|Year : 2019 | Volume
| Issue : 1 | Page : 239-249
|Hepatitis C virus-induced glomerular disease and posterior reversible encephalopathy syndrome after liver transplant: Case report and literature review
Fabrizio Fabrizi1, Aldo Paolucci2, Barbara Antonelli3, Roberta Cerutti1, Francesca Maria Donato4, Pietro Lampertico4, Piergiorgio Messa5
1 Division of Nephrology, Maggiore Hospital and IRCCS Foundation, Milano, Italy
2 Division of Neuro-Radiology, Maggiore Hospital and IRCCS Foundation, Milano, Italy
3 Division of Liver Transplant Surgery, Maggiore Hospital and IRCCS Foundation, Milano, Italy
4 Division of Gastroenterology and Hepatology, Maggiore Hospital and IRCCS Foundation, Milano, Italy
5 Division of Nephrology, Maggiore Hospital and IRCCS Foundation; School of Medicine, University of Milano, Milano, Italy
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|Date of Submission||21-Jan-2018|
|Date of Acceptance||03-Mar-2018|
|Date of Web Publication||26-Feb-2019|
| Abstract|| |
Chronic hepatitis C virus (HCV) infection is associated with numerous extra-hepatic complications, including neurological and renal manifestations. We describe the case of a 67-year-old Caucasian man with HCV-associated cryoglobulinemic glomerulonephritis, cirrhosis, and hepatocellular carcinoma. The early posttransplant course was complicated by fibrosing cholestatic hepatitis due to recurrent HCV in the graft (HCV RNA up to 44,944,438 IU/mL). Proliferative glomerulonephritis (nephritic and nephrotic syndrome) with mixed cryoglobulinemia (purpura) was also recorded. Seventy-two days after surgery, the patient presented with seizures and arterial hypertension; brain magnetic resonance imaging indicated the diagnosis of posterior reversible encephalopathy syndrome (PRES). PRES responded well to medical treatment with complete resolution of neurological changes. Antiviral therapy (sofosbuvir and ribavirin, six months) gave a sustained viral response with the improvement of cryoglobulinemic symptoms (including glomerular disease). Repeat liver biopsy revealed the regression of cholestatic damage and perisinusoidal fibrosis. The current follow-up shows stable chronic renal failure (serum creatinine: 1.4 mg/dL) and mild nephritic syndrome. The impact of extrahepatic manifestations of HCV on patient outcomes is highlighted from novel observational studies reporting a relationship between HCV cure (as expressed by the sustained viral response) and a decrease in both liver-related and renal complications. Clinical trials evaluating the efficacy and tolerance of novel direct-acting antiviral agents for the management of HCV-associated glomerular diseases are underway.
|How to cite this article:|
Fabrizi F, Paolucci A, Antonelli B, Cerutti R, Donato FM, Lampertico P, Messa P. Hepatitis C virus-induced glomerular disease and posterior reversible encephalopathy syndrome after liver transplant: Case report and literature review. Saudi J Kidney Dis Transpl 2019;30:239-49
|How to cite this URL:|
Fabrizi F, Paolucci A, Antonelli B, Cerutti R, Donato FM, Lampertico P, Messa P. Hepatitis C virus-induced glomerular disease and posterior reversible encephalopathy syndrome after liver transplant: Case report and literature review. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2020 Jun 1];30:239-49. Available from: http://www.sjkdt.org/text.asp?2019/30/1/239/252918
| Introduction|| |
Hepatitis C virus (HCV) infection has obvious hepatic manifestations, but it has been associated with multiple extrahepatic disorders. It has been estimated that 40%–70% of patients with chronic HCV may develop at least one extrahepatic disorder during the course of the disease. Extra-hepatic manifestations may develop through immunologic mechanisms, in which the chronic persistence of virus leads to the circulation of immune complexes, and viral mechanisms which are related to the tropism of HCV to other organs or tissues. Derangements of numerous organs systems such as the cutaneous, urinary, cardiovascular, and nervous systems have been observed among HCV-infected patients; moreover, chronic HCV has debilitating psychosocial effects.
The most common form of kidney disease associated with HCV infection is Type I membranoproliferative glomerulonephritis (MPGN) usually but not invariably in the context of type II cryoglobulinemia. Less frequently described lesions are MPGN without cryoglobulinemia and membranous nephropathy. The nervous system is another target of HCV, and a wide variety of neurological complications have been observed in patients with chronic HCV. Receptors required for HCV entry are expressed on all brain microvascular endothelial cells, the major component of the blood-brain barrier. HCV receptor expression is not exclusive to hepatocytes. HCV can affect all three parts of the neuron (cell body, myelin and axon) and patients with hepatitis C can experience axonal neuropathies (including sensorimotor polyneuropathy, large or small fiber sensory neuropathy, motor polyneuropathy, mononeuritis multiplex, or overlapping syndrome) which represent the most common neurological complications of chronic HCV. In addition, some peripheral demyelinating disorders are encountered, such as cryoglobulin-associated polyneuropathy with demyelinating features.
The aim of this paper is to address the extra-hepatic activity of chronic HCV infection, particularly at the kidney and neurologic level. Furthermore, we present the case of an HCV-infected liver transplant (LT) recipient who experienced posttransplant, the onset of fibrosing cholestatic hepatitis (FCH) and posterior reversible encephalopathy syndrome (PRES); renal impairment related to mixed cryoglobulinemic glomerulonephritis was also observed.
| Neurological Complications of Hepatitis C Virus and Posterior Reversible Encephalopathy Syndrome|| |
Extra-hepatic syndromes may represent the first signal of HCV infection in some patients. It has been shown that HCV can infect both hepatocytes and lymphocytes; thus, lymphoproliferative disorders such as lymphoma and mixed cryoglobulinemia are closely linked to HCV. Neurological complications of chronic HCV occur due to the invasion of the virus in neural tissue or indirect stimulation by neurotoxic cytokine pathways; the development of central nervous system vasculitis has been also cited. Viral kinetic models suggest that most infected individuals produce 10–13 trillion virions/day, primarily, but not exclusively from hepatocytes. It appears that the virus replicates in various tissues or organs other than the liver even if the levels of HCV in the central nervous system are usually lower than in the hepatic parenchyma. The most frequent neurological manifestations observed among HCV-infected patients are cognitive dysfunction (particularly abnormalities in the power of concentration and speed of working memory), fatigue and abnormalities in executive functions.,,
An uncommon neurological disease, also known as PRES has been linked to chronic HCV. Since its first description in the late 1990s, PRES has been characterized by some features including a variety of neurological symptoms, the similarity of neuroimaging findings, and the reversible resolution of the symptoms and imaging by appropriate management of etiologies. PRES has been observed after solid organ transplantation (liver, lung, heart, or kidneys),,,, either among adult or pediatric populations and after allogeneic hematopoietic stem cell transplant.
The most frequent clinical symptoms of PRES are seizures, acute encephalopathy syndrome, and visual abnormalities. The typical neuroimaging is a hyper-intense signal mostly distributed in the parietal and occipital lobes (hence the name “posterior”) on fluid-attenuated inversion recovery images. The incidence of PRES shows an upward trend related to the increasing number of the transplantations; it has been calculated that the incidence of PRES after solid organ transplantation is approximately 0.5%–5%.
The mechanisms of PRES development are unclear and its etiology is complex and encompasses immunosuppressive agents (i.e., calcineurin inhibitors), autoimmune diseases, arterial hypertension, eclampsia, and renal failure.,,,, Other risk factors are thrombotic thrombocytopenic purpura, sepsis, human immunodeficiency virus infection, peritoneal dialysis, and erythropoietin., The molecular mechanisms of PRES after solid organ transplantation are still unclear, the final pathophysiological manifestation of PRES appears to be cerebral edema with a frequent coexistence of vasogenic and cytotoxic edemas. Endothelial dysfunction or injury leads to cerebral edema in several ways, and the endo-thelial changes induced by HCV might have a role in predisposing our patient to PRES. Some studies described endothelial injury by HCV-induced cryoglobulinemic vasculitis, others gave a role to HCV per se. Scant data exist in the medical literature regarding the occurrence of PRES in patients with HCV infection,,, [Table 1].
| Case Report|| |
Informed consent was obtained from the patient/relatives before writing this report. A 67-year-old Caucasian male underwent orthotopic liver transplantation due to HCV-related cirrhosis and hepatocellular carcinoma (HCC; HCV genotype 1b). His medical history included chronic obstructive pulmonary disease (he had already stopped smoking), cardiac ablation due to Wolff-Parkinson-White syndrome and arterial hypertension (for 10 years). He had prematurely interrupted combination anti-viral therapy [pegylated interferon (IFN) plus ribavirin] due to mood changes. Diagnosis of de novo HCC was made a few years ago, since then he had been managed with percutaneous ethanol injection, radio-frequency thermal ablation, and transarterial chemoembolization. He had been referred (pre-transplant workup) to nephrologists due to the onset of cryoglobulinemic glomerulonephritis; nonnephrotic proteinuria (<1 g/24 h), and mild, stable renal failure (serum creatinine, 1.2–1.5 mg/dL). Repeat urine sediment, analyzed by phase-contrast microscopy, showed microscopic hematuria (10–20 erythrocytes/ microscopic field), many dysmorphic erythrocytes and casts (hyaline, granular, and red cell casts) ; renal biopsy was not performed due to logistic reasons. Medical therapy at discharge from the hospital included tacrolimus, lamivudine (liver donor being hepatitis B core antibody positive), ranitidine, and corticosteroids; arterial hypertension was managed with ace-inhibitors.
Posttransplant follow-up was immediately complicated by the onset of type-2 diabetes mellitus with the initiation of insulin therapy. One month after transplant, he was again admitted to the hospital due to poor general condition; obstructive jaundice had occurred, and liver biopsy showed FCH due to recurrent HCV infection in the graft. An enormous increase of serum HCV RNA load was noted (HCV RNA up to 44,944,438 IU/mL). In addition, symptomatic mixed cryoglobulinemia was recorded with cutaneous and renal manifestations. Acute-on-chronic renal failure developed with nephritic/nephrotic syndrome and fluid overload. We initiated immunosuppressive therapy (high-dose intravenous corticosteroids) for the treatment of HCV-related cryoglobulinemic vasculitis with prompt relief on the skin only [Figure 1] (61 days after surgery). Seventy-two days after surgery, he developed generalized tremors with psychomotor agitation and transient loss of consciousness (trough levels of tacrolimus, 12.3 ug/L). The first brain computerized tomography (CT) scan showed no significant changes; two days later, brain CT was repeated due to one episode of seizures: multiple and bilateral cortico-subcortical areas of low density were noted. Brain magnetic resonance imaging demonstrated bilateral several hyper-intensity areas on T2- [Figure 2]a and [Figure 2]b and fluid-attenuated inversion recovery-weighted images (cortical-subcortical occipitoparietal and frontal regions with no diffusive restriction); normal size and morphology of the ventricular system were noted, with enlarged arachnoid spaces [Figure 2]c, [Figure 2]d, [Figure 2]e, [Figure 2]f. The electroencephalogram demonstrated a slow global activity with lateralized epilepti-form changes (occipito-parietal areas). These findings indicated the diagnosis of PRES. Arterial hypertension was successfully managed with calcium channel blockers (nifedipine). We discontinued tacrolimus (repeated testing for through levels indicated an appropriate range); we continued immunosuppressive therapy with oral steroids and mycophenolate mofetil for one week along with cyclosporine (50 mg ×/day). After a few days, the patient recovered fully; anti-epileptic therapy was discontinued one month later without any neurological signs or symptoms.
|Figure 1: The clinical picture at liver transplant and over the follow-up.|
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|Figure 2: (a-f) Multiple hyperintensities on T2-weighted (a and b) and FLAIR (c-f) images in parietal and occipital lobes.|
FLAIR: Fluid-attenuated inversion recovery.
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Three months after surgery, the patient developed oliguria despite improvement in neurological changes; a short course of continuous venovenous hemofiltration was administered [Figure 1]. Antiviral therapy with direct-acting antivirals [DAAs (sofosbuvir, 400 mg/day and ribavirin, 200 mg/day)] was initiated with rapid clearance of HCV viremia (by week 4), and resolution of jaundice. After recovery of appropriate circulatory conditions, he underwent plasma-exchange (five sessions) with reduction of cryoglobulins and HD (10 sessions). Clearance of the virus was accompanied by significant improvement of urinary changes, and renal function; most biochemical liver tests were again in the normal range [Table 2]. Tolerance to antiviral therapy was not very good; he needed two units of red blood cells, but completed anti-HCV therapy (6 months). Repeat biopsy showed a consistent improvement of cholestatic liver injury and perisinusoidal fibrosis. He is currently doing well on regular posttransplant follow-up (39 months), serum creatinine being stable around 1.3–1.5 mg/dL; nonnephrotic proteinuria and microscopic hematuria are still present. Nephritic syndrome is currently managed with prednisone (5 mg day), mycophenolate mofetil (500 mg ×2/day), enalapril (20 mg/day), and valsartan (20 mg/day). Other medications include cyclosporine (75 mg/day), lamivudine (100 mg/day), omeprazole, insulin, furosemide, clopidrogel and subcutaneous erythropoietin (6000 IU/week). Clearance of HCV viremia (sustained viral response) has persisted over prolonged observation time.
|Table 2: Case study: blood chemistries and urine changes at presentation and over follow-up.|
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| Discussion|| |
In addition to involvement of the central nervous system with PRES, our patient had multiple complications related to HCV infection (FCH) or HCV-associated cryoglobulinemic vasculitis (skin and kidneys). The post-transplant course of our patient was characterized by a long history of HCV infection, an enormous increase in serum HCV RNA levels, and symptomatic cryoglobulinemia with glomerular disease. Furthermore, recurrent hepatitis occurred in the graft; clinical and histological features of FCH were observed. FCH is a severe and rare form of recurrent hepatitis C after solid organ transplant commonly found during the period of maximal immunosuppression. It is invariably associated with very large HCV viral load causing direct liver injury without support from host immune responses. FCH was a serious concern during the IFN era as this drug had been associated with allograft rejection. However, recent data (including our patient) from LT literature demonstrate successful treatment of FCH with current DAAs;,, we observed a fall of serum aminotransferase and bilirubin levels in the normal range within a few weeks after HCV RNA clearance. Antiviral therapy with DAAs also gave benefit to the kidneys as a close relationship occurred between clearance of HCV RNA, remission of nephrotic syndrome and amelioration of renal function; this is in keeping with recent data showing the efficacy of antiviral therapy on HCV-related glomerulonephritis. Of note, HCV RNA clearance and coincidental changes in liver and kidneys occurred several weeks after complete resolution of PRES. HCV-infected LT recipients presenting with symptoms involving the central nervous system should be carefully evaluated with radiographic imaging to confirm or rule-out PRES.
Our case report emphasizes the possibility of occurrence of PRES among LT recipients, especially in the early post-LT months, with chronic HCV. It has been already mentioned that neurologic complications are more common among LT recipients than other solidorgan transplants. This is probably due to the poor clinical condition of the patients at the time of LT: they frequently show malnutrition, coagulation abnormalities, and defects in electrolyte balance. In addition, the complex and lengthy surgical procedure is often complicated by hemodynamic changes with blood/ fluid changes. A multifactorial origin of PRES is probably in our patient; in addition to arterial hypertension and immunosuppressive medications (tacrolimus and high-dose steroids) less obvious risk factors for PRES included hepatitis C, renal failure, fluid retention, and the posttransplant setting. Appropriate control of arterial hypertension and switching the immunosuppressive regimen were enough to obtain complete and persistent remission of neurological disturbances.
The current focus by medical care providers on liver disease stage to obtain access to DAAs lacks the recognition of the burden of extra-hepatic manifestations of HCV. The impact of extra-hepatic (such as renal and neurological) complications on patient outcomes has been recently ascertained in some observational clinical studies. The effectiveness of HCV antiviral treatment usually is evaluated by the surrogate end-point of sustained virologic response (SVR) ; however, the ultimate goal of antiviral treatment is lowering mortality. The long-term consequences of SVR have been mostly concentrated on the incidence of HCC and liver-related morbidity and mortality.
Various observational studies observed that SVR is independently associated with a lower risk of all-cause and nonliver related mortality.,,,, Other reports observed a relationship between IFN-based treatment of HCV and improved renal and cardiovascular outcomes.
We need to highlight these associations as we must justify high treatment costs and adverse events related to antiviral therapies. Adjustment for potential confounders is important because patients who did not achieve SVR may have other unfavorable factors such as arterial hypertension and diabetes, which may underlie the lack of treatment response and also may lead to higher mortality rates.
As listed in [Figure 3], some recent multivariate analyses reported an association between SVR and lower risk of chronic kidney disease (or chronic glomerulonephritis).,,, The mechanisms underlying these associations are an area of active research; it appears that viral eradication reduces chronic inflammation which commonly occurs in HCV-infected patients including atherosclerotic disease. The renal impairment observed in patients with HCV has been associated with atherosclerotic disease, glomerulonephritis or subclinical immune complex deposition. These multivariate analyses are based on observational studies and may present limitations inherent in this type of studies (as an example, underreporting of some diagnoses of interest). Residual confounding could also account for the differences in mortality that were observed in association with SVR.
|Figure 3: Impact of HCV treatment on the risk of chronic kidney disease.|
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Data are missing on the regression of extra-hepatic manifestations with the new HCV treatment regimens, particularly protease inhibitors and/or polymerase inhibitors, which promise to increase SVR rates in the near term. Future work will be required to assess the effectiveness of DAAs in routine medical care, but it is reasonable to anticipate that the beneficial effect of SVR may accrue to greater numbers of patients.
| Acknowledgments|| |
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
| Disclosure|| |
Fabrizio Fabrizi: consultant or advisor to AbbVie, Merck & Co; Maria Francesca Donato: speaker bureau AbbVie, Gilead, MSD.
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Division of Nephrology, Maggiore Hospital, IRCCS Foundation, Milano
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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