Abbreviations 1 INTRODUCTION

Arterial hypertension is a very common and serious complication in both adult and pediatric kidney transplant recipients.1-4 It is an established risk factor for cardiovascular disease (CVD) morbidity and mortality as well as for impaired graft survival in transplanted patients.5-11 Therefore, office blood pressure (OBP) must be measured during every outpatient visit of a transplanted child according to the recommendations of the 2017 American Academy of Pediatrics Clinical Practice Guidelines or the 2021 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.12, 13 However, in the last two decades, it has become clear that 24-h ambulatory blood pressure monitoring (ABPM) is a better diagnostic tool for post-transplant hypertension compared to OBP because ABPM has the ability to detect white-coat hypertension, masked hypertension, and nocturnal hypertension, which are common phenomena among transplanted children. Isolated nocturnal hypertension (INH), a sub-type of nocturnal hypertension, is recognized to be a CVD risk factor in pediatric kidney transplant recipients. The purpose of this review is to highlight the epidemiology, risk factors, and treatment of INH in the context of pediatric kidney transplantation (KTx).

2 DEFINITION OF INH

Isolated nocturnal hypertension was first described in 2007 by Li et al. in a general adult population study.14 It is defined as nighttime hypertension in the setting of normal daytime blood pressure (BP). Specifically, INH is diagnosed when mean nocturnal systolic and/or diastolic BP are ≥95th percentile for age and height with normal mean daytime systolic and diastolic BP (<95th percentile for age and height) on 24-h ABPM.15 Most studies do not take into account the result of OBP. If OBP is normal, INH is a subgroup of masked hypertension (masked isolated nocturnal hypertension). If OBP is elevated but mean daytime BP on ABPM is normal, isolated nocturnal hypertension can be regarded as a nighttime part of masked hypertension (Figure 1).

Definitions of different types of hypertensions according to office BP in combination with daytime and nocturnal ambulatory BP

Normal BP patterns follow circadian rhythms to be lower in the nighttime and higher during the daytime. Most individuals experience a 10%–20% drop in BP at night; these people are considered “dippers.” Individuals who have a drop in BP of less than 10% are “non-dippers.” INH is associated with a “non-dipping” phenomenon. Individuals with rising BP overnight are considered “reverse dippers”.16 The non-dipper phenomenon indicates that there is dysregulation of BP cycles over a 24-h period.

3 PREVALENCE OF INH

In adults, the prevalence of INH has been reported to be between 4% and 20% in the general population and in patients with diabetes and chronic kidney disease (CKD).17-19 The highest prevalence of INH in adults is reported in CKD patients (20%).19 In adults with CKD after KTx, the prevalence of INH is even higher than in non-transplanted CKD patients, reaching 30%.20 Nocturnal hypertension is far more prevalent than daytime hypertension.21, 22

In children, the prevalence of INH has never been prospectively studied in the general population. Therefore, the European Society of Hypertension (ESH) stated in its current guidelines that INH is a topic for future research to refine its clinical significance in children.23 In several retrospective studies, it has been shown that 11%–51% of children with CKD without kidney failure, children with diabetes, obesity, obstructive sleep apnea syndrome, systemic lupus erythematosus, and children born preterm with intrauterine growth retardation have INH.24-31 In the 4C study (Cardiovascular Comorbidity in Children with Chronic kidney disease), which is large multicenter longitudinal observational study investigating cardiovascular comorbidity in children with CKD such as LVH or carotid intima-media thickness, INH was present in 13% of children with CKD stages 2–5.32 In the CKiD study, nocturnal hypertension was more common than daytime hypertension in children with CKD.33

Similar to adults, the prevalence of INH is even higher in children after KTx than in CKD-non KTx children. Several studies on ABPM and INH in pediatric kidney transplant recipients have been published which showed that INH is present in an average 33% of children after KTx.34-37

In one of the first studies on ambulatory hypertension in pediatric kidney transplant recipients, Matteucci et al showed that INH is present in 29% of their patients.38 Interestingly, no child had isolated daytime hypertension. In the next 20 years, several other authors demonstrated a similarly high prevalence of INH in kidney transplant patients. McGlothan et al titled their paper in 2006 “Predominance of nocturnal hypertension in allograft recipients” to underscore the high prevalence of INH being with 41% the most common type of hypertension in their cohort.39 In a retrospective study done in our single center, we demonstrated a prevalence of 36% for INH and again no isolated daytime hypertension. A similar lack of isolated daytime hypertension has been shown in many other studies,35, 40-45 indicating that nocturnal hypertension is present in transplanted children, either as INH or combined daytime-nighttime hypertension (Table 1).

TABLE 1. Prevalence of isolated nocturnal hypertension (INH) in children after kidney transplantation. Summary of current literature Author [reference] Definition of HT Overall prevalence of HT (n) Prevalence of isolated nighttime hypertension Prevalence of isolated daytime hypertension Non-dipping (definition) systolic/diastolic dip Other findings Matteucci et al. 1999 [36] Any value >95th percentile regardless of drugs 36% (n = 10/28) 29% (most common form of HT) 0% n.d. systolic dip 3% diastolic dip 10% Mean 24-h systolic BP correlates with LVMI Morgan et al. 2001 [40] Daytime BP >95th centile for clinic BP or nighttime BP >95th centile for clinic BP minus 10% regardless of drugs 64% (n = 29/45) 22% 0% 58% (<10% systolic or diastolic dip) 9%/14% No significant relationship between ABPM data and LVM Seeman et al. 2006 [42] Daytime or nighttime BP ≥95th centile or use of drugs 89% (n = 32/36) 40% 0% 64% (<10% systolic or diastolic dip) 7%/13% Better control of HT with ACEI and lower CyA/Tac dose/level McGlothan et al. 2006 [37] 24-h, daytime, and nighttime mean BP >95th percentile or systolic load >35% and diastolic load >25% regardless of drugs 21/7% for daytime syst./diast. HT (n = 6/2 of 29) 48/41% for nighttime syst./diast. HT 41% (most common form of HT) n.d.

60% for systolic

37% for diastolic

(<10% syst. or diast. dip)

40% for systolic

30% for diastolic

(<5.5%)

8%/9%

Isolated nocturnal HT is more common than daytime HT, children on ACEI/ARB had lower systolic BP than on CCB Ferraris et al. 2007 [39] Daytime or nighttime BP >95th centile regardless of drugs (only treated children) n.a. (only treated hypertensive children) 38% 0%

36% (<7% systolic or <14% diastolic dip)

n.d.

Office BP readings miss a substantial number of hypertensive by ABPM criteria Paripovic et al. 2010 [41] Daytime or nighttime BP ≥95th centile regardless of drugs 44% (n = 18/41) 36% (most common form of HT) 0% 71% (<10% systolic or diastolic dip) 6%/12% Hidden (masked) uncontrolled daytime HT in 21% of treated children Tangeraas et al. 2010 [43] Daytime or nighttime BP ≥95th centile or use of drugs 73% (n = 16/22) 16% 0%

79% (<10% systolic or diastolic dip)

n.d.

Children with metabolic risk factors incl. HT have lower cardiorespiratory fitness Basiratnia et al. 2011 [38] Daytime or nighttime BP ≥95th centile or use of drugs 76% (n = 33/66) 25% 0%

73% (<10% systolic or diastolic dip)

n.d.

Inverse correlation between ABP and time after Tx, ABPM parameters correlate with LVMI Gülhan et al 2014 [34] Daytime or nighttime BP ≥95th centile or use of drugs 93% (n = 27/29) 24% 7% 55% (<10% systolic or diastolic dip) 8%/11% Pts with alternate-day steroids had lower nocturnal and 24-h BP Bulum et al 2015 [35] Daytime or nighttime BP >95th centile or use of drugs 88% (n = 21/24) 29% 0% 67% (<10% systolic or diastolic dip) 7%/8% Predominance of nocturnal hypertension Pais et al. 2020 [21] Daytime or nighttime BP ≥95th centile or use of drugs 83% (n = 24/30) 43% (most common form of HT) n.d. 83% (<10% systolic or diastolic dip) 5%/7% Prednisone dose predicted nocturnal diastolic BP and ambulatory BP improved on long-term follow-up but the pattern of INH persisted Median values from all studies n.a. 76%

29%

0%

66% (for all definitions) 6% 12% n.a. Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; BP, blood pressure; CCB, calcium channel blockers; CyA, cyclosporine A; HT, hypertension; LVMI, left ventricular mass index, n.a., not applicable; n.d., not determined; Tac, tacrolimus; Tx, transplantation.

The reproducibility of INH on ABPM in adults was shown in one study to be poor (kappa 0.21), suggesting that the diagnosis of INH should not be based off of one ABPM study.46 The reproducibility of INH in children has never been investigated.

4 ASSOCIATION OF INH WITH CARDIOVASCULAR AND KIDNEY OUTCOMES

INH is associated with increased CVD morbidity and mortality and with an increased prevalence of hypertension-mediated organ damage (HMOD) such as left ventricular hypertrophy (LVH), arterial stiffness, and CKD in adults.14, 47, 48 Nighttime BP and the nocturnal dip, but not OBP, are also independently associated with atherosclerosis (intima-media thickness, IMT).21 Therefore, nocturnal BP may provide unique information for the assessment of CVD risk attributable to elevated BP in kidney transplant recipients.21

Our group reported that in children without advanced CKD, the INH phenotype was associated with increased left ventricular mass index (LVMI) and LVH, similar to those with isolated daytime hypertension.49 Furthermore, in the 4C study, similar to adults, INH was associated with altered cardiovascular morphology and function such as LVH, arterial stiffness of increased carotid intima-media thickness.32

The importance of nocturnal BP in transplanted patients is stressed by its stronger correlation with left ventricular mass than daytime BP. In the largest retrospective study on ABPM in children after KTx, Hamdani et al demonstrated that abnormal BP, mainly masked nocturnal hypertension, was an independent predictor of LVH among patients not receiving anti-hypertensive treatment.50 In a recent study, Pais et al showed that LVMI was directly related to nocturnal BP index while there was a lack of association between LVMI and daytime BP index and OBP.22 Furthermore, LVH was present only in hypertensive children, of which 43% had isolated nocturnal hypertension.

Moreover, in adult transplant recipients, it has been shown that nocturnal BP, but not OBP, correlated negatively with graft function at 1-year post-transplant, suggesting that nocturnal hypertension plays an important role in predicting poor kidney transplant outcomes.51 The non-dipping phenomenon has been shown to be more strongly associated with lower renal allograft dysfunction than daytime hypertension.52 In children, no study has found an association of nocturnal BP with long-term graft function. However, in diabetic children, nocturnal hypertension has been associated with development of microalbuminuria in the long term, indicating the nephrotoxic effect of nocturnal hypertension at least in children with diabetes.53 Further studies are needed to determine whether the same is true also for children after KTx.

5 RISK FACTORS FOR INH

The risk factors associated with INH can be divided in three groups: (1) disease-associated, (2) medication-associated, and (3) patient-associated.

5.1 Disease-associated risk factors

Among the disease-associated factors, the most important reported in adults are older age, higher serum cholesterol and glucose, sleep disorders such as obstructive sleep apnea syndrome (OSAS), CKD, increased arterial stiffness, and lower 24-h urinary sodium excretion.14 Blunted sodium urinary excretion or increased dietary sodium intake are currently the most plausible hypotheses for the pathophysiology of INH.18, 54-56 Moreover, diuretics that improve sodium retention have been shown to decrease nocturnal BP more than daytime and to restore nocturnal BP dip.57

In children, OSAS, obesity, diabetes mellitus, prematurity, low birth weight, and CKD with decreased renal function were shown to be associated with INH.24-30, 54, 58, 59 OSAS directly disturbs sleep quality during the night; however, the other risk factors of INH are mainly associated with sodium retention similar to the adults.

5.2 Medication-associated risk factors

The medications that are often associated with IHN are steroids and calcineurin inhibitors (CNIs). Steroids are well-known medications that are associated with nocturnal hypertension. Pais et al have found that prednisone dose predicted nocturnal DPB in pediatric renal transplant recipients.22 Furthermore, in another study, steroid withdrawal was associated with improved nocturnal BP.60 Van den Dorpel et al have shown that cyclosporin A (CyA) increases nocturnal BP and impairs nocturnal BP dip in transplant patients.61 These observed BP changes were associated with elevated plasma atrial natriuretic peptide and suppressed plasma renin concentrations, suggesting that intravascular volume expansion with sodium retention may contribute to the CyA-induced elevation of nocturnal BP. Similar reduced nocturnal BP dip has been shown in tacrolimus-treated transplant patients.62

5.3 Patient-associated risk factors

Sleep disturbances have been shown to increase the risk of nocturnal hypertension.63 For this purpose, our group asks patients to answer a simple question along with the 24-h activity protocol, “How did you sleep during the ABPM? very well – well – not well – bad – very bad.” With this question, we have been able to rule out severe sleep disturbances during ABPM that can produce falsely elevated nocturnal BP. Poor sleep during the night must be excluded before diagnosing a patient with INH. In pediatric CKD patients, the obstructive apnea-hypopnea-index, a marker for obstructive sleep apnea syndrome, was strongly correlated with nighttime (but not daytime) BP.64 Furthermore, the night shift workers in adults have higher BP levels at night (but not during sleep) than during daytime.56, 65 The SHIP-AHOY (Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth) investigators have shown worse tolerability of ABPM in 17% children during wake period and in 25% of children during sleep period and the ABPM intolerance during wake (but not sleep) hours was independently associated with wake ambulatory hypertension.66

The factors that have been shown to be associated with increased risk of INH are depicted in Figure 2.

Summary of factors that have been shown to be associated with increased risk of INH

6 TREATMENT OF INH 6.1 Should we treat INH and non-dipping?

There is evidence to show that INH and non-dipping are correlated with an increase in risk for CVD and destabilization of kidney grafts in transplant patients in adults.67 The 2017 Clinical Practice Guidelines by the American Academy of Pediatrics and the 2016 European Society of Hypertension guidelines emphasize the importance of managing hypertension in pediatric transplant patients.12, 23 Given that INH and non-dipper status are modifiable risk factors for CVD morbidity and mortality, optimization of anti-hypertensive therapy to normalize circadian variation in BP is a valuable therapeutic target. While there is less research on children, we can use some of the conclusions from adult research to hypothesize the importance of addressing INH and non-dipping in children. Attenuation of nocturnal BP with chronotherapy has been shown to reduce the risk of CVD events, CKD, LVMI, and diabetes mellitus in adults.15, 68-70 However, it is critical to mention here that there are no studies of chronotherapy in adult transplant patients. By compiling the conclusions of research in related populations, we can hypothesize that treating non-dipping BP in transplanted children is a valuable treatment avenue.

6.2 Which drug should we use?

In a recent review comparing the effects of calcium channel blockers (CCB) with angiotensin-converting enzyme inhibitors (ACEI), we concluded that CCB was the preferable choice for first line of treatment in post-transplant adults and children.49 While the long-term effects have not yet been extensively studied, CCB treatment was associated with improvement in graft function in the studies that were reviewed. However, randomized, control studies have yet to be conducted comparing the two treatments in children. Generally, retrospective studies have indicated that CCB and ACEI have positive effects on graft survival and kidney function in post-transplant children. In our review of meta-analyses, it was found that CCB improves graft survival and decreases BP to a greater extent than ACEI.49 However, ACEI has been shown to decrease proteinuria more effectively. Common medications for transplant patients can interact with ACEI to cause hyperkalemia; for this reason, doctors may choose to prescribe CCB. We suggest that the choice of drug should be tailored to the individual case, but we recommend that CCB should be used as the first-line therapy in transplanted children without proteinuria or albuminuria. ACEI should be used in children with persistent proteinuria or albuminuria. However, ACEI should be avoided in the days immediately post-transplant, as ACEI has the potential to impair graft function, induce hyperkalemia, and aggravate anemia. In the time shortly after transplant, ACEI can be less effective in addressing volume- and sodium-dependent elevated BP. The use of combination therapy has been suggested for adults with persistent high BP, but more research is needed to determine the efficacy of this treatment in children post-transplant.12

6.3 Which time should the drug be administered (chronotherapy)?

Research has been developing surrounding the relationship between kidney function and circadian rhythms. RNAseq analysis of mouse tissue revealed that the kidney is second to the liver in terms of the number of genes expressed in a circadian pattern.71 Additional research has demonstrated that aldosterone, the regulator of the kidney's sodium balance, controls the epithelial sodium channel via the core clock gene, Period 1.72 These genetic discoveries have pointed to important mechanisms in the kidney that rely on circadian patterns.68 Subsequently, there has been research conducted to determine whether treating with medication at different times of the day can impact the 24-h cycle of BP. Chronotherapy is the practice of administering medications in synchrony with circadian patterns in order to maximize health benefit while minimizing adverse effects. Chronotherapy of hypertension can be accomplished by the specific timing of conventional anti-hypertensive medications based on individual needs. For those with INH and non-dipping status, evening administration of BP medications may be ideal.67 Without large scale studies in pediatric chronotherapy for hypertension, evidence of adults successfully treating INH can guide treatment for pediatric transplant patients. In randomized control studies of varying sizes, treating with 1 or more hypertension medications before bed was associated with decreased nighttime BP.73, 74 A meta-analysis comparing 5 clinical trials of evening BP medication administration with 170 clinical trials of morning dosing reported a 48% reduction in relative risk of adverse CVD events in the evening group.75 The results of these studies also reported lower risk of CVD in some cases for patients receiving medication before bed. The extent of causation in these cases requires further research, but preliminary data indicate that administration of hypertension medication before bed can improve nocturnal hypertensive status in pediatric transplant patients by inducing normal BP dipping during sleep. The effect of nocturnal hypertension on CV health in the pediatric literature is limited.

A pilot study that we conducted found that nighttime administration of hypertension medication restored dipper status in pediatric kidney transplant recipients with no effect on target organ damage markers.76 Pediatric kidney transplant non-dippers with normal daytime BP received a new evening BP medication (enalapril or isradipine, N = 17) or control (no medication changes, N = 16) in an open-label randomized controlled trial. Conversion to dipper status occurred in 53% vs. 8% (p = 0.02) at 6 months for intervention vs. controls. Systolic dipping was greater, and nocturnal SBP was lower in the intervention group compared to controls at 6 months (Figure 3). In the intervention group, nocturnal SBP at 6 months was lower compared to baseline.

Changes of nocturnal BP and non-dipper status during evening dosing of anti-hypertensive drugs in pediatric kidney transplant recipients (adapted from Sethna et al. 2019)76

The association of nocturnal BP dysregulation with CV target organ damage over time has not been analyzed in a pediatric study. Using the adult literature and limited pediatric literature, we suggest that administering BP medication in the evening could be an option for pediatric transplant patients with INH. However, more research should be conducted to analyze the effects on target organ damage.

6.4 What is the nocturnal target BP in transplanted children?

There are currently no published guidelines for target BP in transplanted children.13 Therefore, the targets used for CKD patients are extrapolated and used for kidney transplant patients. The current clinical guidelines state that children and adolescents with CKD and HTN should be treated to lower 24-h MAP to <50th percentile by ABPM.67 However, in our first randomized controlled study on the strict control of BP pediatric kidney transplant recipients (ESCORT trial), we could not demonstrate any improvement in graft function during 3 years in children with a strict target 24-h MAP <50th percentile in comparison with children with a standard 24-h MAP between 50th and 95th percentile.77 This strict target BP could be used for transplanted children, but there is still some debate regarding how low becomes dangerous to target for pediatric BP. In young kidney transplant children with a greater misalignment of cardiac output and nephron mass, these low BP targets might not be as safe.78 However, in the ESCORT trial, no serious adverse effects were seen in the group with target BP <50th percentile during the 3-year study. There is still more research to be conducted to determine whether decreasing BP to these levels will decrease blood flow to the kidney and cause secondary negative long-term effects beyond 3 years.

6.5 How often do treated patients have normalized INH after change of therapy?

There is limited research on INH in children after kidney transplant. However, the research conducted in adults shows that there is a decrease in nocturnal BP dipping post-transplant. Many adults suffer from INH post-transplant and struggle to control BP post-transplant. Anywhere from 50% to 80% of adults will not have controlled BP within 1 year following transplant, this includes nocturnal and diurnal BP control.76, 79

The extent to which treatment for INH is effective has not been well described, but the use of ACEI has been questioned after outcomes were not significantly better for patients taking ACEI post-transplant.80 Additionally, research has shown that there may be a link between INH and treatment-resistant HTN. Irvin et al found that adults with apparent treatment-resistant hypertension (aTRH) were 1.2 times more likely to have INH than patients with hypertension that was not treatment-resistant. Additionally, aTRH was associated with higher prevalence of non-dipping status.81 These associations raise concern about the ability to control INH in patients with aTRH. For patients with aTRH, chronotherapy may not change the outcome of their INH treatment, because they are resistant to any treatment for HTN. However, this study was conducted in adults, and more information is needed to determine its relevance to pediatric transplant patients specifically.

In pediatric patients, one study used ABPM results from CKD patients to show that masked hypertension increases over time for pediatric CKD patients.82 The study demonstrated that despite publication of hypertension recommendations for children, hypertension continues to go undiagnosed and undertreated in children.82 The prevalence of treatment-controlled INH in pediatric transplant patients is not well described in the literature, but it is likely similar to the prevalence of controlled of total hypertension, which is only 50%.35 However, there is research to support that INH is a prevalent problem in all transplant patients and that hypertension is under-diagnosed in many pediatric transplant patients. More research must be conducted to determine whether changing the course of treatment for the patient can normalize INH.

6.6 Can normalization of INH improve hypertension-mediated organ damage?

Most research on INH has involved adult patients, and we have used this information to make conclusions about pediatric patients. There is evidence that INH can cause hypertension-mediated target organ damage. This damage can be in the form of LVH, increased carotid intima-media thickness or arterial stiffness, and decreased GFR.32, 69, 83 Some studies have indicated that treating INH can prevent progression of target organ damage in adults.72 In pediatric patients, we conducted a study to treat nocturnal hypertension using chronotherapy. While nocturnal hypertension decreased, the study was not powered to determine whether treating INH affected outcomes in target organ damage. Preliminary results seemed to indicate a decrease in LVMI and improvement in GFR in patients receiving hypertension medication at night.76 However, in order to understand the causal relationship between INH and target organ damage in pediatric patients, larger studies are needed. A small single-center retrospective longitudinal study has shown that the ABPM-guided therapy of hypertension in pediatric kidney transplant patients has shown a significant decrease in LVMI with substantial decrease in LVH from 27% to 5%.84

7 MONITORING OF PEDIATRIC KIDNEY TRANSPLANT RECIPIENTS WITH INH

Isolated nocturnal hypertension can only be definitively diagnosed by ABPM, and the condition is best monitored by ABPM. Since the non-dipping or reverse dipping phenomenon cannot be measured by clinical BP monitoring alone, ABPM is the most effective for measuring INH status. However, studies have recently shown that home BP monitoring is also a viable option for tracking the progress of BP during the night in adults.67, 85 ABPM should be used when INH is diagnosed, and we suggest that either ABPM or maybe home BP monitoring continue to be used to record the progress of treatment for the patient. It is not possible to determine whether the treatment plan for the patient is having a positive effect on INH status unless nighttime BP is measured in some way. Once the patient is stabilized in their treatment plan, we suggest that ABPM be used annually.

Hypertension is common in children after any solid organ transplants, and it has been demonstrated that hypertension rates are higher in 24-h ABPM assessments than in clinical BP measurements.86, 87 This is likely due to the prevalence of INH in transplant patients. The current clinical practice guidelines state that annual ABPM is appropriate for children with CKD.67 While there are not specific recommendations for ABPM use in pediatric transplant patients, we consider the recommendations for CKD patients to be appropriate also for children after kidney transplantation. Monitoring transplant patients, who are at a higher risk for hypertension, using ABPM in conjunction with regular clinic or home BP measurements, has been shown to be effective in decreasing BP and uncontrolled hypertension over time. This result was in part due to treating hypertension as it was diagnosed during transplant follow-up.86 The decrease in hypertension over time could also have been a result of stabilization in transplant patients as they recover from transplant. For this reason, it could be hypothesized that more frequent ABPM monitoring could be useful in the early stages post-transplant. In the first year following kidney transplant, conducting ABPM every 4 to 6 months could help to more closely monitor the changes in BP cycles during the recovery. As hypertensive status stabilizes over time, annual ABPM should be conducted.88 It has also been shown that ABPM results have a stronger correlation with hypertension-mediated target organ damage than office BP measurement in adults.15 Monitoring possible masked or (isolated)