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the efficacy of RAAS inhibition in slowing the rate of decline of renal function was done in patients with T1DM and
overt proteinuria (>500 mg/day), and randomization to the ACE inhibitor captopril demonstrated a 48% reduction
in the risk for doubling of serum creatinine concentration and a 50% reduction in the composite endpoint of death,
dialysis, or transplantation compared to placebo. The irbesartan diabetic nephropathy (IDNT) trial randomized
patients with T2DM, hypertension, and proteinuria to one of three groups: the ARB irbesartan, amlodipine, or
placebo. IDNT demonstrated a statistically significant reduction in the primary composite outcome of doubling of
serum creatinine, ESRD, or death in the irbesartan group compared to placebo and to the amlodipine group after
a mean follow-up duration of only 2.6 years. There was identically achieved BP control in the subjects randomized
to either amlodipine or irbesartan, demonstrating the benefit of RAAS inhibition was independent of lowering BP.
Similarly, the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study showed
that, in patients with T2DM (96.5% also had hypertension) and proteinuria, the ARB losartan significantly reduced
the same primary composite by 16%. At the end of the study there was a small but significant BP difference (SBP
140 mm Hg vs. 142 mm Hg in the losartan and the placebo group, respectively) but the losartan benefit was
independent of BP reduction. Together the trials show that the renoprotection of RAAS-blocking agents in T2DM
with hypertension is likely a class effect that is independent of BP reduction. It is important to note that in both trials the ARB dose for maximum renoprotection was the maximum dose of 300 mg daily for irbesartan and 100 mg
daily for losartan.
Taken together, the evidence supports the use of ACE inhibitors and ARBs across the continuum of diabetic
nephropathy. Other RAAS-blocking agents, including aldosterone receptor antagonists (such as spironolactone)
and renin inhibitors (aliskiren), have been shown to reduce albuminuria and thus likely have renal benefits beyond
BP reduction, but, unlike ACE inhibitors or ARBs, they have not been demonstrated to preserve renal function.
Table 18.3 summarizes major RAAS inhibitor trials on diabetes and kidney disease.
8. Do all patients with diabetes and chronic kidney disease have diabetic nephropathy?
In classically observed diabetic nephropathy, patients progress over years from microalbuminuria to frank proteinuria to declining GFR and, if not censored by cardiovascular death, to ESRD. Prospective renal biopsy studies
in these patients reveal diabetic nephropathy often with hypertensive nephrosclerosis. However, a subset of about
25% of patients with diabetes and decreased GFR who have little or no albuminuria have been described. It is not
clear if they have an altered form of diabetic nephropathy or a different mechanism of disease because biopsy
studies have not been done in these patients. They are described as having diabetic kidney disease in contrast
to diabetic nephropathy. As discussed previously, RAAS inhibition has been shown to slow the progression of
diabetic nephropathy in all stages. RAAS inhibitors have been shown to be beneficial in many other renal diseases
including chronic kidney disease due to hypertensive nephrosclerosis in Blacks. Although not studied, it is thus
prudent to treat diabetic kidney disease first line with RAAS inhibitors as well. As even in normoalbuminuric
patients with diabetes RAAS inhibitors prevent the development of microalbuminuria, one might consider RAAS
inhibitors as first line in all diabetic patients with hypertension. Of note, 25% of patients randomized to captopril
in the captopril trial described earlier were not hypertensive but nevertheless had a slower rate of decline of renal
function, indicating that RAAS inhibition may also be a good option for diabetic patients even in the absence of
hypertension.
9. How does one manage the side effects of RAAS inhibitors?
Because RAAS inhibition is proven to be beneficial in diabetes, efforts to continue these medications long term
must be continuously reassessed, especially by adjusting treatment in response to side effects. A common
side effect of ACE inhibitors is nonproductive cough in 15% of patients, which is more common in Asians.
This is likely due to bradykinin accumulation in the pulmonary vasculature as a consequence of local ACE
inhibition. In agreement with this mechanism, patients can safely be switched to ARBs, which specifically do
not lead to bradykinin accumulation in the lung. ACE inhibitors and ARBs are contraindicated during pregnancy
because of their teratogenic effects, including cardiovascular and central nervous system malformations, and
their negative effect on fetal renal hemodynamics to cause anuria, oligohydramnios, and renal failure after
delivery.
Other side effects of RAAS inhibition are hyperkalemia and transient deterioration of kidney function.
Hyperkalemia is the result of decreased angiotensin II generation resulting in aldosterone inhibition and impaired
renal potassium excretion. The renoprotective effect of decreased angiotensin II–dependent efferent arteriolar
resistance resulting in lower intraglomerular pressure can be detrimental in situations in which the kidney is
depending on increased efferent arteriole constriction to maintain glomerular perfusion such as in renal artery
stenosis and decreased intravascular volume. In the setting of volume depletion and decreased renal perfusion,
the decreased GFR and decreased distal sodium delivery for exchange with potassium may further exacerbate
hyperkalemia. Elderly patients with T2DM with low renal function at baseline, significant vascular disease, or
patients on NSAIDs (that reduce glomerular perfusion by abolishing prostaglandin-mediated afferent arteriolar
vasodilation) are especially at risk for these side effects. A creatinine increase greater than 30% above baseline
within 6 weeks of initiating RAAS inhibition or hyperkalemia that cannot be controlled warrants discontinuation
of RAAS inhibition. It is prudent to check serum potassium and creatinine levels within 10 to 14 days of starting
RAAS inhibitors. If no other cause for a greater than 30% serum creatinine increase, such as volume depletion,
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Table 18.3 Summarizing Select Pivotal RAAS Inhibitor Trials
TRIAL POPULATION N INTERVENTION CONCLUSION COMMENTS
BENEDICT Hypertensive patients
with T2DM and
without microalbuminuria
1204 Trandolapril plus
verapamil vs.
each alone vs.
placebo
Trandolapril signifi-
cantly delayed the
onset of microalbuminuria by a factor
of 2.1
ROADMAP T2DM patients without
microalbuminuria
4449 Olmesartan vs.
placebo
Significant delay in
onset of microalbuminuria with
olmesartan
The olmesar-
tan group
achieved
a lower BP
compared to
placebo
IRMA 2 Hypertensive T2DM
patients with microalbuminuria
Captopril
trial
T1DM patients with
proteinuria >500
mg/day and sCr ≤
2.5 mg/dL 1.0–3.0
(men) and 1.2–3.0
mg/dL (women)
IDNT Hypertensive T2DM
patients with proteinuria and reduced
kidney function (sCr
1.2–3.0 for men and
590 Irbesartan 150 mg
vs. irbesartan
300 mg vs.
placebo
409 Captopril vs.
placebo
1715 Irbesartan vs.
amlodipine vs.
placebo
Irbesartan significantly
decreased the time
to onset of overt
proteinuria
Captopril significantly
reduced the primary
outcome (doubling
of sCr) and secondary outcome (death,
dialysis, transplant)
Irbesartan significantly
reduced the primary
composite outcome
of doubling of sCr,
ESRD, or death
Likely dose-
dependent
effect
76% had
hypertension
at baseline
1.0–3.0 mg/dL for
women)
RENAAL T2DM patients with
proteinuria and reduced kidney function (sCr 1.3–3.0
and 1.5–3.0 for men
>60 kg BW)
BENEDICT, Bergamo Nephrologic Diabetes Complications Trial; BW, body weight; ESRD, end-stage renal disease; IDNT, Irbesartan
Diabetic Nephropathy Trial; IRMA 2, IRbesartan in MicroAlbuminuria, Type 2 Diabetic Nephropathy Trial; RAAS, renin-angiotensin-
aldosterone system; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; ROADMAP, Randomized
Olmesartan and Diabetes Microalbuminuria Prevention; sCr, serum creatinine; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes
mellitus.
1513 Losartan vs.
placebo
Losartan significantly
reduced the primary
composite outcome
of doubling of
serum creatinine,
ESRD or death
96.5% had
hypertension
at baseline
is found, evaluation for renal artery stenosis should be considered. Maintaining background RAAS inhibition at
an optimal dose is key for maximum renal protection in hypertensive patients with diabetes and kidney disease,
but opportunities are often limited due to hyperkalemia. Education on a low potassium diet is important and
can address this problem. Also, with the availability of new safe daily oral potassium binders (patiromer, sodium
zirconium cyclosilicate ZS-1) it may be possible to combine their use with ACE inhibitor/ARB therapy and reduce
discontinuations due to hyperkalemia.
Angioedema is a rare but serious complication of ACE inhibitors, most often manifest as swelling of the
lips or tongue, leading to airway obstruction in severe cases. This event occurs more often in Blacks, women,
smokers, and nondiabetic patients. ACE inhibitors should be discontinued in patients with suspected ACE inhibitor
associated angioedema, and this should be clearly documented in the allergy list to deter future prescription.
Alternative treatment with an ARB may be initiated after a sufficient washout period of 2 to 3 months.
10. As most patients will require more than one antihypertensive drug, is dual RAAS blockade
(ACE inhibitor + ARB) a good option?
Combining an ACE inhibitor with an ARB leads to modest additional SBP lowering of 2 to 4 mm Hg, but there are
other adverse consequences. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint
Trial randomized 25,620 patients with CVD of which 9612 and 2781 had diabetes and microalbuminuria,
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respectively, to ramipril, telmisartan, or the combination of both. Two thirds had a diagnosis of hypertension at
baseline. The primary outcome was a cardiovascular composite, and there were no differences in the primary
outcome between the groups despite greater BP reduction in the combination group. Although the combination
group had lower proteinuria, it showed higher rates of hyperkalemia, renal impairment, need for dialysis, hypotension, syncope, and medication discontinuation rates due to poor tolerability. The VA-Nephron D trial specifically
tested the safety and efficacy of a losartan-lisinopril combination in patients with T2DM with diabetic nephropathy
(albuminuria of at least 300 mg/g creatinine). Due to safety concerns and the increased risk of hyperkalemia and
acute kidney injury in the combination group, the trial was stopped early. Similarly, the ALTITUDE study failed
to demonstrate a benefit when adding the direct renin inhibitor aliskiren to either an ACE inhibitor or an ARB in
patients with diabetic nephropathy but showed increased adverse events largely due to increased stroke risk
with the combination and was terminated early as well. In summary, there is likely no net benefit in dual RAAS
blockade, and, given the increased risk of adverse events such as hyperkalemia and acute kidney injury, it is not
generally recommended.
11. What is the role of SGLT2 inhibitors in treating hypertension in patients with T2DM?
Despite the demonstrated renoprotection of ARB therapy, many patients on RAAS blockade still ultimately
progress to ESRD. Another pathologic mechanism in the diabetic nephron besides RAAS activation is SGLT2
upregulation. This luminal proximal tubular glucose-sodium cotransporter (SGLT2) is upregulated in the diabetic
kidney in response to the hyperglycemic state with the aim of increasing the renal resorptive capacity and
glucosuria threshold. This results in decreased sodium delivery to the macula densa and impaired tubuloglomerular feedback. The glomerular afferent arteriole remains vasodilated, promoting glomerular hyperperfusion,
hyperfiltration, and hypertension. SGLT2 inhibitors (canagliflozin, empagliflozin, and dapagliflozin) were developed
as antidiabetic drugs; however, in addition to causing glucosuria and lowering the HbA1c, they induce weight loss,
are mildly diuretic, and cause a 3- to 4-mm Hg reduction in SBP. Cardiovascular safety trials were conducted with
these glucose-lowering agents. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
trial (EMPA-Reg Outcome) demonstrated a significant reduction in major adverse cardiovascular events (nonfatal
MI, stroke, or cardiovascular death) in patients with T2DM at increased cardiovascular risk (>90% on antihypertensive therapy) randomized to empagliflozin. SGLT2 inhibition was associated with a marked reduction in heart
failure hospitalizations. Although not designed as a renal outcome trial, a prespecified renal outcome of incident
nephropathy (worsening albuminuria, serum creatinine doubling, renal replacement therapy, renal death) was
significantly lower with empagliflozin. The majority of patients (>80%) were already on RAAS blockade and had
an eGFR greater than 60 mL/min/1.73 m2 (>50%). Similarly, the Canagliflozin Cardiovascular Assessment Study
(CANVAS), also a cardiovascular outcome trial, demonstrated significant cardiovascular benefits with canagliflozin.
Secondary renal outcomes (40% reduction in composite of 40% eGFR reduction, renal replacement therapy, or renal death) were also lower with canagliflozin. These trials establish SGLT2 inhibitors as attractive add-on therapy
for lowering blood sugar, BP, and reducing cardiovascular risk in patients with T2DM with hypertension who are at
increased cardiovascular risk.
12. Should SGLT2 inhibitors be used in hypertensive patients with T2DM with diabetic
nephropathy?
Kidney disease is a major comorbidity in hypertensive patients with T2DM, and the primary outcome in the
EMPA-Reg and CANVAS trials was cardiovascular, which leaves the primary effect of SGLT2 inhibition on renal
progression in these settings unanswered. Furthermore, the overall renal event rate and levels of proteinuria
were low in these trials, thus capturing a lower renal risk population. The CREDENCE trial was a large randomized placebo-controlled trial using canagliflozin 100 mg daily on top the of maximum tolerated RAAS blockade in
patients with T2DM with significant diabetic kidney disease (GFR of 30-90 mL/min/1.73m2; mean eGFR 56 mL/
min/1.73 m2, and median albuminuria of 927 mg/g creatinine) and a primary renal composite of ESRD (dialysis, transplant, eGFR <15 mL/min/1.73 m2), serum creatinine doubling, and renal or cardiovascular death. The
prespecified efficacy criteria for early cessation of the trial were achieved with a reduction of the primary outcome
in the canagliflozin group by 30% compared to placebo. Canagliflozin reduced SBP on average by 3.3 mm Hg
compared to placebo, but the renoprotection was independent of the BP-lowering effect. This was the first renalspecific primary outcome trial for SGLT2 inhibition. In summary, SGLT2 inhibition (e.g., with canagliflozin 100 mg
daily), in addition to reducing cardiovascular events in hypertensive patients with T2DM, also can be used as a
renoprotective agent on top of RAAS blockade in those with significant diabetic kidney disease (eGFR as low as
30 mL/min/1.73 m2 and albuminuria >300 mg/g). Given their established cardiovascular and renal protection, one
may consider adding SGLT2 inhibitors as a second-line agent on top of RAAS blockade in all hypertensive patients
with diabetes.
13. What is the side effect profile of SGLT2 inhibitors?
Likely due to increased glucosuria, SGLT2 inhibition is associated with more frequent genital mycotic infections
(candida vaginitis in women and balanitis in men). However, most infections are mild and resolve with topical
antifungals. The CREDENCE study did not find a difference in hyperkalemia and acute kidney injury risk between
canagliflozin and placebo. A recent metaanalysis found a significant beneficial effect of SGLT2 inhibitors in
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decreasing acute renal failure episodes. SGLT2 inhibitor use was not associated with increased hypoglycemic
episodes. The CANVAS Program reported an increased amputation and fracture risk with canagliflozin in patients
with known risk factors such as peripheral vascular disease or previous amputations, but this was not confirmed
in CREDENCE or seen with SGLT2 inhibitors other than canagliflozin. Until more data emerges, the amputation risk
remains controversial, but, generally, in the presence of risk factors (history of amputations, active foot ulcer) of
SGLT2 inhibition, the risks versus the benefits of canagliflozin should be weighed.
KEY POINTS
1. There are conflicting guideline-based recommendations on BP targets in patients with diabetes, but currently the
best available evidence supports an individualized approach with an SBP goal of at least 140 mm Hg or less.
2. First-line antihypertensive agents (thiazide, calcium channel blocker, ACE inhibitor, or ARB) are effective at
reducing BP and reducing cardiovascular events in patients with T2DM.
3. Most patients will need a combination of two to three agents of different classes to reach goal BP.
4. Kidney disease (with or without albuminuria) is common in diabetic patients with hypertension, and RAAS
activation is a key pathomechanism.
5. Given their effectiveness at preventing and delaying the progression of kidney disease in diabetes, RAAS
inhibitors are preferred first-line treatment of hypertension in diabetes and also may be considered in the
absence of hypertension.
6. In hypertensive patients with T2DM, SGLT2 inhibitors (canagliflozin, empagliflozin) are effective at reducing
the cardiovascular risk and protecting the kidney in addition to inhibiting RAAS in those with significant kidney
disease and may thus be considered second line after RAAS inhibitors in this setting.
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TRANSPLANTATION
Saed Shawar, MD, and Beatrice P. Concepcion, MBBS
QUESTIONS
1. What is the definition of hypertension in transplant recipients?
The definition of hypertension in transplant recipients follows that of the general population. Most guidelines
for the general population define hypertension as a persistent systolic blood pressure on two separate days of
140 mm Hg or higher and/or diastolic blood pressure of 90 mm Hg or higher if age is 18 years or older. More
recent hypertension guidelines have established a definition of 130/85 mm Hg, but the applicability to transplant
patients is unclear.
2. What is the incidence and prevalence of hypertension after transplantation?
The reported incidence of hypertension varies among different solid organ transplants. In kidney transplant recipients, it ranges from 50% to 80% in adult recipients and from 47% to 82% in pediatric recipients. According to the
International Society of Heart and Lung Transplantation registry, among heart transplant survivors with a 10-year
follow-up between April 1994 and June 2006, hypertension was present in 98% of patients. In liver transplant
recipients, the range has been reported to be from 50% to almost 100% in some series.
3. What is the clinical importance of hypertension in kidney transplant recipients?
Hypertension in kidney transplant recipients is associated with an increased risk of cardiovascular death (CVD),
increased risk of allograft failure and mortality, and increased risk of hospitalization.
• Increased risk of cardiovascular disease
• Hypertension is a traditional risk factor for CVD, which is the leading cause of death in patients with a
functional kidney transplant. The annual rate of fatal or nonfatal CVD events is 3.5% to 5.0% in kidney
transplant recipients, 50-fold higher than in the general population. Uncontrolled systolic and diastolic blood
pressures are associated with worsening left ventricular hypertrophy at 5 years posttransplant, which is also
associated with increased CVD.
• In addition, it has been reported that for every 20-mm Hg increase in systolic blood pressure, there is an as-
sociated 32% increase in the risk for cardiovascular events. Of note, each 10-mm Hg decrease in diastolic
blood pressure below the 70-mm Hg level was found to be associated with a 31% increase in cardiovascular risk, but no such association emerged for diastolic blood pressure levels less than 70 mm Hg.
• Increased risk of allograft failure and mortality
• Hypertension is a potent nonimmunological risk factor and is independently associated with an increased
risk of both allograft failure and mortality. The Collaborative Transplant Study, a large cohort study of nearly
30,000 kidney transplant recipients showed a graded association between both systolic and diastolic blood
pressure and allograft failure. Moreover, increasing systolic pressure was associated with decreased graft
survival at any level of diastolic blood pressure. In addition to decreased allograft survival, hypertension
after transplant was associated with decreased patient survival. Each 10-mm Hg increase in systolic blood
pressure above 140 mm Hg was associated with a hazard ratio (HR) of death of 1.18 (95% confidence
interval [CI], 1.12–1.23). This risk persisted after adjusting for allograft function.
• Increased risk of hospitalization
• Among kidney transplant recipients, hypertension is the second most common cause of cardiovascular-
related hospitalization in the first year after transplantation, accounting for approximately 13% of admissions after heart failure. It is the fourth leading cause of hospitalization (approximately 7%) in the second
year after transplantation.
CHAPTER 19
4. What is the pathogenesis of hypertension after kidney transplantation?
The pathogenesis of hypertension after kidney transplantation is related to several factors which are discussed
below and are summarized in Fig. 19.1.
• Endothelial dysfunction
Endothelial dysfunction is associated with hypertension, and it predicts atherosclerosis progression and cardio-
vascular events in the general population. This is related to one or more of the following factors:
• The imbalance between vasoconstrictive molecules (endothelin, thromboxane, and prostaglandins) and
vasodilatory nitric oxide. This can be caused by calcineurin inhibitors (CNIs).
103
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Fig. 19.1 Hypertension after transplantation. GFR, Glomerular filtration rate; GR, glucocorticoid receptor; MR, mineralocorticoid
receptor; RAAS, renin-angiotensin-aldosterone system; VSMC, vascular smooth muscle cell.
• Increased generation of reactive oxygen species which can be seen in chronic inflammation, ischemia-
reperfusion injury (which can manifest as delayed graft function after transplant), and increased angiotensin
II (Ang II).
• Acute rejection episodes, whether T-cell or antibody-mediated, leading to endothelial injury. This can alter
renal blood flow, impair kidney function, and increase the risk of fibrosis and loss of kidney function.
• Arterial stiffness
Arterial stiffness is a manifestation of hypertension but may also represent a cause of hypertension. Some
studies have shown that CNIs accelerate the arterial stiffness process, whereas belatacept-based regimens
seem to offer better vascular protection compared with CNIs.
• Renin-angiotensin-aldosterone system (RAAS) activation
Activation of the RAAS leads to the production of Ang II, and acting through angiotensin II type 1 (AT1) receptors
on cell membranes, leads to potent vasoconstriction of all blood vessels. It also causes the adrenal glands to
release aldosterone, which increases reabsorption of salt and water, thereby leading to an increase in blood
volume and elevated blood pressure. Increased activity of RAAS is seen in the presence of remaining ischemic
native kidneys, transplant renal artery stenosis, increased sympathetic stimulation, and CNIs, among others.
• Sodium and water retention
Sodium and water retention can be seen in those with low nephron mass and low glomerular filtration rate (GFR),
due to the kidney’s reduced capacity to excrete sodium. CNIs cause increased sodium reabsorption via the increased
activity of the thiazide-sensitive sodium-chloride cotransporter (NCC) and Na-K-2Cl cotransporter (NKCC2). As mentioned previously, upregulation of RAAS increases Ang II, leading to stimulation of aldosterone release. This induces
the upregulation of Na+/K+-ATPase and epithelial sodium channel (ENaC) in the distal convoluted tubule and collecting duct. Ang II also stimulates the production of arginine vasopressin (AVP), which also modulates NCC function.
• Sympathetic nervous system activation
Increased sympathetic nervous system activity has been implicated in the initiation, maintenance, and pro-
gression of posttransplant hypertension. Several factors can increase the activity of the sympathetic nervous
system such as conditions that increase Ang II, comorbidities such as obesity and obstructive sleep apnea, and
drugs such as CNIs.
5. What are the risk factors for hypertension after kidney transplantation?
Risk factors for hypertension after transplantation can be divided into recipient factors, transplant factors, and
donor factors. These are summarized in Table 19.1.
6. How do CNIs affect hypertension after transplantation?
Both cyclosporine and tacrolimus induce or exacerbate hypertension in transplant recipients. Cyclosporine has
a more potent effect on hypertension than tacrolimus. Multiple mechanisms have been suggested, all of which
cause potent vasoconstriction and systemic hypertension. These include the following:
• Activationofthesympatheticnervoussystem
• Upregulationofendothelin,mediatedviaanimbalanceofTregandTh17cell
• IncreasedthromboxaneA2production
• ActivationoftherenalNCC(thiazide-sensitivecotransporter)
• Decreasedprostaglandinproduction
• Decreasednitricoxideproduction
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Table 19.1 Risk Factors for Hypertension after Transplantation
Recipient Factors
Older age
Black ethnicity
Male gender
Obesity
Smoking
Diabetes mellitus
Pretransplant chronic kidney disease
Presence of native kidneys
Pretransplant hypertension
Obstructive sleep apnea
Hypercalcemia
Transplant Factors
Volume overload
Delayed graft function
Acute rejection mainly with angiotensin II type 1 receptor agonist antibody
Poor allograft function for any reason
Immunosuppressive medications, in particular calcineurin inhibitors
Renal artery stenosis
Page kidney
Transplant obstruction: ureteral stenosis, lymphocele, large perinephric fluid collection
Hyperuricemia
Primary hyperaldosteronism
Donor Factors
Older age
Donor hypertension or a donor with a family history of hypertension
Baseline allograft vascular disease and fibrosis
Donor-recipient size discrepancy
7. How do steroids affect hypertension after transplantation?
Corticosteroids are thought to mediate about 15% of hypertension after transplantation, with the effect highest in
those with preexisting hypertension. Their hypertensive effect is dose-dependent and is particularly crucial in the
early posttransplant period. Hypertension may be mediated in part by stimulation of mineralocorticoid receptors, promoting sodium and water retention. Glucocorticoid receptor activation in vascular smooth muscles may
also promote increased vascular tone, increased responsiveness to vasoconstrictors, and decreased vasodilator
production.
8. How does belatacept affect hypertension after transplantation?
Belatacept-based immunosuppression is associated with a reduction of approximately 10 and 5 mm Hg in systolic
and diastolic blood pressures, respectively, compared to CNI-based immunosuppression. In the Belatacept Evaluation of Nephroprotection and Efficacy as a First-line Immunosuppression Trial (BENEFIT), systolic and diastolic
blood pressures were lower in kidney transplant recipients who received belatacept compared with those who
received cyclosporine for immunosuppression even though both treatment groups had the same baseline level of
blood pressure.
9. What is the goal of blood pressure after kidney transplantation?
There are no randomized controlled trials (RCTs) to determine the optimal blood pressure in kidney transplant
recipients. Expert recommendations include the following:
• TheKidneyDisease:ImprovingGlobalOutcomes(KDIGO)Guidelinesuggestsabloodpressureoflessthan
130/80 mm Hg in kidney transplant recipients.
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• The2017AmericanCollegeofCardiology/AmericanHeartAssociationGuidelinesuggeststhatbloodpressure
target should be similar to that of the general chronic kidney disease population, a blood pressure of less than
130/80 mm Hg.
• TheEuropeanBestPracticeGuidelinesrecommendabloodpressuregoaloflessthan125/75mmHgfor
proteinuric patients.
10. What is the significance of low diastolic blood pressure on kidney transplant recipients?
The FAVORIT trial showed that cardiovascular disease risk increased by 31% for each 10-mm Hg decrease in diastolic blood pressure less than 70 mm Hg. In the absence of aortic valve insufficiency, the pattern of high systolic
blood pressure, low diastolic blood pressure, and increased pulse pressure is a marker of vascular stiffness.
11. What approaches should be utilized for treatment of hypertension after kidney transplanta-
tion?
• Nonpharmacologic
• Avoid agents that can worsen hypertension, including nonsteroidal antiinflammatory drugs, decongestants,
birth control pills, cocaine/amphetamine, and ergot-derived medicines.
• Increase diet rich in vegetables, fruits, and whole grains such as the Dietary Approaches to Stop Hyperten-
sion (DASH) diet
• Smoking cessation and limiting alcohol intake
• Weight loss. Reduction in systolic blood pressure with a 10-kg weight loss is 5 to 10 mm Hg.
• Pharmacologic
There are no RCTs that have investigated the optimal antihypertensive regimen in kidney transplant
recipients. No single agent has been found to be more efficient than another. The choice of medications should be
individualized and based on various comorbidities.
12. How should calcium channel blockers be utilized in the treatment of hypertension after
kidney transplantation?
Dihydropyridine calcium channel blockers (CCBs) are considered first-line agents, particularly in the early transplant period. These agents counteract the vasoconstrictive effect of CNIs, possibly leading to improvements in
GFR and graft survival.
• InasystematicreviewandmetaanalysisbyPisanoandcolleagues,CCBswerefoundtodecreasebloodpres-
sure, increase GFR, and reduce the risk for graft loss.
• AsystematicreviewandmetaanalysisbyCrossandcolleaguesanalyzed60RCTswith3802transplant
patients. Twenty-nine trials compared CCBs with placebo or absence of treatment, 10 trials compared
angiotensin-converting enzyme inhibitors (ACEIs) with a placebo or absence of treatment, and seven studies
compared CCBs with ACEIs. The study found that CCBs improved GFR by a mean difference of +4.5 mL/min
and reduced graft loss by 25%. The authors concluded that CCBs may be preferred as a first-line antihypertensive medication in adult kidney transplant recipients
Nondihydropyridine CCBs such as verapamil and diltiazem are usually avoided due to their inhibition of
cytochrome P450 which results in an increase in blood levels of CNIs and mTOR inhibitors. Alternatively, they may
be useful in patients whose CNI levels remain subtherapeutic despite high doses of CNIs.
13. How should diuretics be used in the treatment of hypertension after kidney transplantation?
The use of loop and thiazide diuretics can help manage hypervolemia and hyperkalemia, which are seen frequently in transplant recipients. Moes and colleagues performed a randomized crossover trial comparing chlorthalidone
with amlodipine in hypertensive kidney transplant recipients on tacrolimus immunosuppression. The study noted
similar blood pressure control for chlorthalidone and amlodipine, with slightly lower estimated GFRs and less
proteinuria with chlorthalidone and more lower extremity edema with amlodipine.
14. How should ACEIs and Ang II receptor blockers be used in the treatment of hypertension
after kidney transplantation?
ACEIs and Ang II receptor blockers (ARBs) are usually avoided in the first 3 to 6 months after transplant due to
concerns for worsening of anemia, hyperkalemia, and a possible decline in kidney function. In general, ACEIs and
ARBs are usually used in kidney transplant recipients who have cardiovascular indications for RAAS inhibition,
posttransplant erythrocytosis, or in patients with proteinuria. The KDIGO guideline has an ungraded recommendation of considering ACEIs or ARBs as first-line antihypertensive medications in transplant recipients with
proteinuria. Although ACEIs and ARBs are effective in slowing the progression of chronic kidney disease in the
nontransplant population, particularly those with proteinuria, there is no strong evidence that these medications
confer a benefit on graft or patient survival in kidney transplant recipients.
• Ibrahimandcolleaguesconductedadouble-blind,prospectiverandomized,placebo-controlledtrialinvolving
155 patients comparing the effect of losartan versus placebo initiated within 3 months of transplantation and
continued for 5 years. The study found no significant effect difference between the two groups on a composite
outcome of doubling of the fraction of renal cortical volume occupied by interstitium from baseline to 5 years,
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or end-stage renal disease (ESRD) from interstitial fibrosis/tubular atrophy. The study also found no significant
effect of losartan on time to a composite of ESRD, death, or doubling of creatinine level.
• KnollandcolleaguesconductedanRCToframiprilversusplaceboinkidneytransplantrecipientswithproteinuria. The study enrolled 213 adult kidney transplant recipients who were at least 3 months from transplant
with an estimated GFR of at least 20 mL/min/1.73m2 and had proteinuria of at least 0.2 g/d. There was no
significant difference between the ramipril and placebo groups in terms of the primary outcome, which was a
composite of doubling of serum creatinine, ESRD, or death.
• CheungpasitpornandcolleaguesperformedasystematicreviewandmetaanalysisofthreeRCTsandtwo
cohort studies including 20,024 kidney transplant patients. This showed no significant reduction in the risk of
allograft loss or mortality among kidney transplant recipients treated with ACEIs or ARBs.
• Hiremathandcolleaguesfoundsimilarresultsbasedonasystematicreviewandmetaanalysisofeight
RCTs with a total of 1502 participants. They found no significant difference in the risk of death in the group
with renin-angiotensin system (RAS) blockade compared to the control group (risk ratio [RR], 0.96; 95% CI,
0.62–1.51), transplant failure (RR, 0.76; 95% CI, 0.49–1.18), or doubling of creatinine level (RR, 0.84; 95% CI,
0.51–1.39). There was a more than twofold greater risk of hyperkalemia with RAS blockade.
15. Discuss the role of beta-blockers in the treatment of hypertension after kidney transplantation.
• Beta-blockersarecardioprotectiveinpatientswithcoronaryarterydiseaseandcongestiveheartfailure,andso
patients who are already on beta-blockers should continue to take them in the peritransplant period. Perioperative initiation of beta-blockers may be considered in kidney transplant candidates with established coronary
artery disease or those who have two or more cardiovascular risk factors. However, caution must be taken in
starting beta-blockers immediately prior to surgery as this has been associated with an increased risk of 30day all-cause mortality and stroke in the nontransplant population.
• AretrospectivestudybyAftabandcolleaguesof321kidneytransplantrecipientsfollowedfor10yearsfound
that the use of beta-blockers was associated with reduced mortality (HR, 0.60; 95% CI, 0.36–0.98). This
benefit was seen in all subgroups of patients with different comorbidities.
KEY POINTS
1. Hypertension in kidney transplant recipients is associated with an increased risk of CVD, increased risk of
allograft failure and mortality, and increased risk of hospitalization.
2. Risk factors for hypertension after transplantation are due to a combination of recipient, transplant and donor
factors.
3. Dihydropyridines CCBs are considered first-line agents, particularly in the early transplant period as they
counteract the vasoconstrictive effect of CNIs.
4. ACEIs and ARBs are usually avoided in the first 3 to 6 months after transplant due to concerns for worsening
anemia, hyperkalemia, and a possible decline in kidney function.
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