic markers did not significantly affect patient or graft survival; however, their presence may be an indicator of long-term incidence of chronic rejection.
Volume : 17
Issue : 1
Pages : 79 - 83
DOI : 10.6002/ect.2017.0161
From the 1Department of Dialysis and Transplantation, The Urology-Nephrology
Center, Mansoura University, and the 2Department of Clinical Pathology, Faculty
of Medicine, Mansoura University, Mansoura, Egypt
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Ahmed Abdelfattah Denewar, Urology Nephrology Center, Mansoura, Egypt
Phone: +20 502202222
Table 1. Pretransplant Characteristics of 273 Recipients According to Their Viremic State and Hepatic C Virus Activity
Table 2. Hepatic Impairment (According to Alanine Aminotransferase Results) in 273 Recipients According to Their Viremic State and Hepatitis C Virus Activity
Table 3. Differentiation of Hepatitis C Virus Active Group According to C3/C4 Consumption and/or Cryoglobulin/Rheumatoid Factor Positivity
Table 4. Frequency of Posttransplant Complication According to Their Viremic State and Hepatitis C Virus Immunogenic Activity
Table 5. Frequency and Type of Rejection Episode in 273 Recipients According to Their Hepatitis C Virus RNA Viremic State and Activity Markers
Table 6. Mean Serum Creatinine Levels at Comparable Time Points in Renal Allograft Recipients According to Their Viremic State and Hepatitis C Virus Activity
Table 7. Condition at Last Follow-Up of 273 Patients According to Their Viremic State and Hepatitis C Virus Activity