Pediatric kidney transplantation in Nepal

Received: 18 April 2019 | Revised: 25 July 2019 | Accepted: 1 September 2019 DOI: 10.1111/petr.13588 ORIGINAL ARTICLE Pediatric kidney transplantation in Nepal Mukunda Prasad Kafle1 1 Department of Nephrology and Transplantation Medicine, Tribhuvan University Teaching Hospital, Kathmandu, Nepal 2 Central Department of Public Health, Institute of Medicine, Maharajgunj, Nepal 3 Department of Urology and Kidney Transplant Surgery, Tribhuvan University Teaching Hospital, Kathmandu, Nepal Correspondence Mukunda Prasad Kafle, Department of Nephrology and Transplantation Medicine, Tribhuvan University Teaching Hospital, Maharajgunj, Kathmandu, Nepal. Email: [email protected] | Amod K. Poudyal2 | Pawan Raj Chalise3 | Dibya Singh Shah1 Abstract Background: Success in pediatric kidney transplantation is great achievement for the emerging countries. This report is the first of its kind from Nepal. It demonstrates the status of pediatric kidney transplantation in Nepal. Methods: This is a retrospective review of transplants done in Tribhuvan University Teaching Hospital, Kathmandu, Nepal. Living donor kidney transplant recipients ≤17 years transplanted till September 2018 were included. Demographic data, renal function, rejections, and other complications recorded in the charts were noted. Descriptive analysis was done in September 2018. Results: A total of 517 living donor kidney transplants were done till September 2018 since August 2008. Twenty‐three were ≤17 years. Eighteen (78.26%) were male. Mean ± SD age was 15.35 ± 1.7 years, and weight was 41.8 ± 9.8 kg. One received ABO‐incompatible transplantation. Fifteen (65.22%) donors were female, 14 (60.87%) were mothers, and seven were fathers (30.43%). Mean donor age was 40.21 ± 8 years. Patient and graft survival at 1 year were 100% and 89.2%, respectively. One patient died on dialysis in second year after graft failure due to FSGS. One is on dialysis after losing graft to oxalate nephropathy. Three (13.3%) had biopsy‐proven acute rejec‐ tions. Two had acute cellular rejection, and 1 had antibody‐mediated rejection. Conclusions: Children from poor countries are also entitled to the benefits of medical advancements. KEYWORDS emerging countries, FSGS, living donor, Nepal, pediatric transplantation 1 | BAC KG RO U N D A N D O B J EC TI V E S program is not yet well established. While some emerging nations have also demonstrated effective deceased donor transplantation, it KT is the treatment of choice for ESRD. It is financially and techni‐ cally demanding modality. Whether that is for the emerging or the prosperous nations, the cost incurred is proportionately high. is more common than LDKT in the richer countries. Moreover, living donors are readily available for adults but, when a child is to be benefitted, living donor organs are few. This Living and deceased donor organs are the main foundations of is because living donor pool is smaller in children as compared to any transplant program. In general, living donors are the predomi‐ adult. As an adult, one can have spouse and in‐laws as donors in nant contributors to KT in poor countries,1 where deceased donor addition to what a child has. Furthermore, access of children to renal Abbreviations: BP, blood pressure; CAPD, Continuous ambulatory peritoneal dialysis; CMV, Cytomegalovirus; CNI, Calcineurin inhibitor; DJ, Double J; EBV, Ebstein‐Barr Virus; eGFR, Estimated glomerular filtration rate; ESRD, End‐stage renal disease; FSGS, Focal segmental glomerulosclerosis; HD, Hemodialysis; HLA, Human leukocyte antigen; KT, Kidney transplantation; LDKT, Living donor kidney transplantation; LRTI, Lower respiratory tract infection; MMR, Measles, mumps, and rubella; MR, Magnetic resonance; NA, Not available; OT, Operating theater; PCN, Percutaneous nephrostomy; PCR, Polymerase chain reaction; TUTH, Tribhuvan University Teaching Hospital; URTI, Upper respiratory tract infection. Pediatric Transplantation. 2019;00:e13588. https://doi.org/10.1111/petr.13588 wileyonlinelibrary.com/journal/petr © 2019 Wiley Periodicals, Inc. | 1 of 6 2 of 6 | KAFLE Et AL. replacement therapies has been scarce in emerging countries. A 0.01 mg/kg/day in two divided doses) and mycophenolate mofetil child getting a kidney transplant is a great achievement for the family (at 500 mg twice daily) were started 2 days prior to surgery. On the and even the healthcare facilities in these poor countries. Above all, day of operation, morning doses were skipped. KT in the young is not the same as in adult. 2 LDKT started in Nepal in 2008, and deceased program was Current induction protocol is with rabbit antithymocyte globulin 1 mg/kg on Day 0 and Day 1. All patients got intravenous methyl‐ initiated in 2017. As deceased program is in nascent phase, LDKT prednisolone (500 mg) at OT, followed by oral prednisolone at 20 mg is the typical transplant as of now. First LDKT in a minor occurred per day from Day 1 till completion of 4 weeks. Thereafter, it was in December 2008 in TUTH, Kathmandu, Nepal.3 Pediatric kidney reduced by 2.5 mg every week and maintained at 5 mg per day for transplantation, however, started in August 2012 when 11‐year‐old lifelong. Tacrolimus levels were initially measured on Day 0 and Day boy weighing 23 kg was transplanted. 2, then on as and when required basis. Target tacrolimus levels were The objective of this study was to look at the characteristics of LDKT in children transplanted in TUTH. 10‐15 ng/mL in the first 4 weeks, 8‐10 ng/mL in the first 6 months, and 5‐6 ng/mL thereafter. Mycophenolate mofetil was given at doses of 1 g twice daily for first 2 weeks and then maintained at 500 mg three times daily. 2 | M ATE R I A L S A N D M E TH O DS This is a retrospective review of hospital records of kidney trans‐ 2.4 | Infection prevention strategies plants done in TUTH. LDKT recipients ≤17 years transplanted till Currently, Nepali children are immunized against 11 antigens as de‐ September 2018 were included in the analysis. Demographic data, scribed by the government of Nepal. Updated schedule of national renal function, rejections, and other complications recorded in the immunization program of Nepal is described elsewhere.4 As the charts were noted. Descriptive analysis was done in September number of antigens included in the national system is periodically 2018. Our protocols for LDKT are described below. revised, kids getting transplant could have missed some antigens because they were not included in the national program when they 2.1 | Patient monitoring were eligible to get the vaccines. Patients are monitored thrice a week for first 2 weeks post‐trans‐ coccus, meningococcus, and MMR completed at least 1 month be‐ plant, then weekly for next 1 month, and every fortnight till comple‐ fore transplant. tion of 3 months. Thereafter, patients visit every month or earlier if required, till completion of 6 months. On every visit, patients are We ensured vaccination against hepatitis B, influenza, pneumo‐ Intravenous ceftriaxone 1 g and cefazolin 1 g stat doses were given just before OT. interviewed for adherence to treatment and monitored for general well‐being, weight, BP, systemic examination, kidney function test, complete hemogram, and urine routine and microscopic examina‐ tion. We measured tacrolimus trough levels as and when needed. 2.5 | Post‐transplant prophylaxis We practice universal prophylaxis with valganciclovir for 3 months All patients are monitored using ultrasonography from the very (based on donor & recipient CMV IgG status and adjusted with beginning of the transplantation. Allograft Doppler is done within eGFR), cotrimoxazole SS for 6 months, and clotrimazole oral solution 3 hours of transfer to post‐operative ward. Before discharge from four times daily for 3 months. As strategy of universal prophylaxis hospital, subsequent evaluations are done as per the decision of is followed for CMV, there is no provision for periodic CMV surveil‐ surgeon. Then, patients are followed up with ultrasonography every lance. Institutional protocol is to monitor CMV DNA by PCR for sus‐ 3 months (or earlier if need be) for 1 year. pected cases. All patients are prescribed yearly flu shots. 2.2 | Screening protocol 2.6 | Stent Patients and donors are screened for communicable and non‐com‐ All kidney transplant recipients have DJ stent which is removed municable diseases. All donors and recipients underwent serological 2 weeks post‐transplant. During removal, all patients are prescribed testing for CMV IgG status, human immunodeficiency virus, hepa‐ ciprofloxacin 500 mg BD for 3 days. titis B, and hepatitis C; chest X‐ray; sputum test for acid‐fast bacilli; and cultures of blood, urine, and sputum. Throat, ear, and nose swab cultures were additional tests for recipients. 2.3 | Institutional immunosuppression protocol 3 | R E S U LT S 3.1 | General characteristics Among 517 transplantations done till the end of September 2018, 23 LDKT patients were kept on triple immunosuppression with tac‐ were 17 years or younger. Eighteen (78.26%) were male. Mean ± SD rolimus, mycophenolate mofetil, and prednisolone. Tacrolimus (at age was 15.35 ± 1.7 years, and weight was 41.8 ± 9.8 kg. Eighteen KAFLE Et AL. TA B L E 1 S. No Case‐wise follow‐up of renal function Age (in years) at transplant Cause of ESRD Transplanted year Weight (in kg) at transplantation eGFRa (in mL/ min/1.73 m2) Serum creatinine (in µmols/L) by time (in months) 1 6 12 24 36 181 Died on dialysis 48 60 1 16 FSGS 2008 55 52.6 111 132 2 17 Undetermined 2009 35 94.6 61 83 Migrated abroad with a functioning graft 3 15 CSGN 2011 29 78.1 65 69 80 79 88 88 71 4 11 MPGN 2012 23 101.1 52 67 97 62 70 79 88 5 17 Obstructive 2012 33 74.5 75 115 142 124 132 124 154 6 15 Undetermined 2014 62 41.3 106 113 124 132 NA 177 7 17 Undetermined 2014 47 67.9 92 106 106 106 142 124 8 16 IgA Nephropathy 2014 50 47.6 115 88 115 124 97 141 9 15 Crescentic HSP 2014 50 57.2 97 79 70 79 88 10 14 Undetermined 2015 40 78.2 70 79 100 97 106 11 16 Undetermined 2015 39 57.3 79 62 89 89 83 12 16 Obstructive 2016 49 48.3 115 135 281 268 13 17 Undetermined 2016 50 50.8 120 138 101 88 14 15 CSGN 2016 39 72.2 87 116 128 88 15 12 Obstructive 2016 37 48.8 89 89 102 16 14 CSGN 2017 32 74.9 79 92 70 17 16 IgA Nephropathy 2017 40 60.8 96 105 83 18 13 Nephrocalcinosis 2017 28 61.2 77 572 795 159 Transfer to dialysis 19 17 Undetermined 2017 55 41.4 150 157 20 14 Obstructive 2017 41 95 63 79 21 16 CSGN 2018 42 46.5 124 108 22 17 Undetermined 2018 50 62.8 93 118 23 17 IgA Nephropathy 2018 36 NA Transplanted within a month before analysis ABO‐incompatible transplantation Abbreviations: CSGN, chronic sclerosing glomerulonephritis; FSGS, focal and segmental glomerulosclerosis; IgA, immunoglobulin A; NA, not available. Calculated by Schwartz bedside equation at 1 mo after transplantation. a | 3 of 6 4 of 6 | KAFLE Et AL. were on hemodialysis at the time of transplantation. Median dura‐ viral infections were noted, namely Tinea in 3, oral thrush in 1, and tion on dialysis was 8 months. Two were preemptive. Herpes zoster in 1. BK virus infection was suspected in 1 patient but failed to prove viremia. 3.2 | Cause of renal failure Cause of ESRD was glomerular diseases in 10 (43.48%) patients com‐ 3.6 | Surgical complications prising of biopsy‐proven IgA nephropathy in 3, crescentic Henoch– All children were transplanted with adult kidneys. Majority of Schönlein purpura (HSP) in 1, FSGS in 1, and mesangioproliferative donor kidneys were recovered from the left (20 vs 3). Twenty kid‐ glomerulonephritis (MPGN) in 1. Four patients had chronic scleros‐ neys were placed in the right iliac fossa. In 18 patients, the renal ing glomerulonephritis on presentation. Other causes were obstruc‐ artery was anastomosed end to side to the external iliac artery. tive in 4, and etiology was undetermined in 8 patients. The renal vein was anastomosed end to side to the external iliac vein in 20 patients. One patient required pretransplant unilateral 3.3 | Transplant characteristics nephrectomy due to pyonephrosis in a grossly hydronephrotic kidney. Among these 23 transplants, 1 was ABO‐incompatible transplanta‐ Transplant renal artery stenosis occurred in 1, lymphocele in 1, per‐ tion. Median duration of hospital stay during and after surgery was inephric collection in 1, and graft kidney hydronephrosis in 1 patient. 9 days (Range 6‐28 days). All these surgical issues were treated. One case of valve bladder syn‐ Fifteen (65.22%) donors were female, 14 (60.87%) were moth‐ ers. Fathers donated in 7 (30.43%) cases. Mean donor age was 40.21 ± 8 years. Eighteen had ≤3 HLA mismatches. drome is being managed with clean intermittent self‐catheterization. Patient with post‐transplant hydronephrosis due to distal ure‐ teric stricture was evaluated with ultrasonography, serum creati‐ nine, and diuretic renography. MR urography was done for better 3.4 | Graft and patient survival outcomes anatomical delineation and planning. Immediate diversion of the Individual progress over time is presented in Table 1. antegrade study performed after 2 weeks of PCN. The patient was In general, our institutional patient and graft survival at 1 year are urine was done with PCN. Long distal ureteric stricture was noted in managed with open vesicopyelostomy at a later date. 96.4% and 95% and at 5 years 90.47% and 86.78%, respectively. For the pediatric patients, patient and graft survival at 1 year were 100% and 89.2%, respectively. One patient died on dialysis in second year 3.7 | Other medical complications after graft failure due to FSGS. One is on dialysis after losing graft Two patients developed post‐transplantation diabetes mellitus. to oxalate nephropathy. Oxalate nephropathy was diagnosed on al‐ Leukopenia occurred in 7 patients. Two patients required admin‐ lograft biopsy done for rising serum creatinine 4 months post‐trans‐ istration of subcutaneous filgrastim when leukopenia did not re‐ plant. This graft loss could have been prevented by a simultaneous cover on temporarily stopping mycophenolate, cotrimoxazole, and liver and kidney transplant if the actual cause of kidney failure had valganciclovir. been revealed before transplant. Three (13.3%) had biopsy‐proven acute rejections. Two had acute cellular rejection, and 1 had antibody‐mediated rejection. Unless contraindicated, we almost invariably use diltiazem to boost CNI levels in our patients. Five of our patients were on neither diltiazem nor any other antihypertensive medications at discharge. Seven (30.43%) patients were on 2 or more classes of antihyperten‐ 3.5 | Infections sive medicines at discharge. This number was 11 (50%) at 6 months and 8 (42.1%) at 1 year. Apart from diltiazem, we use other calcium A total of 80 episodes of infections occurred in these children. Leading channel blockers, beta receptor blockers, angiotensin‐converting were 22 episodes of upper respiratory tract infections, 20 episodes enzyme inhibitors, angiotensin receptor blockers, alpha blockers, of urinary tract infections, and 19 episodes of gastroenteritis. and clonidine in a case‐wise basis. Respiratory tract infections were classified either as upper (URTI) or as lower (LRTI) tract infections based on clinical signs and symptoms or radiologic changes. As microbiologic testing to distin‐ 4 | D I S CU S S I O N guish between various viruses is not available locally, further testing to identify the etiology of URTI was not done. There were seven ep‐ First successful kidney transplantation in man was possible in isodes of lower respiratory tract infections. Further microbiological December 23, 1954.5 While centers in the west have been practic‐ findings were not available for study. ing pediatric transplantation since 1960s, the exact time of initiation Urine culture revealed Escherichia coli in five episodes, of pediatric transplantation in a developing country is unavailable.6,7 Acinetobacter in four occasions, and Burkholderia, Enterococcus, and Much progress has been achieved in the field of organ transplan‐ Klebsiella in one episode each of the total UTI episodes. There were tation till date. Indicators of outcomes associated with kidney no growths on other occasions. Apart from these, few fungal and transplantation in children are also improving over time.8 Though | KAFLE Et AL. TA B L E 2 5 of 6 Comparison of findings with similar publications from the region S. No 1 Feature Sathe et al Bijalwan et al Current study Reported Year 2014 2017 2019 Location Mumbai, India Kerala, India Kathmandu, Nepal Total subjects (n) 20 32 23 2 Age (y) 14.6 (6‐18) 14.5 (10‐17) 15.35 (11‐17) 3 Sex M:F = 18:2 M:F = 14:18 M:F = 15:8 4 Mean weight (kg) NA 35 (17‐63) 41.8 5 Major cause of ESRD Glomerular diseases (30%) Glomerular diseases (53%) Glomerular diseases (43.5%) 6 Living donors 95% 100% 100% 7 Parents as donor (n) 16 30 21 8 Dialysis type HD 14 29 18 CAPD 3 2 3 Preemptive 3 1 2 1y 73.4 96.7 89.2 3y 72.8 92.9 81 5y NA 85 80 Graft survival (%) 9 Abbreviations: CAPD, continuous ambulatory peritoneal dialysis; ESRD, end‐stage renal disease; HD, hemodialysis; NA, not available. measured with the same indicators, kidney transplantation in chil‐ donors. Not only in children, females have comprised over 60% dren is different in many aspects. 2 donor population in our institute.11 The ratio of children with ESRD availing the advantages of KT is Our institute has recently started ABO‐incompatible kidney lower in the emerging economies as compared to developed coun‐ transplantation. One pediatric recipient had the benefit of ABOi KT. tries.7 Data on kidney transplantation in the children are scarce from The protocol followed in such transplantation is described in detail the developing world. in another publication.12 Kidney transplantation started in Nepal in 2008. Living donor Recurrence of FSGS is a well‐known cause of significant graft kidney transplant is archetypal. Deceased donor kidney transplant loss especially in children.8,13 For management of recurrent dis‐ is currently emerging. Nepal government provides financial support ease, we introduce and uptitrate antiproteinuric agents for patients to ESRD patients to get a kidney transplant. Though it is a one‐time who develop minimal proteinuria. We perform plasmapheresis support, it is a great funding for the poor to manage the initial costs for patients who develop biopsy‐proven recurrence of FSGS after of surgery, induction agents, and other expensive medications in the transplantation.14 During the study period, one patient died of sus‐ initial months. pected recurrence of FSGS. He got kidney transplant for ESRD due This report on renal transplantation in children is the first to biopsy‐proven FSGS. Post‐transplant biopsy was suboptimal, and of its kind from Nepal. Total number of patients is not that large, re‐biopsy could not be done. Our patient underwent therapeutic but we have demonstrated comparable survival outcome results. plasma exchange, but graft was lost. Patient remained in hemodialy‐ Table 2 shows comparison of our results with similar publications sis for few months before he died. from India.9,10 Primary hyperoxaluria is another known evil that damages kid‐ In our study, less than 5% of the transplantation beneficiaries ney‐only transplants.13 One of our patients lost graft to oxalate ne‐ were children. More children would be benefitted by deceased phropathy which was first diagnosed on graft kidney biopsy done for donor transplantation because living related donor pool is very small rising serum creatinine in fourth month post‐transplantation. for them. 2 We did not find any of malignancies or lymphoproliferative dis‐ Male recipients outnumber the female. Kidney diseases are orders in our pediatric follow‐up patients. As this is a report of our reportedly more common in males. This could also be an image of initial follow‐up, this could be due to short follow‐up time and small social security skewed toward the male child. Similar findings have number of patients. Furthermore, EBV screening and surveillance been reported from neighborhood.9 Parents were the main donors are not available locally, thus making it very expensive to transport in 91.3% cases. They are also the main caregivers, thus improving the blood sample abroad. Although the number of patients is not patient's adherence to medications. Mothers comprised 60.8% of that high, our study demonstrates the results of efforts put by the 6 of 6 | KAFLE Et AL. treating team including the nephrologists, surgeons, radiologists, anesthetists, nurses, and others as a team. This work will set mile‐ stone for future researchers and also direct the officials and other stakeholders in the community to mobilize resources in favor of chil‐ dren suffering from kidney failure. As the speciality of pediatric nephrology is currently emerging in Nepal, this publication will also encourage pediatricians to take nephrology as a career and the leadership of kidney transplanta‐ tion in children. When a pediatrician leads the renal transplantation in children, outcomes would probably improve. As stated earlier, transplantation in children is different in many ways from that in adults. Perioperative patient management demands appropriate age‐related physiological considerations. Follow‐up of a pediatric recipient also involves multiple avenues including physical, social, and mental growth, and physiological and psychological changes in pre‐ and peripubertal period. These are few examples that de‐ mand leadership of a pediatrician in a pediatric kidney transplant program. 5 | CO N C LU S I O N S Outcome results of pediatric renal transplantation are comparable. Graft and patient survival results are encouraging. 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Disease recurrence in paedi‐ atric renal transplantation. Pediatr Nephrol. 2009;24(11):2097‐2108. 14. Verghese PS, Rheault MN, Jackson S, Matas AJ, Chinnakotla S, Chavers B. The effect of peri‐transplant plasmapheresis in the pre‐ vention of recurrent FSGS. Pediat Transplant. 2018;22(3):e13154. Mukunda P Kafle: Participated in research design, analyzed the data, and prepared the manuscript; Amod Poudyal: Participated in data analysis; Pawan Raj Chalise: Participated in writing of the paper; and Dibya Singh Shah: Participated in research design, supervision, and writing of the paper. Shah DS. Pediatric kidney transplantation in Nepal. Pediatr Transplant. 2019;00:e13588. https://doi.org/10.1111/ petr.13588 ORCID Mukunda Prasad Kafle How to cite this article: Kafle MP, Poudyal AK, Chalise PR, https://orcid.org/0000‐0001‐8635‐7497