Clinical characteristics and short-term outcomes of Nigerians with living donor kidney transplantation at the University College Hospital, Ibadan, Nigeria

¹Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria, ²Department of Medicine, University College Hospital, Ibadan, Oyo State, Nigeria, ³Department of Clinical Sciences, Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria

^&Corresponding author
Yemi Raheem Raji, Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria

Introduction    

End-stage kidney disease (ESKD) is defined as the severe form of chronic kidney (CKD) disease that requires renal replacement therapy (dialysis or kidney transplantation) to sustain life, and it is typically characterized by an estimated Glomerular Filtration Rate (eGFR) of less than 15ml/min/1.73m² [1]. It is associated with high morbidity, mortality, poor quality of life, and exorbitant cost of treatment [2,3]. The incidence of ESKD is estimated to be about 6% among patients with chronic kidney disease and the overall prevalence appears to be on the rise worldwide [4]. End-stage kidney disease (ESKD) is treated with renal replacement therapy, which includes maintenance dialysis (haemodialysis and peritoneal dialysis) and kidney transplantation. The preferred treatment option for ESKD is kidney transplantation for its many advantages that include improved quality of life, freedom from frequent visits to the hospital for dialysis, obviation of the need for erythropoietin, and return to near normal lives [5,6]. In Nigeria, ESKD is responsible for 8-10% of all medical admissions while community prevalence of early stages of CKD has been estimated to be between 20-30% [7]. The poor outlook of CKD/ESKD in Nigeria has been adduced to the late presentation in the hospitals and lack of access to maintenance dialysis or kidney transplantation [8]. Due to the high cost of kidney transplantation and the absence of medical insurance for the care of patients with the disease, only a small proportion of the patients with ESKD in the country were able to get kidney transplantation and sustained the follow-up immunosuppressive medications [9,10].

Patients with ESKD embarked on kidney transplantation both within and outside Nigeria, with India and South Africa being the chosen destinations in most cases. With more private centers and several public hospitals offering kidney transplantation services, more Nigerian patients with ESKD are getting the opportunity for kidney transplantation. There have been reports, though unpublished, suggesting that the short and long-term kidney graft survival among Nigerians is sub-optimal compared to what is obtained in the high-income countries. The outcome of kidney transplantation varies across centers and regions of the world, but data on epidemiology and outcomes of patients in low-and-middle-income-countries may not be comparable to that of the developed nations of the world. Furthermore, this information on patients with kidney transplantation in Nigeria is sparse. This study aimed to describe the epidemiology, clinical characteristics, and short-term outcomes of patients with kidney transplantation in Nigeria. Other research questions to be answered by this study will include determining the prevalence of new onset diabetes after kidney transplantation, as well as identifying factors that determine grafts and patient´s survival.

Methods     

This was a prospective study of adult patients (18 years and above) with living donor kidney transplantation who were receiving care at the University College Hospital, Ibadan, irrespective of where the kidney transplantation procedures were carried out.

Study population: the study was conducted between 1^st July 2016 and 30^th June 2020 among patients with ESKD who have had kidney transplantation. To be eligible for the study, individuals must be 18 years and above with ESKD and have had a living donor kidney transplantation, excluded were individuals less than 18 years of age and those with kidney transplantation failure who were back on dialysis.

Sample size: consecutively presenting and consenting kidney transplant patients were recruited into the study, and a total of 43 participants were enrolled during the period of the study.

Data collection: the participants were assessed at the baseline and followed up for 36 months. During the baseline encounter, pre-tested interviewers´ administered questionnaires were used to obtain relevant information from the participants. The information obtained was demographic characteristics, lifestyle, medical and surgical histories, medication history, as well as duration and aetiology of ESKD and dialysis vintage before the kidney transplantation. The date, place, and types of donors for the kidney transplantation procedures and types and adherence to immunosuppressive medications were obtained. History of dialysis in the first-week post kidney transplantation was obtained from all participants to establish the occurrence of delayed graft function. Details of the immunological tests (tissue typing and crossmatching), and warm and cold ischaemic time were not available in most patients and were therefore not included in the analysis. Anthropometric measurements (weight, height, waist, and hip circumferences) and blood pressure were obtained. Patients were followed up at three-month intervals, except where indications for earlier reviews existed. During the follow-up phase, participants were interviewed for features of graft dysfunction, drug toxicity, and side effects. Physical and systemic examinations were carried out during each visit for signs of kidney dysfunction and other complications.

Laboratory analysis: during the baseline clinic visit, ten milliliters of a spot urine for urinalysis and urinary albumin creatinine ratio (ACR) were obtained, while 10ml of blood was taken for serum electrolytes, urea, and creatinine, fasting plasma glucose, glycated haemoglobin (HBA1c), lipid profile, complete blood count, serum tacrolimus or cyclosporine level. Also obtained from participants during each follow-up visit were 10mls of spot urine and 10mls of blood for urinalysis, complete blood count, serum electrolytes, urea and creatinine, fasting plasma glucose, and serum tacrolimus or cyclosporine drug levels.

Definition of terms: chronic renal allograft dysfunction was defined as increased serum creatinine concentration ≥ 2 mg/dL, estimated glomerular filtration rate (eGFR; calculated according to chronic kidney disease -epidemiology collaboration equation) <60 mL/min/1.73m², occurrence of proteinuria or an increase in serum creatinine of 15% from baseline [11,12]. Delayed graft function was defined as failure of the transplanted kidney to function immediately, with the need for one or more sessions of dialysis in the first week post-transplantation [13,14]. The international congress guidelines on post-transplant diabetes defined new-onset diabetic after transplantation (NODAT) as the presence of one or more of the following criteria (a) fasting glucose ≥ 126 mg/dL (7 mmol/L) on more than one occasion; (b) random glucose ≥ 200 mg/dL (11.1 mmol/L) with symptoms; (c) two-hour glucose after a 75-g oral glucose tolerance test ≥ 200 mg/dL (11.1 mmol/L); or (d) hemoglobin A1C ≥ 6.5% [15].

Statistical analysis: data obtained was entered into Microsoft Excel and was subsequently transferred to the Statistical Package for Social Science version 23 for analysis. Baseline descriptions of socio-demographic and clinical variables were reported as proportions for categorical variables and mean (standard deviation) for continuous variables. The association between categorical variables was tested using chi-square analysis, while Student´s t-test was used to test the association between continuous variables. Linear and logistic regression models were employed to predict the risk of allograft dysfunction among the participants, while graft and patients´ survival analysis was carried out using Kaplan Meier survival curve. Statistical significance was set as p-value < 0.05.

Ethical considerations: this study adhered to the declaration of Helsinki and ethical approval was obtained from the Joint University of Ibadan and University College Hospital, Ibadan Institutional Review Board with the approval number UI/EC/15/0310. Informed consent was obtained from all participants.

Results     

Demographic and clinical characteristics of patients with kidney transplantation: a total of 43 patients with living donor kidney transplantation were followed up for at least 36 months, 11 (25.6%) females and 32 (74.4%) males, and the mean age was 49.4 ± 10.3 years. The majority of the participants, 27 (62.8%) were employed, 34 (76.1%) were married and 28 (65.1%) earned less than $1,000 monthly, (Table 1). Hypertension 18 (41.9%) and chronic glomerulonephritis 8 (18.6%) were the two leading causes of ESKD among the cohort. The majority of the patients had their kidney transplantation procedure outside Nigeria 31 (72.1%) with India being the preferred destination in most patients 29 (67.5%) (Table 1). The donors were unrelated to the recipients in 25 (58.1%) while about half of the recipients had co-morbidities (Table 1). Among the 43 patients that were followed up for 36 months, only 38 and 25 were available for review at the end of 12 and 36 months, respectively. The mean plasma tacrolimus and Cyclosporine levels were significantly lower while glycated haemoglobin was significantly higher at the end of the 36 months of follow-up compared to baseline and 12 months values (Table 2).

Short-term outcomes and complications associated with kidney transplantation: among the patients who had kidney transplantation, 11 (25.6%) had delayed graft function at the time of kidney transplantation. Chromic allograft dysfunction was observed in 10 (23.3%), 9 (23.7%) and 12 (48.0%) of the kidney transplantation patients at baseline, 12 months, and 36 months, respectively, while 1(2.3%), 5 (13.2%), and 9 (40.0%) needed dialysis at baseline, 12- and 36- months, respectively (Table 3). At the end of 12 months 29 (67.4%), 9 (21.0%), 1 (2.3%) and 4 (9.3%) kidney transplantation recipients had preserved graft function, chronic allograft dysfunction, lost to follow and dead, respectively, while at 36 months 19 (44.1%), 6 (14.0%), 9 (20.9%) and 10 (23.3%) had preserved graft function, chronic allograft dysfunction, lost to follow and dead, respectively (Table 3). Following kidney transplantation, NODAT progressively increased for follow-up, 10 (23.3%), 12 (31.6%), and 9 (36.0%) at baseline, 12 months, and 36 months, respectively (Figure 1). The cumulative graft survival at 12- and 36-month were 87.0% and 79.0%, respectively (Figure 2, Figure 3) while that of the patient´s survival at 12- and 36-month were 90.7% and 76.7%, respectively (Figure 4, Figure 5).

Factors associated with chronic allograft nephropathy: on univariate analysis marital status (OR:012, 95% CI 0.03 - 0.76, p = 0.01) and delayed graft function (OR:6.25, 95% CI 1.41- 7.65 p = 0.01) were associated with chronic allograft dysfunction (Table 4) while only delayed graft function was independently associated with chronic allograft dysfunction (aOR:3.77, 95% CI 1.50 - 9.02, p = 0.02) on multivariate analysis (Table 5).

Discussion     

This study's objective was to describe the epidemiology, clinical characteristics, and short-term outcomes of patients with kidney transplantation in Nigeria, in addition to determining the prevalence of new onset diabetes after kidney transplantation, as well as identifying factors that determine grafts and patient´s survival. Our study showed that the cumulative graft survival at 12- and 36-month were 87.0% and 79.0%, respectively, while that of patient survival at 12- and 36-month were 90.7% and 76.7%, respectively. The study also identified Delayed Graft Function (DGF) at the time of the kidney transplantation as the single most important factor associated with chronic allograft dysfunction while the study observed that the prevalence of New Onset Diabetes After Transplantation (NODAT) was high among the participants and rose progressively over the 36 months of follow up (23.3%, 31.6% and 36.0% at baseline, 12 months and 36 months, respectively).

This study showed that there is a high prevalence of chronic allograft dysfunction among Nigerians with kidney transplantation, 23.3%, 23.7%, and (14.0%) at baseline, 12 months, and 36 months post kidney transplantation. Delayed graft function was observed to be the single most important factor associated with the development of allograft dysfunction. The high prevalence of chronic allograft dysfunction was both at baseline and during follow-up, the prevalence of chronic allograft dysfunction observed in our study was lower when compared to the 43.1% reported by Boratynska et al. [16]. The disparity in the prevalence of chronic allograft dysfunction may be because their post-transplant follow-up was for 10 years, unlike this study, where participants were followed up only for 3 years. In addition, the recipients had kidneys from deceased donors, unlike the index study where all recipients got kidneys from living donors. The prevalence of chronic allograft dysfunction in our study is also at variance with the report by Solez et al. [17] in a multi-center study where the prevalences of chronic allograft dysfunction were 72.3% and 62.0% for kidney transplantation recipients on cyclosporine and tacrolimus after 2 years, respectively. In all these cases, chronic allograft dysfunction was a kidney biopsy-proven diagnosis, compared with the index study, it appears that the lack of protocol or diagnostic biopsy for histology may have underestimated the prevalence of chronic allograft dysfunction in the current study. There are many causes of chronic allograft dysfunction, but prominent among them are chronic allograft nephropathy (CAN), calcineurin inhibitor (CNI) toxicity, and reoccurrence of primary kidney disease. Rather than make a non-specific diagnosis of chronic allograft dysfunction, biopsy histology will offer the chance to make a specific diagnosis and guide in choosing the appropriate interventions towards reversing or retarding the kidney dysfunction. The occurrence of high prevalence of allograft dysfunction in this population implies that the patient´s and graft´s survival would be shortened and affected patients may require another kidney transplantation or return to dialysis. It was therefore imperative that allograft dysfunction is prevented and, when present, identify promptly and measures put in place to retard progression.

The high prevalence of chronic allograft dysfunction in this study may be due to a multiplicity of factors. Delayed graft function was observed in 25.6% of the kidney transplantation recipients and identified as the main predictor of chronic allograft dysfunction in the study. The incidence of delayed graft function observed in this study was similar to 24.6% reported by Albano et al. [18] among deceased donor recipients who were on everolimus and 29.1% reported by Francesc et al. [19]. This finding of delayed graft function being a major risk factor for chronic allograft dysfunction was in tandem with earlier studies, where delayed graft function is a predictor of chronic allograft dysfunction, particularly when the DGF has lasted for more than 6 days [20,21]. Although the significance of human leucocyte antigen (HLA) mismatch is being downplayed in kidney allograft survival, the majority of the transplanted patients in this study received kidneys from unrelated donors, (58.1%) and the accompanying HLA mismatch may have contributed to the high prevalence of chronic allograft dysfunction in the cohort. Previous studies in both living and deceased donor kidney transplants have demonstrated the deleterious impacts of HLA mismatch on graft survival [22,23]. Other factors previously reported to be associated with chronic allograft dysfunction are the level of adherence with immunosuppressive therapies, while sustainability of immunosuppression is to a large extent dependent on the affordability of the medications, more so that most patients in sub-Saharan Africa pay out-of-pocket. It has also been suggested that the poor outcomes of kidney graft survival in the region are majorly due to the non-affordability of the required immunosuppression [24]. This has once again signified the urgent need for holistic change in government policies towards boosting kidney transplantation and its outcomes in the region. Of importance is the inclusion of kidney transplantation procedures and follow-up immunosuppressive medications in the various national health insurance schemes of the sub-Saharan African countries.

Immunosuppressive medications have side effects despite their ability to prevent graft rejection, commonly seen among patients with kidney transplantation is the New-Onset Diabetes Mellitus After Transplantation (NODAT). We observed the incidence of NODAT to be 23.3%, 31.6%, and 36% at first contact, 12- and 36-month post kidney transplantation, respectively. The incidence of NODAT among the participants also increased over time. The observation is similar to the NODAT incidence of 17.2% reported by Choudhury et al. [25]. Likewise, the progressive rise in the incidence of NODAT observed in our study was similar to the report from the review of data on 11,659 non-diabetic recipients of first kidney transplantation performed between 1996 and 2000 in the United States Renal Data System, where the cumulative incidence of NODAT were 9.1%, 16.0%, and 24.0% at 3-, 12-, and 36- months after transplantation, respectively [26]. The immunosuppressive medications that have been implicated in NODAT include calcineurin inhibitors (CNI - tacrolimus and cyclosporine) and prednisolone [27]. However, pancreatic beta islet dysfunction independent of the calcineurin inhibitors is a strong risk factor for NODAT [28]. The high incidence of NODAT among patients with kidney transplantation requires adequate education of the patients on lifestyle modifications toward its prevention, particularly among kidney transplant patients with a family history of diabetes mellitus.

The 12- and 36-month graft survival of 87.0% and 79.0% in this study were lower compared to reports of living donor kidney transplantation graft survival in high-income countries [29,30]. This finding was lower despite the similar incidence of delayed graft function. Montgomery et al. [31] reported 1-year and 5-year living donor kidney transplantation graft survival of 97.1% and 92.8%, respectively at 5 years. The poor graft survival observed in our study could be attributed to the multiplicity of factors that include the high incidence of delayed graft function, high rate of infection, affordability and poor adherence with immunosuppressive medications, and poor compliance to post-kidney transplant lifestyle modifications. Adequately educating the prospective kidney transplantation recipients before, during, and after the procedure with emphasis on personal hygiene, diet, and adherence to immunosuppressive medications, has the potential to improve the graft survival outcomes.

Limitations: the study limitations include small sample size, absence of kidney biopsy for histology, and lack of long-term follow-up, in addition, the data on donor-recipient compatibility was not available in most of the participants. However, it is a prospective study of graft and patients´ short-term outcomes of kidney transplantation in the West Africa region.

Conclusion     

This study has demonstrated a high prevalence of chronic allograft dysfunction among Nigerians with living donor kidney transplantation recipients, and delayed graft function was identified as a predictor of allograft dysfunction. The graft and patients´ survival are modest among the study population. The incidence of New Oset Diabetes after transplantation was also observed to be high and appears to progressively increase over time. Prevention of delayed graft function during kidney transplantation and lifestyle modifications post-transplantation will enhance graft and patient survival and reduce morbidity and mortality.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Conception and study design: Yemi Raheem Raji and Samuel Oluwole Ajayi. Data collection: Yemi Raheem Raji and Samuel Oluwole Ajayi. Data analysis and interpretation: Yemi Raheem Raji, Samuel Oluwole Ajayi and Babatunde Lawal Salako. Manuscript drafting: Yemi Raheem Raji. Manuscript revision: Yemi Raheem Raji, Samuel Oluwole Ajayi, Babatunde Lawal Salako. Guarantor of the study: Yemi Raheem Raji. All the authors have read and agreed to the final version of this manuscript.

Tables and figures     

Table 1: demographic characteristics of patients with kidney transplantation

Table 2: laboratory characteristics of patients with kidney transplantation at baseline and follow-up visits

Table 3: clinical characteristics of patients with kidney transplantation at baseline and follow-up visits

Table 4: factors associated with renal allograft dysfunction among the participants

Table 5: logistic regression of factors associated with renal allograft dysfunction

Figure 1: prevalence of new onset diabetes after transplantation (NODAT) over the 36 months follow up period

Figure 2: cumulative grafts´ survival at 12 months

Figure 3: cumulative grafts´ survival at 36 months

Figure 4: cumulative patients´ survival at 12 months

Figure 5: cumulative patients´ survival at 36 months

References