There is clear evidence from observational studies on the correlation between BP and cardiovascular morbidity, mortality, and graft function that posttransplant hypertension must be treated at least as it is in the general pediatric population. Most other issues related to treating hypertension in children after renal hypertension are less clear.
Which drug(s) should we use?
There are no studies comparing different classes of antihypertensive drugs in children after renal transplantation. Therefore, it is not known whether one class of drugs is better than another in transplanted patients. Historically, calcium-channel blockers (CCB) have been considered the drugs of choice for posttransplant hypertension because they counteract the afferent arteriolar vasoconstriction caused by calcineurin inhibitors and reduce their nephrotoxicity [
1,
75,
76]. Furthermore, in a double-blind randomized trial on adult patients, it was shown that after 2 years, long-acting nifedipine improved allograft function more effectively than did the ACE inhibitor lisinopril [
77]. However, one can still speculate as to whether or not the increased GFR induced by CCB will have detrimental long-term effects on allograft survival by increasing glomerular filtration due to predominant afferent arteriolar vasodilation. Longer randomized controlled trials are needed to answer this question.
There has been some concern that ACE inhibitors or angiotensin-receptor blockers (ARB) may deteriorate graft function in a case of graft-artery stenosis or due to the preferential efferent arteriolar vasodilation and reduction of intraglomerular pressure. However, it has been recently demonstrated that ACE inhibitors are safe and efficient in adult and pediatric transplanted patients [
78,
79]. Furthermore, ACE inhibitors and ARB can slow progression of chronic native kidney diseases in adults mainly by long-term reduction of intraglomerular pressure [
80]. Data on the renoprotective ability of ACE inhibitors in children are still lacking. The ability of ACE inhibitors to slow progression of chronic allograft nephropathy (CAN), which is the most common cause of late graft loss [
81], has never been proven in a prospective interventional trial on adult or pediatric patients. Some retrospective studies have shown promising results, such as stabilization or even an improvement in patient survival and graft function in patients with CAN [
79,
82,
83]. However, results from CTS published recently showed no improvement in patient or graft survival with ACE-inhibitor treatment [
84]. Therefore, this issue is still controversial and needs prospective interventional trials to be resolved.
Beta-blockers are also effective drugs in transplanted patients. Hausberg et al. showed that atenolol is an effective and safe antihypertensive drug in transplanted patients [
85]. However, beta-blockers are not able to reduce proteinuria as ACE inhibitors do. A further disadvantage of beta-blockers is their negative metabolic effects (increased lipid levels or impaired glucose tolerance), which may further contribute to the increased risk of cardiovascular disease in these patients.
Sodium retention is often present after renal transplantation, and therefore, diuretics are important antihypertensive drugs in these patients as well. Thiazide diuretics should be preferred in patients with normal graft function, whereas loop diuretics should be given in patients with impaired graft function. Diuretics may also have detrimental metabolic effects, such as hyperlipidemia, hyperuricemia, or hyperglycemia. Potassium-sparing diuretics are used rarely due their risk of hyperkalemia.
There are no data on the use of ARB in children after renal transplantation. However, in adults, there are several small, single-center studies showing that ARB can also be used in transplanted patients [
86].
All four major classes of antihypertensive drugs can therefore be used in transplanted patients. Posttransplant hypertension has a multifactorial etiology and is often severe; therefore, a combination therapy of two to three antihypertensive drugs is usually needed to control it. Which drug should be used as a first-line treatment remains the individual decision of the physician because it has not been consistently shown that one class is better than another in renal transplant recipients [
1,
76]. In most pediatric renal transplantation centers, the most commonly used antihypertensive drugs are CCB, which are given to 38–65% of transplanted children [
14,
24‐
26,
28,
29]. The second most commonly prescribed drugs are ACE inhibitors and beta-blockers. Diuretics are given less frequently. Data on the prescription of antihypertensive drugs in different pediatric studies are summarized in Table
2.
Table 2
Classes of antihypertensive drugs used in children after renal transplantation
| 76% | 62% | 33% | 5% | 21% | 0% |
| 49% | 49% | n.d. | 0% | n.d. | 0% |
Serdaroglu et al. 2005 [ 26] | 62% | 62% | 0% | 0% | 0% | 0% |
| 86% | 58% | 64% | 19% | 39% | 0% |
McGlothan et al. 2006 [ 29] | 59% | 38% | 23% | 24% | 0% | 3% |
Ferraris et al. 2007 [ 14] | 75% | 65% | 23% | 12% | 0% | 12% |
Nonpharmacological lifestyle measures (reduction of increased body weight, reduction of salt intake, physical activity) should be encouraged, even during antihypertensive drug therapy, as they target the risk factors not only for hypertension but also for cardiovascular morbidity and mortality (obesity, increased salt intake, physical inactivity).
What is the target BP in transplanted children?
What the target BP should be for patients after renal transplantation is still a matter of debate. The National Kidney Foundation Task Force on Cardiovascular Disease recommends a target BP level < 130/85 for adult renal allograft recipients and < 125/75 for proteinuric patients, similar to guidelines for hypertension management in patients with diabetic nephropathy [
87]. However, there are no prospective interventional trials showing that target BP lower than the conventional cutoff of 140/90 will improve graft function and long-term graft survival. The same is true for pediatric renal transplant recipients. Furthermore, there are no data demonstrating that, even in chronic native kidney diseases, more aggressive hypertension treatment can slow chronic renal insufficiency progression in children. The results of an ongoing European multicenter study [Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) trial] will answer this question. The current recommendation of the fourth report of the NHBPEP Working Group on High Blood Pressure in Children and Adolescents recommends target BP < 90th percentile for children with chronic kidney diseases [
11]. Although no such recommendation has yet been made for managing hypertension after renal transplantation, adoption of this target would seem logical [
88].
How is hypertension controlled in transplanted children?
Only a minority of children treated for hypertension after kidney transplantation have BP at least below the target level recommended for the healthy population, i.e. < 95th centile [
23,
26,
28]. Therefore, antihypertensive therapy in children after renal transplantation is insufficient, leading to poor BP control. The prevalence of persistent hypertension despite antihypertensive treatment (i.e. prevalence of uncontrolled hypertension) ranged between 45% and 82% in recent pediatric studies using ABPM [
21,
23,
25,
26,
28]. This means that only 18–55% of children after renal transplantation had hypertension controlled by drugs with BP at least < 95th centile. Data on hypertension control from several cross-sectional studies are summarized in Table
3. The reasons for the insufficient antihypertensive therapy in transplanted patients have not been thoroughly investigated. Many factors, such as chronic allograft dysfunction, need for lifelong use of BP-elevating immunosuppressive drugs (steroids, cyclosporine, tacrolimus), obesity, salt retention, renin secretion from diseased native kidneys, and the fear of ACE inhibitors in transplanted patients are discussed as the major reasons for inadequate BP control in transplanted patients [
1,
51]. However, there is increasing evidence from several recent studies that posttransplant hypertension is not truly therapy resistant but is not appropriately treated. In studies with a low number of prescribed antihypertensive drugs, there was a higher prevalence of uncontrolled hypertension [
14,
24‐
26,
28,
29] (Table
3). The results of a recent retrospective study on ACE inhibitors in children further emphasizes this concept [
79]. The authors could achieve adequate hypertension control in 100% of transplanted children 1 year after addition of an ACE inhibitor in patients with refractory hypertension using CBP measurement. Whether the use of ACE inhibitors can improve BP control in a prospective study still needs to be investigated. Current results on posttransplant hypertension control highlight a high potential for improved antihypertensive therapy in children after renal transplantation. The key issue is whether the poor hypertension control can be improved. A recent prospective interventional trial on intensified treatment of hypertension showed that ambulatory BP could be significantly reduced after 2 years by increasing the number of antihypertensive drugs, especially ACE inhibitors and diuretics [
71].
Table 3
Hypertension (HT) control in children after renal transplantation using ambulatory blood pressure monitoring (ABPM)
| Only daytime BP >95th centile for ambulatory BP despite use of drugs | 17 (63%) | 65% (11/17) | n.d. |
Giordano et al. 2000 [ 23] | Daytime, nighttime, or 24-h BP >95th centile despite use of drugs | 25 (68%) | 72% (18/25) | 1.5 |
| Daytime BP >95th centile for clinic BP or nighttime BP >95th centile for clinic BP minus 10% despite use of drugs | 22 (49%) | 82% (18/22) | 1.4 |
Serdaroglu et al. 2005 [ 26] | Daytime or nighttime BP >95th centile for ABPM and BP load >30% despite use of drugs | 16 (62%) | 81% (13/16) | 1.0 |
| Daytime or nighttime BP >95th centile despite use of drugs | 31 (86%) | 45% (14/31) | 2.1 |
Lastly, noncompliance can play an important role, particularly in adolescents. Therefore, adherence to the recommended antihypertensive drugs should be checked during every outpatient visit. Furthermore, home BP measurement should be encouraged, as it increases therapeutic compliance in hypertensive patients [
19].
Can improved BP control improve graft survival?
There is enough evidence from studies on adults and children to show that hypertension is associated with decreased graft function and subsequent shorter graft survival [
3,
5‐
7,
10,
73,
74]. However, it is still unclear whether posttransplant hypertension is a cause or only a marker of allograft dysfunction. Indirect evidence from recent retrospective studies demonstrates that increased BP is not only a marker but also a true cause of graft damage. Mitsnefes et al. have shown that hypertension was also associated with graft failure in children with well-preserved renal function, strongly suggesting, a causal relation between increased BP and poor graft survival [
10]. Furthermore, Mange et al. demonstrated that the effect of elevated BP on graft function was independent of baseline allograft function in predicting poor long-term allograft survival [
7]. Other studies have clearly shown that not “hypertension per se” (especially if defined only on the basis of the use of antihypertensive drugs) but the actual BP level (regardless of using antihypertensive drugs or not) is the decisive factor influencing graft function and survival [
30‐
32,
56]. Several observational studies have demonstrated that patients with controlled hypertension (i.e. normal actual BP in a patient on antihypertensive medication) have similar graft survival to patients with spontaneous normotension that is significantly better than in patients with uncontrolled hypertension [
30‐
32,
56]. However, there are no interventional studies on pediatric or adult patients showing that improved BP control in transplanted patients can improve graft survival. On the other hand, a recent retrospective study from the CTS demonstrated that improved BP control in the last seven years was independently associated with improved long-term graft survival [
89]. Further smaller retrospective studies provided clear evidence that not hypertension “per se” (defined often on the basis of the use antihypertensive drugs regardless of actual BP level) but the actual BP level is the decisive factor influencing graft function and graft survival regardless of whether normal BP level is achieved by antihypertensive drugs or is spontaneous [
31,
56]. These results provide a clinical rationale for rigorously controlling hypertension in transplanted patients. In a recent prospective interventional study on intensified hypertension control it was shown that hypertensive children in whom BP was lowered during a 2-year period of time to normotension had stable graft function, in contrast to children who remained hypertensive after 2 years and who lost significantly GFR [
71] (Fig.
3). This is the first prospective interventional study showing that the hypertension control in transplanted children can be improved and that improved BP control can stabilize graft function.
Can improved BP control improve patient survival?
It is well established that hypertension is a strong and independent risk factor for increased cardiovascular mortality seen in transplanted adult and pediatric patients [
4,
74,
90]. And whereas no prospective interventional studies have been conducted to test the hypothesis that hypertension treatment can decrease cardiovascular mortality in this specific patient population, the recent retrospective study from the CTS showed that improved BP control was associated with improved long-term patient survival [
89]. Patients whose systolic BP decreased from > 140 mmHg at 1 year to < 140 mmHg at 3 years posttransplant had a significantly lower risk of cardiovascular death than did patients whose systolic BP remained > 140 mmHg. These data, although derived retrospectively, are the most convincing to date and suggest that BP control, even if instituted late after renal transplantation, improves cardiovascular and graft outcome. The observed improvements in long-term graft survival and patient survival associated with improved hypertension treatment underline the potential value of aggressive hypertension control in all transplanted patients, even late after transplantation.