Pediatric Kidney Transplant And Cardiometabolic Risk: A Cohort Study Ⅱ

Results 

The 23 children and adolescents included in the study had a median (25th-75th percentile, P25-P75) age of 6.3 (4.4-10.1) years at kidney transplant and 17 (74%) were male. Baseline characteristics of pediatric kidney transplant recipients according to pre-transplant BMI status, non-overweight (n=15, 65%) and overweight (n=8, 35%), are shown in Table 1. Most of the patients (n=14, 60%) had a CAKUT as the cause of ESRD. Only one patient was submitted to a preemptive transplant; 59% (13) were on peritoneal dialysis, 14% (3) on hemodialysis, and 27% (6) on both therapies before kidney transplant for a median (P25-P75) time of 19 (7-51) months before kidney transplant. The participants had a median (P25-P75) Cr-eGFR of 68.9 (57.7-76.8) mL/min/1.73 m2 at 6 months post-transplant. All transplant recipients were initially maintained on standard immunosuppression therapy with tacrolimus (median dose 6.5 (5.49.6) mg/day), mycophenolate mofetil [median dose 600.0 (370.0-950.0) mg/day], and steroids [median dose 15.0 (10.0-15.0) mg/day]. At the end of the study, the immunosuppression therapy included for all patients a lower median dose of corticosteroids (2.5 mg/day) and tacrolimus 5.0 (4.4-6.0) mg/day.

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In the pre-transplant evaluation, the median (P25-P75) BMI and BMI z-score in the overweight group were 15.8 (15.0-16.9) and 1.4 (1.2-2.3), respectively. Patients in the overweight group had a shorter median follow-up time after transplant compared with the non-overweight patients [3.2 (2.7-4.3) vs. 8.2 (7.4-10.9), p<0.001]. Regarding office BP data, no differences in SBP, diastolic BP (DBP), and respective z-scores were found between the BMI groups. Nine (39%) patients presented high BP and were being treated with anti-hypertensive drugs before kidney transplant (Table 1).

The distribution of patients by BMI classes during the study period is shown in Figure 1, by the presence of high BP is shown in Figure 2, and the variation of cardiometabolic parameters are reported in Table 2. The median BMI was higher at the end of the study compared with the 6-month evaluation [20.6 (18.0- 24.4) vs. 18.0 (15.5-20.9), p=0.003] but the BMI z-score values were significantly lower [0.3 (-0.8-1.3) vs. 0.8 (-0.1-1.6), p=0.040], as was the prevalence of children classified as overweight (43.5 vs. 52.2%, p=0.019). A higher percentage of patients were overweight at the end of the study compared to the pre-transplant period, but the difference was not significant (35 vs. 43.5%, p=0.179); median BMI z-score values were similar [0.4 (-0.3–1.3) vs. 0.3 (-0.8–1.3), p=0.651]. The median SBP and DBP values were significantly higher at the end of the study compared to the 6-monthevaluation values, but the differences in SBP and DBP z-score values and the number of patients with high BP were not different. A lower percentage of patients presented high BP at the end of the study compared to the pre-transplant period, but the difference was not significant (52 vs. 13%, p=0.075) and SBP and DBP z-score values were significantly lower [1.2 (-0.2–2.3) vs. 0.3 (-0.4–0.6), p=0.027 and 0.8 (-0.4–1.3) vs. 0.1 (-0.6–0.7), p=0.028; for SBP and DBP, pre-transplant and at the end of the study, respectively]. Total cholesterol and triglycerides values were significantly lower at the end of the study compared to the 6-month evaluation after transplant [163.0 (139.8–187.5) vs. 149.0 (136.0–170.0), p=0.008 and 111.0 (77.3–139.5) vs. 86.0 (72.0–125.0), p=0.035, respectively]. No differences were found in the levels of LDL and HDL cholesterol or in the fasting glucose levels. Fasting insulin and HOMA-IR were only available for the last follow-up visit.

During the follow-up period, creatinine increased and Cr-eGFR values significantly decreased [68.9 (57.7–76.8) vs. 58.6 (48.9–72.9), p=0.033, at 6 months and at the end of the study, respectively]. Cr-Cys-eGFR also significantly decreased over the follow-up period [66.1 (57.1–71.9) vs. 47.6 (42.8–64.3), p=0.015; at 6 months and at the end of the study, respectively] (Table 3). The comparison of the actual median eGFR values (CreGFR, Cys-eGFR, and Cr-Cys-eGFR) evaluated at the last follow-up visit between BMI classes at 6 months, 12 months, and at the end of the study is shown in Figure 3. No differences were found between groups in either of the GFR estimations considered.

Spearman's correlation between eGFR at the last follow-up visit and cardiometabolic variables during follow-up is shown in Table 4. A marginally significant correlation was found between SBP evaluated 6 months after transplant and Cys-eGFR (ρ=0.42, p=0.048) and between SBP evaluated 12 months after transplant and Cr-eGFR (ρ=0.46, p=0.046). Significant negative correlations between triglycerides at the end of the study and both Cys-eGFR (ρ=-0.47, p=0.028) and Cr-Cys-eGFR (ρ=-0.45, p=0.043) were found (Table 4). No other significant correlations were found between eGFR and the cardiometabolic variables evaluated.

Discussion and Conclusion

In the present study, we described the impact of preand post-transplant overweight status on the allograft function of pediatric patients following kidney transplant. We found a very high percentage of overweight children/ adolescents before the transplant (around 35%) and this percentage was about 43.5% at the end of the study. Although a decline in eGFR values was observed over time, no significant differences were found in the median values of eGFR between the non-overweight and the overweight group at 6 months, 12 months, or end of the study. Concerning the other cardiometabolic variables analyzed, we found that BP z-score values were significantly lower at the end of the study compared to the pre-transplant evaluation. Triglycerides were significantly lower at the end of the study and negatively correlated with Cys-eGFR and Cr-Cys-eGFR at that point.

Overweight is a common problem after renal transplantation, which can be explained by several factors, including increased appetite and improved taste sensation associated with the resolution of uremia and the use of steroids, a reduction in dietary restrictions due to improved renal function, and a sedentary lifestyle and poor physical fitness16. 

A high percentage of children (35%) were overweight in before the transplant, and this number was even higher by the end of the follow-up period, although not significantly. The median BMI z-score remained stable during the follow-up period, with a slight increase in the 6-month evaluation. The prevalence of overweight/obesity found in our study was slightly higher than that reported in some previous pediatric studies 24,25. This difference might be explained by the use of different reference values for BMI classification. In fact, the WHO definition of pediatric obesity usually yields the highest estimations of overweight and obesity compared to other definitions26. We should also consider that the prevalence of overweight and obesity in children is among the highest in Europe27, so it is to be expected that the nutritional status of the pediatric CKD population follows this trend, at least in part. Another 2013 study reporting the prevalence of overweight/obesity in the European pediatric renal replacement therapy population reported a prevalence of overweight/obesity of over 30% in transplant patients, especially in those over 6 years of age28, which is consistent with what we found in our study

The finding of such a high prevalence of overweight among pediatric kidney transplant patients is particularly concerning since it has been increasingly acknowledged that overweight acts as an independent risk factor for decreased graft function and survival 6,24. Investigating this association was our main goal because contradictory findings are reported in the literature, especially in children, for which strong evidence is scarce. Due to the size of our sample, the power may not have been enough to find a significant difference between non-overweight and overweight patients in the eGFR estimations considered, regardless of the formula used to estimate GFR (Cr-eGFR, Cys-eGFR and Cr-Cys-eGFR) and at different time points. Another possible explanation for this could be that, in our study, overweight patients had a shorter follow-up period than the non-overweight group. This might indicate that the problem of excessive weight gain in ESRD patients is more likely to affect those patients who have been transplanted in recent years. Previous studies with larger samples have found that GFR levels were significantly lower among overweight/obese patients29, while other authors have found no significant differences in terms the effects of overweight on renal function6,29,30, indicating the need for further studies in this age group.

CKD is known to be associated with increased CV risk in pediatric patients, which may be 3 to 5 times higher compared to their age-matched counterparts. Renal transplantation is thought to reverse some of the CV risk in these patients, but cardiometabolic factors continue to play an important role in the global risk of death in this population31,32.

The median SBP and DBP z-score values in our study were significantly lower at the end of the study compared to pre-transplant or even to the first evaluation after renal transplant, despite the difference at 6 months not being statistically significant. Hypertension is frequent among ESRD patients before transplant and usually persists after transplant, with a reported prevalence varying from 20% to almost 90%. 31,33,34 In our study, high BP, including patients with high or normal-high BP, was present in more than half of the patients before transplant but in a significantly lower percentage of patients at the end of follow-up (around 13%). Our results regarding BP values seem to indicate that effective efforts have been made toward BP control after the kidney transplant. This is especially relevant considering that a higher percentage of patients were overweight at the end of the study, which could have contributed to higher BP values.

The main reason for poor BP control after transplant seems to be the inappropriate use of anti-hypertensive drugs35. Multiple factors are known to be involved with post-transplant hypertension, and previous studies have reported a negative association between BP and GFR12,13. In our sample, we found a marginally significant positive correlation between SBP at 6 months and Cr-eGFR and between SBP at 12 months and Cr-eGFR, which is in contrast with previous findings, and might be explained by the low number of children with high BP in our sample.13 We did not have data on ambulatory blood pressure monitoring that would have helped us better assess the association with GFR, since transplant patients are known to have an increased prevalence of both masked hypertension and nocturnal hypertension, with loss or reverse dipper pattern, which may have escaped us in the present analysis 5,11,12. The benefits of using ambulatory blood pressure monitoring as a diagnostic tool to complement the study of hypertension and consequently increase graft survival have been shown in previous studies11,12.

The association between CKD and dyslipidemia is frequently reported in the literature16,19. After renal transplant, dyslipidemia is believed to contribute to a faster decline of the allograft function, especially when associated with proteinuria36,37. Evidence suggests that total cholesterol concentration 12 months after kidney transplant is an independent predictor of mortality17. Guidelines recommend early screening for dyslipidemia after transplantation, which should then be repeated at least annually 38,39. A negative correlation between triglycerides and eGFR was found at the end of the study, which reinforces the importance of this recommendation. Similar findings have been reported in a previous study in pediatric kidney transplant patients, with no significant association between eGFR and both total and LDL cholesterol concentrations but a negative association with plasma levels of triglycerides 40. Other previous studies failed to find an association between GFR and any lipid parameter after transplant, even when adjusting for age, BMI status, or primary kidney disease40.

Our study had several limitations. Although it was a prospective longitudinal study designed after the transplant, data were obtained from medical records and retrospectively analyzed. Besides, our study was a single-center study and included a relatively small number of patients. We could not access data from patients transplanted in the pediatric age but who were older than 18 years and followed up in adult facilities at the time of the study. Another important limitation was that we considered the end of the follow-up as a temporal mark for several comparisons, but in fact, the follow-up time after kidney transplant varied among patients and a difference between BMI classes may have been present. Additionally, we did not have access to waist circumference measurements during follow-up, thus precluding the analysis of the impact of abdominal obesity in the associations studied. Another important limitation was the fact that BP evaluation was solely based on office BP, measured in an oscillometric automated device, with data on ambulatory BP monitoring only being available for about half of the patients, which was not reported in the present study. Ambulatory BP monitoring would have provided us with more complete information, allowing the diagnosis of masked and nocturnal hypertension and perhaps for a more reliable association with renal function.

Despite all limitations, our study showed that a high number of children and adolescents submitted to kidney transplants are overweight or obese. Considering the increasingly recognized impact of this risk factor on allograft function decline, our results should draw attention to the importance of better managing nutritional status in the high-risk group of ESRD patients. We observed a decline of eGFR over time, but we could not find differences in renal function between BMI groups probably due to a lack of power related to the sample size. Additionally, the negative association between triglycerides and GFR should also raise awareness to the importance of regular evaluation and management of blood lipids after kidney transplant. Although the number of studies on pediatric renal transplant has increased in recent years, more studies are needed to understand the best way to manage these patients. We believe that long-term studies, with larger samples and perhaps multicenter, are necessary to better assess the effect of obesity and its associated comorbidities on renal allograft function in children.

We hope to be able to continue to follow this sample in the future by adding ambulatory BP monitoring to their regular screening visits to monitor not only the evolution of kidney function but also the impact of cardiometabolic risk factors, which are expected to become more significant as time progresses.

Acknowledgments The authors gratefully acknowledge the contribution of all members of the research team, parents, and patients involved in this study. 

Authors' Contribution All authors played a significant role in one or more of the following aspects of this project: development of the concept, protocol/study design, data collection, data analysis, and manuscript writing/editing. All authors read and approved the final manuscript. 

Conflict of Interest The authors have no conflict of interest to declare

References

1. Hogan J, Audry B, Harambat J, Dunand O, Garnier A, Salomon R, et al. Are there good reasons for inequalities in access to renal transplantation in children? Nephrol Dial Transplant. 2015 Dec;30(12):2080-7. 

2. Saeed B. Pediatric renal transplantation. Int J Organ Transplant Med. 2012;3(2):62-73

3. Dobrowolski LC, Van Huis M, Van Der Lee JH, Sengers HP, Liliën MR, Cransberg K, et al. Epidemiology and management of hypertension in pediatric and young adult kidney transplant recipients in the Netherlands. Nephrol Dial Transplant. 2016 Nov;31(11):1947-56. 

4. Val ML, Menezes FS, Massaoka HT, Scavarda VT, Czapkowski A, Leite HP, et al. Cardiovascular risk in children and adolescents with end stage renal disease. Clinics. 2019;74(11):e859. 

5. Hooper DK, Mitsnefes M. A systems-based approach to managing blood pressure in children following kidney transplantation. Pediatr Nephrol. 2016 Oct;31(10):1593-604.

6. Mitsnefes MM, Khoury P, McEnery PT. Body mass index and allograft function in pediatric renal transplantation. Pediatr Nephrol. 2002 Jul;17(7):535-9.

7. Johnson CP, Gallagher-Lepak S, Zhu YR, Porth C, Kelber S, Roza AM, et al. Factors influencing weight gain after renal transplantation. Transplantation. 1993 Oct;56(4):822-7. 

8. Mallamaci F, D'Arrigo G, Tripepi R, Leonardis D, Porto G, Testa A, et al. Office, standardized and 24-h ambulatory blood pressure and renal function loss in renal transplant patients. J Hypertens. 2018 Jan;36(1):119-25. 

9. Chan W, Bosch JA, Jones D, McTernan PG, Phillips AC, Borrows R. Obesity in kidney transplantation. J Ren Nutr. 2014 Jan;24(1):1-12.

10. John EG, Domingo LT. Hypertension and obesity after pediatric kidney transplantation: Management based on pathophysiology: a mini-review. Int J Prev Med. 2014 Mar;5(Suppl 1):S25-S38. 

11. Hamdani G, Nehus EJ, Hooper DK, Mitsnefes MM. Masked hypertension and allograft function in pediatric and young adults kidney transplant recipients. Pediatr Transplant. 2016 Dec;20(8):1026-31. 

12. Charnaya O, Moudgil A. Hypertension in the pediatric kidney transplant recipient. Front Pediatr. 2017;5(May):1-10. 

13. Silverstein DM, LeBlanc P, Hempe JM, Ramcharan T, Boudreaux JP. Tracking of blood pressure and its impact on graft function in pediatric renal transplant patients. Pediatr Transplant. 2007 Dec;11(8):860-7. 

14. Gimpel C, Wühl E, Arbeiter K, Drozdz D, Trivelli A, Charbit M, et al. Superior consistency of ambulatory blood pressure monitoring in children: implications for clinical trials. J Hypertens. 2009 Aug;27(8):1568-74. 15. Krmar RT, Ferraris JR. Clinical value of ambulatory blood pressure in pediatric patients after renal transplantation. Pediatr Nephrol. 2018 Aug;33(8):1327-36.

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