Impact of schistosomiasis on patient and graft outcome after renal transplantation: 10 years' follow-up

Khaled M. Mahmoud, M. A. Sobh, A. E. El-Agroudy, F. E. Mostafa, M. El Baz, A. A. Shokeir and M. A. Ghoneim

Urology and Nephrology Center, Mansoura University, Mansoura, Egypt



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Schistosomiasis is a major health problem in some areas of the world. Schistosomal-specific nephropathy is a well-known occurrence and eventually leads to end-stage renal failure. Patients with schistosomal infection were considered to be suitable recipients for renal transplantation. However, the long-term impact of schistosomiasis on kidney transplantation is not yet been reported.

Methods. The long-term impact of schistosomiasis on patient and graft outcomes was studied by comparing two groups of subjects from a total of 243 patients. Group I consisted of cases with schistosomal infections and group II consisted of schistosoma-free controls. Schistosomiasis was documented in group I by identifying schistosoma eggs in urine, stool or rectal mucosal biopsy. Also intra-operative biopsies from bladder mucosa of the graft recipients and from the lower end of the ureter of living donors were obtained to search for schistosoma eggs.

Results. Sixty-three cases of schistosomiasis were diagnosed in both recipients and donors, 65 cases in recipients only, and eight cases in donors only. Infected recipients and donors with active lesions were treated at least 1 month before transplantation by combined antischistosomal drugs (praziquantel and oxamniquine). The 243 patients (136 schistosoma-infected cases and 107 controls) were followed regularly for a period of 10 years after transplantation. We found that there was no significant difference in the incidence of acute and chronic rejection between the groups; however, higher cyclosporin doses were needed for the infected group with subsequent higher incidence of both acute and chronic cyclosporin nephrotoxicity. Moreover, the schistosomal group had a significantly higher incidence of urinary tract infection and urological complications with no evidence of schistosomal re-infection.

Conclusions. Despite a higher incidence of schistosoma-related complications after renal transplantation, schistosomal infection is not a major risk factor for transplantatioefore, infected patients can be considered as suitable recipients if they have been properly treated before transplantation.

Keywords: kidney; schistosomiasis; transplantation



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Schistosomiasis is possibly the most important helmenthic disease because of its worldwide distribution and the extensive pathological changes it causes in the host. It has been estimated that over one thousand million people are exposed to Schistosoma and 200 million are actually infected [1,2].

Renal effects are known to occur in schistosomiasis, either directly through glomerular immune complex deposition in Schistosoma mansoni infection [3] or indirectly following damage to the urinary tract in Schistosoma haematobium infection [4].

It is known that schistosomiasis affects both cell-mediated and humoral immune responses [5]. Barrou et al. [6] found that patients with schistosomal infection are suitable recipients for renal transplantation, while Sobh et al. [7], after a 2-year follow-up reported that schistosomiasis may affect the outcome of renal transplantation. However, the long-term effect is not yet reported.

The aim of this work is to study the long-term impact of schistosomiasis on patient and graft outcomes up to 10 years after renal transplantation.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Out of 300 living related-donor patients who received a kidney graft between 1985 and 1987, 243 patients were included in this study. The remaining patients were excluded because the presence or absence of schistosomal infection was not definite. The data on these 243 patients were reviewed retrospectively for a period of 10 years.

Patients were classified into two groups. Group I comprised of 136 cases with definite diagnosis of schistosomal infection (Table 1Go). Group II comprised 107 controls in whom schistosomal infection could be excluded.


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Table 1. Diagnosis of schistosomiasis

 
All patients were subjected to the following examinations.
 (i) Urinanalysis for S. haematobium eggs (characteristic terminal spine).
 (ii) Stool analysis for S. mansoni eggs (characteristic lateral spine).
 (iii) Rectal mucosal biopsy for detection of schistosomal eggs when stool analysis was negative.
 (iv) Indirect haemagglutination assay test (IHA) for detection of antischistosomal antibodies.
 (v) Circumoval precipitation test (COPT), as described by Yogore et al. [8].
 (vi) Radiological evaluation searching for schistosoma-related complications such as bladder calcifications (UTP), hepatosplenomegly (ultrasonography), ureteric stricture in donors (IVP) or in recipients (retrograde pyelography).
(vii) Endoscopic evaluation. Urethrocystoscopy and biopsy from visible lesions was carried out for all recipients and for donors with suspected bladder lesions. Oesophago-gastro-dudenoscopy for detection of varices was carried out for all cases with abnormal liver size.
(viii) Bladder mucosa of the recipients and the lower part of the ureter of donors were biopsied and examined histopathologically for schistosomal ova and reactions.

All infected cases were treated with praziquantel (15 mg/kg) single oral dose and oxamniquine (40–60 mg/kg) in two divided doses for three successive days 1 month before transplantation.

Uretero-neo-cystostomy was carried out using the technique of Politano-Leadbetter in 56 infected and 38 control cases, the Leich Grigoir technique in 76 infected and 65 control cases, and uretero-ureteral anastomosis in four infected and four control cases.

Following transplantation, patients were immunosuppressed by prednisolone plus cyclosporin, or by triple immunosuppression. Azathioprine was given in a dose of 1.5–2.5 mg/kg/day adjusted according to the white blood cell count; prednisolone was initially given at a dose of 1.5 mg/kg/day which was later tapered to reach a dose of 0.15 mg/kg/day by the end of the first year; cyclosporin was given initially at a dose of 10 mg/kg/day, and was adjusted according to the cyclosporin whole blood trough level. The target level was 200–400 ng/ml in the first month and 100–150 ng/ml after that (Sandoz RIA-H3 kets-monoclonal specific antibody).

Patients were evaluated after transplantation for the following.

 (i) Acute rejection: documented by fine needle aspiration cytology (FNAC) and graft biopsy.
 (ii) Chronic rejection: documented by graft biopsy.
 (iii) Acute cyclosporin nephrotoxicity (graft impairment especially in the presence of high CsA level and its improvement after reduction of the dose): confirmed by graft biopsy.
 (iv) Chronic cyclosporin nephrotoxicity: documented by graft biopsy.
 (v) Hepatotoxicity (high serum bilirubin and/or high liver enzymes), either drug induced (e.g. azathioprine) or viral induced (e.g. HCV).
 (vi) Medical complications such as hypertension, diabetes mellitus, malignancy, and infections with special emphasis on urinary tract infections: documented by urinalysis and urine culture.
(vii) Surgical complications such as urinary leakage, obstruction, lymphocele or fistula.
(viii) Drug dosage: mean cyclosporin and azathioprine maintenance doses in mg/kg/day were evaluated.

At the end of the study, most of the patients were evaluated for schistosomal re-infection by sandwich ELISA to detect schistosomal antigen in the serum [9].

Statistical analysis
Chi-square and Chi-square with Yates correction were used to test for associations between categorical variables and schistosoma. The Mann–Whitney U test was used to test for significant differences in quantitative variables between the two groups. Life table and Kaplan–Meier tests were used to evaluate differences in graft and patient survival. These tests were run on an IBM-compatible computer using SPSS/PC for Windows version 7.5 (SPSS Inc. Chicago, IL, USA).



   Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study included 243 patients, who were divided into two groups: group I (136 schistosoma-infected cases) and group II (107 control cases).

In group I, schistosomal infection was documented in 63 paired donors and recipients, in 65 recipients and in eight donors.

In the 128 recipients infected with schistosomiasis, mixed infections (S. haematobium and S. mansoni) were present in 53 cases, S. mansoni only in 58 cases and S. haematobium only in 17 cases. In addition, the stage of schistosomal disease was studied in these 128 transplant recipients. Twenty-five patients had the intestinal form of the disease, 40 patients had the hepato-intestinal form, and 63 patients had the hepato-splenic form (Table 2Go).


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Table 2. Schistosoma type and stage in infected recipients

 
Histopathological documentation of schistosomal infection was possible in 63 donor-recipient pairs. This took the form of bladder lesions in 37 recipients, ureteric lesions in five donors and in 21 transplant pairs both recipient-bladder and donor-ureteric lesions were found.

Table 3Go shows the demographic data of the recipients. There was no difference in mean age between infected and control groups, with mean age 30.4±7.9 years in group I and 28.5±9 years in group II. There were more males in the infected group (89.8 vs 70.5%). No significant differences were found with respect to the cause of end-stage renal disease. Pyelonephritis was the most commonly identified cause of end-stage renal disease in both groups (24% in group I and 20% in group II).


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Table 3. Demographic data of the recipients

 
Table 4Go shows the characteristics of the donors: there was no difference in the mean age and sex distribution between the two groups, the majority were males and of middle age (31.5±7 years in group I and 31.6±7 in group II).


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Table 4. Age and sex of kidney donors

 
The type of immunsuppression and the degree of tissue matching were not statistically different between the two groups. Nine patients in group I and eight in group II had fully matching grafts, one in group I and none in group II had a completely mismatched graft.

HBV infection (HBs Ag +ve and/or HBe Ag +ve) had a significantly higher incidence (P=0.02) in the infected group where it occurred in 18 of 136 cases of group I and only in three of 107 cases of group II. On the other hand, there was a similar incidence in both groups of HCV infection (HCV antibody+ve detected by ELISA and confirmed by PCR for HCV Ag).

With respect to drug dosage, cyclosporin doses were significantly higher throughout the study period in the infected group (P=0.001) with a mean value of 3.6±1.3 mg/kg/day in group I and 2.3±0.6 mg/kg/day in group II (Figure 1Go). On the other hand, azathioprine doses did not show any significant differences between the groups throughout the period of the study.



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Fig. 1. Mean dose of cyclosporin (mg/kg/day)/2 years.

 
Graft function, incidence of acute rejection, incidence of chronic rejection, and incidence of acute and chronic cyclosporin nephrotoxicity did not show any significant difference between the two groups (Figure 2Go, Table 5 andGo Table 6,Go respectively).



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Fig. 2. Graft function (mean serum creatinine) every year.

 

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Table 5. Incidence of acute rejection during the 10-year follow-up period

 

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Table 6. Medical complications in schistosomal and control groups

 
The only medical complication which showed a significant difference between the two groups was urinary tract infection. This complication occurred in 45% of the infected group and in 31.5% of the control group. Hypertension, diabetes mellitus, hepatic dysfunction and malignancy had a similar occurrence in the two groups (Table 6Go).

Table 7Go shows the surgical complications which occurred in both groups. There were no significant differences in the occurrence of urinary leakage, fistulae, lymphocele, haematoma, bleeding, stone formation, and wound dehiscence. The only surgical complication where there was a significant difference was the urinary anastomotic obstruction (P=0.03).


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Table 7. Surgical complications in schistosomal and control groups

 
The technique used for ureteral implantation had no significant impact upon the incidence of urological complications in either group.

Although the mortality was higher in group I (32.3%) than in group II (21.7%) the difference was not significant. Also, the incidence of graft loss either due to patient death or graft failure was not significantly different (P=0.11) between the two groups (Table 8Go).


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Table 8. Causes of graft loss in schistosomal and control groups

 
Table 9Go shows the impact of the type of schistosomal infection on patient and graft outcomes, where no significant difference was found between the urinary schistosomiasis (S. haematobium) and intestinal schistosomiasis (S. mansoni).


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Table 9. Impact of type of schistosomal infection on patient and graft outcome

 
The impact of donor schistosomal infection versus recipient schistosomal infection on the outcome was not statistically significant. However, combined donor and recipient schistosomal infection had a statistically significant impact on the incidence of urinary tract infection (P=0.03); moreover the incidence of acute and chronic rejection, and malignancy was higher but the difference did not reach statistical significance (Table 10Go).


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Table 10. Impact of donor schistosomal infection versus recipient schistosomal infection

 
At the end of the study most of the patients were evaluated for schistosomal re-infection by sandwich ELISA to detect schistosomal antigens. None of the patients showed re-infection.

Figures 3Go and 4Go show patient and graft survival in both groups. There was no significant difference between the two groups during the 10-year study period.



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Fig. 3. Patient survival in both groups.

 



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Fig. 4. Graft survival in both groups.

 


   Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Schistosomiasis is a major disease and of public health importance. An association between schistosomiasis and nephropathy has been known for many years. Sobh et al. [10] reported that schistosomal-specific nephropathy exists in clinical settings and can lead to end-stage renal failure.

Regarding schistosomiasis and renal transplantation, Azevedo et al. [11] found that recurrence of nephropathy occurred in two of 11 schistosoma-infected patients who received renal transplantation; also Falcao and Gould [12] reported that the nephropathy might recur in the transplanted kidney and this led to attempts to eradicate the schistosomal infection prior to transplantation. Weeden et al. [13] reported that three out of six kidney transplant recipients with S. haematobium infection had complications which appeared to be related to their schistosomiasis. Hefty and McCorkel [14] found no complications related to schistosomiasis in 16 live-donor transplantations in the presence of schistosomal infection. Barrou et al. [6] retrospectively evaluated 20 kidney transplant recipients infected with S. haematobium and concluded that schistosoma-infected patients are suitable recipients for renal transplantation, although they are at higher risk of urological complications.

Most of the previous studies were carried out on a small number of patients. Sobh et al. [7] studied the impact of schistosomiasis on renal transplantation in a relatively large number of patients who were examined and followed for a period of 2 years. They concluded that schistosomiasis may affect the outcome of renal transplantation. Therefore, a longer follow up (10 years) to study the impact of schistosomiasis on patient and graft outcome was the objective of this work.

This work included 243 living, related-donor kidney transplant recipients who had been previously reported [7]. They were classified into two groups, group I (136 schistosoma-infected cases) and group II (107 control cases). Both groups were retrospectively followed regularly for a period of 10 years.

It was found that the mean dose of cyclosporin during the study period was significantly higher in the schistosoma group than in the control group. This could be due to schistosomal infection with resultant periportal fibrosis and decreased bile flow which may lead to decreased intestinal absorption of cyclosporin. Another explanation could be a direct local effect of schistosomiasis on the small intestine, leading to decreased drug absorption as reported by Takaya et al. [15]. That report suggested that hepatic dysfunction not only alters the elimination of cyclosporin but also impairs its absorption. However, the mean dose of azathioprine was not significantly different between the two groups: this may be due to the fact that its absorption is not affected by bile flow.

Rejection of the graft remains a challenging problem. Capron et al. [16] observed that there is a suppression of the immune response in chronic schistosomiasis. However, Ottesen and his group [17] stated that the progressive loss of cellular response is not an indication of a state of generalized cellular immune depression, and that there was no evidence of significant deficiency in humoral responsiveness in those patients.

No significant differences were found in the incidence and frequency of early and late acute rejection episodes. It should be noted that the incidence of chronic rejection did not show statistically significant differences between the groups. This may be due to the same incidence and frequency of acute rejections and the same primary immunosuppression.

The occurrence of hypertension, diabetes mellitus, hepatic dysfunction and malignancy was not significantly different between the groups. The only medical complication which showed a significant difference was urinary tract infection. This may be attributed to complications of schistosomiasis known to occur in the urinary tract such as stricture of the ureter, hydroureter, stone disease or bilharzial pathological changes in the bladder or ureteric mucosa.

However, carcinoma of the bladder occurred only in the infected group (three males), 8, 9, and 16 years post-transplantation. Two of these patients were on conventional immunosuppression, and the third was receiving CsA therapy. All had both urinary and intestinal schistosomiasis. The main symptom was haematuria. Cystoscopy, biopsy, and DNA analyses of bladder washes confirmed the diagnosis. Two cases had transitional cell carcinoma grade II, while the last case developed carcinoma in situ. Modulation of immunosuppressive drugs was adopted; however, radical cystectomy and urethral Kock were carried out for two cases, while immuno-modulating therapy by intravesical BCG was tried on the third case. Two patients died with impaired graft function, while the third patient died with good graft function but with widespread metastasis.

Serum levels of hepatitis B surface antigen were significantly higher in the schistosomal group. Nevertheless, no significant complications related to HBV infection such as liver cell failure or oesophageal varices were observed. This may be attributed to the careful selection of transplant recipients and the complete eradication of schistosomiasis before transplantation. Occurrence of HCV infection showed no significant difference. This could be explained by the fact that both groups had been immunosuppressed and on haemodialysis before transplantation, through which they might have acquired HCV infection.

Shokeir et al. [18] studied urological complications in 310 live-donor kidney transplants: S. haematobium was histologically documented in 76 cases. The incidence of urological complications reported by them was 15%, which is statistically significant. In our study, a similar incidence was observed in the schistosomal group (15.7%) and in the control group (1.9%). The cause of this high incidence of urological complications may be the high incidence of ureteral obstruction, ureteral necrosis and fistula due to pathological changes in the mucosa and submucosa in the ureter and bladder produced by ova deposition with subsequent inflammation and poor tissue healing. The surgical techniques used for uretero-neo-cystostomy seem to have no significant impact on the high incidence of urological complications. This may be due to the fact that the numbers of patients subjected to the various techniques was not significantly different between the two groups.

With respect to graft function, in our study there was no significant difference observed between the groups which could be explained by the same incidence of acute rejections, chronic rejection and cyclosporin nephrotoxicity which are the major determinants of late graft function.

Although there was a higher mortality incidence in the infected group (32.3%) than in the control group (21.7%) this did not rise to statistical significance and the causes of death were not attributable to schistosomal infection.

The type of schistosomal infection, whether S. haematobium or S. mansoni, and donor schistosomal infection were found to have no significant impact on patient and graft outcome.

At the end of the study most of the patients were evaluated for schistosomal re-infection. No re-infection was detected. This may be due to patient awareness or possibly due to the high degree of protection provided by cyclosporin as reported by Bout et al. [19].

In conclusion, although we found that there is a higher incidence of acute and chronic cyclosporin nephrotoxicity, and significantly higher incidence of urologic complications and urinary tract infection in the schistosomal group, this had no significant impact on patient or graft outcome after 10 years of follow up. Furthermore, no evidence of schistosomal re-infection was observed. Careful selection of kidney donors and recipients with appropriate antischistosomal treatment for at least 1 month before transplantation are highly recommended.



   Acknowledgments
 
The authors would like to thank Mrs Hend Sharabi, Mrs Ola Ali, Mrs Eman Galal and all the secretarial team for their work during preparation of the manuscript.



   Notes
 
Correspondence and offprint requests to: Dr Khaled M. Mahmoud, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt. Email: khaledmahmoud2000{at}hotmail.com Back



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 2.12.00
Revision received 22. 6.01.



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