Abstract. In this work the impact of schistosomiasis on kidney transplantation was investigated by com- paring two groups of patients, group 1 (Schistosoma-.
Nephrol Dial Transplant (1992) 7: 858-864 © 1992 European Dialysis and Transplant Association-European Renal Association
Nephrology Dialysis Transplantation
Original Article
Impact of schistosomiasis on patient and graft outcome after kidney transplantation M. A. Sobh 1 , A. E. El-Agroudy 1 , F. E. Moustafa 1 , A. A. Shokeir1, A. El-Shazly2 and M. A. Ghoneim 1 'Urology and Nephrology Center, and 2Department of Parasitology, University of Mansoura, Egypt
Abstract. In this work the impact of schistosomiasis on kidney transplantation was investigated by comparing two groups of patients, group 1 (Schistosomainfected cases) and group 2 (control cases). In group 1, schistosomiasis was diagnosed in both donor and recipient in 63 cases, in recipient only in 65 cases, and in donor only in eight cases. Schistosomal infection among kidney transplant recipients was S. haematobiwn in 17 cases, S. mansoni in 58 cases, and mixed in 53 cases. Schistosomiasis was diagnosed by finding Schistosoma eggs in urine, stools, rectal mucosal biopsy, recipient bladder mucosal biopsy, or in the donor ureter obtained during surgery. Patients and donors with active lesions were treated at least 3 weeks before transplantation by the antischistosomal drugs praziquantel and oxamniquine. Follow-up after kidney transplantation showed no significant difference between the two groups regarding the incidence of acute and chronic rejection. Nevertheless, dose of cyclosporin, HBs antigenaemia, incidence of urinary tract infection, renal stones, ureteric stricture, and urinary leakage were significantly greater among schistosomal patients when compared to control cases. Schistosomal reinfection was observed in 23% of cases at high risk. Antischistosomal treatment did not affect the graft function. We have concluded that schistosomiasis may affect the outcome of kidney transplantation.
Key words: kidney; schistosomiasis; transplantation
Introduction Schistosomiasis (S) is an endemic disease that infects man and animals [1,2]. One thousand million people are at risk and approximately 200 million are infected throughout the world [1]. The disease is endemic in South East Asia, South America, and a wide area of Africa and the Middle East [1]. Schistosomiasis is known to cause kidney lesions, either directly through glomerular immune complex deposition in Schistosoma mansoni infection [3,4] or indirectly following damage to the urinary tract in Schistosoma haematobium infection [5]. Schistosomiasis is known to have an effect on the immune response whether cell mediated [6] or humorally mediated [7]. The effect of schistosomiasis on patient and graft outcome after kidney transplantation is not known. A review of the literature disclosed a lack of information in this area. The objective of this work was to study the impact of schistosomiasis on the outcome of kidney transplantation.
Subjects and methods Correspondence and offprint requests to' Dr Mohamed Sobh. Uro-In this work recipients and living related donors of 267 logy and Nephrology Center. Mansoura University. Mansoura, consecutive kidney transplantations performed in our centre Egypt. were studied. The following was done:
Schistosomiasis and kidney transplantation outcome
859
1. Diagnosis of schistosomal infection: a. Thorough history taking. b. Urine analysis for S. haematobium eggs (characteristic terminal spine). c. Stool analysis for S. mansoni eggs (characteristic lateral spine). d. Rectal mucosai biopsy which was examined for schistosomal eggs. This was done when negative stool analysis was obtained. e. Indirect haemagglutination test (IHA) for detection of circulating antischistosomal antibodies. The method described by Boyden (1951) and Kagan (1955) was followed [8,9]. Diagnosis was considered positive when reaction occurred at a serum dilution of 1 16 or more. f. Circumoval precipitation test (COPT), the test described by Yogore et al. [10] was performed. g. Radiological examination searching for any complication related to schistosomal infection, e.g. bladder calcification or renal stones by UTP, hepatosplenomegaly or stones by ultrasonography, ureteric strictures by IVP (in donors) or retrograde pyelography (in recipients). h. Endoscopy including (1) urethrocystoscopy and biopsy from any visible lesion. This was done for all recipients and for donors with suspected bladder lesions. (2) Oesophagogastroduodenoscopy for detection of varices. This was done for recipients and donors with abnormal liver size. i. Recipient bladder mucosai and donor lower ureteric biopsies were taken during surgery and examined histopathologically for bilharzial ova and reaction. Paraffin blocks were made, sections were stained with H & E and examined by light-microscopy. 2. Urinary recontinuity was established using the technique described by Lich el al. [11] and Gregoir [12] in 76 schistosomal and 65 non-schistosomal cases, by Politano and Leadbetter [13] in 56 schistosomal and 38 nonschistosomal cases and ureteroureteral in four schistosomal and four non-schistosomal cases. 3. Patients were immunosuppressed by prednisolone plus azathioprine, or prednisolone plus cyclosporin, or by triple immunosuppression. Azathioprine was given in a dose of 1.5-2.5 mg/kg per day according to the white blood cell count, Prednisolone was given initially in a dose of 1.5mg/kg per day and tapered to 0.16mg/kg per day over 1 year. In the cyclosporin-treated group, cyclosporin was given initially in a dose of 12 mg/kg per day which was tapered gradually over 1 month to reach a maintenance dose of 6 mg/kg per day. Cyclosporin dose was adjusted to give a whole-blood trough level of 400ngml (Sandoz RIA-H 3 Kets monoclonal, specific) at first week post-transplantation and 100150 ng/ml at the end of first month and thereafter. The initial prednisolone dose in the cyclosporin-treated group was 0.6 mg kg, which was tapered more quickly to reach the same maintenance dose as the azathioprinetreated group. Acute rejection episodes were treated by five pulses of methylprednisolone, these were 750 mg each in the azathioprine-trcatcd group and 500 mgeach in the cyclosporin group. 4. Following kidney transplantation evaluated regarding:
the patients
were
a. Acute rejection episodes. This was documented by
b. c. d. e. f. g. h.
fine-needle aspiration cytology (FNAC) or graft core biopsy. Chronic rejection. This was documented by graft core biopsy. Cyclosporin acute and chronic nephrotoxicity. This was diagnosed by FNAC and by graft core biopsy respectively. Urinary tract infection. This was documented by repeated urine analysis and cultures. Hypertension. Cyclosporin hepatotoxicity. Surgical complications such as urinary leakage, obstruction, and lymphocele. Drug dosage. Cyclosporin and azathioprine maintenance doses by mg kg were evaluated.
5. Schistosomal reinfection: Transplanted patients were instructed not to come into contact with contaminated water, although it is known that due to socioeconomic reasons this is sometimes unavoidable. Patients at risk of reinfection were screened. They were subjected to urine and stool analysis, rectal mucosai biopsy was performed when negative results were obtained. When reinfection was diagnosed, patients were hospitalized and subjected to: a. Evaluation of their graft function (serum creatinine, endogenous creatinine clearance), 24-h urinary protein excretion, urine analysis for proteinuria and RBC excretion, and complement component (C 3 and C 4 ). b. Antischistosomal treatment. Praziquantel in a dose of 60 mg/kg was given once. This was given in conjunction with oxamniquine in a total dose of 60 mg/kg, given in six divided doses, two doses were given daily for 3 days. c. Serum creatinine, creatinine clearance, 24-h protein excretion, and C 3 and C 4 were re-evaluated 3 days, 7 days, and 1 month after antischistosomal treatment.
Statistics 22-test was carried out to compare findings observed in schistosomal and non-schistosomal cases. Patient and graft survival in the two groups were analysed using the KaplanMeier method, and the Mantel-Haenzel test was used to test for the statistical significance of differences.
Results Each recipient and donor pair were considered as one case. Evaluation for schistosomal infection" showed definite positive findings in 136 cases (group 1) and definite negative findings in 107 cases (group 2). Twenty-four cases were excluded from the study as the presence or absence of schistosomiasis was not definite. In group 1. Schistosoma infection was documented in the donor and recipient in 63 cases, in recipient only in 65 cases, and in donors only in eight cases. In the 128 Schistosoma-positive recipients, schistoso-
860
mal infection was mixed (S. mansoni and S. haematobium) in 53 cases, S. mansoni only in 58 cases, and S. haematobium only in 17 cases. S. haematobium infection was in the form of recipient bladder lesions (Figure 1) in 27 cases, recipient bladder lesions plus donor ureteric lesions in 21 cases and donor ureteric lesions in five cases (Figure 2). None of these cases was suffering from lower urinary tract symptoms at presentation. S. mansoni disease was intestinal in 25 recipients, hepatointestinal in 40, and hepatosplenic in 63 cases. Routine biochemical evaluation in these cases showed normal liver function. Upper gastrointestinal endoscopy showed no oesophageal varices in any of our cases. There was no difference in age between the two groups, with mean age of 30.4 + 7.9 years in group 1 and 28.5 ± 9 years in group 2. Males were more in the schistosomal group (89.8 versus 70.5%). There was no significant difference in the degree of tissue compatibility and type of immunosuppression in the two groups. Nine patients in group 1 and eight in
Fig. 1. Part of recipient bladder mucosa showing thin transitional epithelial lining and dense subepithelial infiltration by calcified bilharzia ova. (H & E x400).
M. A. Sobh elal.
group 2 had fullhouse matching grafts, one in group 1 and none in group 2 had complete mismatching graft. The rest in the two groups had one-haplotype matching grafts. Fifty-four per cent of the schistosomal patients and 60% of the non-schistosomal patients were given cyclosporin plus prednisolone with or without azathioprine, and the rest were given prednisolone and azathioprine. A significantly higher (/> = 0.02) incidence of HBs antigenaemia was observed in schistosomal cases where 14 of 136 in group 1 and three of 107 cases in group 2 were HBsAg positive. Regarding the drug dosage, there was no difference in azathioprine. Nevertheless there were significantly higher doses of cyclosporin in group 1 than in group 2. This was observed both at 1 month (P = 0.001) and at 6 months after transplantation (P = 0.001). The mean cyclosporin dose was 9.21+2.3 mg/kg and 5.49 + 2.2 mg/kg at 1 month in groups 1 and 2 respectively, while it was 3.98+1.2 mg/kg and 2.42 + 0.7 mg/kg at 6 months. Evaluations of graft function, incidence of chronic rejection, and incidence and frequency of acute rejection episodes showed no significant differences between the two groups (Tables 1,2). Figures 3 and 4 show survival curves in schistosomal and nonschistosomal groups. There was no significant difference in patient and graft survival between the two groups. Statistical analysis of Schistosoma infected cases showed no correlation between the titre of antischistosomal antibodies as evaluated by the IHA test and acute rejection, chronic rejection, or graft function (Table 3). Table I. Graft function in schistosomal and non-schistosomal cases at 2 years post-transplantation Serum creatinine (umol 1)
Schistosomal Non-schistosomal
s; 133
133-267
»267
48 46
46 35
11 8
Total no.
P
105 89
0.70
Table 2. Graft rejection ini schistosomal and non-schistosomal cases Acute rejection (3 months) Incidence n
Fig. 2. Donor ureter showing multiple Brunn's nests and uretentis cystica. (H & E x 100).
Schistosomal Non-schistosomal P
Chronic rejection (2 years) Frequency
%
77% 101 131 85 107 79% 0.45
1
2
i
46 42
36 19 23 20 0.21
22 105 13 89 0.52
861
Schistosomiasis and kidney transplantation outcome Table 4. Medical complications in schistosomal schistosomal kidney transplant recipients
v
Probability C°/«)
and
Schistosomal Non-schistosomal
Complication
09
n
%
n
%
61 6 27 78 12
45
34 2 19 65 14
31.5 1.5 17.5 60 13
non-
P
\
• Schistosomal o Non schistosomal
08 -
0.7
Urinary tract infection Malignancy Hepatic dysfunction Hypertension Diabetes mellitus
1
1
1
1
1
1
1
i
1
8 10 12 14 16 Duration in months
i
18
i
i
20 57 9
0.023 0.27 0.88 0 54 0.29
1
20 22
Table 5. Surgical complications in schistosomal schistosomal kidney transplant recipients
Fig. 3. Actuarial patient survival curves for the two groups. Mantel-Hanzel statistics = 0.605; ^=0.44.
and
Schistosomal
Non-schistosomal
n
%
n
%
6.0 2.0 2.0 0.0 1.0
4.5 1.5 1.5 0.0 0.7
1.0 1.0 0.0 2.0 4.0
0.9 0.9 0.0 1.5 3.4
non-
P
Probability ('/.) Obstruction Urinary leakage Stone Haematoma Lymphocele
0.9
Schistosomal o Non schistosomal
0.8
07
6
8
10 12 14 16 Duration in months
18 20
22 24
Fig. 4. Renal allograft survival curves for the two groups. MantelHaenzel statistics = 0.705; P = 0A Table 3. Correlation between anti-schistosomal antibody titre and graft outcome Acute graft rejection
Kendall's tau b P
Graft function
3 months
1 year
3 months
1 year
0.22 0.14
-0.26 0.11
-0.02 0.46
-0.04 0.4
Table 4 shows the medical complications reported in the two groups. Only urinary tract infection was significantly higher in schistosomal cases. Thirtyseven patients presenting with UTI had mixed infection, eight had 5. mansoni infection, while six showed S. haematobium infection. Kaposi's sarcoma was diagnosed in two non-schistosomal and four schistosomal cases. In addition, a case of dissiminated malignant fibrous histiocytoma and a case of recurrent nasopharyngea! carcinoma were reported in the schistosomal group. Table 5 shows the surgical complications in both groups. There were significantly more complications related to the ureteral anastomosis and stone forma-
0.001 0.176 0.033 0.169 0.101
tion in the schistosomal group. Of patients suffering from obstruction, four had mixed infection, one had S. haematobium and one had S. mansoni. The two patients with leakage had mixed schistosomal infection, as did the two patients with stones. Reinfection with S. mansoni was diagnosed in 10 patients out of 43 patients re-evaluated after transplantation. The mean serum creatinine 4-6 months before infection was 1.91 ±0.86 mg/dl, while it was 1.8 + 0.79 mg/dl when schistosomal infection was first diagnosed. Four patients were under triple immunosuppression, four under cyclosporin plus prednisolone treatment, and two were on prednisolone plus azathioprine. Patients were given antischistosomal treatment. Re-evaluation after antischistosomal treatment showed no significant changes in serum creatinine, creatinine clearance, 24-h urinary protein excretion or C 3 , C 4 levels (Table 6).
Discussion In spite of the fact that schistosomiasis is a major health problem and that this disease is known to cause renal failure, review of the literature regarding the impact of this disease on kidney transplantation disclosed a major gap in information. Few reports were found describing the experience in small numbers of patients. The objective of this work was to study the effect of schistosomiasis on patient and graft outcome in our patients. A relatively large number of patients were examined and followed up. Schistosomiasis was diagnosed in 136 cases (group 1)
M A. Sobh el al.
862 Table 6. Effect of antischistosomal treatment on graft function and serum complement
S. Cr. (umol'l)
M SD
Basal
3 day
7 day
30 day
160 70
182 90
165 79
141 52
M Cr. Cl. (ml/min) so
54.2 33.79
55 7 34.28
c3
97.3 17.2
93 6 33.66
30.68 7.04
37.18 5.389
34.03 16.96
1.08 1.24
1.26 1.25
0.89 0.93
M
(mg/dl) SD M Q (mg/dl) so 24-h urine Protein (g)
69.66 30.82 103.3 21.5
58.5 28.25 88.5 18.71 29.1 10.33 0.800 0.200
M = mean value: so = Standard deviation.
and 107 cases used as negative controls (group 2). Schistosomiasis was present in the recipient alone, recipient and donor, or donor only, as S. mansoni alone, S. haematobium alone, or mixed infection. There was a greater number of males in group 1, which could be explained by the fact that males are more liable to schistosomal infection than females, since they are more exposed to sources of infection [14]. After kidney transplantation there were no significant differences between schistosomal and nonschistosomal patients regarding the incidence and frequency of graft rejection, whether acute or chronic, and graft function. This may signify that schistosomiasis does not affect the host immune response to the graft. Ottesen el al. [15] stated that despite the progressive loss of the host cellular response to 5. mansoni when infection became chronic, this loss is not a manifestation of a state of generalized cellular immune depression; it is rather limited to a response to schistosoma antigen. This was shown by the response to the non-schistosoma antigen (phytohaemagglutinin), which was normal. They also reported absence of deficiency in humoral responses in their patients [15]. There was no correlation between the schistosomal antibody titre and incidence or frequency of graft rejection. Gazzinelli et al. [16] demonstrated that the titres of antischistosomal antibodies decline and stabilize as infection progresses. HBs antigenaemia was observed more frequently in schistosomal patients. It has been reported that patient survival is less in hepatitis B virus carriers [17]; this is due to the increased incidence of liver cell failure and hepatocellular carcinoma [18]. Since our patients additionally have schistosomal liver disease, with its known complications such as development of liver cell failure and oesophagogastric varices, we
expected increased patient mortality among this group of patients. However, these are long-term effects and so long-term follow-up of these patients will clarify this issue. To achieve the target cyclosporin whole blood trough level, significantly greater doses (65-67% higher) were needed in schistosomal than in control patients. This could be due to an effect of schistosomiasis on the intestinal mucosa leading to impairment of absorption of cyclosporin. It is known that S. mansoni ova may be deposited in the submucosa and surrounded by inflammatory reaction and granuloma formation [19]. Shrief et al. [20] reported malabsorption in his patients with S. mansoni infection; this was attributed to jejunal involvement with bilharziasis. In a histochemical study of jejunal biopsies from cases with hepatointestinal schistosomiasis, a decreased enzymatic activity and dilated central lacteals were observed [21]. Moreover, embolization of ova and dead adult worms, especially after antischistosomal treatment, may occur in the portal tract with consequent portal tract fibrosis [22], which may affect bile flow. Previous studies in animals and humans indicate that bile is essential for cyclosporin absorption [23]. Takaya et al. [23] stated that hepatic dysfunction may not only alter the elimination of cyclosporin, but also impair its absorption. Further work is needed to find out the exact mechanism of this observation. Long-term follow up of our patients showed significantly more urinary tract infections, obstruction, and stone formation in schistosomal patients. This could be explained by the effect of S. haematobium on the urinary tract, leading to damage of the mucosal lining, ulceration, and stricture formation [5]. These mucosal changes predispose to recurrent urinary tract infection and stone formation. In fact, most of our patients with these urological complications had S. haematobium infection either as single or as part of mixed infection. Hefty and McCorkell [24] reported their experience in four schistosomal patients received a living related donor kidney transplant and followed up for 4-37 months; one had S. haematobium infection, one had S. mansoni and two had combined infections. They observed no complications of renal transplantation related to schistosomiasis; serum creatinine, abdominal radiographs, renal scans, and ultrasonography remained normal during follow-up. Nevertheless. Weeden et al. [25] reported that three of their six schistosomal kidney transplant recipients developed obstruction or leakage at the ureteroneocystostomy. The small number of cases reported by these two groups and their different approach to treatment of the schistosomal infection could explain the great difference in their results. Hefty and McCorkell
863
Schistosomiasis and kidney transplantation outcome
treated the infection before transplantation while Weeden et al. gave treatment after transplantation. Schistosomal reinfection was diagnosed in 10 of 43 patients re-evaluated after kidney transplantation. All 10 patients had a history of contact with potentially infective water, so the detected living eggs in stool or rectal mucosal biopsy were probably due to reinfection rather than reactivation of adult worms. The problem of reactivation of surviving sterile worms recovering from the toxic effects of the host's previous uraemic intoxication is an interesting one which needs further study. Reinfection was not associated with change in graft function. Patients were hospitalized and given antischistosomal treatment. Follow-up for 30 days after antischistosomal treatment showed no significant change in serum complement (C 3 ,C 4 ), serum creatinine, creatinine clearance, or the 24-h urinary protein excretion. Falcao and Gould [26] described a patient with nephropathy of possible schistosomal specific aetiology who was kidney transplanted. When antischistosomal treatment (niridazole) was given, this was followed by a transient increase in serum creatinine from 1.0 to 1.8mg/dl, urinary protein excretion to 2.4 g/dl, and a reduction in serum complement (C 3 ,CH 50 ). They attributed this to a sudden increase in serum schistosomal antigens due to adult worm killing by the antischistosomal drug. This causes an increase in circulating immune complexes which are trapped in the glomeruli, causing nephropathy. We believe that this effect could be due to the antischistosomal drug itself. Instances of niridazole-induced proteinuria and reversible azotaemia in subjects with S. haematobium infection have been reported [27]. Moreover, we previously reported the effect of antischistosomal treatment using praziquantel and oxamniquine in patients with schistosomal-specific nephropathy. There was no significant immediate or short-term changes in serum creatinine. proteinuria or serum complement in any of our patients examined [28]. Interestingly eight of the 10 patients presenting with schistosomal reinfection were receiving cyclosporin as a part of their immunosuppression. Bout et al. [29,30] reported a curative and protective effect of cyclosporin against primary and secondary S. mansoni infection in mice and rats. It seems that this effect may only occur in these experimental animals and not in humans. From this work we have concluded that schistosomiasis may have an effect on kidney transplantation. This is mainly through increasing the incidence of urinary tract infection and complications related to the ureteral implantation such as leakage and stricture. Moreover, schistosomiasis may lead to administration of increased doses of cyclosporin to achieve
the target cyclosporin level with its economic consequences. Furthermore, schistosomiasis is significantly associated with an increased incidence of HBs antigenaemia with its possible long-term negative effect on patient survival. Despite these effects, schistosomiasis did not significantly affect the eventual graft and patient outcome within 2 years of followup. Routine cystoscop> and bladder biopsy for recipients and donors coming from endemic areas and proper treatment of schistosomiasis at least 3-8 weeks before transplantation are highly recommended. Acknowledgements. The authors would like to thank Mrs Fateheya Gado and Miss Amal Nour for their technical help, and Miss Heind Sharabi for her secretarial work during preparation of the manuscript.
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25. Weeden D, Hopwell JP, Morehead JF, Sweny P, Fernando ON. Schistosomiasis in renal transplantation Br J Urol 1982: 54: 478-479 26. Falcao HA, Gould DD. Immune complex nephropathy in schistosomiasis. Ann Intern Med 1975; 83' 148-157 27. Sankale M, Baylet R, Moulanier M. Efficacy of nrndazole in schistosomiasis haematobium Ann NY Acad Sci 1969; 160: 705-712 28. Sobh MA, Moustafa FE, Sally SM, Deelder AM, Ghoneim MA. Effect of anti-schistosomal treatment on schistosomalspecific nephropathy. Nephrol Dial Transplant 1988: 3: 744-751 29. Bout DT, Deslee D, Capron AR. Protection against schislosomiasis produced by cyclosponn-A Am J Trap Med Hvg 1984; 33(1): 185-186 30. Bout D, Deslee D, Capron A. Anti-schistosomal effect of cyclosponn A. Cure and prevention of mouse and rat schistosomiasis mansoni. Infect Immunol 1986; 52(3): 823-827
Received for publication 10.4.91 Accepted in revised form 5.2.92
