ABSTRACT
Background
Solid organ transplant (SOT) recipients are at risk for long‐term comorbidities and polypharmacy, potentially affecting quality of life. This study assessed the prevalence of chronic medication use among young adults following pediatric SOT.
Methods
We included 215 individuals in Finland who underwent kidney (n = 135), liver (n = 41), or heart (n = 39) transplantation before age 16 between 1982 and 2015 and were ≥18 years at follow‐up. Age, sex, and hometown‐matched controls (n = 1067) were selected from the Finnish Population Information System. The analyses involved data on prescription drug purchases and reimbursements for chronic conditions derived from the registry of Social Insurance Institution, which covers all prescription medicine purchases in Finland.
Results
The SOT recipients had an average of 1.53 reimbursed chronic conditions beyond immunosuppression (median follow‐up time:18.0 years, IQR 11.0–23.0), with the highest burden among kidney and lowest among liver transplant recipients. Compared to controls, SOT recipients had significantly more reimbursement for cardiovascular diseases, hormonal deficiencies, and epilepsy (p < 0.001). Kidney transplant recipients had a significantly higher risk of cardiovascular‐related reimbursements than liver transplant group (p < 0.001); no significant differences were observed between the transplant groups for other conditions.
Conclusions
Young adults after pediatric SOT had an elevated need for chronic disease medications, with the highest burden observed in kidney transplant recipients and the lowest in liver transplant recipients. These findings highlight the importance of long‐term follow‐up and individualized transitional care to address multimorbidity and support quality of life.
Keywords: comorbidity, morbidity, outcome, pediatric organ transplantation, polypharmacy, quality of life
Abbreviations
- ATC
anatomical therapeutic chemical
- CVD
cardiovascular disease
- HT
heart transplant
- ICD
international classification of diseases
- IQR
interquartile range
- KT
kidney transplant
- LT
liver transplant
- SOT
solid organ transplantation
1. Introduction
Solid organ transplantation (SOT) is a lifesaving treatment modality for children with severe organ failure. SOT has significantly improved both the short‐ and long‐term prognosis in these patient groups. However, along with improved prognosis, our awareness of long‐term morbidity and mortality after pediatric SOT has increased [1, 2, 3].
It is well known that children with chronic organ failure typically have comorbidities related either to their primary disease and organ failure or to treatments, such as medications, dialysis, or extracorporeal membrane oxygenation [4, 5]. In addition, lifelong immunosuppressive medication, which is required to prevent allograft rejection, increases the risk for posttransplant comorbidities [6, 7, 8]. Pre‐existing or transplant‐related comorbidities, on the contrary, have been shown to affect long‐term survival even after SOT [9]. In pediatric patients, the exposure to immunomodulative drugs may last several decades, and the susceptibility to drug‐induced side effects, such as diabetes, osteoporosis, cardiovascular diseases (CVD), and malignancies, is likely to be increased over time [2, 7, 10, 11].
This study aimed to assess prescription drug utilization and reimbursement patterns for chronic conditions in adolescents and young adults with a history of solid organ transplantation during childhood, with the objective of elucidating the occurrence of comorbidities within this cohort. The analysis focused specifically on medications prescribed for CVD, endocrine disorders such as diabetes, growth failure, hypothyroidism, neurological conditions, and mental health conditions. Comparative drug usage patterns were examined between pediatric recipients of kidney, liver, and heart transplants and their population‐matched controls based on age, sex, and geographic region.
2. Materials and Methods
2.1. Study Population
This is a retrospective national register study including all pediatric SOT patients who underwent kidney (KT), liver (LT) or heart (HT) transplantation between January 1982 and December 2015 in Finland. Inclusion criteria were age under 16 years at transplantation, patient being alive at least one year after transplantation, and age over 18 years at the time of the last follow‐up day (December 31st, 2015).
A total of 233 SOT recipients were identified from the transplantation database. The majority of the patients had received a kidney transplant (n = 137; 58.8%). Fifty‐three (22.7%) patients were LT and 43 (18.5%) HT recipients. All patients were followed up at our institution at least once yearly until being transferred to adult care at the age of 18 to 22 years. For each SOT recipient, 3–5 controls were randomly selected from the Finnish Digital and Population Data Services Agency registry; altogether, there were 1157 age, sex, and area of residence matched population controls (median age 26.4 years [IQR 22.9–31.3]). Patients who died (n = 18) during the first post‐transplant year were excluded. Finally, data from 215 SOT recipients (KT 135, LT 41, and HT 39) and 1067 controls were analyzed.
2.2. Data Analysis
We collected data on diagnosed chronic conditions and all prescription drug purchases from all eligible SOT recipients from two registries. The Finnish healthcare system provides reimbursed medications for the treatment of chronic diseases. The National Reimbursement Register, maintained by the Social Insurance Institute (Kela), contains patients entitled to reimbursed drugs for chronic conditions. For a patient to get eligibility for reimbursement, a physician needs to write a note with a description of the patient's clinical condition. The eligibility criteria for the reimbursement are based on the International Classification of Diseases (ICD) codes and, in general, follow international recommendations. The reimbursement is disease specific, and patients may get one or more medications reimbursed by the same reimbursement eligibility. For long lasting condition, such as diabetes, the reimbursement is lifelong. The data of entitlement to reimbursements by type of chronic condition was collected from the National Reimbursement Register. The National Prescription Register, maintained also by Kela, contains records from 1993 onward on all prescription drug purchases, including data on purchase dates and Anatomical Therapeutic Chemical (ATC) Classification System codes. This registry includes drug purchases for both acute and chronic conditions. Table S1 provides the ATC codes included in different drug categories. This study focused to drug usage for chronic conditions and therefore short‐term reimbursements connected to immediate post‐transplant care were excluded. Reimbursements for chronic conditions and prescription drug purchases of each SOT recipient were analyzed from the first post‐transplant year onward; for the population controls, analyses included data ≥ 1 year after the index patient's transplantation date. The data on identified chronic conditions and drug purchases are presented separately in the results section. Reimbursements describe the presence of chronic health conditions and drug purchases reflect overall usage of medication for both acute and chronic conditions.
The National Causes of Death Register, maintained by Statistics Finland, supplied data on causes of death. These were categorized into four groups: infections, cancer deaths (resulting from relapse or secondary cancer), cardiovascular diseases, and other causes. Data collection ended either December 31st, 2015, or on the date of death.
2.3. Statistics
Continuous data is expressed as means and standard deviations (SD) (normal distribution) or as medians and interquartile ranges (IQR) (not normal distribution); due to small numbers, differences between groups were analyzed with Fisher's exact test. Cumulative incidence function curves were drawn for different SOT groups and population controls; death served as a competing event. Differences in the occurrence rate of reimbursements for chronic diseases were assessed with Cox proportional hazards models with time (years) from transplantation serving as time scale; patients and controls were censored at the date of death or December 31st, 2015. The results are reported as hazard ratios (HR) and their 95% confidence intervals (95% CI). As age at first drug purchase was not available (register data available from 1993 onward), the prescription drug data were analyzed with logistic regression models in two ways: as purchases ever after the transplantation and during the last year of follow‐up or the last year before death. The results are reported as odds ratios (OR) and their 95% CIs. All data was first analyzed between SOT recipients and population controls. Then, analyses were performed within the SOT group with KT serving as the reference group. Statistical analyses were performed using R software version 4.0.3 (Foundation for Statistical Computing, Vienna, Austria). All tests were two‐tailed, and p values under 0.05 were considered statistically significant.
2.4. Ethical Considerations
This study was approved by the Research Ethics Committee of Helsinki and Uusimaa Hospital District (59/13/03/03/2016, HUS/149/2017), the Finnish Institute for Health and Welfare (THL/585/5.05.00/2016), and the Office of the Data Protection Ombudsman.
3. Results
3.1. Patient Characteristics
The median follow‐up time of the study population was 18.0 (IQR 11.0–23.0) years, and the median age at the time of the study was 25.1 (IQR 21.5–29.6) years. Of the SOT recipients, 129 (60.0%) were men and 86 (40.0%) were women (Table 1). There were 27 patients (12.6%) who underwent re‐transplantation. Altogether, 42 recipients and 1 population control had died before the end of the follow‐up. Of the SOT recipients, 23% had died due to cardiovascular diseases, 22% due to infections, 17% due to malignancies, and 38% due to other causes [12]. Eighteen (13.3%) of the KT recipients and one (2.3%) HT recipient had started dialysis during the follow‐up due to chronic kidney failure. The data about kidney function was not available.
TABLE 1.
The key clinical characteristics of the kidney, liver, and heart transplant recipients and the control subjects.
| Characteristic | All patients | KT | LT | HT | Population controls |
|---|---|---|---|---|---|
| Total, n (%) | 215 | 135 (62.8) | 41 (19.1) | 39 (18.1) | 1067 |
| Males, n (%) | 129 (60.0) | 90 (66.7) | 18 (43.9) | 21 (53.8) | 641 (60.1) |
| Median age at time of transplant, years (IQR) | 8.4 (2.6–13.4) | 8.1 (2.5–13.3) | 5.6 (1.4–13.9) | 10.5 (6.8–13.3) | — |
| Median age at time of study, years (IQR) | 25.1 (21.5–29.6) | 25.6 (22.3–29.7) | 25.3 (21.9–28.4) | 22.1 (19.3–30.5) | 26.7 (22.8–31.4) |
| Dead, n (%) | 42 (19.5) | 18 (13.3) | 11 (26.8) | 13 (33.3) | 1 (0.1) |
| Median age at death, years (IQR) | 20.8 (17.6–25.5) | 22.5 (18.5–27.0) | 21.6 (15.9–26.3) | 19.3 (15.0–21.8) | — |
| Median time from Tx to death, years (IQR) | 10.2 (7.1–16.5) | 12.8 (9.6–19.1) | 11.4 (7.0–16.1) | 7.9 (4.9–10.2) | — |
Abbreviations: HT, heart transplant; IQR, interquartile range; KT, kidney transplant; LT, Liver transplant.
3.2. Reimbursements for Chronic Conditions and Prescription Drug Purchases in SOT Recipients and in Controls
The SOT patients had significantly more reimbursements for conditions other than transplantation compared to controls (1.53 vs. 0.1, p < 0.001). KT recipients had an average of 2.6 conditions for which they received drug reimbursement, LT recipients 0.9, and HT recipients 1.1, respectively. The most common reimbursed chronic conditions for SOT recipients are listed in Table 2. In a vast majority of the SOT patients, the chronic condition eligible for reimbursements was hypertension (n = 57, 26.5%), while other cardiovascular conditions, such as coronary disease, cardiac dysfunction, and arrhythmias, covered only 4.6% of the reimbursements (Table 2). SOT recipients had more reimbursement for hypertension, epilepsy, diabetes, anemia in chronic kidney disease (CKD), and growth hormone deficiency compared to the controls (Table 2). On the other hand, there was a noticeable trend of increased reimbursements for chronic asthma in the control population compared to SOT recipients, although the difference was not statistically significant (p = 0.29). There was no significant difference in the frequency of reimbursements for psychosis and other mental disorders between the SOT recipients and the population controls (Table 2).
TABLE 2.
Chronic conditions eligible for reimbursements in solid organ transplantation recipients and in population controls.
| Reimbursement, n (%) |
SOT (n = 215) |
Controls (n = 1,067) |
HR (95% CI) |
|---|---|---|---|
| Hypogonadism | 3 (1.4) | 1 (0.1) | – a |
| Hypothyroidism | 0 | 2 (0.2) | – a |
| Heart failure | 2 (0.9) | 0 | – a |
| Ischemic heart disease | 8 (3.7) | 0 | – a |
| Hypertension | 57 (26.5) | 3 (0.3) | 118.2 (37.0–377.5) |
| Diabetes | 6 (2.8) | 12 (1.1) | 2.68 (1.01–7.15) |
| Epilepsy | 17 (7.9) | 15 (1.4) | 6.12 (3.06–12.3) |
| Growth hormone deficiency b | 59 (27.4) | 1 (0.1) | 356.5 (49.4–2573.8) |
| Rheumatic arthritis c | 4 (1.9) | 9 (0.8) | 2.46 (0.76–8.00) |
| Multiple sclerosis | 0 | 1 (0.1) | – a |
| Psychosis and other mental disorders | 4 (1.9) | 17 (1.6) | 1.35 (0.45–4.02) |
| Chronic asthma | 3 (1.4) | 30 (2.8) | 0.52 (0.16–1.72) |
| Anemia of chronic kidney disease | 62 (28.8) | 1 (0.1) | 434.4 (60.2–3136.4) |
| Ulcerative colitis, Crohn's disease | 4 (1.9) | 10 (0.9) | 2.20 (0.69–7.03) |
| Dyslipidemia | 4 (1.9) | 0 | |
| Hyperparathyroidism | 22 (10.2) | 0 | – a |
| Severe hyperphosphatemia | 11 (5.1) | 0 | – a |
Abbreviations: HR, hazard ratio; SOT, solid organ transplantation. Bold HR values denote p < 0.05.
Analysis not performed due to low number of events or zero events in one group.
Includes first occurrence of reimbursement for growth hormone or first purchase of growth hormone.
Schoenfeld‐residuals p < 0.05 (suggesting violation of proportional hazard assumption).
SOT recipients had significantly more drug purchases compared to controls in almost all drug categories, as shown in Table 3. SOT recipients purchased more antidepressants than controls during the whole follow‐up period, but there was no significant difference between the groups during the last follow‐up year. As expected, control subjects purchased non‐steroidal anti‐inflammatory drugs (NSAID) more frequently (OR; 95% CI, 0.36 [0.26–0.48]). In contrast, SOT recipients purchased weak and strong opiates more frequently, particularly during the last year of follow‐up or before death.
TABLE 3.
Prescription drug purchases in solid organ transplantation recipients and in population controls.
| Drug category, n (%) |
SOT a (n = 214) |
Controls (n = 1062) |
OR b (95% CI) |
|---|---|---|---|
| Testosterone c | |||
| Ever | 7 (5.5) | 3 (0.5) | 12.3 (3.33–58.0) |
| Within the last year | 1 (0.8) | 0 | – d |
| Estrogen e | |||
| Ever | 6 (7.0) | 12 (2.8) | 3.72 (1.21–10.6) |
| Within the last year | 1 (1.2) | 4 (0.9) | – d |
| Thyroxine | |||
| Ever | 10 (4.7) | 37 (3.5) | 1.46 (0.67–2.92) |
| Within the last year | 10 (4.7) | 30 (2.8) | 1.85 (0.84–3.78) |
| Growth hormone | |||
| Ever | 59 (27.6) | 1 (0.1) | 428 (92.8–7601) |
| Within the last year | 3 (1.4) | 0 | – d |
| Antihypertensives | |||
| Ever | 186 (86.9) | 90 (8.5) | 97.4 (60.5–163) |
| Within the last year | 134 (62.6) | 41 (3.9) | 53.3 (34.2–85.3) |
| Lipid‐lowering drugs | |||
| Ever | 69 (32.2) | 7 (0.7) | 79.0 (37.7–194) |
| Within the last year | 50 (23.4) | 2 (0.2) | 162 (49.4–998) |
| Antithrombotic drugs | |||
| Ever | 32 (15.0) | 20 (1.9) | 10.2 (5.67–18.7) |
| Within the last year | 12 (5.6) | 7 (0.7) | 9.01 (3.55 24.7) |
| Diabetic drugs | |||
| Ever | 9 (4.2) | 22 (2.1) | 2.28 (0.98–4.93) |
| Within the last year | 3 (1.4) | 16 (1.5) | 0.97 (0.22–2.98) |
| Anxiolytics/sedatives | |||
| Ever | 56 (26.2) | 112 (10.5) | 3.83 (2.60–5.62) |
| Within the last year | 22 (10.3) | 30 (2.8) | 4.66 (2.57–8.35) f |
| Antidepressants | |||
| Ever | 48 (22.4) | 175 (16.5) | 1.64 (1.13–2.36) |
| Within the last year | 22 (10.3) | 78 (7.3) | 1.54 (0.91–2.50) |
| Antipsychotics | |||
| Ever | 19 (8.9) | 72 (6.8) | 1.41 (0.81–2.35) |
| Within the last year | 10 (4.7) | 36 (3.4) | 1.45 (0.67–2.88) |
| Antiepileptics | |||
| Ever | 37 (17.3) | 69 (6.5) | 3.51 (2.24–5.44) |
| Within the last year | 21 (9.8) | 27 (2.5) | 4.60 (2.5–8.36) |
| NSAIDs | |||
| Ever | 98 (45.8) | 765 (72.0) | 0.36 (0.26–0.48) |
| Within the last year | 16 (7.5) | 246 (23.2) | 0.28 (0.16–0.46) |
| Opioids (weak) | |||
| Ever | 94 (43.9) | 254 (23.9) | 2.86 (2.08–3.91) |
| Within the last year | 36 (16.8) | 65 (6.1) | 3.42 (2.17–5.31) |
| Opioids (strong) | |||
| Ever | 18 (8.4) | 5 (0.5) | 22.0 (8.54–68.1) |
| Within the last year | 12 (5.6) | 1 (0.1) | 69.6 (13.5–1277) g |
| Pulmonary drugs | |||
| Ever | 63 (29.4) | 278 (26.2) | 1.17 (0.84–1.62) |
| Within the last year | 12 (5.6) | 65 (6.1) | 0.89 (0.45–1.62) |
| Antibiotics | |||
| Ever | 213 (99.5) | 990 (93.2) | 18.4 (4.01–327) |
| Within the last year | 131 (61.2) | 289 (27.2) | 4.23 (3.11–5.78) |
| Drugs for bone diseases | |||
| Ever | 17 (7.9) | 1 (0.1) | 157 (30.1–2922) |
| Within the last year | 5 (2.3) | 0 | – d |
Note: Prescription drug purchase data are available from 1993 to 2015. Drug purchases within the last year denote purchases within one year from the study date (December 31, 2015) or the date of death. Bold OR values denote p < 0.05.
Abbreviations: NSAID, non‐steroidal anti‐inflammatory drug; OR, odds ratio; SOT, solid organ transplantation.
One patient (and corresponding controls) was excluded due to death before 1993.
Adjusted for age at the study date and gender.
Only males included in the analyses.
Analysis not performed due to low number of events or zero events in one group.
Only females included in the analyses.
Difference remains significant if model is also adjusted for survival status (OR 2.71, 95% CI 1.28–5.38).
Difference remains significant if model is also adjusted for survival status (OR 49.4, 95% CI 8.68–929).
3.3. Reimbursements for Chronic Conditions and Prescription Drug Purchases in Different SOT Groups
The chronic conditions for reimbursements differed between the SOT groups (Table 4). Among the KT recipients, hypertension, anemia in CKD, growth failure, and hyperparathyroidism were the most common reimbursed chronic conditions (Table 4). In LT recipients, growth hormone deficiency, hypertension, rheumatoid arthritis, and inflammatory bowel disease were the most common posttransplant conditions for reimbursement, while in the HT group, epilepsy, hypertension, ischemic heart disease, and growth failure were the most common conditions (Table 4). The cumulative incidence of anemia in CKD and hypertension among KT recipients increased gradually with age, the latter showing a plateau at approximately 15 years of follow‐up (Figure 1). In contrast, the cumulative incidence of hypertension in the LT and HT groups began to increase at an older age and remained lower compared to the KT group (Figure 1). The occurrence rate of reimbursement for hypertension was lower in LT when compared to KT, whereas no significant difference occurred between HT and KT. Reimbursement for anemia in CKD occurred significantly more frequently in KT than in LT or HT, whereas there was no difference in reimbursement for epilepsy or growth hormone between the SOT groups (Table 4).
TABLE 4.
Frequency of chronic conditions eligible for reimbursements in different solid organ transplantation groups.
| Reimbursement, n (%) |
KT (n = 135) |
LT (n = 41) |
HT (n = 39) |
|---|---|---|---|
| Hypogonadism | 1 (0.7) | 1 (2.4) | 1 (2.6) |
| Hypothyroidism | 0 | 0 | 0 |
| Heart failure | 1 (0.7) | 0 | 1 (2.6) |
| Ischemic heart disease | 1 (0.7) | 0 | 7 (17.9) |
| Hypertension a | 45 (33.3) | 5 (12.2) | 7 (17.9) |
| Diabetes | 4 (3.0) | 0 | 2 (5.1) |
| Epilepsy b | 12 (8.9) | 1 (2.4) | 4 (10.3) |
| Growth hormone deficiency c | 42 (31.1) | 9 (22.0) | 8 (20.5) |
| Rheumatic arthritis | 0 | 4 (9.8) | 0 |
| Multiple sclerosis | 0 | 0 | 0 |
| Psychosis and other mental disorders | 3 (2.2) | 0 | 1 (2.6) |
| Chronic asthma | 1 (0.7) | 2 (4.9) | 0 |
| Anemia in chronic kidney disease d | 60 (44.4) | 1 (2.4) | 1 (2.6) |
| Ulcerative colitis, Crohn's disease | 1 (0.7) | 3 (7.3) | 0 |
| Hyperparathyroidism | 22 (16.3) | 0 | 0 |
| Severe hyperphosphatemia | 11 (8.1) | 0 | 0 |
Note: Bold HR values denote p < 0.05. Cox proportional hazard models were adjusted for gender.
Abbreviations: HR, hazard ratio; HT, heart transplant; KT, kidney transplant; LT, liver transplant.
LT vs. KT: HR 0.32 (95% CI 0.13–0.81); HT vs. KT: HR 0.56 (95% CI 0.25–1.24).
LT vs. KT: HR 0.28 (95% CI 0.04–2.17); HT vs. KT: HR 1.38 (95% CI 0.44–4.28).
Includes first occurrence of reimbursement for growth hormone or first purchase of growth hormone.
LT vs. KT: HR 0.04 (95% CI 0.01–0.28); HT vs. KT: HR 0.05 (95% CI 0.01–0.40).
FIGURE 1.
Cumulative incidence of reimbursements for hypertension (A), epilepsy (B), anemia in chronic kidney disease (C), and growth hormone (D) in kidney (black solid line), liver (black dotted line), heart (gray solid line) transplant recipients and in control subjects (gray dotted line).
When compared to KT recipients, LT recipients had purchased antihypertensives less frequently, whereas HT recipients had more purchases of lipid‐lowering drugs. In addition, LT and HT recipients had purchased significantly more NSAIDs compared to KT recipients. There were no differences in the purchases of antithrombotic agents, anxiolytics/sedatives, antidepressants, antipsychotics, antiepileptics, opioids, pulmonary drugs, or antibiotics between the different SOT groups (Table S2).
3.4. Reimbursements for Chronic Conditions Among SOT Recipients Who Died Before the End of Follow‐Up
The most common chronic conditions eligible for reimbursement among SOT recipients who died during the follow‐up were anemia in CKD (18.8%), hyperparathyroidism (15.6%), growth hormone deficiency (14%), and severe hypertension (9.4%). There was no statistically significant difference in the occurrence of these conditions between patients who died and those who were alive at the end of the follow‐up.
4. Discussion
The present study confirms previous findings about significant morbidity among young adults with a history of SOT during childhood [1, 2, 3, 4, 5, 6, 7, 13]. According to our data, approximately 10% of the SOT recipients had reimbursements for five or more drug categories other than immunosuppressive medicines. The predominant underlying chronic conditions were cardiovascular diseases and endocrine disorders. The present study provides an overview on significantly increased late morbidities in young adult recipients of pediatric SOT and emphasizes the need for meticulous lifelong follow‐up of this patient group [3, 5].
In the present cohort, SOT recipients presented for reimbursement of chronic conditions an average of 1.53 times. Multimorbidity and polypharmacy, which is defined as concurrent use of five or more medications, are known problems among SOT recipients and other patient groups with chronic conditions and are likely to lead to a decreased quality of life [13, 14, 15]. The number of reimbursements was the highest among KT recipients, especially compared to the LT recipients. This is at least partly explained by the fact that approximately 13% of the KT had experienced graft loss and were on dialysis. Information on kidney function was not available, so we were unable to analyze the correlation between graft function and compensation.
Cardiovascular comorbidities are prevalent among SOT recipients [12, 16, 17, 18, 19]; however, comparative data between the SOT population and individuals without a history of transplantation are limited. In the present study, the number of chronic conditions requiring special reimbursed drugs was approximately 30‐fold higher in comparison to population controls. Brar et al. have recently shown in a Canadian transplant cohort that the number of cardiovascular events was 34 times higher in the pediatric SOT group than in non‐transplanted asthmatic patients [20]. These two studies have different designs, making their results not directly comparable. However, it is evident that the risk and occurrence of CVD are significantly higher in SOT recipients when compared to the general population. Interestingly, in our cohort, KT recipients had the highest rate of reimbursement for cardiovascular disease (CVD), even compared to heart transplant (HT) recipients. Previous studies indicate that CVD is the leading cause of mortality for kidney transplant recipients [18, 21]. This may be due to the primary kidney diagnosis, increased frequency of cardiovascular risk factors including hypertension, dyslipidemia, and insulin resistance, as well as declining graft dysfunction and CKD [18]. Additionally, the long‐term mortality (33%) in HT patients is likely higher due to the nature of graft vasculopathy, and less availability of supportive measures, unlike KT recipients who can rely on dialysis when graft dysfunction progresses. The reimbursements for CV medications are more prevalent in KT than HT recipients.
Earlier studies have indicated that 3%–20% of the pediatric SOT patients develop new‐onset diabetes [22, 23, 24]. In the present study, 3% had reimbursement for diabetes. This is consistent with our previous findings, which indicate a 14%–19% prevalence of metabolic syndrome and a 3%–5% prevalence of type 2 diabetes among 210 Finnish KT [25]. It is important to note that the national reimbursement data utilized in this study does not distinguish between temporary and permanent reimbursements. Consequently, patients with persistent hyperglycemia and those with new‐onset diabetes following transplantation are all included in the data. This may explain the higher number of patients with diabetes medication in KT and HT patients compared to LT recipients, because they typically receive higher doses of glucocorticoids with a risk of prolonged hyperglycemia.
Antiepileptic medication was prescribed to more than 15% of the KT and HT patients at some point after transplantation, exceeding the rates reported in earlier studies [26]. The difference may be partly explained by the primary diagnosis leading to SOT. Congenital nephrosis of the Finnish type is the most common diagnosis leading to KT during childhood in Finland. These patients are known to have an increased risk for thromboembolic events because of massive proteinuria and loss of antithrombotic factors before nephrectomy and KT. The incidence of thrombotic events in the central nervous system and concomitant epilepsy was relatively common, especially in the 1980s and 1990s [27]. In HT recipients, the need for antiepileptic therapy may be related to prior use of a ventricular assist device (VAD) as a bridge to HT. The prevalence of neurological events during VAD is reportedly around 30%; however, the risk for epilepsy appears to be lower, at least in pediatric population [28, 29, 30]. The present analysis was based on ATC codes, and indications for drug purchases were unavailable.
Despite significant improvement in the post‐transplant quality of life, the mental burden among SOT remains common both before and after the transplantation [31, 32]. Samsel et al. demonstrated that heart disease is a significant risk factor for the use of psychopharmacological medication among SOT patients [33]. Also, more than a third of pediatric transplant patients use psychotropic medications at some point in their lives [33, 34]. In the present cohort, SOT recipients had significantly more drug purchases in anxiolytics, sedatives, and antidepressants; however, no difference in the reimbursements for psychotropic drugs could be found between the transplant recipients and the controls. This difference is likely explained by that eligibility for reimbursement for antipsychotic drugs includes only psychoses and other severe psychiatric diseases. Additionally, none of the deceased patients who died by suicide had reimbursement for mental disorders. This may indicate the possibility that these patients did not seek help for their anxiety and depression or did not apply for reimbursement and are therefore not considered in this study. However, since psychiatric illnesses can deteriorate medication adherence and have an adverse impact on survival, it is crucial to consider the need for psychiatric support for transplantation patients [35].
Opioid use among SOT recipients is a significant concern due to the high prevalence of chronic pain in this population [36]. In the present study, significantly more SOT recipients purchased both strong and weak opioids compared to the general population. This difference was particularly pronounced during the last year of follow‐up or before death. The need for pain management in these patients often leads to continued prescription of opioids, increasing the risk of long‐term dependency. This highlights the critical importance of careful monitoring and the implementation of alternative pain management strategies to mitigate the risks associated with chronic opioid use in SOT recipients.
This study has several caveats. First, although the total number of participants was 215, the sample size in organ‐specific subgroups was relatively small. However, it is important to note that all patients who were alive were included and the special reimbursement register has 100% coverage, which enhances the data quality. Some patients may not appear in registers if reimbursement was not sought at all. Additionally, the indications for drug purchases were based on ATC codes and the exact indications were unavailable, which may have influenced some of our findings. Second, the data were collected after the transplantation, and information on medication use prior to SOT was not available. Therefore, we cannot definitively determine whether the comorbidity was associated with the transplantation. However, data on the increase in reimbursement rates over time after transplantation (Figure 1) indirectly indicate increasing morbidity after transplantation. A clear strength of the study was the long follow‐up time. In addition, since all patients were treated and followed up by the same center in childhood and adolescence, the variation in treatment protocol is likely to be minimal. The study based on register data enabled the analysis of an extensive cohort of population controls with no participation or self‐reported bias. The Finnish healthcare system is rather uniform and follows national guidelines, meaning that the indications for special reimbursed medication in control patients are likely to be comparable. Finally, register data on drug reimbursements and purchases have been available since 1993. This leaves a gap of about ten years since the first SOT for children in Finland. However, our main area of interest was multimorbidity and drug purchases among long‐term survivors, and all patients alive when the registry data became available were included in the study.
In conclusion, young adults with a history of SOT during childhood have an increased number of reimbursements for cardiovascular diseases, hormonal deficiencies, and epilepsy over a median of 18 years post‐transplant. This suggests premature cardiovascular aging, significant multimorbidity, and increased risk for decreased quality of life compared to population controls. The present study does not provide any guidance as to any interventions; however, it may help healthcare professionals to inform transplant recipients about potential future challenges. The data also indicate that meticulous lifelong follow‐up and support of young SOT recipients is warranted even after transition to adult care.
Author Contributions
Rebekka Salonen: data collection, data analysis/interpretation, drafting article, approval of article. Kira Endén: Concept/design, data collection, data analysis/interpretation, drafting article, approval of article. Kirsi Jahnukainen: Data analysis/interpretation, critical revision of article, approval of article. Atte Nikkilä: data analysis/interpretation, statistics, approval of article. Timo Jahnukainen: Concept/design, critical revision of article, approval of article, funding secured. Mikael Koskela: data analysis/interpretation, statistics, approval of article.
Conflicts of Interest
The other authors declare that they have no conflict of interest.
Supporting information
Table S1 ATC codes included in different drug purchase categories.Table S2 Frequency of prescription drug purchases in different solid organ transplantation groups
Acknowledgments
Open access publishing facilitated by Helsingin yliopisto, as part of the Wiley ‐ FinELib agreement.
Rebekka Salonen and Kira Endén equally contributed to this study.
Funding: This study was funded by the Foundation for Pediatric Research.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1 ATC codes included in different drug purchase categories.Table S2 Frequency of prescription drug purchases in different solid organ transplantation groups
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.