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Hypertension after kidney transplantation
Dobrowolski, L.C.
Publication date
2016
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Final published version
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Citation for published version (APA):
Dobrowolski, L. C. (2016). Hypertension after kidney transplantation.
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Hypertension after Kidney Transplantation
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Linn Charlotte Dobrowolski
HYPERTENSION AFTER
KIDNEY TRANSPLANTATION
PhD thesis, University of Amsterdam, The Netherlands ISBN: 978–94–6169–975-6
Online: http://dare.uva.nl
© 2016 Linn Charlotte Dobrowolski, Amsterdam, The Netherlands
All rights reserved. No part of this thesis may be reproduced, stored or transmitted in any form or by any means without prior permission of the author.
Cover design: Magnolia Branch with Four Flowers, anonymous, 1910-1925 (X-ray, gelatin silver print) Rijksmuseum Amsterdam
Lay-out: Myrthe Yeh, Linn Dobrowolski Paranymphs: Sofie Jansen, Sophie Jutte
Printed by: Optima Grafische Communicatie B.V. Rotterdam
The studies presented in this thesis have been prepared and conducted at the Department of Internal Medicine, division of Nephrology and Kidney Transplantation, Academic Medical Center at the University of Amsterdam, The Netherlands and partly at the Department of Internal Medicine, division of Nephrology and Kidney Transplantation at the University of Groningen, The Netherlands.
The Dutch Kidney Foundation (Innovation Grant IP-11.40) financially supported the research published in this thesis, which is gratefully acknowledged.
Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged.
Financial support for the printing of this thesis was gratefully received from the Academic Medical Center Amsterdam.
Further financial support for the printing of this thesis was kindly provided by Astellas Pharma B.V, Chiesi Pharmaceuticals B.V., Chipsoft B.V. and Shire Pharmaceuticals Plc.
ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor
aan de Universiteit van Amsterdam op gezag van de Rector Magnificus
prof. dr. ir. K.I.J. Maex
ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Aula der Universiteit
op woensdag 7 december 2016, te 11.00 uur
door
Linn Charlotte Dobrowolski geboren te Rotterdam
Promotores: Prof. dr. R.J.M. ten Berge Universiteit van Amsterdam Prof. dr. F.J. Bemelman Universiteit van Amsterdam Co-promotor: Dr. C.T.P. Krediet Universiteit van Amsterdam Overige leden: Prof. dr. T. van Gelder Erasmus Universiteit Rotterdam
Prof. dr. J. Booij Universiteit van Amsterdam Prof. dr. G. Navis Rijksuniversiteit Groningen Prof. dr. J.J. Homan van der Heide Universiteit van Amsterdam Prof. dr. E.S.G. Stroes Universiteit van Amsterdam Dr. P.J. Blankestijn Universiteit Utrecht
You are bound to be successful, bound to be successful. S.N. Goenka
123I-mIBG 123I-meta-Iodobenzylguanidine
ABPM ambulatory blood pressure measurement ACEi angiotensin converting enzyme inhibitor ARB angiotensin II receptor blocker
BP blood pressure CKD chronic kidney disease CNI calcineurin inhibitor
CTS Collaborative Transplant Study CVD cardiovascular disease
eGFR estimated glomerular filtration rate ESRD end stage renal disease
HTN hypertension IQR interquartile range
KDIGO kidney disease improving global outcomes KTR kidney transplant recipient
MDRD modification of diet in renal disease MSNA muscle sympathetic nerve activity NE norepinephrine
NOTR Netherlands Organ Transplantation Registry ODT once day prolonged release tacrolimus p.i. post-injection
PRA plasma renin activity
RAAS renin-angiotensin-aldosterone system
RDN catheter-based renal sympathetic denervation RHT resistant hypertension
RICH-Q Renal Insufficiency Therapy in Children: Quality Assessment and Improvement ROI region of interest
SNA sympathetic nerve activity
SPECT single photon emission computed tomography TDT twice day tacrolimus
Chapter 1 General introduction and outline of the thesis 9 Chapter 2 Treatment efficacy of hypertension in kidney transplant
recipients in The Netherlands
29
Chapter 3 Epidemiology and management of hypertension in paediatric and young adult kidney transplant recipients in The Netherlands
41
Chapter 4 Effects of dietary sodium restriction in kidney transplant recipients treated with renin-angiotensin-aldosterone system blockade: a randomized clinical trial
59
Chapter 5 Blood pressure dipping in kidney transplant recipients on regular and prolonged release tacrolimus
77
Chapter 6 Kidney transplant ¹²³I-mIBG scintigraphy and functional sympathetic reinnervation
89
Chapter 7 Renal sympathetic nerve activity after catheter-based renal denervation.
103
Chapter 8 Renal denervation for drug-resistant hypertension after kidney transplantation
119
Chapter 9 General discussion and perspectives 128
Summary of the thesis 131
Samenvatting (Dutch summary) 134
Appendices Supplementary documents 140
Portfolio 142
Bibliography 144
Curriculum Vitae 145
Linn C. Dobrowolski, Frederike J. Bemelman,
Ineke J. ten Berge, C.T. Paul Krediet
CHAPTER 1
GENERAL INTRODUCTION AND
OUTLINE OF THE THESIS
GENERAL INTRODUCTION Kidney transplantation
Epidemiology and survival rates
Since the first kidney transplantation in 1950 and the introduction of robust immunosuppressive regimens in the 1970s, kidney transplantation has evolved as the most durable and quality of life improving renal replacement modality. Five-year survival probability for a kidney transplant recipient (KTR) is 86.8%, compared to 53% for a patient on dialysis (Figure 1a).1 The expected unadjusted remaining lifetime for
a 40 year old patient on dialysis is 11.5 years, compared to 25.5 years of a transplant recipient (Figure 1b).1
Successful transplantation results from various partially modifiable factors, including surgical techniques, donor characteristics and effective immunosuppression.2
Post-transplant complications involve predominantly manifestation of cardiovascular disease (CVD), allograft rejection, infections attributable to compromised immune status and development of malignancies.
Most kidney transplant recipients die with a functioning allograft, i.e. without returning to dialysis and the main cause of death of KTRs is of cardiovascular disease.3-6 But
non-fatal cardiovascular disease is also highly prevalent in kidney transplant recipients (Figure 1c). Both fatal and non-fatal cardiovascular disease such as ischemic heart disease and stroke in KTRs are intertwined with transplant related factors such as allograft and donor characteristics and comorbid conditions.
Cardiovascular disease and hypertension after transplantation
Adult KTRs have an annual 50-fold increased risk for a cardiovascular event compared to the general population.7 In pediatric KTRs the risk of dying from a CVD event is also
40 times higher than in their healthy peers.8 CVD accounts for approximately 36% of
deaths in kidney transplant recipients.
Hypertension and graft loss and mortality
There is convincing (i.e. grade Ia) evidence that blood pressure (BP) reduction substantially decreases the risk for CVD events and death including coronary events, stroke, heart failure and end stage renal disease (ESRD) in the general population.9-13 For KTRs no
such level of evidence is available but observational data suggest that lowering blood pressure in hypertensive KTRs improves graft survival and lowers patients mortality.14
Landmark data from Opelz and colleagues show a strong association between BP and both graft and recipient survival (Figure 1d).15 Any 10 mmHg increase in systolic
BP is associated with a risk of graft failure up to 15%.16 Also, patient survival rates
are superior in patients without hypertension: each 10 mmHg rise in systolic blood pressure > 140 mmHg, is associated with a hazard ratio of 1.18 (95% CI 1.12 to 1.23) even after adjustment for allograft function.15-17
These data also suggest that the damage to the allograft caused by prolonged elevated BP is partially reversible. Graft survival improved in patients with high systolic blood pressure (SBP) at 1 and 3 years and a normalised SBP (< 140 mmHg) at year 5, compared to patients who remained hypertensive in the 1st, 3rd and in the 5th year after
transplantation. Lowering BP can provide significant benefits for graft and patient survival even several years after transplantation, which stresses the importance of BP control.18
Randomized controlled intervention studies in kidney transplant recipients that assess the effect of BP control, various BP targets or different antihypertensive regimens are scarce. Therefore, extrapolation of data from randomised trials on the effects of hypertension on CVD in chronic kidney disease (CKD), combined with data for large observational studies (KTR database cohorts) provides the rational for strict blood pressure control in the transplant population.15,18
Figure 1. Figure 1a: Survival by modality. European cohort 2003-2007 ERA EDTA Rep 2012).
All = transplantation and dialysis patients, Figure 1b: Life expectancy, Figure 1c: Mortality rate by cause of death, Figure 1d: Graft survival (data from Opelz et al. Kidney Int 1998).1,6,15
Definitions of hypertension and blood pressure targets after kidney transplantation
Definition of hypertension and blood pressure targets
For the general population < 60 years, adults with diabetes as well as adults with non-diabetic chronic kidney disease, hypertension is defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg. Blood pressure goals in adults > 60 years are < 150/90 mmHg.9,19 For children < 18 years, BP ≥ 95th percentile for gender, age and height
is regarded as hypertension. For kidney transplant recipients, BP target is defined at < 130/80 mmHg by the guidelines of the Kidney Disease: Improving Global Outcomes (KDIGO) because they are classified in the high-risk for CVD. For children, guidelines vary between BP thresholds of p90 and p95.14,20,21
‘Resistant hypertension’ is the term to indicate failure to reach BP targets despite the use at minimum three different antihypertensive agents, including a diuretic.22 Although
many patients seem to meet this condition, by far the most patients have secondary hypertension or are incompliant to medication or lifestyle changes.22-24 ‘Apparent
resistant hypertension’ is therefore the preferred wording. Also, rare causes of secondary hypertension should not be overlooked: Figure 2 shows a rare but treatable cause of treatment resistant hypertension in a KTR.25
Diagnosis
Diagnosing hypertension using home BP measurement or ambulatory BP monitoring (ABPM) is preferred since reliance exclusively on office-based BP measurements would result in under- or overestimation of KTRs with hypertension.26-28 BP self-measurements
can improve adherence. ABPM offers 24 hour registrations and is required when ‘white coat’ hypertension, drug resistance, symptomatic hypotension during antihypertensive therapy, or autonomic dysfunction is suspected.9
Nocturnal blood pressure
In the treatment of hypertension, nocturnal blood pressure is also of importance. Blood pressure falls with > 10% during night-time. However, as a result of altered circadian regulation, the absence of a nocturnal drop, so-called 'non-dipping', is common amongst ESRD and renal transplant patients.27,29,30 A non-dipping pattern
is an additional, independent risk factor for CVD and all-cause mortality in essential hypertensives, ESRD patients and KTRs.27,31-34 In the long term, successful transplantation
can significantly improve circadian BP profiles.35
Prevalence of post-transplant hypertension
Due to the heterogeneity in literature of definitions for hypertension in kidney transplant recipients, its true prevalence can only be estimated. Nevertheless, hypertension is observed in the majority of kidney transplant recipients and BP control rates are low. Overall prevalence in adults reaches up to 85%.16,36,37 Only 8% of patients treated with
are derived from research dated more than 20 years ago.15 Of the paediatric transplant
recipients, approximately 60-70% meet hypertension criteria.21,38-40
Pathophysiology of hypertension after kidney transplantation
Factors contributing to the pathophysiology of hypertension as well as traditional factors for hypertension are listed in Table 1. During the progression of CKD, nephrogenic factors, atherosclerosis and/or arteriosclerosis cause the increase in arterial stiffness and contribute to hypertension.41,42 The increased arterial stiffness is largely irreversible
and although transplantation prevents progression, the KTR maintains this vascular status.43,44 The allograft factors and effects of immunosuppressive agents are additional
contributing hypertension inducing factors in KTRs. Hypertension occurring in the peri-operative period is often caused by volume overload, delayed graft function and higher immunosuppressive dosages.
Figure 2. An unusual case of therapy resistant hypertension. Therapy resistant hypertension
resulting from hypoperfusion of the kidney allograft: an abdominal aortic stenosis located at the level of the superior mesenteric artery caused a severe stenotic segment (arrowhead) of the infrarenal aorta that induced hypoperfusion of the lower body including the kidney allograft (located in the right ileac fossa). Collateral circulation from the proximal to the distal aorta had developed via the superior mesenteric artery, flowing retrogradely through the hypertrophic inferior mesenteric artery (arrow).25
Donor factors
A recipient who has been transplanted with the kidney of a hypertensive donor is more likely to develop hypertension after transplantation, suggesting a genetic predisposition in the donor kidney.45-48 This theory of the primacy of the kidney is well shown by
studies that observed remission of hypertension in patients after transplantation with a normotensive donor.46
Immunosuppressive agents
After transplantation hypertension is attenuated by immunosuppressive regimens (Table 1).49,50 The corner stones of modern immunosuppressive regimens are
corticosteroids and the calcineurin inhibitors (CNI) (i.e. cyclosporine and tacrolimus). Corticosteroids cause hypertension only by both increased renal sodium absorption and alterations in the vascular tone causing increased systemic vascular resistance.51-53
Although CNIs are strong pharmacological agents preventing allograft rejection, paradoxically, exposure is associated with nephrotoxicity, which causes irreversible, progressive tubulo-interstitial fibrosis and glomerulosclerosis possibly via blood pressure and intra-renal hemodynamic effects.54 CNIs cause sodium retention and also reduce
vasodilator nitric oxide and consequently alterations in vascular diameter and flow occur.55 These effects may promote the progression of hypertension. Besides the sodium
dependency, effects on vascular tone and elevation of sympathetic nerve activity are involved in the pathogenesis of CNI induced hypertension.56-58 The more frequently
prescribed tacrolimus has a more favourable side effect pattern than cyclosporine.59,60
Sympathetic nerve activity
The renal sympathetic nervous system is thought to play an important role in blood pressure regulation. The tubules, juxtaglomerular apparatus and the vasculature are innervated by sympathetic nerves arising from the spinal cord in the ganglia T11 to L1.61
Postganglionic nerves cross the celiac and aorto-renal ganglia and reach the kidney through the walls of the extra- and intrarenal arteries. Elevated sympathetic nerve activity (SNA) induces changes in tubular sodium and water reabsorption, mediates renin-angiotensin-aldosterone system (RAAS) activation by the juxtaglomerular apparatus and adjusts glomerular filtration by vasoconstriction (Figure 3). Kidney failure is associated with a rise in SNA, manifested in early stages of CKD and is directly related to disease severity.62,63 Kidney transplantation itself has no deactivating effect on SNA. However,
bilateral nephrectomy does decrease SNA.64,65 This suggests that a neural factor arising
from the native kidneys is a centrally acting, hypertension inducing element. Kidney allografts are surgically fully denervated at the time of transplantation, but post-transplant nerve restoration is histological confirmed in both experimental and human studies.66,67
Reinnervation in time after transplantation is a continuous process, but whether nerve restoration after transplantation has beneficial or detrimental effects on graft function is yet unknown. Since overactive sympathetic drive may contribute to hypertension, (re)innervation of the kidney allograft could potentially contribute to progression of hypertension. Remarkably, renal sympathetic innervation in CKD has recently been
proposed as a supplementary factor causing renal fibrosis.68 The immunomodulatory
capacities of SNA and the possible driving factor in low-grade inflammation open a new window on nephropathy and are subject of current research. A potential link between sympathetic driven neurotransmission and fibrotic, inflammatory processes was determined in mouse models with chronic kidney injury: innervated kidneys with CKD expressed more fibrosis than chemically denervated kidneys.68 These experimental
data give ground to the idea that that renal innervation could possibly contribute to progression of allograft nephropathy.
Therapy for post-transplant hypertension
To reach BP targets in kidney transplant recipients, a uniform management strategy is essential that consists of modifying lifestyle, adequate antihypertensive medication and therapy adherence.69 Previously, bilateral nephrectomy of the native kidneys was a last
resort therapy for refractory hypertension in ESRD patients.70,71 However, over the last
Table 1. Factors contributing to post-transplant hypertension
Transplantation related Transplantation unrelated
Severe ischemia-reperfusion injury Native kidney disease Warm and Cold ischemia Systemic sympathetic activity
Delayed graft function RAAS activation (by native kidneys, sodium intake, SNA) Volume status: hypervolemia Pre-existing hypertension & left ventricular hypertrophy
Primary hyperaldosteronism
Donor: Vascular abnormalities causing renal hypoperfusion
Sex (female > male)
Donor age Traditional risk factors for hypertension:
Donor hypertension Genetic predisposition to hypertension Size of the kidney allograft Sex (male > female)
Genetic polymorphisms Age
Obesity**
Impaired graft function mostly due to: Hypercholesterolaemia
Chronic allograft nephropathy Obstructive sleep apnoea syndrome (OSAS) Thrombotic microangiopathy High sodium – diet
Rejection* Smoking
Recurrent / de novo kidney disease in graft Alcohol intake
Graft artery stenosis Chronic psychological stress Arteriovenous fistula after biopsy
Obstructive uropathy with hydronephrosis Immunosuppressive regimen:
Glucocorticosteroids Calcineurin-inhibitors / toxicity (cyclosporine > tacrolimus)
* acute, chronic, cellular or antibody mediated; ** may be transplant-related since BMI increases after transplantation
decades the procedure has been barely performed due to the risks and development of more potent antihypertensive drugs.16
Pharmacological approaches are the current foundations of antihypertensive therapy. Dose modification or alteration of immunosuppressive drugs should also be considered at all times. Steroid avoidance reduces the need for antihypertensive drugs, without affecting risk of graft loss.72,73 Tacrolimus has less hypertension inducing effects than
cyclosporine and conversion from cyclosporine to tacrolimus significant decreases BP.74-77
CNI-free regimens may be superior for amelioration of cardiovascular risk profiles, but currently they are only restricted for specific patient groups.78,79
Lifestyle
Several life style interventions have been proven to be effective in the treatment of hypertension. These include: weight reduction (to ideal body weight), physical activity (30 min per day 5 times a week), cessation of smoking, sodium restriction (to 90 mmol/
Figure 3. Renal sympathetic nerve activity and blood pressure regulation. Afferent and efferent
neural factors arising from diseased native kidneys contribute to hypertension via RAAS activation and increased vascular resistance. Abbreviations: SNA = sympathetic nerve activity; Ang II = angiotensin II; BP = blood pressure.
day) and moderation of the use of alcohol (maximum of 2 alcohol containing drinks a day).80,81 Obesity adversely affects graft outcome. Weight loss is of special interest to
KTRs because increase in body mass composition, especially body-fat, is a common finding after transplantation.82,83 Causal factors of weight gain in KTRs include physical
and metabolic effects of restored kidney function and effects of corticosteroids on food intake.84 Low physical activity in KTRs is strongly associated with a higher CVD risk
and all-cause mortality, stressing the necessity for physical activity.85 Sodium restriction
needs to be an integrated part of each antihypertensive therapy. The KDIGO guideline on this aspect prescribes a target daily sodium excretion of < 90 mmol. However, 85% of Dutch kidney transplant recipients exceed this target with a daily urinary sodium excretion of 150-176 mmol/24 h.86-88
Pharmacology
The choice of antihypertensive pharmacotherapy is based on co-morbidity, efficacy, tolerability and interactions with other drugs. Predominantly, the calcium channel blockers (CCB), beta- and alpha-1 blockers, angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blocker (ARB) are prescribed. CCBs are often first line therapy because they counteract vasoconstrictive effects of CNIs.89 Diuretics are
beneficial since CNI induced hypertension is sodium dependent, however they are cautiously used.90,91 Although the use of ARBs and ACEi are controversial due to
intrinsic effects of glomerular filtration rate that may mimic rejection, their use results in clinically significant reduction in proteinuria.92 The effects on graft or patient survival
are unknown.93
Adherence to medication
Low medication compliance, observed in of 30-50% of the KTRs, is a modifiable behavioural factor that negatively influences graft and patient survival.94-96 In adult KTRs,
adherence to immunosuppressive agents is better than to non-immunosuppressive agents.97 Puberty as well as the transition from the small-scale, child-and-parent focused
paediatric care at the age of 18, to a large-scale, adult care program can be accompanied with significant effects of non-compliance to medication regimens.98-100 Transition occurs
in a period in which adolescents grow into young adults, increase their independency from parents and can experience less monitoring of their medical routine.101
Adherence can be improved using fixed-combined agents and by limiting the frequency of medication-intake.102 Non-adherence rates falls from 79% with taking medications
once daily to 51% with 4 times daily dosing.103 A cohesive transition program in which
paediatric and adult healthcare services are integrated may improve compliance.104
Encouraging prescription of combination/fixed-dose antihypertensive agents may increase compliance and blood pressure regulation.101,105
Innovative hypertension therapies
Because of the unmet needs for controlling BP as discussed above, over recent years innovative interventional strategies have been developed, while antihypertensive
pharmacological developments decline.106 As an advantage, interventional therapies
omit medication adherence pitfalls. Furthermore, regulation for medical devices development has been more lenient than those for pharmacological agents, therefore the devices are easier launched.
Figure 4 provides an overview of recently developed antihypertensive intervention therapies. Electric stimulation of the baro-receptors, ‘baro-receptor activation therapy’, using an implantable device may lower BP (Figure 4a).107-109 Furthermore, in a selected
group of patients, short term effects on BP reduction have been achieved using an mechanical implant in the carotid sinus that can enhance the baroreflex response and amplifies the blood pressure lowering response (Figure 4b).110-112 Also surgical
‘neurovascular decompression’ of looping arteries that compress rostral ventrolateral medullae, have shown to reduce BP in selected patients (not illustrated).113-116 Creating an
arteriovenous fistula by implantation of an anastomosis device between the iliac artery and vein may reduce systemic vascular resistance and thereby reduces BP (Figure 4c).117,118
Importantly, most trials with innovative techniques are feasibility studies. Also it should be noted that the reported effects are mostly short-term (i.e. hours-days). The exciting positive open-label results create enthusiasm and quick developments lead to a rise in mainly small-scale, single centre studies. The Symplicity HTN-3 trial showed that sham-controlled as well as long-term follow-up confirmative studies are obligatory to further the role and learn the durability of the new technique and its long-term safety profile.
Renal sympathetic denervation
In the first decade of this century, a catheter based technique for resistant hypertension was developed disrupting renal sympathetic nerves without affecting other innervation (Figure 4d).119 Renal sympathetic nerve denervation (RDN) is achieved percutaneously via
the lumen of the renal artery, using a catheter connected to a radiofrequency generator. Renal sympathetic nerves in the artery wall are disrupted by applying a number of radio frequent ablations in a quadratic pattern up to 8 Watt, lasting for 120 seconds (Symplicity catheter). Since the proof of principle study in 2009 led to substantial BP reduction, RDN mushroomed as a treatment potential for resistant hypertension.120
Renal sympathetic nerve modification has been used long before pharmacological antihypertensive therapies were introduced. Radical surgical thoracic, abdominal and pelvic sympathetic denervation appeared a successful treatment for malignant hypertension. However, the high per-operative comorbidity, mortality and long-term complications replaced the technique by pharmacological agents.121 Observations from
bilateral nephrectomy in transplant patients that resulted in a decrease of systemic sympathetic nerve activity, lower renin activity and BP, suggests that native kidneys contribute to hypertension possibly by both afferent and efferent neural factors (Figure 3). These observations founded the pathophysiological rationale for RDN in non-transplant therapy resistant hypertensive patients.
RDN has been proven in non-kidney-transplant patients with therapy resistant hypertension to be safe, even for kidney function. In two studies (Symplicity HTN-1
and HTN-2), a pronounced offi ce based BP reduction of 22/11 to 32/12 mmHg was achieved after RDN, persisting for at least 6 months.120,122. These promising fi ndings
were countered by the Symplicity HTN-3 trial in which patients were randomized 2:1 to denervation or sham. The trial confi rmed feasibility and safety of RDN but failed to demonstrate effects on systolic BP.123 In non-sham studies, patient and
physician-related biases confounded in the positive results. Technical procedural and a large inter-individual variety in BP responses after RDN in Symplicity HTN-studies may be caused by incomplete nerve disruption.124
Nowadays, the initial widespread enthusiasm fuelled by Symplicity 1 and HTN-2 studies, has been tempered by the outcome of Symplicity HTN-3.125 At least the
Symplicity HTN trials have highlighted the importance of confounding in hypertension research, the trial effects, the importance of correctly diagnosing treatment resistant hypertension and the importance of medication adherence verifi cation. Native kidney denervation has a strong pathophysiological rationale in hypertensive renal transplant patients: it may decrease daily drug dose, thereby increasing adherence and following this one-time intervention and it is unlikely that the native kidney is harmed. Finally, the lowering of CVD risk can be of substantial benefi t. A feasibility study in renal transplant recipients was designed in 2012 (Netherlands Trial Registry number 3866, Academic Medical Center, Amsterdam).
Figure 4. Innovati ve strategies to lower blood pressure. Figure 4a: Electric baro-receptor
sti mulati on, Figure 4b: Mechanical baro-receptor sti mulati on, Figure 4c: Ileac arteriovenous fi stulati on, Figure 4d: Cathether-based renal sympatheti c denervati on.
4a. 4b.
Figure 5. 123I-mIBG pathway
Assessment of renal sympathetic nerve activity
To further our understanding of the pathogenesis of hypertension and the interplay of the kidney (either transplanted or not) and the autonomic nervous system, assessment of the human renal sympathetic nerves is essential. Assessment of renal sympathetic nerve activity in-vivo can only be performed using indirect methods. Norepinephrine spillover methods using radiotracer dilution is the gold standard method: regional venous sampling quantifies the norepinephrine released from the kidneys into the circulation. However, this method is invasive and the compound is not easily available in Europe. 123I-mIBG scintigraphy
We proposed the minimal-invasive renal 123Iodide-metaiodobenzylguanidine (123I-mIBG)
scintigraphy to measure sympathetic nerve activity. In nuclear cardiology, 123I-mIBG
is used to assess adrenergic integrity and functionality of nerves in myocardial tissue. Principally in heart failure patients, 123I-mIBG uptake and washout rates are
routinely used as prognostic factors.126-129
MIBG is a chemical modification of the false-neurotransmitter guanethidine (a former anti-hypertensive agent and potent neuron blocking agent). Uptake pathways for norepinephrine into the presynaptic terminals take up guanethidine into the presynaptic terminals. When mIBG is labelled to 123-I, visualization of sympathetic nerve terminals containing 123I-mIBG is possible (Figure
5). The amount of uptake of 123I-mIBG reflects density and functional intactness of
neural tissue within the organ, whereas washout, the rate at which the labelled mIBG is cleared from the synaptic cleft, reflects sympathetic activity. After heart transplantation, a progressive increase in myocardial uptake of 123I-mIBG is seen, proving reinnervation
of the myocardium.130 The changes in sympathetic nerve activity after RDN have been
OUTLINE OF THIS THESIS
Kidney transplant recipients are at a high risk for cardiovascular disease, for which hypertension is a prime modifiable risk factor.
Chapter 2 evaluates prevalence of hypertension and treatment efficacy in Dutch
kidney transplant recipients.
In Chapter 3, the epidemiology of hypertension after kidney transplantation is further
elaborated in paediatric and young adult kidney transplant recipients. It provides an analysis of the effects of transition from the paediatric to adult nephrologic care on hypertension control.
Since lifestyle interventions are thought a paramount antihypertensive therapy but have hardly been studied in kidney transplant recipients, dietary restriction of sodium chloride on blood pressure reduction in kidney transplant recipients is studied in Chapter 4.
The absence of nocturnal dipping in blood pressure, an additional risk factor for cardiovascular disease, may be related to the immunosuppressive regimens in kidney transplant recipients. Therefore, we evaluated the prolonged release vs. twice daily calcineurin inhibitor tacrolimus in Chapter 5.
Since the sympathetic nervous system contributes to the pathophysiology of hypertension and the rationale for renal catheter-based denervation, interruption of the nerves is a possible treatment target. In order to assess the changes in renal sympathetic nerve activity, we studied the nuclear imaging technique ¹²³I-mIBG scintigraphy in kidney transplant recipients.
In Chapter 6, this technique quantified reinnervation of renal sympathetic nerves in
kidney allografts at various time periods after transplantation.
In Chapter 7 we assessed the changes in renal sympathetic nerve activity after renal
denervation using ¹²³I-mIBG scintigraphy.
To conclude, we describa the case case of a kidney transplant recipient treated with renal denervation of his native kidneys for the treatment of resistant hypertension in
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Linn C. Dobrowolski, Frederike J. Bemelman,
Karlijn A.M.I. van der Pant, Andries J. Hoitsma,
Ineke J.M. ten Berge, C.T. Paul Krediet
CHAPTER 2
TREATMENT EFFICACY OF HYPERTENSION
IN KIDNEY TRANSPLANT RECIPIENTS
IN THE NETHERLANDS
ABSTRACT Background
Hypertension in kidney transplant recipients jeopardises graft and patient survival. Guidelines suggest blood pressure targets of ≤ 130/80 mmHg and sodium intake < 90 mmol/day.
Methods
Since the efficacy of antihypertensive treatment among kidney transplant recipients is unknown, we analysed data on office-based blood pressure and use of antihypertensive drugs from the Netherlands Organ Transplant Registry on 5415 kidney transplant recipients. Additionally, we studied dosages, prevalence of treatment-resistant hypertension and 24 hour sodium excretion in 534 kidney transplant recipients from our centre to explore possibilities for therapy optimisation.
Results
In patients registered in the Netherlands Organ Transplant Registry, median blood pressure was 134/80 mmHg (interquartile range 122-145/70-85). In 77.2%, the blood pressure was ≥ 130/80 mmHg; of these patients 10.4% had no registered use, 30.0% used one and 25.9% used ≥ 3 classes of antihypertensive agents. Parameters from our centre were comparable: 78.7% had a median blood pressure of ≥ 130/80 mmHg of whom 14.5% had no registered use of antihypertensives and 26.4% used ≥ 3 classes. Sub-maximal dosages were prescribed in 74.0% of the kidney transplant recipients with a blood pressure of ≥ 130/80 mmHg while using at least one antihypertensive agent. Treatment-resistant hypertension was present in 7.7%. Median 24 h sodium excretion was 147 mmol/day (interquartile range 109-195).
Conclusions
This study suggests that therapeutic optimisation of antihypertensive treatment in kidney transplant recipients is, in theory, frequently possible by intensifying pharmacological treatment and by providing more advice on dietary sodium restrictions.
INTRODUCTION
Although kidney transplantation is the superior treatment for end-stage renal disease, kidney transplant recipients continue to have a high risk for cardiovascular morbidity and mortality. The annual risk for cardiovascular death is about 50-fold as compared with the general population and cardiovascular disease is the leading cause of morbidity and mortality in kidney transplant recipients.1-3
Hypertension is the foremost modifiable medical risk factor for cardiovascular disease in kidney disease. In addition, hypertension jeopardises renal allograft function, leading to graft loss.4-7 Various studies, dating from before 2009, indicated that hypertension
amongst kidney transplant recipients was prevalent in up to > 90%.4,8,9 Authoritative
guidelines recommend a target blood pressure of < 130/80 mmHg in kidney transplant recipients.7,10 The efficacy of antihypertensive treatment in kidney transplant recipients
has not been studied since. Against this background, we set out to study the efficacy of the current treatment of hypertension in kidney transplant recipients and to assess the number and dosages of prescribed antihypertensive drugs. Since sodium intake is a recognised determinant of blood pressure and sodium restriction is a major therapeutic antihypertensive intervention, we also surveyed the dietary sodium intake.
METHODS
We performed two separate, retrospective cross-sectional analyses: i.e. on data retrieved from the Netherlands Organ Transplant Registry (NOTR) and from the clinical files of kidney transplant recipients at our own institution, respectively.
Netherlands Organ Transplant Registry
The NOTR registry is a nationwide registry of kidney transplant recipients from the eight kidney transplant centres in the Netherlands, including our institution. The NOTR registry is managed by the Dutch Transplant Foundation and includes patient and donor characteristics and a variety of clinical parameters, such as office blood pressure and prevalent medications. In the first year after transplantation, registry follow-up is at month 3, thereafter on a yearly basis. We retrieved data on patient characteristics, kidney graft function, office-based systolic and diastolic blood pressure and the number of classes of antihypertensive drugs in the patients registered on 31 December 2011. For patients within the first year after transplantation, we included data from the latest visit. Table 1 summarises these variables.
Local data
To provide additional information about determinants of hypertension that could not be retrieved from the NOTR, we performed a retrospective survey on the medical files of the prevalent kidney transplant recipients at our kidney transplant centre in Amsterdam in September 2012. On average these patients visit the outpatient clinic
four times per year. We collected data on patient characteristics including ethnicity, kidney graft function, office-based systolic and diastolic blood pressure and prevalent classes of antihypertensive and immunosuppressive drugs and their dosages. In all patients 24-hour urine collections are routinely performed at each outpatient clinic visit. There we were able to assess daily sodium excretion as a proxy of dietary intake parallel to the blood pressure readings. Urine sodium excretion was measured at least four weeks after adjustment or initiation of diuretic treatment. Therefore these measurements represented a steady state in which sodium intake and excretion were equal. We defined the possibility for optimisation of antihypertensive treatment as the option to initiate antihypertensive treatment or the option to increase the number and/ or dosage of the prescribed antihypertensive agents up to the maximum recommended dosage in our local protocol (Table 2).
Statistical analysis
All data were included in a master file and statistical analyses were performed using SigmaStat (Jandel Scientific Software, San Jose, California USA). Normally distributed data are represented as mean and SD; non-normally distributed data as median and interquartile ranges. Under Dutch law this retrospective, descriptive study was exempt from medical ethics review.
RESULTS
Netherlands Organ Transplant Registry data
On 31 December 2011, 5770 patients of 18 years and older were registered in the NOTR as living with a functioning kidney transplant. Recent blood pressure measurements were missing in 355 patients (6.2%), who were excluded from further analysis. Median age was 48 years (interquartile range (IQR) 36-58) and time after transplantation 5.0 years (IQR 2-11). Median plasma creatinine was 126 μmol/l (IQR 101-163) and proteinuria was 0.11 g/l (IQR 0.03-0.30). Most patients were treated with a calcineurin inhibitor (CNI). Tacrolimus was prescribed in 58.2% and cyclosporine in 36.9% of the patients. Prednisolone was prescribed in 89.5% of the patients, mostly in combination with a CNI. Mycophenolate mofetil (MMF) was used in addition to the CNI and/or prednisolone regimen in 73.8%. Azathioprine was given to 5.3% of the kidney transplant patients and a mammalian target of rapamycin (mTOR) inhibitor to 5.1%. Median blood pressure was 134/80 mmHg (IQR 122-145/70-85). These data are summarised in Table 1 and Figure 1. The examination of the numbers of classes of antihypertensive drugs prescribed showed that at least one class of blood pressure lowering agents was prescribed in 87.8% of the patients. Of all kidney transplant recipients with a blood pressure ≥ 130/80 mmHg, 10.4% had no prescription for any antihypertensive drug, 30.0% used one antihypertensive agent, 33.7% used two and 25.9% used three or more different classes of antihypertensive drugs (Figure 2).
Local data
Patient characteristics are shown in Table 1. Data on n=539 prevalent patients living with a functioning kidney transplant on 1 September 2012 were included. There were missing data on recent blood pressure in five patients. Therefore, we further analysed the data on 534 patients. There were nine patients who had missing data on 24-hour urine specimens. In this cohort, the median age of 54.5 years (IQR 43-64) was slightly higher and time after transplantation of 4.4 years (IQR 1.3-9.7) was shorter than in the NOTR survey. Ethnic diversity was broad with 76% being Caucasian and of whom 64% were of Dutch descent. Median plasma creatinine was 143 μmol/l (IQR 112-183) and proteinuria was 0.09 g/l (IQR 0.06-0.18). The CNI tacrolimus was prescribed in 53.4% of the patients, with median dosages of 6 mg/day (IQR 4-8) and with associated plasma trough levels of 7.4 μg/l (IQR 5.5-9.2). Cyclosporine was prescribed in 20.8%, and 93.6% of the kidney transplant recipients were treated with prednisolone with median daily dosages of 10 mg (5-10 mg).
In our centre, 58.1% of our kidney transplant recipients received MMF, 14.0% azathioprine and 4.1% an mTOR inhibitor.
Kidney transplant recipients had a median blood pressure of 134/81 mmHg (124- 146/76-88). In 420 patients (78.6%) blood pressure was ≥ 130/80 mmHg, of whom 14.5% were not taking an antihypertensive drug, 29.3% used one, 29.8% two and 26.8% used three or more different classes of blood pressure lowering agents. Blood pressure ≥ 140/90 mmHg was found in 43.8% of our patients. Of the 420 patients with blood pressure ≥ 130/80 mmHg, 24.8% were taking three or more antihypertensive
Figure 1. Blood pressure of kidney transplant recipients (data from the NOTR). Blood pressure
is classified into three categories (≤ 129/79 mmHg, between 130/80 and 139/89 mmHg and ≥ 140/90 mmHg).
