THE DEVELOPING WORLD

Economic and technological inequalities between countries have divided the world into two regions. The developed world principally comprises Europe, North America, Australasia and Japan; all other countries constitute the developing world. Economically the developing world owns merely 25% of the total wealth, but is inhabited by 80% of the world population. The health spending in this region is between 0.8 and 4% of the gross national product (GNP) as opposed to 10 to 15% in the developed world. Poor health spending for example renders infections as the major cause of mortality in developing countries, where 43% deaths are due to infections as compared to 1% in the developed world³. Pakistan is fairly representative of a developing country. It has a population of 140 million, with 2/3 of the people living in rural areas. The per capita income is less than US$500 and health expenditure by the government is 0.9% of GNP. Overall, 33% people live below the poverty line with only $1 a day for sustenance. Life expectancy is 61 years for males and 63 for females. The adult literacy rate is 58% for males and 29% for females. Expenditure on education is 2.7% of the GNP. Only 60% have access to potable water and 30% to sanitation. Against this backdrop transplantation is beset with cultural, societal and economic hurdles that need to be crossed to achieve ultimate success.

RENAL TRANSPLANTATION

Economic constraints

Economic deprivation in developing countries and the meager expenditure on health care translates into poor transplantation activity, with a rate of less than 10 per million population (pmp) in contrast to the developed world at 45 to 50 pmp. With an estimated world incidence of end-stage renal failure between 80 and 110 pmp, developed countries fulfill 30 to 35% of their needs as compared to 1 to 2% of the developing world. In Pakistan the reported, though not necessarily true prevalence of ESRD is 100 pmp. For a population of 140 million there are 150 dialysis centers, mostly in the private sector where dialysis costs US$ 25/session. Although this appears low by Western studies, it is clearly beyond the means of 90% of the population. Of the 15 transplant centers, ten are in the private sector where a transplant costs between US$6 to 10,000, which is exorbitant for the vast majority of the population. The annual transplant rate is 8 pmp. All transplants are from living donors with 40% from living unrelated, almost exclusively performed in private centers⁴. The Sindh Institute of Urology and Transplantation (SIUT), a public sector organization, performs more than 130 transplants/year, all from living related donors.

Generally, post-operative care and follow-up is undertaken by nephrologists. At SIUT post-operative care is handled by a team of urologists, nephrologists and pathologists, and the immunosuppression strategy is a shared responsibility of nephrologists and immunologists. There are three transplant teams at SIUT with a total of eight transplant surgeons and six nephrologists, and a team of seven pathology specialists. The Radiology Department is equipped with color Doppler, computed tomography (CT) scan and nuclear medicine.

Cultural drawbacks

Although economic constraint is the main reason for poor transplantation activity in the region, it is not the only reason. For example, the wealthy countries of the Middle East suffer from a lack of education and societal motivation for organ donation. Furthermore, the infrastructure to support transplantation is absent in many of these economically viable countries. In contrast, South Asian countries, which have the necessary technical expertise, suffer jointly from economic difficulties and cultural and societal apathy toward organ donation. This stems from a lack of public awareness. Although brain death laws have been implemented in many countries, organ donation remains minimal. A classical example of socio-cultural resistance toward transplantation is to be found in technologically advanced Japan, where a law relating to cadaveric donation has only recently been enacted, largely because Japanese society has been unwilling to accept the concept of brain death. In Pakistan the bill for cadaveric organ donation has sat in the Senate awaiting approval for the last nine years because of the apathy of the legislature.

Donor issues

Donor shortage is a universal problem. In developing countries living donors provide 85 to 100% of donations as compared to 1 to 25% in the developed world. Interestingly, brain death cases are similar in the two groups, at around 200 pmp annually. Although living donors provide the majority of organs in the developing world, medical problems, social issues, and cultural beliefs are a barrier to donation. In our own experience, there is an initial average of 6 donors/recipient from the donor family. However, after counseling and assessment the final outcome is not more than 1.6 donor/recipient⁵. Furthermore, religious beliefs in many Asian countries regard organ retrieval as mutilation of the body and this results in low donation rates. In countries where there is a willingness to donate after death, the priority for donation is first to close relatives, then community members and lastly to strangers⁶. With the exception of some Latin American countries cadaveric donation rates are generally low. This has lead to "renal commerce" in many developing countries, where kidneys can be purchased from $1000 to 3000 depending on the purchaser's ability to pay. In Pakistan paid organ donation has increased from none in 1993 to about 45% of total transplants in year 2000, when the government offered free transplantation to patients on dialysis in both the public and private sectors. Paid donation now constitutes almost 50% of all transplants in Pakistan. In India with the introduction of a law permitting retrieval of kidneys from cadavers there has been an increase in transplantation activity. However, paid donation continues in "back alley" centers. Often extreme poverty makes this option attractive, since the majority of donors are uneducated and they fall prey to unscrupulous brokers who siphon off half of the promised payment.

The solutions are to alleviate poverty, increase education and increase organ transplantation in public sector hospitals where commerce is less likely to play a major role. Paid organ donation in actual effect becomes a hindrance to both living related and cadaver organ donation, as it tarnishes the reputation of transplantation and inhibits the development of transplant programs in many of the developing countries⁷.

Tissue matching

Tissue matching is performed in seven centers in Pakistan. Four centers perform only serological matching and three DNA typing. In 1994 SIUT initiated DNA typing methods using polymerase chain reaction (PCR) with sequence specific premiers. The majority of the transplant centers, both public and private, select donors based on a minimum two antigen match with at least one at the HLA-DR locus. With the exception of SIUT all centers perform whole lymphocyte cross match. At SIUT separate T and B cell cross matches are performed both by lymphocytotoxicity assay and by flow cytometry. Panel reactive antibodies are performed only at SIUT and recipients with a positive auto-cross match, negative with dithiothreitol (DTT) are routinely transplanted at SIUT.

Viral screening

Donors and recipients are routinely screened for hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV) and cytomegalovirus (CMV). HbsAg positive transplants are not performed at any center. HCV positive recipients are transplanted at SIUT when the liver histology indicates benign disease with a good prognosis⁸. Almost 100% of recipients and donors in our series of more than 1000 transplants were CMV IgG positive. Patients who develop CMV infection are treated by gancyclovir. Furthermore, recipients receiving anti-rejection therapy at SIUT with monoclonal or polyclonal agents are given gancyclovir prophylaxis during the treatment period. The diagnosis of CMV at SIUT is based on a rapid antigen assay and PCR. However, all other centers follow infections by observing the serological markers IgM and IgG.

Immunosuppression

Appropriate and optimum immunosuppression is not always possible in developing countries. The main problems are non-availability of all the usable drugs and high costs. The majority of the recipients receive a triple drug regimen of cyclosporine (CsA), steroids and azathioprine. Several strategies are undertaken at SIUT to reduce the cost of immunosuppression. CsA starting at 8 mg/kg body weight is reduced to 1 to 2 mg/kg at six months in HLA identical pairs. Of these, those who are without rejections at one year are made CsA free at one year, while others are maintained at 1 to 2 mg/kg. One haplotype matched transplants are maintained at 3 to 5 mg/kg. Furthermore, stable recipients with creatinine <1.5 are converted to cheaper generic cyclosporine, thus reducing the cost by one third. In recent years many new patients have been treated with generics in a number of countries with good results⁹. Anti-rejection therapy by ATG or OKT3 at SIUT is tailored by CD3 counts in the peripheral blood by flow cytometry. CD3 counts are maintained at around 100/cmm.

Post-transplant tuberculosis

Post-transplant tuberculosis (TB) is a special problem of the developing countries. Pakistan is no exception and 15% of the recipients of renal transplant develop tuberculosis, almost 75% within the first year. Although 54% have pulmonary TB, 29% have extra-pulmonary lesions, and in 14% treatment is given on a high index of suspicion. This is against a backdrop of diagnosis at SIUT by cultures and molecular techniques using PCR. Immunosuppression in these cases requires frequent monitoring because of the interaction of CsA with anti-tuberculous drugs, as the doses have to increased by 75% in most of the cases. The high TB rate has initiated prophylaxis for TB in high risk groups particularly in those with a history of TB and inadequate treatment, radiographic evidence, close contact with a infectious case, and in recipients with allografts from a donor with history of TB. The results of these are encouraging as none of these groups of patients developed TB¹⁰.

TRANSPLANTATION MODEL FOR DEVELOPING COUNTRIES

Economic stringency is the main barrier to the initiation of renal support for either dialysis or transplantation in developing countries. SIUT has constructed a model for acquiring funds by developing a community-government partnership¹¹. The government provides about 40% of the total budget and the rest is derived from the community as donations. The scheme has been extremely successful in providing free medical care and renal support to thousands of patients. It has been sustained over the last 15 years by complete transparency, public audit, and accountability. This pattern has built confidence in the model and provided encouragement to the community to come forward and donate money, equipment and medicines.

TRANSPLANTATION AT SIUT

This model of funding free patient care has enabled SIUT to increase transplantation activity from 20 per year in the early 1990s to 50 by 1995. In the last three years more than 110 transplants have been performed each year. To date more than 1000 transplants have been performed with one- and five-year graft survival of 92% and 75% and one- and five-year patient survival of 94% and 81%, respectively Figure 1. Of all the transplants performed at SIUT almost 50% have been into patients who have come from cities other than Karachi. Since drugs are given free to all patients, we can ensure regular follow-up and after care. The frequency of follow-up depends on the distance from the center and the time that has elapsed post-transplant; thus it varies from monthly to six monthly to yearly follow-up. In many of the private centers follow-up is sporadic, especially when patients come from other cities. As a result, SIUT follows up more than 120 patients transplanted in other centers and they are provided with the same level of care, including the provision of free drugs to those who cannot afford them. Post-transplant infections are a major problem in developing countries. Around two infections episodes/patient/year require hospitalization at SIUT. After transplantation, 15% develop TB, 30% CMV infection and almost 50% develop bacterial infections. The most common cause of patient loss is infection, while chronic rejection and infection are the main causes of graft loss Figure 2. Second transplants are few in number due to the unavailability of donors. At SIUT 20 second transplants have been performed from living donors, and two using cadaveric donors sent from Eurotransplant.

Figure 1.

Patient and graft survival (N = 1000). 

Full figure and legend (11K)

Figure 2.

Causes of patient (A) and graft (B) loss. 

Full figure and legend (59K)

PEDIATRIC TRANSPLANTATION

SIUT is the only center that undertakes pediatric transplantation in Pakistan. There are few centers in the region where living related pediatric transplants are performed. SIUT so far has performed over a hundred transplants, all in the age range 6 to 17 years. This low figure is largely due to the fact that kidney donation for younger children in renal failure is considered by parents a sacrifice in vain as the children are prone to die of respiratory and gastrointestinal infections. At SIUT special care is given to immunosuppression monitoring by area under the curve (AUC) studies in each case with frequent monitoring in the early period. Drug compliance is ensured as far as possible by the donation of free medications and parental support with a compliance rate of 93%. Overall, the one- and five-year graft and patient survival is 88% and 65% and 90% and 75%, respectively¹².

CONCLUSION

The "free" transplantation costs to SIUT are $1640 for transplant surgery and $300 per month for immunosuppressive drugs. SIUT spends $1.6 million each year only on transplantation. The most frequently asked question is, "Is this model sustainable in a developing country?" We are confident about the answer. We have a motivated team of committed workers, providing the best possible patient care. There is absolute transparency in the government and community support program, and newer technologies are made available at SIUT, which allows services to be offered to a greater number of people.

Thus, SIUT has made itself a role model for transplant institutions in all developing countries. We practice the third option at SIUT. "We don't let anyone die because he or she cannot afford to live".

References

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