Hypertensive Kidney Transplant Research Articles

WHITE-COAT HYPERTENSION AND MASKED HYPERTENSION IN HYPERTENSIVE KIDNEY TRANSPLANT RECIPIENTS

Objective: Patients suffering from chronic kidney disease (CKD) have inadequate control of blood pressure (BP) ranging between 30 to 40%. In addition 35% of them have white-coat hypertension or masked hypertension. Recent epidemiologic data in the general population associate both of the aforementioned BP patterns with poor outcomes. The objective of this study is to examine the prevalence of these hypertension phenotypes in hypertensive kidney transplant recipients. Design and method: 150 kidney transplant recipients were included in this study. They underwent 24-hour ABPM with the Mobil-O-Graph NG device. Hypertension was defined as: (1) office BP (oBP) > or = 140/90 mmHg or use of antihypertensive agents, (2) ambulatory BP > or = 130/80 mmHg or use of antihypertensive agents. Patterns of BP control were defined as follows: (1) truly controlled BP (oBP < 140/90 and 24-hr BP < 130/80mmHg), (2) uncontrolled hypertension (oBP > or = 140/90 and 24-hr BP > or = 130/80mmHg), (3) white-coat hypertension (oBP > or = 140/90 and 24-hr BP < 130/80mmHg), (4) masked hypertension (oBP < 140/90 and 24-hr BP > or = 130/80mmHg). Results: The prevalence of hypertension was 88.0% according to office BP readings and 93.3% according to ABPM (p = 0,112). 125 individuals (89,3% of the total) were hypertensives receiving antihypertensive agents. Among them, according to office BP readings and 24-hr ABPM, 44 (31,0%) hypertensive patients had BP control and 30 (21,1%) had uncontrolled hypertension. Moreover, among the hypertensive patients, 10 (7,0 %) had the white-coat hypertension phenotype and 58 (40,8%) had masked hypertension (Fig 1). Conclusions: The use of ABPM in kidney transplant recipients reveals low control of BP, low prevalence of white-coat hypertension and markedly high prevalence of masked hypertension. The last finding is particularly important, considering the established association between masked hypertension and increased cardiovascular risk.

Prevalence of primary aldosteronism in hypertensive kidney transplant recipients: A cross-sectional study.

Due to high prevalence of primary aldosteronism (PA) in the general hypertensive population, and its association with worse cardiovascular and renal outcomes, the 2016 Endocrine Society Guidelines explicitly recognize PA as a major public health issue requiring urgent attention. Its prevalence in hypertensive kidney transplant recipients (KTRs) is unknown. In this cross-sectional study, we screened KTRs with hypertension who were on ≥4 antihypertensive medications, on 3 antihypertensive medications with BP≥140/90, and on potassium supplements, or were hypokalemic. 172 of 280 eligible patients successfully completed the testing. A positive screen for PA defined by an aldosterone-to-renin ratio of ≥20 and a plasma aldosterone concentration of >15ng/dL yielded a prevalence of 15.7%. Potassium supplement requirement (52% vs 27%, P=.01) and hypokalemia (25.9% vs 4.8%, P<.01) were more common in patients who screened positive compared with those who screened negative. 67% of patients who screened positive were on potassium supplements and/or were hypokalemic. Our study is the first to systematically explore the prevalence of PA among the hypertensive KTR population, which has inherently high cardiovascular risk. Further studies are needed to determine the cardiovascular and renal risk attributable to PA, and define optimal therapy for KTRs with PA.

"Smartphone Medication Adherence Saves Kidneys" for Kidney Transplantation Recipients: Protocol for a Randomized Controlled Trial.

BackgroundKidney transplant recipients’ poor medication adherence and poor control of comorbidities, particularly hypertension, are risk factors for graft rejection, graft loss, and death. Few randomized controlled trials (RCTs) have been successful in improving sustained medication adherence and blood pressure control among kidney transplantation recipients. We provide rationale for an RCT evaluating a mobile health medical self-management system for kidney transplantation recipients called Smartphone Medication Adherence Saves Kidneys (SMASK).ObjectiveOur objective is to determine whether SMASK is efficacious in improving medication adherence and sustaining blood pressure control among kidney transplantation recipients with uncontrolled hypertension and poor medication adherence compared to an enhanced standard care.MethodsThis two-arm, 6-month, phase II single-site efficacy RCT will involve 80 kidney transplantation recipients. Participants will be randomly assigned to the SMASK intervention arm or control arm. SMASK includes multilevel components: automated reminders from an electronic medication tray; tailored text messages and motivational feedback, guided by the self-determination theory; and automated summary reports for providers. Evaluations will be conducted preintervention, at 3 and 6 months, and posttrial at 12 months. Specific aims are to test the hypotheses that compared to standard care, the SMASK cohort will demonstrate significantly improved changes at 3, 6, and 12 months in the primary outcome variables medication adherence (proportion with electronic monitor-derived score >0.90) and blood pressure control (proportion meeting and sustaining adherence to the Kidney Disease Improving Global Outcomes [KDIGO] guidelines for blood pressure control); the secondary outcome variables provider adherence to KDIGO guidelines, measured by timing of medication changes and changes in self-determination theory constructs; and the exploratory outcome variables estimated glomerular filtration rate, variability in calcineurin inhibitor trough levels, and proportion of patients meeting and sustaining the 24-hour ambulatory blood pressure below 130/80 mm Hg. After the 6-month evaluation, interviews with a random sample of SMASK subjects (n=20) and health care providers (n=3-5) will assess user reactions including acceptability, usability, and aids/barriers to sustainability. Data from the RCT and interviews will be triangulated to further refine and optimize SMASK and prepare for a multisite effectiveness RCT.ResultsThe SMASK project received funding from National Institute of Diabetes and Digestive and Kidney Diseases in June 2016, obtained institutional review board approval in April 2016, and began data collection in July 2016. As of July 2018, we completed enrollment with a total of 80 participants.ConclusionsThis study will provide data regarding the efficacy of SMASK to improve medication adherence and blood pressure control in a cohort of hypertensive kidney transplant recipients. An efficacious SMASK intervention will pave the way for a larger, multicenter, effectiveness RCT powered sufficiently to evaluate clinical events in a real-world setting and with the potential to demonstrate improved outcomes at lower cost than standard care.International Registered Report Identifier (IRRID)DERR1-10.2196/13351

NaCl cotransporter abundance in urinary vesicles is increased by calcineurin inhibitors and predicts thiazide sensitivity.

Animal studies have shown that the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus can activate the thiazide-sensitive NaCl cotransporter (NCC). A common side effect of CNIs is hypertension. Renal salt transporters such as NCC are excreted in urinary extracellular vesicles (uEVs) after internalization into multivesicular bodies. Human studies indicate that CNIs also increase NCC abundance in uEVs, but results are conflicting and no relationship with NCC function has been shown. Therefore, we investigated the effects of CsA and Tac on the abundance of both total NCC (tNCC) and phosphorylated NCC at Thr60 phosphorylation site (pNCC) in uEVs, and assessed whether NCC abundance in uEVs predicts the blood pressure response to thiazide diuretics. Our results show that in kidney transplant recipients treated with cyclosporine (n = 9) or tacrolimus (n = 23), the abundance of both tNCC and pNCC in uEVs is 4–5 fold higher than in CNI-free kidney transplant recipients (n = 13) or healthy volunteers (n = 6). In hypertensive kidney transplant recipients, higher abundances of tNCC and pNCC prior to treatment with thiazides predicted the blood pressure response to thiazides. During thiazide treatment, the abundance of pNCC in uEVs increased in responders (n = 10), but markedly decreased in non-responders (n = 8). Thus, our results show that CNIs increase the abundance of both tNCC and pNCC in uEVs, and these increases correlate with the blood pressure response to thiazides. This implies that assessment of NCC in uEVs could represent an alternate method to guide anti-hypertensive therapy in kidney transplant recipients.

Chlorthalidone Versus Amlodipine for Hypertension in Kidney Transplant Recipients Treated With Tacrolimus: A Randomized Crossover Trial

Chlorthalidone is a very effective antihypertensive drug, but it has not been studied prospectively in kidney transplant recipients with hypertension. Recent data indicate that calcineurin inhibitors activate the thiazide-sensitive sodium chloride cotransporter, providing further rationale to test thiazides in this population. Randomized noninferiority crossover trial (noninferiority margin,-2.8mmHg). Hypertensive kidney transplant recipients using tacrolimus (median duration, 2.4 years after transplantation; mean estimated glomerular filtration rate, 63±27 [SD] mL/min/1.73m2; mean systolic blood pressure [SBP], 151±12mmHg). Amlodipine (5-10mg) and chlorthalidone (12.5-25mg) for 8 weeks (separated by 2-week washout). Average daytime (9 am to 9 pm) ambulatory SBP. Blood pressure and laboratory parameters. 88 patients underwent ambulatory blood pressure monitoring, of whom 49 (56%) with average daytime SBP>140mmHg were enrolled. 41 patients completed the study. Amlodipine and chlorthalidone both reduced ambulatory SBP after 8 weeks (mean changes of 150±12 to 137±12 [SD] vs 151±12 to 141±13mmHg; effect size,-4.2 [95% CI,-7.3 to 1.1] mmHg). Despite these similar blood pressure responses, chlorthalidone reduced proteinuria by 30% (effect size,-65 [95% CI,-108 to-35] mg/g) and also reduced physician-assessed peripheral edema (22% to 10%; P<0.05 for both). In contrast, chlorthalidone temporarily reduced kidney function and increased both serum uric acid and glycated hemoglobin levels. Open-label design, short follow-up, per-protocol analysis. Chlorthalidone is an antihypertensive drug equally effective as amlodipine after kidney transplantation.

Hypertensive emergency in kidney transplant recipient with autosomal dominant polycystic kidney disease

Background: Aldosterone agonist is used for calcineurin inhibitor (CNI)-induced hyperkalemia in kidney transplant recipient; however, it potentially causes uncontrolled blood pressure (BP). We report a hypertensive kidney transplant recipient with hyperkalemia resolved by aldosterone agonist. Case Description: A 65-year-old man with ESRD from type 2 diabetes mellitus underwent uneventful kidney transplantation. Tacrolimus and prophylaxis trimethoprim/sulfamethoxazole (TMP/SMZ) was started. He had persistent hyperkalemia with serum potassium (K) of 5.1-5.7 mmol/L and non-anion gap metabolic acidosis (NAGMA). BP was uncontrolled with average SBP and DBP of 180 and 60 mmHg, respectively (Figure 1). On posttransplant day 11, K increased up to 6.4 mmol/L even good urine output (UOP) of 1.6-2.2 L/day and serum creatinine (SCr) of 2.3 mg/dL from the pretransplant SCr of 10.31 mg/dL. In addition to low K diet, he was treated with sodium polystyrene sulfonate with several bowel movements; however, K still elevated. Therefore, fludrocortisone was started and K was normalized. BP medications were adjusted. Discussion: Tacrolimus causes distal tubular defect mimicking type 4 renal tubular acidosis (T4RTA) by inhibiting basolateral Na-K ATPase at the collecting duct causing impaired transepithelial K secretion from decreased sodium uptake. It also causes hypertension (HTN) from renal afferent arteriolar vasoconstriction and activation of Na-Cl cotransporter (NCC) in the distal collecting tubule (DCT) and subsequently HTN. Hyperkalemia in our patient is from tacrolimus since he had posttransplant hyperkalemia even with improving renal allograft function. TMP/SMX could contribute to hyperkalemia. Aldosterone agonist corrects hyperkalemia but causes uncontrolled BP. Conclusions: Uncontrolled HTN limits the utility of aldosterone agonist for the treatment of CNI-induced hyperkalemia. Since tacrolimus stimulates NCC, thiazide diuretics could potentially be used for BP control once renal allograft function is stable.

Aldosterone agonists: Limited utility for calcineurin inhibitor-induced hyperkalemia in hypertensive kidney transplant recipient

Aldosterone agonists: Limited utility for calcineurin inhibitor-induced hyperkalemia in hypertensive kidney transplant recipient

24hr Ambulatory Blood Pressure Monitoring (ABPM) Risk Stratifies Hypertensive Kidney Transplant Recipients (KTRs).

Background and Methods: Systolic hypertension has been shown to be associated with adverse clinical outcomes after renal transplantation. In non-transplant patients, 24hr ambulatory blood pressure monitoring (ABPM) has been shown to be a superior predictor of clinical outcomes when compared to clinical blood pressure readings alone. In this study we have prospectively analysed129 kidney transplant recipients (KTR) diagnosed with hypertension based on the clinic blood pressure (CBP) of >130/80mm Hg. All these patients underwent ABPM and groups were stratified based on ABPM systolic (>/<130mm Hg) and diastolic blood pressure (</>80mm Hg) values (SBP & DBP). The primary outcome measure was a composite of graft loss, cardiovascular event or death over a 5year follow-up. Results: Of the 129 KTRs, only 64 had average 24hr SBP>130 mm Hg on ABPM. Overall, CBP significantly overestimated SBP even in the true hypertensive KTRs based on ABPM (CBP, 164± 16 mm Hg, ABPM, 143± 9 mm Hg, P<0.0001). Based on the ABPM readings, 33% of hypertensive KTRs required an increase in their anti-hypertensive therapy (P=0.01). Day time (P=0.002) and 24hr average SBP (P<0.001) were strongly associated with the composite end point in a univariate Kaplan Meier analysis. Whilst the 24hr average DBP (P=0.03) was significantly associated with poor event free survival, nocturnal dipper status was not significant. The influence of 24hr average SBP on event free survival was more significant in KTRs with diabetes (P=0.02), lower eGFR (P=0.001), proteinuria (P=0.007), who are younger (P=0.02) and female (P=0.01). Similar non-significant trends were seen with DBP as well. Despite a significant improvement in CBP in both the groups over 5 years, eGFR and proteinuria remained significantly worse in the true hypertensive group based on the assessment of ABPM during this period.Figure: No Caption available.Conclusions: To conclude, 24hr ABPM helps to risk stratify apparent hypertensive KTRs based on CBP. True hypertensives based on ABPM represent a significantly high risk population with adverse medium term outcomes despite appropriate therapy.

Mobile Health Medication Adherence and Blood Pressure Control in Renal Transplant Recipients: A Proof-of-Concept Randomized Controlled Trial

BackgroundMobile phone based programs for kidney transplant recipients are promising tools for improving long-term graft outcomes and better managing comorbidities (eg, hypertension, diabetes). These tools provide an easy to use self-management framework allowing optimal medication adherence that is guided by the patients’ physiological data. This technology is also relatively inexpensive, has an intuitive interface, and provides the capability for real-time personalized feedback to help motivate patient self-efficacy. Automated summary reports of patients’ adherence and blood pressure can easily be uploaded to providers’ networks helping reduce clinical inertia by reducing regimen alteration time.ObjectiveThe aim of this study was to assess the feasibility, acceptability, and preliminary outcomes of a prototype mobile health (mHealth) medication and blood pressure (BP) self-management system for kidney transplant patients with uncontrolled hypertension.MethodsA smartphone enabled medication adherence and BP self-management system was developed using a patient and provider centered design. The development framework utilized self-determination theory with iterative stages that were guided and refined based on patient/provider feedback. A 3-month proof-of-concept randomized controlled trial was conducted in 20 hypertensive kidney transplant patients identified as non-adherent to their current medication regimen based on a month long screening using an electronic medication tray. Participants randomized to the mHealth intervention had the reminder functions of their electronic medication tray enabled and received a bluetooth capable BP monitor and a smartphone that received and transmitted encrypted physiological data and delivered reminders to measure BP using text messaging. Controls received standard of care and their adherence continued to be monitored with the medication tray reminders turned off. Providers received weekly summary reports of patient medication adherence and BP readings.ResultsParticipation and retention rates were 41/55 (75%) and 31/34 (91%), respectively. The prototype system appears to be safe, highly acceptable, and useful to patients and providers. Compared to the standard care control group (SC), the mHealth intervention group exhibited significant improvements in medication adherence and significant reductions in clinic-measured systolic blood pressures across the monthly evaluations. Physicians made more anti-hypertensive medication adjustments in the mHealth group versus the standard care group (7 adjustments in 5 patients versus 3 adjustments in 3 patients) during the 3-month trial based on the information provided in the weekly reports.ConclusionsThese data support the acceptability and feasibility of the prototype mHealth system. Further trials with larger sample sizes and additional biomarkers (eg, whole blood medication levels) are needed to examine efficacy and effectiveness of the system for improving medication adherence and blood pressure control after kidney transplantation over longer time periods.Trial RegistrationClinicaltrials.gov NCT01859273; http://clinicaltrials.gov/ct2/show/NCT01859273 (Archived by WebCite at http://www.webcitation.org/6IqfCa3A3).

Normal adiponectin levels in kidney transplant patients with hypertension

Kidney transplant patients are a unique population where despite correction of their kidney function they are still considered to be at high cardiovascular (CV) risk. Adiponectin, an adipokine secreted from adipocytes, has protective CV properties. Patients with essential hypertension (HTN) have low adiponectin levels that are associated with a high CV risk. The aim of this study was to assess adiponectin levels in hypertensive renal transplant recipients. Fasting blood adiponectin levels were measured in hypertensive kidney transplant patients (n = 18), patients with essential HTN (n = 17) and healthy subjects (n = 14). Patients with diabetes mellitus and renal failure were excluded from the study. Anthropomorphic and metabolic parameters were also measured. Patients with essential HTN had lower adiponectin levels than healthy controls (6 ± 0.7 μg/mL vs. 11 ± 0.9 μg/mL, p < 0.001), whereas hypertensive kidney transplant patients had adiponectin levels that were similar to adiponectin levels found in normal controls (11 ± 1.1 μg/mL). Adiponectin levels in healthy subjects were inversely correlated with plasma triglycerides (r = -0.876, p < 0.001) and with body weight (r = -0.7, p < 0.001). There was no such a correlation in patients with HTN. Adiponectin in hypertensive kidney transplant recipients is not an appropriate CV risk marker as it does not adequately distinguish these patients from normal controls.

Ambulatory Blood Pressure Monitoring in Kidney Transplant Patients: RETENAL Study

Hypertension is common following renal transplantation, affecting up to 80% of transplant recipients. It is generally accepted that hypertension is associated with poor graft survival and reduced life expectancy, contributing to increased cardiovascular risk factors and mortality rates. The aim of the study was to compare the blood pressure (BP) control in kidney transplant patients through the use of ambulatory BP monitoring (ABMP) versus office BP measurements (oBP). A multicenter, cross-sectional, observational study was conducted in 30 nephrology/kidney transplant units. Eligible patients included hypertensive cadaveric kidney transplant recipients aged <70 years, with a functioning kidney for at least 1 year and with an estimated glomerular filtration ≥30 mL/min/1.73 m2 and a serum creatinine < 2.5 mg/dL. Recorded data included demographic characteristics, oBP, and ABPM and labroatory investigations. The 868 patients showed a mean recipient age of was 53.2 ± 11.6 years and mean follow-up after transplantation, 5.5 ± 2.8 years. Mean systolic and diastolic oBP were 140.2 ± 18 and 80.4 ± 10 mm Hg, respectively. Seventy-six percent of patients had oBP higher than or equal to 130/80 mm Hg. Mean 24 hour ABPM were 131.5 ± 14 and 77.4 ± 8.7 mm Hg for systolic and diastolic BP, respectively. Using the ABPM, we observed that 36.5% of subjects were controlled (mean 24-hour BP < 130/85 mm Hg). The two methods (oBP and ABPM) showed significant agreement. After ABPM, 65% of patients diagnosed as true controlled hypertension were considered to have white-coat RH. In clinical practice ABPM may help for better adjustment of drugs for adequate BP control.

Urinary and dietary sodium and potassium associated with blood pressure control in treated hypertensive kidney transplant recipients: an observational study

BackgroundIn kidney transplant (Kt) recipients , hypertension is a major risk for cardiovascular complications but also for graft failure. Blood pressure (BP) control is therefore mandatory. Office BP (OBP) remains frequently used for clinical decisions, however home BP (HBP) have brought a significant improvement in the BP control. Sodium is a modifiable risk factor, many studies accounted for a decrease of BP with a sodium restricted diet. Increased potassium intake has been also recommended in hypertension management. Using an agreement between office and home BP, the present study investigated the relations between the BP control in Kt recipients and their urinary excretion and dietary consumption of sodium and potassium.MethodsThe BP control defined by OBP <140/90 mmHg and HBP <135/85 mmHg was tested in 70 Kt recipients (mean age 56 ± 11.5 years; mean graft survival 7 ± 6.6 years) treated with antihypertensive medications. OBP and HBP were measured with a validated oscillometric device (Omron M6®). The 24-hour urinary sodium (Na+) and potassium (K+) excretions as well as dietary intakes were compared between controlled and uncontrolled (in office and at home) recipients. Non parametric Wilcoxon Mann–Whitney Test was used for between groups comparisons and Fisher's exact test for frequencies comparisons. Pearson correlation coefficients and paired t-test were used when sample size was >30.ResultsUsing an agreement between OBP and HBP, we identified controlled (21%) and uncontrolled recipients (49%). Major confounding effects susceptible to interfere with the BP regulation did not differ between groups, the amounts of sodium excretion were similar (154 ± 93 vs 162 ± 88 mmol/24 h) but uncontrolled patients excreted less potassium (68 ± 14 vs 54 ± 20 mmol/24 h; P = 0.029) and had significantly lower potassium intakes (3279 ± 753 vs 2208 ± 720 mg/24 h; P = 0.009), associated with a higher urinary Na+/K + ratio. Systolic HBP was inversely and significantly correlated to urinary potassium (r = −0.48; P = 0.002), a positive but non significant relation was observed with urinary sodium (r = 0,30;P = 0.074).ConclusionsHalf of the treated hypertensive Kt recipients remained uncontrolled in office and at home. Restoring a well-balanced sodium/potassium ratio intakes could be a non pharmacological opportunity to improve blood pressure control.

Antihypertensives for Kidney Transplant Recipients: Systematic Review and Meta-Analysis of Randomized Controlled Trials

In nontransplant populations, effects of different antihypertensive drug classes vary. Relative effects in kidney transplant recipients are uncertain. We performed a systematic review including random effects meta-analysis of randomized controlled trials, using Cochrane Collaboration methodology. We identified 60 trials, enrolling 3802 recipients. Twenty-nine trials (2262 patients) compared calcium channel blockers (CCB) with placebo or no treatment, 10 trials (445 patients) compared angiotensin-converting enzyme inhibitors (ACEi) with placebo or no treatment, and seven studies (405 patients) compared CCB with ACEi. CCB compared with placebo or no treatment (plus additional agents in either arm as required) reduced graft loss (risk ratio [RR] 0.75, 95% confidence intervals [CI] 0.57-0.99) and improved glomerular filtration rate (GFR; mean difference [MD] 4.5 mL/min, 95% CI 2.2-6.7). Data on ACEi versus placebo or no treatment were inconclusive for GFR (MD -8.1 mL/min, 95% CI -18.6-2.4) and inconsistent for graft loss, precluding meta-analysis. In direct comparison with CCB, ACEi decreased GFR (MD 11.5 mL/min, 95% CI 7.2-15.8), proteinuria (MD 0.28 g/day, 95% CI 0.10-0.47), hemoglobin (MD 11.5 g/L, 95% CI 7.2-15.8), and increased hyperkalemia (RR 3.7, 95% CI 1.9-7.7). Graft loss data were inconclusive (RR 7.4, 95% CI 0.4-140). These data suggest that CCB may be preferred as first-line agents for hypertensive kidney transplant recipients.

Antihypertensive treatment for kidney transplant recipients.

In some nontransplant populations, effects of different antihypertensive drug classes vary. Relative effects in kidney transplant recipients are uncertain. To assess comparative effects of different classes of antihypertensive agents in kidney transplant recipients. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, conference proceedings and reference lists of identified studies were searched. Randomised controlled trials of any antihypertensive agent applied to kidney transplant recipients for at least two weeks were included. Data was extracted by two investigators independently. Study quality, transplant outcomes and other patient centred outcomes were assessed using random effects meta-analysis. Risk ratios (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, both with 95% confidence intervals (CI) were calculated. Stratified analyses and meta-regression were used to investigate heterogeneity. We identified 60 studies, enrolling 3802 recipients. Twenty-nine studies (2262 participants) compared calcium channel blockers (CCB) to placebo/no treatment, 10 studies (445 participants) compared angiotensin converting enzyme inhibitors (ACEi) to placebo/no treatment and seven studies (405 participants) compared CCB to ACEi. CCB compared to placebo/no treatment (plus additional agents in either arm as required) reduced graft loss (RR 0.75, 95% CI 0.57 to 0.99) and improved glomerular filtration rate (GFR), (MD, 4.45 mL/min, 95% CI 2.22 to 6.68). Data on ACEi versus placebo/no treatment were inconclusive for GFR (MD -8.07 mL/min, 95% CI -18.57 to 2.43), and variable for graft loss, precluding meta-analysis. In direct comparison with CCB, ACEi decreased GFR (MD -11.48 mL/min, 95% CI -5.75 to -7.21), proteinuria (MD -0.28 g/24 h, 95% CI -0.47 to -0.10), haemoglobin (MD -12.96 g/L, 95% CI -5.72 to -10.21) and increased hyperkalaemia (RR 3.74, 95% CI 1.89 to 7.43). Graft loss data were inconclusive (RR 7.37, 95% CI 0.39 to 140.35). Other drug comparisons were compared in small numbers of participants and studies. These data suggest that CCB may be preferred as first line agents for hypertensive kidney transplant recipients. ACEi have some detrimental effects in kidney transplant recipients. More high quality studies reporting patient centred outcomes are required.

Role of rho-kinase in the regulation of vascular tone in hypertensive renal transplant recipients

Activation of rho-kinase (ROK) is involved in the development of hypertension as it is a potent regulator of vascular smooth muscle cell (VSMC) contractility. Here we evaluated whether activation of ROK is present in hypertensive kidney transplant recipients (NTX). We tested the effect of the ROK-inhibitor fasudil on the regulation of forearm blood flow (FBF) in NTX and in healthy control subjects (CTL). In addition potential modulating effects of ROK-inhibition on local vascular nitric oxide (NO) release were studied. The effect of intra-arterial infusion of fasudil on FBF was studied by venous-occlusion plethysmography in NTX and CTL. To unmask the role of NO fasudil was infused with/without clamping of vascular NO in NTX and CTL. To unravel the basal NO-mediated tone the NO-synthase inhibitor l-NMMA was infused. Fasudil markedly but comparably increased FBF in NTX and CTL. The vascular response to fasudil was blunted during NO-clamp in CTL (104 ± 18% vs. 244 ± 48% for NO-clamp + fasudil vs. fasudil alone; baseline = 0%, P < 0.05) but not in NTX. The l-NMMA-induced vasoconstriction was impaired in NTX compared to CTL. In NTX and CTL basal vascular tone equally depends on ROK. Fasudil-induced vasodilatation is partly mediated by vascular NO in CTL but not in NTX. The greater NO-insensitive fasudil-induced increase in FBF in NTX suggests an increased ROK-mediated VSMC constrictor tone in these patients. Basal NO-mediated tone is attenuated in hypertensive NTX.

Is RAS blockade routinely indicated in hypertensive kidney transplant patients?

There is a high incidence of hypertension after kidney transplantation, which has been associated with the development of left ventricular hypertrophy, an increased risk for acute rejection, lower graft survival, and increased mortality. The pathogenesis of post-transplant hypertension is multifactorial, and therefore optimum therapy for it is not clearly defined. Historically, use of renin-angiotensin system (RAS) blockade in post-transplant hypertension has been limited given concerns of inducing worsening allograft function. Recent data demonstrated that subjects with post-transplant hypertension can be treated effectively with RAS blockers, and that these agents may offer significant additional benefits beyond blood pressure control. Review of the literature suggests that RAS blockers should be considered as useful agents for treatment of post-transplant hypertension not due to transplant renal artery stenosis.

Strategies to reduce clinical inertia in hypertensive kidney transplant recipients

BackgroundMany kidney transplant recipients have hypertension. Elevated systolic blood pressures are associated with lower patient and kidney allograft survival.MethodsThis retrospective analysis examined the prevalence of clinical inertia (failure to initiate or increase therapy) in the treatment of hypertension before and after the introduction of an automated device (BpTRU) in the kidney transplant clinic.ResultsHistorically only 36% (49/134) of patients were prescribed a change in therapy despite a systolic blood pressure ≥ 130 mmHg. After the introduction of BpTRU, 56% (62/110) of the patients had a change in therapy. In a multivariate logistic regression analysis of the entire cohort (n = 244) therapeutic changes were associated with higher blood pressures (OR 1.08 per mmHg, 95% CI 1.04–1.12) and use of the BpTRU (OR 2.12, 95% CI 1.72–3.83). In addition patients on more medications were also more likely to have a change in therapy.ConclusionBlood pressure measurement with automated devices may help reduce clinical inertia in the kidney transplant clinic.

Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

In 1984, Loskutoff et al. ([1][1]) purified plasminogen activator inhibitor-1 (PAI-1) from conditioned media of cultured endothelial cells. This 50-kd glycoprotein is the primary physiologic inhibitor of the serine proteases tissue-type and urokinase-type plasminogen activators (tPA and uPA,

Thrombin Activatable Fibrinolysis Inhibitor in Hypertensive Kidney Transplant Recipients

Kidney transplant recipients are prone to hypertension, dyslipidemia, and cardiovascular death. Hypertension is associated with hemostatic abnormalities. Thrombin activatable fibrinolysis inhibitor (TAFI) is a glycoprotein that links coagulation and fibrinolysis. The purpose of this study was to assess TAFI concentrations in renal transplant recipients in relation to blood pressure. Additionally, we evaluated thrombin activity (thrombin-antithrombin complex [TAT], prothrombin fragments 1+2 [F1+2]), thrombomodulin (TM), and the degree of plasmin generation (plasmin-antiplasmin complex [PAP]) using commercially available kits. The studies were performed on 86 renal allograft recipients (48 women, 38 men) at age range 26 to 73 years. The immunosuppressive regimen consisted of cyclosporine (CsA), prednisone, and azathioprine (n = 58) or mycophenolate mofetil (MMF; n = 28). All patients maintained sufficient and stable graft function, showing no clinical signs of rejection. In patients with hypertension (n = 68), we observed significantly higher concentrations of TAFI and of markers of thrombin generation (F1+2, TAT), and of thrombomodulin with significantly prolonged euglobulin clot lysis time (ECLT), which reflects overall fibrinolytic activity and lower fibrinolytic activity index (FAI). Both groups did not differ with respect to age, creatinine clearance, body mass index, time after transplantation, albumin, fibrinogen, and PAP. Diastolic blood pressure correlated significantly with TAFI concentrations, uric acid, and prednisone dose, whereas systolic blood pressure correlated with urea, uric acid, creatinine clearance, and MCV. Elevated TAFI concentrations and enhanced thrombin generation in hypertensive kidney transplant recipients may contribute to the hypofibrinolysis and progressive atherosclerosis in this population. Blood pressure was related to kidney function, maintenance prednisone dose, and TAFI concentration.

Inhibition of Plasminogen Activator Inhibitor-1 by Angiotensin II Receptor Blockers on Cyclosporine-Treated Renal Allograft Recipients

Introduction We previously showed that proteinuria from a renal graft was significantly decreased by administration of losartan potassium, an angiotensin II receptor blockers (ARB). To further evaluate the mechanism, we performed another clinical study focusing on the change in plasma plasminogen activator inhibitor-1 (PAI-1) levels among cyclosporine (CyA)-treated renal allograft recipients. Methods Among 12 hypertensive CyA-treated kidney transplant patients, four received 25 to 50 mg/day of losartan; four, 4 to 8 mg/day of candesartan cilexetil; and another four, 20 to 40 mg/day of nifedipine. Four CyA-treated kidney-transplanted patients without hypertension were selected as a control group. Informed consent was obtained from all participants. PAI-1 and serum creatinine (S-Cr) levels were monitored every 3 months for 1 year. Results Considering the pretreatment of PAI-1 as 100%, the mean percent of PAI-1 at 1 year after the onset of study for losartan, candesartan, nifedipine, and control groups were 78.6 ± 6.7%, 81.4 ± 8.0%, 96.7 ± 7.6%, and 110.4 ± 9.2%, respectively. The ARB groups demonstrated significant differences from the control group ( P < .01), while the nifedipide group did not. S-Cr levels among ARB-administered groups were increased slightly but temporarily. As for S-Cr levels, no significant differences were seen among the four groups. Conclusions Control of hypertension itself is important for all renal graft recipients; however, PAI-1 reduction by ARBs was thought to be a key for renal preservation. We expect that ARBs will contribute to prolonged renal allograft survival.