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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2009  |  Volume : 20  |  Issue : 5  |  Page : 876-882
Treatment of a common problem in Hemodialysis patients: Is the juice worth the squeeze?


1 Prince Salman Center for Kidney, Riyadh, Saudi Arabia
2 Mansoura Urology and Nephrology Center, Mansoura University, Egypt

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Date of Web Publication2-Sep-2009
 

   Abstract 

Chronic infection with hepatitis C virus (HCV) is a serious public health problem affecting an estimated 2% of the world's population. The natural history of HCV infection in hemodialysis patients remains incompletely understood and the management is difficult. HCV infection in hemodialysis patients is usually asymptomatic. Given the diminished life expectancy of hemodialysis patients, complications such as decompensated cirrhosis and hepatocellular carcinoma may not have time to develop. The frequency of advanced fibrosis or cirrhosis ranges from 0% to 28 %. We discuss in this presentation several aspects of HCV infection in chronic kidney disease (CKD) patients such as relationship with glomerulopathy, renal allograft outcome, prevalence in hemodialysis patients in the kingdom of Saudi Arabia, treatment of HCV in hemo­dialysis patients in the kingdom of Saudia Arabia, and finally our experience at Prince Salman Center for kidney disease (PSCKD) in the management of HCV infected hemodialysis patients.

How to cite this article:
Al-saran K, Sabry A, Shaheen N, Yehia A. Treatment of a common problem in Hemodialysis patients: Is the juice worth the squeeze?. Saudi J Kidney Dis Transpl 2009;20:876-82

How to cite this URL:
Al-saran K, Sabry A, Shaheen N, Yehia A. Treatment of a common problem in Hemodialysis patients: Is the juice worth the squeeze?. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Nov 24];20:876-82. Available from: https://www.sjkdt.org/text.asp?2009/20/5/876/55384

   Introduction Top


In spite of the marked reduction in the pre­valence of HCV in the western world, it remains high in developing countries and ranges from 40% to 80%, often reflecting lower resources for maintenance of hemodialysis (HD) facili­ties and inadequate provision of erythropoietin treatment. [1]

Diseases of the native kidneys associated with HCV infection includes: cryoglobulinaemic glo­merulonephritis (GN), membranoproliferative GN, membranous GN, fibrillary GN, immuno­tactoid glomerulopathy and IgA nephropathy. [2]

HCV proteins have been detected in renal tissues in few studies including our study in which we successfully detected HCV RNA in renal biopsies from HCV infected patients with nephropathy by the method of polymerase chain reaction (PCR) and we also detected viral like inside the immune dense deposits in the sub­endothelial space and in the cryoprecipitates. [2]

We further proceeded to treatment of 20 pa­tients with HCV- associated glomerulopathy with standard interferon and ribavirin with promising results. [3]

The impact of HCV on renal graft and pa­tients' survival remains controversial, and has been a subject of debate. [4] Although there are many studies that document a negative impact of HCV on renal allograft survival, [5],[6],[7] others reported no effect. [8],[9] We can explain this in­consistency among different studies by many reasons: first the difference in methodology used for HCV detection, the duration of follow­up, and the protocol of immunosuppressive agents used in different studies.

There is a strong association between HCV infection and post-transplantation glomerulo­pathy, including MPGN, de novo or recurrent cryoglobulinemia, Membranous nephropathy, acute and chronic allograft glomerulopathy, acute renal thrombotic microangiopathy. How­ever, whether HCV increases the allograft re­jection is still a matter of debate. [10]

Recently, various reports have suggested an association between HCV and new onset post­transplant diabetes, a complication that may also affect survival. Moreover, preliminary evidence shows that the induction of a pre­transplant sustained virological response (SVR) by interferon (IFN) alpha treatment in patients awaiting kidney transplant may be associated with a lower risk of post-transplant diabetes. [11] Accordingly, it is recommended to eradicate HCV infection while the patients are awaiting renal transplantation.

The negative impact of HCV on patients and graft survival has been reported before by Mit­walli et al [12] from King Khalid University Hos­pital, Riyadh, Saudi Arabia, and by our group from Mansoura Urology and Nephrology Center,Mansoura, Egypt. [13]


   HCV Prevalence and Treatment in HD Patients in Saudi Arabia Top


The prevalence of HCV among HD patients was the main interest for previous publications from the kingdom. Huraib et al [14] reported a prevalence of 68% among 1147 patients in 22 HD centers. Later, Shobokshi et al [15] reported a prevalence that ranged from 48 to 70%. The good news that is reported from the Saudi Center for Organ Transplantation where the prevalence of HCV among HD patients dropped to 29.2% despite the increase in the number of patients on HD. [16]

The most prevalent genotype of HCV in the whole Kingdom of Saudi Arabia is genotype 4 followed by genotypes 1a and 1b, whereas ge­notypes 2a/2b, 3, 5, and 6 are rare. [17],[18]

Results of efficacy and safety clinical trials using INF-a or pegylated INF, alone or in com­bination with ribavirin, have shown great pro­mise for the treatment of chronic HCV in dia­lysis patients. Data on the efficacy of the new pegylated INFs and ribavirin in HD patients in Saudi Arabia, and internationally, are limited. However, there are insufficient data of large randomized controlled studies so far, for defi­nitive recommendations concerning HCV the­rapy in dialysis patients and the type of INF and dosing of antiviral therapy. [19]

However, there are many previous reports from Saudi Arabia about the use of either stan­dard interferon therapy [20] or a combination of standard interferon therapy and ribavirin [21] for the treatment of HCV infection in both chronic HCV and acute HCV infection [22] with an accep­table rate of sustained response.


   Prince Salman Center for Kidney Disease Experience Top


We conducted a controlled study, which in­cluded 35 patients - 20 patients assigned as a treatment group and 15 served as controls. The inclusion criteria were: age of patients ranged from 18-65 years, they were hemodialyzed for at least 6 months, and tested positive for HCV RNA on repeated occasions for more than 6 months. Our exclusion criteria were: Concomi­tant hepatitis B or HIV-infection, Signs of ci­rrhosis or liver cell insufficiency, hemoglobin level < 8.5 g/dL, White blood cell count < 3000/mm 3 , Platelets count < 90000/mm 3 , psy­chiatric disorders, alcohol or drug abuse, con­comitant auto immune disease, and severe chro­nic obstructive lung disease. A negative preg­nancy test and effective contraception during the study period were required for women of childbearing age.

Whenever possible, liver biopsy was done by subcutaneous ultrasound guided technique. Liver specimens were evaluated by one blinded pa­thologist and scored according to Knodell cla­ssification. Furthermore, the necrotic-inflam­matory process, giving the histology activity index (HAI), was graded from 0-18 with the staging of fibrosis being scored from 0-4.

Our treatment regimen included pegylated IFN alpha-2a (PEG IFN 2-a ) (Pegasys, 40 KD peginterferon alpha-2a), at a starting dose of 135 µg subcutaneously once a week following HD. The dose was reduced (i.e. to 90 µg) when there was neutropenia (1.5-3.0/mm3), thrombo­cytopenia (80-100 ×10 9 /L), or anemia (hemo­globin < 8 g/dL). The blood counts were moni­tored twice weekly when abnormal. Pegylated IFN alpha-2a was interrupted upon occurrence of severe neutropenia (< 0.5 mm 3 ), thrombo­cytopenia (< 50 ×10 9 /L) or severe anemia (he­moglobin < 6 g/dL). Treatment was continued for a total duration of 48 weeks. Follow-up was continued for at least 24 weeks after treatment ended. Patients were advised against kidney transplantation during treatment and for 6 months after completion of therapy. Anemia was treated by increasing the dose of erythro­poietin according to the judgment of the atten­ding physician. Ribavirin was added to PEG IFN 2-a (200 mg given every other day after HD session) with dose modification whenever the CBC allows in 10 patients.

Patients' evaluation was done at the baseline, at weeks 1, 2, 4, 6, 8, then every 4 weeks until 6 months after discontinuation of PEG IFN-2a. The HCV RNA level was at the following time points: 1-4 weeks before the treatment was started, during the treatment at weeks 12 and 48, and 6 months after the end of the treatment.

Primary virological response (PVR) was de­fined as the absence of detectable levels of HCV RNA in serum or 2 log drop 12 weeks after therapy, while sustained virological res­ponse (SVR) was defined as the absence of detectable levels of HCV RNA in serum 6 months after the end of treatment. Genotype analysis was carried out by reverse trans­criptase-PCR (Versant-HCV genotype assay (LiPA), Bayer].

The results of our study showed 20.4% (43/ 221 patients) prevalence of HCV and a drop of annual rate of seroconversion (dropped from (5%) in 2005 to (0.6%) in 2008). No statisti­cally significant difference was observed bet­ween the treated patients and the controls regarding the demographic criteria and labo­ratory parameters [Table 1], and [Table 2].

In our study 13 (65%) patients had a PVR, of them 12 (92%) patients maintained SVR, while 7 (35%) patients were non-responders.

IFN-Responders revealed a lower viral titer [Table 3], and required significantly higher doses or erythropoietin therapy 12 months after com­pletion of IFN therapy [Table 4].

The commonest genotype observed in our pa­tients was genotype IV (66%) followed by genotype 1 (34%) of the examined samples. None of the controls seroconverted to HCV RNA negative. Liver biopsy showed chronic persistent hepatitis in 5 patients with varying degrees of activity grading and fibrosis staging [Table 5].

The mean hemoglobin level decreased during the 3 rd , 6 th , and 9 th months of the study, how­ever, it increases again by the end of the study. This happened at the expense of increased the mean monthly erythropoietin dose.

No statistically significant difference was ob­served between monotherapy and combination therapy groups regarding gender, age, original renal disease, viral genotype, viral titer, PVR and SVR [Table 6] and [Table 7]. However, there was a significant decrease in the mean hemoglobin levels in the combination therapy group when compared to monotherapy group during the 3 rd , 6 th month. However, no difference was observed at the end of the study.

Most of the observed side effects such as anorexia, weight loss, insomnia, depression and flu-like symptoms were predictable and manageable.

In summary, there is a strong causal asso­ciation between chronic hepatitis C virus (HCV) infection and glomerular disease. Liver disease is an important cause of morbidity and mor­tality among recepients of transplanted organs. The presence of anti-HCV antibodies increases the risk for death and allograft failure after renal transplantation.

The prevalence of HCV in Saudi Arabia was variable in the 1990s and ranged from 15% to 90% among different HD centers. In the early 1990s, the average prevalence was around 41%, which increased to 55% in the mid-1990s; this prevalence remained at almost 50% in recent years. Pegylated- Interferon alpha2-a, either as monotherapy or in combination with ribavirin, is effective in treating HCV infection in HD patients. Twenty- four weeks of treatment with Peg-IFN alpha 2a resulted in 65% (13/20) PVR and 92 % (12/13) SVR was achieved in of the cases that completed 48 weeks of treat­ment.

Finally, to answer the difficult question, which the title of this presentation is about: does the juice worth squeeze?

I mean by the juice that to have HCV eradi­cation in HD patients who are good candidates for renal transplantation results in a better post­transplant patient's and graft's outcome and lower incidence of post-transplant diabetes. On the other hand, I mean by the squeeze that a long term therapy- at least 24 weeks- requires dedication from the treating physician, and is hampered by side effects and high cost with a possibility of recurrence. The answer is YES the juice deserves more and more squeeze.


   Questions Top


Dr. Akram Askar (acting chairman of Riyadh Nephrology Club, King Khaled University Hospital, Riyadh) : Nice presentation. Now, the presentation is open for discussion. Dr. Dujana Moosa (Armed Forces Hospital, Riyadh ): Your experience with the treatment of HCV is well documented. Your study de­monstrates a high primary and sustained res­ponse rate for this common problem in our dialysis units in Saudi Arabia. A similar un-published experience of our center shows close response rates. Diabetes is a big problem also in our units, and this possible causal relation­ship between HCV and incidence of diabetes should alarm physicians for treatment of HCV Dr. Alaa Sabry (presenter, Prince Salman Center for Kidney Diseases ): I concur with that and believe the complications of HCV should be addressed carefully and this is the message of our study.

Dr. Askar : I believe a multicenter study is required to reach a consensus about therapy including the types of drugs and their dosing. We have to admit that the experiences are scarce in the face of this common problem.

Dr. Moosa : I agree with notion. Considering the high response rates and tolerable side effects of the treatment of HCV, physicians should shy anymore from treating this disease in the dialysis population. There was a pro­posal for a multicenter study a few years ago, and we can reactivate it in the context of the piled experience so far. I believe the Saudi Center for Organ Transplantation SCOT led the proposal at that time and can play a major role again. Dr. Faissal Shaheen, director of SCOT is here and may consider again a project of multicenter study. We can follow the Ribavirin levels in treated patients, which may decrease its side effects.

Dr. Alaa Sabry : But this involves HPLC laboratory technique, which may be difficult to obtain in many centers.

Dr. Askar : Thank you all for your parti­cipation.

 
   References Top

1.Agrawal SB, Pascual M, Moradpour D, Frei1 U, Rubin NT. Hepatitis C virus infection in hemodialysis and kidney transplant patients. Rev Med Virol 2008;18:97-115.  Back to cited text no. 1    
2.Sabry AA, Sobh MA, Irving WL, et al. A com­prehensive study of the association between hepatitis C virus and glomerulopathy. Nephrol Dial Transplant 2002;17:239-45.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Sabry AA, Sobh MA, Sheaashaa HA, et al. Effect of combination therapy (ribavirin and interferon) in HCV-related glomerulopathy.Nephrol Dial Transplant 2002;17:1924-30.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Lin HH, Huang CC, Huang JY, et al. Impact of HCV infection on first cadaveric renal trans­plantation, a single center experience. Clin Transplant 2004;18(3):261-6.  Back to cited text no. 4    
5.Pereira BJ, Wright TL, Schmid CH, Levey AS. A controlled study of hepatitis C transmission by organ transplantation. The New England Organ Bank Hepatitis C Study Group. Lancet 1995;345:484-7.  Back to cited text no. 5    
6.Stempel CA, Lake J, Kuo G, Vincenti F. Hepatitis C- Its prevalence in end stage renal failure patients and clinical course after kidney transplantation. Transplantation 1993;55(2): 273-6.  Back to cited text no. 6    
7.Legendre C, Garrigue V, Le Bihan C, et al. Harmful long-term impact of hepatitis C virus infection in kidney transplant recipients. Transplantation 1998;65(5):667-70.  Back to cited text no. 7    
8.Pol S, Legendre C, Saltiel C, et al. Hepatitis C virus in kidney recipients. Epidemiology and impact on renal transplantation. J Hepatol 1992;15(1-2):202-6  Back to cited text no. 8    
9.Romero E, Galindo P, Bravo JA, et al. Hepatitis C virus infection after renal transplantation. Transplant Proc 2008;40(9):2933-5.  Back to cited text no. 9    
10.Morales JM, Pascual-Capdevila J, Campistol JM, et al. Membranous glomerulonephritis associated with hepatitis C virus infection in renal transplant patients. Transplantation 1997; 63(11):1634-9.  Back to cited text no. 10    
11.Kamar N, Toupance O, Buchler M, et al. Evi­dence that clearance of hepatitis C virus RNA after alpha-interferon therapy in dialysis pa­tients is sustained after renal transplantation. J Am Soc Nephrol 2003;14:2092-8.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Mitwali AH, Alam A, Al-Wakeel J, et al. Effect of chronic viral hepatitis on graft survival in Saudi renal transplant patients. Nephron Clin Pract 2006;102:C27-80.  Back to cited text no. 12    
13.Sabry A, Hassan R, Mahmoud I, Hamed M, Sobh M. Proteinuria after Kidney Transplan­tation Its Relation to Hepatitis C Virus and Graft Outcome. Iran J Kidney Dis 2007;1:88­97.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Huraib S, Al-Rashed R, Aldrees A, Aljefry M, Arif M, Al-Faleh F. A High prevalence of and risk factors for hepatitis C in hemodialysis patients in Saudi Arabia: a need for new dia­lysis strategies. Nephrol Dial Transplant 1995; 10:470-4.  Back to cited text no. 14    
15.Shobokshi OA, Serbour FE, Al-Drees AZ, Mitwalli AH, Qahtani A, Skakni L. Hepatitis C virus seroprevalence rate among Saudis. Saudi Med J 2003;24(7):S81-6.  Back to cited text no. 15    
16.The annual report of SCOT 2008.   Back to cited text no. 16    
17.Shobokshi OA, Serebour FE, Skakni L, Al­Saffy YH, Ahdal MN. Hepatitis C genotypes and subtypes in Saudi Arabia. J Med Virol 1999;58:44-8.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Al-Faleh F, Huraib S, Sbeih F, et al. Hepatitis C virus genotypes in patients with chronic liver disease and hemodialysis patients from Saudi Arabia. J Viral Hepatitis 1995;2:293-6.  Back to cited text no. 18    
19.Karkar A. Hepatitis C in dialysis units: The Saudi Experience. Hemodialysis Int 2007;11: 354-67.  Back to cited text no. 19    
20.Huraib S, Tanimu D, Abu Romeh S, et al. Interferon in chronic hepatitis C infection in dialysis patients. Am J Kidney Dis 1999;34(1): 55-60.  Back to cited text no. 20    
21.Mousa DH, Abdalla GA, Al-Sohail G, Al­Sulaiman MH, Al-Hawas FA, Al-Khader AA. Alpha-Interferon With Ribavirin in the Treat­ment of Hemodialysis Patients With Hepatitis C. Transplant Proc 2004;36:1831-4.  Back to cited text no. 21    
22.Al-Harbi AS, Malik GH, Subaity Y, Mansy H, Abutaleb N. Treatment of Acute Hepatitis C Virus Infection with Alpha Interferon in Patients on Hemodialysis. Saudi J Kidney Dis Transpl 2005;16(3):293-7.  Back to cited text no. 22    

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Correspondence Address:
Khalid Al-saran
Prince Salman Center for Kidney, Riyadh
Saudi Arabia
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PMID: 19736496

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]

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