Arterial hypertension is prevalent among kidney transplant recipients. The
multifactorial pathogenesis involves the interaction of the donor and the
recipient’s genetic backgrounds with several environmental parameters that may
precede or follow the transplant procedure (eg, the nature of the renal disease,
the duration of the chronic kidney disease phase and maintenance dialytic
therapy, the commonly associated cardiovascular disease with atherosclerosis and
arteriosclerosis, the renal mass at implantation, the immunosuppressive regimen
used, life of the graft, and de novo medical and surgical complications that may
occur after a transplant). Among calcineurin inhibitors, tacrolimus seems to
have a better cardiovascular profile. Steroid-free protocols and calcineurin
inhibitor-free regimens seem to be associated with better blood pressure control.
Posttransplant hypertension is a major amplifier of the chronic kidney disease-cardiovascular
disease continuum. Despite the adverse effects of hypertension on graft and
patient survival, blood pressure control remains poor because of the high
cardiovascular risk profile of the donor-recipient pair. Although the optimal
blood pressure level remains unknown, it is recommended to maintain the blood
pressure at < 130/80 mm Hg and < 125/75 mm Hg in the absence or presence of
Key words: Cardiovascular disease, Immunosuppression, Kidney transplant, Atherosclerosis, Genetic
Arterial hypertension is prevalent among kidney transplant recipients. Its
prevalence varies according to transplant center, demographics of transplant
recipient and kidney donor populations, definition of hypertension, time of
diagnosis after the transplant, and when the transplant was performed.1-3
Arterial hypertension has increased from 40% to 85% since the introduction of
calcineurin inhibitors.1-3 Data from the Spanish registry show that
irrespective of the transplant era, a progressive and significant increase in
the prevalence of systolic and diastolic hypertension during follow-up (which
stabilizes after the fourth year after transplant) occurs.4 The
severity of increased systolic blood pressure is most pronounced immediately
after the transplant and declines progressively during the first year.2
Interestingly, the prevalence of posttransplant hypertension remains high
despite a more-aggressive therapeutic approach by transplant physicians,
reflected by administering more antihypertensive medications.1-3
Recent observational data from the Collaborative Transplant Study registry shows
that the fraction of kidney transplant recipients with a systolic blood pressure
< 140 mm Hg rose significantly from 1998 onward because of the increase in the
number in the antihypertensive drugs administered.4 These findings
were in agreement with similar observations reported during the same time.1
Yet, despite this increased vigilance in the transplant community4
and the well-established negative effect of posttransplant hypertension on graft
and patient outcomes5-8; adequate blood pressure control remains poor
in most kidney transplant recipients, leading to 20% to 40% graft loss from
chronic allograft dysfunction or death from cardiovascular disease.8-11
This review highlights the role of posttransplant hypertension as an
amplifier of the chronic kidney disease and cardiovascular disease continuum,
its causes that involve pretransplant, peritransplant, and posttransplant
parameters, and its adverse effects on graft and patient survivals.
Posttransplant hypertension: Amplifier of the chronic kidney disease-cardiovascular
It would be erroneous to consider posttransplant hypertension an isolated
phenomenon. It should be regarded as an integral part, and a major amplifier of,
the chronic kidney disease and cardiovascular disease continuum—a process that
begins with or often precedes the clinical and biological diagnosis of the renal
damage (Figure 1).12,13 The strong link between chronic kidney
disease and cardiovascular disease has been documented in both the general and
chronic kidney disease populations.13-16 The prevalence of
cardiovascular morbidity and mortality is greater in the patients with renal
failure, especially those with end-stage renal disease, and the cardiovascular
events often lead to death with chronic kidney disease more so than with
individuals without chronic kidney disease.17,18 The chronic kidney
disease and cardiovascular disease continuum involves 3 phases: the first phase,
with its different stages; progressing toward end-stage renal disease, which is
the second phase, which requires chronic renal replacement therapies that may
lead in some, but not all, patients to kidney transplant; and the third phase,
after which the renal allograft is lost to chronic allograft dysfunction and a
return of the patient to dialysis, or death of the recipient predominantly from
The chronic kidney disease and cardiovascular disease continuum amplifies
with time according to the duration of each of the phases that may last from
months to years.15-17 It results from the interaction of several
genetic, ethnic, environmental, and demographic factors that contribute to the
development or progression of renal and cardiovascular diseases.12,17-34
Many of these factors are traditional, and commonly and concomitantly present in
chronic kidney disease and cardiovascular disease patients including age, male
sex, diabetes mellitus, dyslipidemia, hyperuricemia, hyperhomocysteinemia and
sympathetic nervous stimulation, in addition to 2 widespread and devastating
factors: obesity and smoking. Other factors are related to the underlying kidney
disease itself and the commonly associated hypertension and proteinuria, the
resulting atherosclerosis and inflammatory state. The progression of the renal
disease leads to the gradual appearance of additional environmental factors
specific to uremia, such as the uremic toxic environment, and resultant anemia,
hyperparathyroidism, oxidative stress, lipoproteins glycation, endothelial
dysfunction, coagulation disorders, increased in tissue calcium deposit, and
resultant accelerated arteriosclerosis. Most of these factors continue to
progress during the end-stage renal disease phase, during which new additional
ones enter into play such as the increase incidence of infections, creation of
an arteriovenous fistula, worsening hypervolemia, and both vascular and tissue
calcifications, leading to an exaggeration in aortic stiffness, left ventricular
hypertrophy, and diastolic dysfunction.15-17,35
Shortening the process through preemptive kidney transplant leads to early
reversal of many of the continuum’s components. This could explain the superior
short-term and long-term kidney allograft and patient survival associated with
preemptive transplant from a living donor compared with transplant after being
on dialysis.36,37 By the time end-stage renal disease patients
ultimately reach the transplant phase, they have renal, cardiovascular
atherosclerotic, and arteriosclerotic comorbid risk factors responsible for
higher cardiovascular mortality than the general population does, when matched
for age, race, and sex.38 While some of these factors (such as aortic
stiffness) could be gradually and either partially or completely reversed by the
process of a successful transplant35,39 (leading to a significant
reduction in the annual adjusted cardiovascular rates in kidney transplant
recipients as compared to end-stage renal disease wait-listed patients)40;
other pre-existing factors such as diabetes mellitus, dyslipidemia,
atherosclerosis, congestive heart failure, and obesity may worsen after
transplant along new ones that could occur as the result of diabetogenic,
dyslipidemic, atherogenic, thrombogenic, infectious, and nephrotoxic potential
of most immunosuppressive drugs, 1,35,39,41-44 in addition to anemia
and chronic graft dysfunction, which are linked to several immunologic and
Most drug-related adverse effects are mediated by the interaction of 2
distinct genetic profiles of the recipient and the donor with the environment.46-55
These gene-gene and gene-environment interactions lead to systemic and
nephrotoxic adverse events that predominantly depend upon the recipient and the
Evidence is emerging regarding the role of donor age and hence, nephron mass,
in the pathogenesis of aortic stiffness in nephrectomized donors56
and kidney transplant recipients.56-58 Data from animal models show
that reduced renal mass is the major factor in the development and maintenance
of arterial hypertension and proteinuria, which lead to glomerular injury in 5/6
nephrectomized rats. Supplementing renal mass reverses these changes. These
observations provide support for the notion that renal mass is a significant,
independent determinant of arterial pressure.59
Atherosclerosis is a major component of the chronic kidney disease and
cardiovascular disease continuum and may occur early in life. Young adults with
end-stage renal disease since childhood exhibit an increase and decrease in
carotid artery stiffness and distensibility, respectively, when compared with
matched healthy individuals. These arterial wall abnormalities, indicators of
arterial dysfunction, are comparable to those measured in the transplant
patients with the same risk factors.60
Mistnefes and coworkers confirmed these findings in a recent study.61
In their study, these markers of atherosclerosis were associated with higher
mean systolic blood pressures taken within 1 year before the study, higher
daytime systolic blood pressure load (via ambulatory blood pressure monitoring),
number of kidney transplants, and deceased-donor transplants.61 These
observations show that pediatric kidney transplant recipients might be at an
increased risk for accelerated atherosclerosis and premature cardiovascular
disease that strongly correlate with systolic blood pressure, deceased-donor
donation, and the duration of renal replacement therapy.
Although renal transplant improves arterial function,39 pulse wave
velocity (a marker of aortic stiffness) remains significantly elevated during
the long term in kidney transplant recipients when compared with healthy
volunteers.56 Interestingly, an increase in pulse wave velocity also
was observed in corresponding live donors but was considerably greater in
recipients independent of age, sex, and blood pressure. Moreover, among healthy
volunteer groups, pulse wave velocity was significantly higher in the recipient-related
than in the non–recipient-related volunteers, indicating a possible genetic
predisposition for developing atherosclerosis and consequently, renal disease.
In all healthy volunteers, pulse wave velocity was exclusively related to age,
sex, and blood pressure. In donors and recipients, it was associated with a
cluster of cardiovascular risk factors including smoking habits, plasma glucose,
and renal factors reflecting nephron mass (eg, time since nephrectomy, age in
donors, and rejection in recipients). More recently, pulse wave velocity, in
addition to proteinuria and systolic blood pressure, has been reported to be an
independent predictor of the rate of decline in renal function in chronic kidney
disease patients,15 and in pediatric62 and adult kidney
While recognizing the likely dual causality between aortic stiffness and
renal failure, these observations provide further evidence that atherosclerosis
and the resulting arterial stiffness play a pathogenic role in renal function
decline. Taken together, these results suggest that the arterial status of the
recipient is the result of possible links between the combined donor-recipient
genetic backgrounds and their interaction with several environmental and
demographic cardio-renal risk factors, the renal mass from the donor at
implantation, and the vascular, and immunologic and nonimmunologic renal changes
that occur in the recipient posttransplant.
This explains why arterial hypertension is prevalent in each phase of the
chronic kidney disease and cardiovascular disease continuum; as the result of
the cumulative and progressive nature of the continuum, its prevalence increases
with progression of the process, being highest during the posttransplant phase.1-3
It represents a strong predictor of renal and patient cardiovascular outcomes1,3,5,6,8,11-13,15,17,35,56,58,60-63
(Figure 2). Therefore, posttransplant hypertension represents a multipathogenic
process that amplifies a vicious cycle where allograft and cardiovascular
outcomes in kidney transplant recipients are determined by the interaction of 2
distinct donor and recipient genetic make-ups, and the inherited cardiovascular
and renal risk factors from earlier phases and new recipient and donor-related
environmental and demographic variables that may occur during implantation and
posttransplant (Figure 1).
Posttransplant hypertension pathogenesis
Arterial hypertension in the kidney transplant population represents a
greater risk for cardiovascular outcome and renal survival then it does in the
general population, and it plays a major role in the cause of chronic graft
dysfunction, and morbidity and deaths from cardiovascular disease.5,63
The various causes for posttransplant hypertension are well-documented in the
literature.1,3,8,64 Given the complexity of the kidney transplant
milieu related to the interaction between recipient and donor parameters, and
the progressive, cumulative nature of the chronic kidney disease-cardiovascular
disease continuum—a proper stratification of the different causes of
posttransplant hypertension should take into account the different phases of the
continuum and the various donor-related and recipient-related factors of each
phase (Figure 3). The causes of arterial hypertension in a kidney transplant
recipient are diverse, and posttransplant hypertension should be considered a
multifactorial disease state rather than a simple phenomenon. This could explain
the more-pronounced effects of hypertension on renal and cardiovascular outcomes
in transplant patients,4,38,63 as compared with non–renal-hypertensive
Uncontrolled blood pressure in renal transplant plays a major role in the
pathogenesis of chronic graft dysfunction, accelerated graft loss, and the
morbidity and mortality associated with cardiovascular disease.2,4,5,8-11,63,67,68
While several epidemiologic studies65,66,69 have shown that systolic
hypertension in the general population is an independent risk factor for
developing chronic kidney disease, fewer than 1% of these cohorts progressed to
end-stage renal disease during a minimum follow-up of 15 years and mainly in
those individuals with systolic blood pressure >180 mm Hg.69 In
contrast, Registry data from kidney transplant recipients show a strong and
graded inverse association between systolic blood pressure levels and graft
outcomes.5,8 In fact, 24% and > 50% of the grafts were lost after 4
and 8 years follow-up in kidney transplant recipients who had a systolic blood
pressure ≥ 180 mm Hg at 1-year posttransplant. These results were still
maintained after censoring for acute rejection and patient death, and whether
the patients were on antihypertensive therapy.5
Several recipient-related factors have been identified in transplant
patients as predisposing risk factors for posttransplant hypertension. Many of
these antedate the transplant process including the ethnic and genetic make-up,
age, body mass index, and male sex of the recipient; the nature of the
underlying kidney disease itself (mainly diabetic nephropathy and
nephrosclerosis), the pre-existing chronic kidney disease-arteriosclerosis that
progresses and worsens with length of the chronic kidney disease and
cardiovascular disease continuum and that of the renal replacement therapy; the
frequently associated atherosclerosis that may be beginning early in life, and
accelerating with advancing age and with the progression of the renal disease
itself; and finally, the commonly associated inherited hypertension that, when
uncontrolled, could contribute to aggravated atherosclerosis and a deterioration
in renal function.1,2,3,9,16-18,20,23,52,55,60,61,64,70
At the time of implantation, additional variables have been shown to be
independent correlates of systolic blood pressure: delayed graft function and
long warm ischemia time,1-3,71 both of which can lead to vascular
damage and fibrosis, and a further reduction in nephron mass. Specific recipient
genotype (CYP 3A5 nonexpressers) seems to be a strong predisposing factor for
delayed graft function and for new-onset diabetes mellitus after transplant in
After kidney transplant, several new parameters emerge as strong correlates
of posttransplant hypertension. They are specific to the kidney transplant
recipients and the transplant process involving the genetic makeup of the
recipient, the technical procedure with its short-term and long-term
complications, the immunosuppressive regimen used and potential new systemic
adverse events that may occur after transplant, the time after transplant, and
the commonly encountered proteinuric chronic graft dysfunction of multiple
immunologic and nonimmunologic origins (ie, acute and chronic rejection,
recurrent native and de novo kidney diseases).1,2,3,9,31,42-45,64,71-88
Surgical complications (eg, lymphocele and ureteral stenosis causing urinary
outflow obstruction) are well-established causes of early onset or aggravating
pre-existing hypertension.3 Transplant renal artery stenosis
occurring soon after transplant may be related to trauma, clamping, or suturing
of the graft artery or the recipient vessels. Kinking of the graft artery from a
right donor kidney (which has a longer artery than the vein) may lead to early
Renal artery stenosis coming late after transplant may be caused by
atherosclerotic changes of the renal artery of the graft or the proximal iliac
artery of the recipient.3,77,78 Postgraft biopsy arteriovenous
fistula caused by an abnormal communication between the artery and the vein may
result in local ischemia and renin-mediated hypertension.88 Modern
immunosuppression (including calcineurin inhibitor-based regimen in combination
with steroids) has drastically transformed posttransplant hypertension by
increasing its prevalence from 40% to > 80%.1,2,3 Although the exact
mechanism of the calcineurin inhibitor-induced hypertension has not been well
clarified, patients treated with cyclosporine are more likely to develop
hypertension than are those on tacrolimus. Registry data, and observations from
clinical trials, reveal that tacrolimus-based regimens are associated with lower
rates of posttransplant hypertension and a significant reduction in
antihypertensive medication requirements.1,42,44,78 Furthermore, the
conversion of stable transplant patients from cyclosporine to tacrolimus is
associated with significant improvement in systolic and diastolic blood
The thrombogenic, atherogenic, hyperlipidemic, diabetogenic, and hypertensive
effects of corticosteroids are well recognized, and steroid-sparing protocols
improve blood pressure control and reduce cardiovascular risk factors—particularly
when used with a low-dose calcineurin inhibitor or combined with sirolimus, or
sirolimus and mycophenolic mofetil.79,80 Poor therapeutic compliance
with antihypertensive medications and immunosuppressive drugs is a well-established
cause, not only of uncontrolled hypertension in kidney transplant recipients,
but also of acute rejection, graft dysfunction, graft loss, and even death of
With the advancing age of the kidney allograft after implantation, the risk
of chronic graft dysfunction increases, translating to a progressive drop in
creatinine clearance by nearly an average of 1.5 to 2 mL/min/y.74,75
Several immunologic and nonimmunologic factors for recipient and donor origins
have been identified.45,76 Acute and chronic rejection, and recurrent
native and de novo kidney disease, in addition to other posttransplant stress
factors (mainly calcineurin inhibitor nephrotoxicity and many of the inherited
factors before transplant), are well-established recipient-dependent pathogenic
factors for chronic graft dysfunction.
Specific recipient ABCB1 haplotypes have been shown to modify the risk
of acute rejection,85 and combined donor-recipient homozygosity for
the C3435T variant in ABCB1, have been significantly associated with
increased susceptibility to chronic allograft damage, independent of graft
quality at implantation.86 Moreover, kidney transplant recipients who
are CYP 3A5*1 expressers are more prone to develop tacrolimus-associated
nephrotoxicity, especially in those who continue corticosteroid therapy.87
Patients with hereditary nephritis may develop recurrent or de novo kidney
disease after transplant.25 Hypertension and proteinuria are commonly
associated features with chronic graft dysfunction, and when present, they may
result into further deterioration in graft function.
Low estimated glomerular filtration rate and albuminuria have been shown in a
recent meta-analysis of large cohorts of chronic kidney disease or increased
risk for chronic kidney disease populations to be independently associated with
progressive chronic kidney disease, end-stage renal disease, and all cause and
cardiovascular mortality.31,83,84 Volume overload is a frequent
complication of advanced renal failure, representing one of the most common
reasons behind the higher proportion of chronic kidney disease patients with
uncontrolled hypertension compared with those hypertensive individuals in the
On these recipient-related factors are superimposed additional variables
that are related to the kidney donor.1-3,9,51-56,59,64,71,73,76,86,88-93
As in the recipient, old age, pre-existing hypertension, diabetes mellitus,
subclinical kidney disease, and nephron under dosing (innate, female to male
donor, old age, and donor-recipient body mass index mismatch) represent
potential causes for development or aggravation of hypertension posttransplant.1-3,9,59,64,71,73,91-92
New evidence is emerging regarding the potential role of the donor genetic
makeup in the pathogenesis of posttransplant hypertension. Kidney recipient-related
healthy volunteers who can be potential donors, exhibit significantly higher
pulse wave velocity (an indicator of atherosclerosis) than do nonrelated donors.56
Family members of consanguineous dialysis patients are at increased risk of
developing renal disease.93 A particular kidney donor, ABCC2
genotype, is associated with delayed graft function in certain kidney transplant
recipients.51 Similarly, kidney grafts obtained from donors carrying
certain polymorphisms of the ABCB1 and CYP 3A5 genes are highly
prone to develop cyclosporine nephrotoxicity,52,53 a major component
of the nonimmunologic cause of chronic graft dysfunction.45,76
Interestingly, these same ABCB1 polymorphisms affecting P-gp
expression in the donor are associated with chronic histologic damage,86
and adversely influence long-term graft outcomes by decreasing renal function
and graft loss in calcineurin inhibitor-treated kidney transplant recipients.55
Transplanting kidney allografts from donors with multiple MYH9 risk
alleles into recipients with similar genetic and ethnic background may lead to
early fulminant nephrotic syndrome, hypertension, and subacute loss of kidney
function soon after transplant.90
In conclusion, arterial hypertension in kidney transplant recipients is a
major amplifier of the chronic kidney disease and cardiovascular disease
continuum. It does not represent a single phenomenon, but rather, is
multifactorial, reflecting a multipathogenic disease state with serious
repercussion affecting graft and patients survival. It is a major cause of graft
loss from chronic graft dysfunction and from patient cardiovascular mortality.
Despite appropriate therapeutic vigilance, blood pressure control remains poor
because of the high cardiovascular risk profile of the donor-recipient pair.
Although optimal blood pressure level remains unknown, it is recommended that
blood pressure be maintained in kidney transplant recipients < 130/80 mm Hg,
94 and maybe ≤ 125/75 mm Hg in the presence of proteinuria (as has
been recently reported in diabetic95,96 and nondiabetic chronic
kidney disease patients97,98).
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Volume : 11
Issue : 2
Pages : 99-108
From the Renal Transplantation Unit, Rafik Hariri University Hospital, Bir
Acknowledgements: The author reports no grant support for this manuscript,
nor any conflicts of interest.
Corresponding author: Antoine Barbari, MD, Director, Renal
Transplantation Unit Rafik Hariri University Hospital, Bir Hassan, Beirut-Lebanon
Phone: +961 3 326 556
Fax: +961 1 832 041
Figure 1. Chronic Kidney Disease-Cardiovascular Disease Continuum
Figure 2. Posttransplant Hypertension
Figure 3. Multifactorial Pathogenesis of Posttransplant Hypertension