Pediatric kidney transplantation in the developing world: challenges and solutions.

The prevalence of pediatric RRT and transplantation are low in developing countries, 6-12 and <1 to 5 per million child population (pmcp), respectively. This is due to low GDP/capita of <$10 000, government expenditure on health of <2.6-9% of GDP and paucity of facilities. The reported incidence of pediatric CKD and ESRD is <1.0-8 and 3.4-35 pmcp, respectively. RRT and transplantation are offered mostly in private centers in cities where HD costs $20-100/session and transplants $10 000-20 000. High costs and long distance to centers results in treatment refusal in up to 35% of the cases. In this backdrop 75-85% of children with ESRD are disfranchised from RRT and transplantation. Our center initiated an integrated dialysis-transplant program funded by a community-government partnership where RRT and transplantation was provided "free of cost" with life long follow-up and medication. Access to free RRT at doorsteps and transplantation lead to societal acceptance of transplantation as the therapy of choice for ESRD. This enabled us to perform 475 pediatric transplants in 25 years with 1- and 5-year graft survival of 96% and 81%, respectively. Our model shows that pediatric transplantation is possible in developing countries when freely available and accessible to all who need it in the public sector.

Experience of fibrosing cholestatic hepatitis with hepatitis C virus in kidney transplant recipients.

BACKGROUND: Fibrosing cholestatic hepatitis C (FCH-C) is a rare entity that occurs among immune-compromised patients resulting from the direct hepatotoxicity of a high intracellular viral load along with an ineffective immune system ultimately leading to a fatal outcome. We have describes herein 4 renal transplant recipients who were diagnosed with FCH-C at our institution in the last 8 months. METHODS: Four renal transplant recipients presented with jaundice and deteriorating liver function tests. They were diagnosed to display FCH-C based on the presence of hepatitis C virus (HCV) RNA and characteristic liver biopsy findings; there was no evidence of any other cause of cholestasis or biliary obstruction. RESULTS: The patients were men of ages 40, 25, 20, and 27 years. The durations after transplantation were 1.5, 10, 1.5 and 2.0 years, respectively. In all cases pretransplantation screening was negative for HCV antibody, HCV RNA, and hepatitis B surface antigen (HBsAg). All 4 patients were infected with genotype 1, whereas case 2 had coinfection with type 3. Cases 1 and 2 who were treated with interferon and ribavirin, showed improvement in cholestasis but did not achieve a rapid virological response. Case 1 developed graft dysfunction secondary to acute cellular rejection at 4 months after initiation of interferon treatment, which was treated with pulse steroids. Interferon-based therapy was stopped prematurely in both cases due to pancytopenia. Case 3 developed florid pyelonephritis and died without receiving therapy for hepatitis C. Case 4 was managed conservatively by decreasing the immunosuppression with regular monitoring. CONCLUSION: FCH-C is difficult to treat and shows high morbidity and mortality rates. Treatment is associated with a risk of graft rejection.

A renal transplantation model for developing countries.

The estimated incidence of end-stage renal disease (ESRD) in Pakistan is 100 per million population. Paucity and high costs of renal replacement therapy allows only 10% to get dialysis and 4-5% transplants. Our center, a government organization, started a dialysis and transplant program in 1980s where all services were provided free of charge to all patients. It was based on the concept of community government partnership funded by both partners. The guiding principles were equity, transparency, accountability and development of all facilities under one roof. This partnership has sustained itself for 30 years with an annual budget of $25 million in 2009. Daily 600 patients are dialyzed and weekly 10-12 receive transplants. One- and 5-year graft survival of 3000 transplants is 92% and 85%, respectively. The institute became a focus of transplantation in Pakistan and played a vital role in the campaign against transplant tourism and in promulgation of transplant law of 2007, and also helped to increase altruistic transplants in the country. This model emphasizes that in developing countries specialized centers in government sector are necessary for transplantation to progress and community support can make it available to the common man.

Living related renal transplants with lifelong follow-up. A model for the developing world.

AIMS: To describe the dynamic of a model of public government partnership for dialysis and transplantation in developing countries. MATERIALS: A model was established on the philosophy of public-government partnership to provide an integrated dialysis and transplant service "Free with dignity" with lifelong follow-up care and medications. The government provided 50% of funds and the public was motivated to donate the rest. This included affluent individuals, corporations, business houses and the general public. RESULTS: This model has been sustained for the last two decades. In 2008, 655,000 patients were treated at SIUT. Over 600 patients are dialyzed each day with a total of 165,411 dialysis sessions/year. Thus far 2,249 transplants have been performed, 431 in 2008. One- and 5-year graft survival rates were 92% and 85%, respectively. The laboratory performed 4.1 million tests and radiological investigations numbered 164,217. Over $ 6 million were spent on medications. Free services offered by the model have motivated the government to increase its funding from $ 2.1 million in 1998 to $ 10 million in 2008 and the public has matched these figures with total donations exceeding $ 20 million. CONCLUSIONS: For transplantation to be successful in developing countries, it has to be made available to the common people who constitute 90% of the population. Our model of public-government partnership has made dialysis and transplantation available to the disenfranchised with lifelong follow-up and medications. Transplantation has become relevant to them, resulting in societal acceptance of transplantation as a preferred mode of therapy. This has motivated society to support both living related and deceased donor programs.

Human organ and tissue transplantation in Pakistan: when a regulation makes a difference.

Organ transplantation must be viewed in relation to the prevailing cultural, religious and economic conditions of a nation. Over the past two decades, Pakistan has emerged as one of the largest centres for commercial renal transplantation. Government efforts, supported by professional associations, civil society organizations and the media, along with World Health Organization technical assistance, have led to the development of legislation regulating this practice and curbing organ trade in conformity with international guidelines. Although only two years have passed since the enactment of the law, there is evidence that conditions have significantly improved, raising hopes for ethical and safe organ transplantation in Pakistan. This study reviews the salient features of the legislation and lists the foreseeable evolving challenges and opportunities.

Human organ and tissue transplantation in Pakistan; when a regulation makes a difference

Organ transplantation must be viewed in relation to the prevailing cultural, religious and socio-economic conditions of a nation. Over the past two decades, Pakistan has emerged as one of the largest centres for commercial renal transplantation. Government efforts, supported by professional associations, civil society organizations and the media, along with World Health Organization technical assistance, have led to the development of legislation regulating this practice and curbing organ trade in conformity with international guidelines. Although only two years have passed since the enactment of the law, there is evidence that conditions have significantly improved, raising hopes for ethical and safe organ transplantation in Pakistan. This study reviews the salient features of the legislation and lists the foreseeable evolving challenges and opportunities

Health status and renal function evaluation of kidney vendors: a report from Pakistan.

Unrelated kidney transplants have lead to commerce and kidney vending in Pakistan. This study on 104 vendors reports demographics, history, physical and systemic examination, ultrasound findings, renal and liver function and GFR by Cockcroft-Gault. Results were compared with 184 age, sex and nephrectomy duration matched living-related donors controls. Comparison of vendors versus controls showed mean age of 30.55 +/- 8.1 versus 30.65 +/- 7.85 (p = 0.91) years, M:F of 4.5:1 versus 4.2:1 and nephrectomy period of 33.89 +/- 30 versus 32.01 +/- 29.71 (p = 0.60) months respectively. Of the vendors 67% were bonded laborers earning <50 $/month as compared to controls where 68% were skilled laborers and self-employed earning >100 $/month. History of vendors revealed jaundice in 8%, stone disease in 2% and urinary tract symptoms in 4.8%. Postnephrectomy findings between vendors versus donors showed BMI of 21.02 +/- 2.8 versus 23.02 +/- 4.2 (p = 0.0001), hypertension in 17% versus 9.2% (p = 0.04), serum creatinine (mg/dL) of 1.17+/-0.21 versus 1.02 +/- 0.27 (p = 0.0001), GFR (mL/min) of 70.94 +/- 14.2 versus 95.4 +/- 20.44 (p = 0.0001), urine protein/creatinine of 0.150 +/- 0.109 versus 0.10 +/- 0.10 (p = 0.0001), hepatitis C positivity in 27% versus 1.0% (p = 0.0001) and hepatitis B positive 5.7% versus 0.5% (p = 0.04), respectively. In conclusion, vendors had compromised renal function suggesting inferior selection and high risk for developing chronic kidney disease in long term.

Anthropometric indices of middle socio-economic class school children in Karachi compared with NCHS standards--a pilot study.

OBJECTIVE: To measure height and weight of school going children (2-18 years of age) in Karachi. By means of these parameters we were able to document where the Pakistani paediatric population plot on NCHS growth centile charts. METHODS: A population based cross-sectional study (in government and private schools, Karachi), in which height and weight were taken using standardized techniques. Two thousand two hundred forty five healthy school-going children 2 to 16 years of age (calculated from date of birth); sex, height and weight were documented. After the survey was completed, height and weight of the children were plotted on NCHS centiles curves. RESULTS: P5, P25 and P50 centiles for height and weight of the Pakistani girls and boys was much below that of NCHS. However, P95 for boys and girls weight and height did not differ markedly in the Pakistani and NCHS centiles. CONCLUSION: Height and weight of these children is below the NCHS centile for height and weight. Children plotting near the P95 NCHS, indicates that obesity may be a serious concern in our population. However, further studies are required for support. This pilot study indicates the need for development of centile charts for Pakistani paediatric population.

Cyclosporine withdrawal in post-renal transplant thrombotic microangiopathy.

INTRODUCTION: Thrombotic microangiopathy (TMA) is a well known complication of cyclosporine (CsA)-treated renal transplantation but optimum treatment strategies are not clearly defined. PATIENTS AND METHODS: All patients transplanted between January 1996 and December 2001 at our center who had biopsy-proven TMA and in whom CsA was withdrawn were studied retrospectively. RESULTS: The TMA was found in nine of 688 patients (1.3%). All except one donor were living related. HLA matching was one haplotype in all except one where both haplotypes were different. There were five males and four females and the mean age was 24.9 +/- 9 yr. All of them developed TMA within 3 months of transplant. Five of nine had evidence of microangiopathic hemolysis on peripheral film. Serum creatinine at the time of diagnosis of TMA was 3.1 +/- 1.3 mg/dL. Cyclosporine was discontinued in all and mycophenolate mofetil was substituted for azathioprine. No episode of acute rejection occurred after CsA withdrawal. Graft function did not improve in four who eventually became dialysis-dependent after a mean duration of 12.6 +/- 8.3 months. Remaining patients showed stabilization or improvement in function and all had serum creatinine below 2 mg/dL after a mean follow up of 24 months. CONCLUSION: The CsA withdrawal in cases with TMA at a stage when significant functional deterioration has not taken place can salvage the graft.

Non-HLA antibodies after rejection of HLA identical kidney transplants.

1. Non-HLA antibodies reactive against CLL and lymphoblast lines were detected by cytotoxicity in sera from 22 patients who had been transplanted with kidneys from HLA identical donors. 2. Whether these antibodies had been responsible for the rejection of the HLA identical grafts remain to be determined. 3. Among 71 patients who received HLA mismatched transplants, and had rejected their grafts, 65 (93%), formed antibodies to HLA or MICA antigens. The 5 patients who did not develop antibodies were shown to have antibodies against CLL and lymphoblast lines, suggesting that these grafts may have been rejected by non-HLA antibodies.

Improving kidney and live donation rates in Asia: living donation.

Organ transplantation started with organs donated by living subjects. Increasing demands brought cadaveric organ donation. The brain-death law, mandatory for this procedure, is prevalent in all countries involved in organ transplantation except Pakistan. Spain is the leading country in cadaveric organ donation (32.5 pmp). Despite the sources of living and cadaveric organs, both heart-beating and non-heart-beating, the gap between the demand and supply has widened. An example is the United States, where the numbers of patients on the waiting list for kidney transplantation have risen from 30,000 in 1988 to more than 116,000 in 2001. This has caused a resurgence in living donors all over the world. These can be related, unrelated, spousal, marginal, or ABO-incompatible donors. Family apprehensions, medical care costs, and nonexistent social security can be barriers to this form of organ donation. Unrelated organ donation can open the doors to commercialism. To make this process more successful, transplantation should be made reachable by all sectors of the population. This is possible when transplantation is taken to the public sector institutions and financed jointly by the government and community. To increase living organ donation especially in Asian countries, which face barriers of low literacy rates, ignorance, and cultural and religious beliefs, more efforts are needed. Public awareness and education play an important role. Appreciation and supporting the donors is necessary and justified. It is a noble act and should be recognized by offering job security, health insurance, and free education for the donor's children.

A survey on the prevalence and management of hepatitis B after renal transplantation in Asian-Pacific countries.

The carrier rate for hepatitis B virus (HBV) varies from 1% to 2% to 10% in Asian-Pacific countries. A survey involving 12 transplant centers from 11 countries in this region showed that 1% to 25% of kidney transplant recipients were infected with HBV, and up to 60% of these subjects showed abnormal liver biochemistry. While nearly all centers tested anti-HBs in potential kidney transplant recipients, HBV vaccination of nonimmune subjects was routine in only 66.7%. One-third of the surveyed units rejected HBsAg-positive subjects as kidney donors, while the others demonstrated differing policies in choosing the respective recipients. Two units (16.7%) excluded HBsAg-positive patients from kidney transplantation, whereas the others only excluded those with severe liver disease. Heterogeneity also applies to the immunosuppressive regimens, the use of HBV DNA in serial monitoring, and the timing of antiviral therapy in HBsAg-positive kidney transplant recipients. The data showed that despite HBV infection being a significant problem in kidney transplantation, there is a lack of uniform management policy, attributable to the clinical complexity and deficiency of research data. Although improvement in clinical outcome is likely with the advent of nucleoside analogue therapy and better monitoring, the financial implications in the adoption of these recent advances remain realistic concerns.

Spectrum of pathological lesions in acute renal failure.

OBJECTIVE: To determine the spectrum of pathological lesions in percutaneous renal biopsies of patients with acute renal failure (ARF) and to compare our findings with reported literature. DESIGN: A single center based retrospective observational study. PLACE AND DURATION OF STUDY: The study was conducted in the Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi over a period of seven years (April 1995 to April 2002). SUBJECTS AND METHODS: All the patients with ARF who presented to the emergency ward of SIUT between April 1995 and April, 2002 and in whom renal biopsy was performed, were included in this study. Patient's demographic and clinical data were collected from a review of patient's original surgical biopsy reports and case files. Pathological diagnosis was retrieved from a review of biopsy reports. Renal biopsies were received in 10% buffered formalin and processed for paraffin embedding and subsequent histopathological examination under the light microscope. RESULTS: A total of 158 patients were studied. Of these 57 were males and 101 females. Mean age of the patients in this series was 30.7 years with a range of 6 to 75 years. Of these 61(38.6%) had acute tubular necrosis, 36 (22.7%) acute cortical necrosis and 49(31%) patients had various types of glomerulonephritis (GN). Eight patients (5%) had acute tubulointerstitial nephritis, 3 (1.8%) acute pyelonephritis and one patient had mucormycosis. CONCLUSION: This study showed that even in the selected population of biopsied ARF cases, there was a high prevalence of ischemic renal disease. A substantial number of cases in unexplained ARF on renal biopsy were due to various forms of glomerulonephritis.

Pediatric urolithiasis: developing nation perspectives.

PURPOSE: We evaluated epidemiology, etiology, dietary and urinary risk factors, and the composition of calculi in pediatric stone formers in Pakistan. MATERIALS AND METHODS: This retrospective study includes 1,440 children treated between 1987 and 2000. Case records were reviewed for demographics, etiology and clinical symptoms. Dietary and urinary risk factors were analyzed prospectively in idiopathic stone formers. Stone composition was analyzed by infrared spectroscopy. RESULTS: There were 1,075 males and 365 females for a male-to-female ratio of 3:1. The peak age for renal and bladder stones was 6 to 10 and 1 to 5 years, respectively. Overall 795 stones (55%) were renal, 198 (14%) were ureteral and 447 (31%) were vesical. Bladder stones were present in 60% of cases in the mid 1980s but decreased to 15% in the mid 1990s. The clinical symptoms were abdominal pain in 511 patients (51%) and fever in 193 (19.5%). There were anatomical abnormalities in 96 patients (12%), metabolic abnormalities in 206 (25%), infection stones in 60 (7%) and idiopathic stones in 444 (55%). Urinary analysis in idiopathic stone formers revealed hypercalciuria in 17 (11%), hyperoxaluria in 62 (40%), hyperuricosuria in 41 (27%) and hypocitruria in 97 (63%). Diet involved a low intake of protein in 60 cases (44%), calcium in 45 (33%), potassium in 105 (77%) and high oxalate in 75 (55%). The composition was calcium oxalate in 362 stones (47%), ammonium hydrogen urate in 210 (27%) and struvite in 49 (6.4%). Stones recurred in 30 patients (2%). CONCLUSIONS: The pattern of calculous disease changed from a predominantly lower tract site in the mid 1980s to the upper tract in the mid 1990s. Stone composition, urinary risk factors and dietary analysis suggest that diet, dehydration and poor nutrition are the main causative factors of stone disease.

Living-related pediatric renal transplants: a single-center experience from a developing country.

We retrospectively analyzed the results of 75 living-related pediatric renal transplants performed at our center between January 1986 and December 1999. The major causes of end-stage renal disease (ESRD) were glomerulonephritis (26%) and nephrolithiasis (16%), while the etiology was unknown in 50%. The mean age of the recipients was 12 yr (range 6-17 yr) and that of the donors was 39 yr (range 20-65 yr). The majority (73%) of donors were parents. Eighty five per cent of donors were one-haplotype matched and the rest identical. Immunosuppression was based on a triple drug regimen. Thirty per cent of recipients were rapid metabolizers of cyclosporin A (CsA) (area under the curve [AUC]: < 6,000 ng/mL/h), while 16% were slow metabolizers (AUC: > 8,000 ng/mL/h). Forty three (57%) children encountered 59 rejection episodes, the majority of which (59%) were recorded in the first month post-transplant. Seventy-four per cent of the rejection episodes were steroid sensitive and the rest, except two, were resolved by therapy with antithymocyte globulin (ATG) or orthoclone thymocyte 3 (OKT3). After a mean follow-up of 37 months, 17 (22%) grafts had chronic rejection and 76% of these recipients had previously experienced acute rejection episodes. The overall infection rate was high, necessitating two hospital admissions/patient/year. The majority (53%) of the infections were bacterial. Urinary tract infections (UTIs) were seen in 17 (23%) recipients. Twelve of these had ESRD as a result of stone disease and eight grafts were lost because of UTIs. Eight per cent of recipients developed tuberculosis (TB), and extra-pulmonary lesions were seen in 50%. Surgical complications were encountered in eight patients. Free medication to all recipients and parental support ensured a compliance rate of 93%. Baseline growth deficit was seen in children of the two groups studied (the 6-12 yr and 13-17 yr age-groups), with Z-scores of - 2.39 and - 2.12, respectively. No growth catch-up was observed at 12 and 24 months in either group. Post-donation complications were seen most commonly in donors > 50 yr of age and included: proteinuria (> 300 mg/24 h, four patients), hypertension (three patients), and diabetes (one patient). Twenty-four grafts were lost, 54% as a result of immunological and the rest as a result of non-immunological causes, and 17 recipients died during the follow-up period. Infections were the main cause of patient and graft loss. Overall 1- and 5-yr graft and patient survival rates were 88% and 65%, and 90% and 75%, respectively.