Normotensive Recipients Research Articles

Effect of Body Composition on Graft Function and Cardiovascular Outcomes in Normotensive Renal Transplant Recipients.

We evaluated the effects of body composition on graft function and cardiovascular outcomes in normotensive renal transplant recipients. In this cross-sectional study, we analyzed ambulatory blood pressure monitoring data from 136 renal transplant recipients with stable allograft function after living related donor transplant. We enrolled 87 normotensive recipients. We analyzed left ventricular mass index, renal resistive index, and body composition of recipients. We divided recipients into 2 groups according to mean lean body mass, defined by bioimpedance analysis, with 38 in group 1 (lean body mass <47 kg) and 49 in group 2 (lean body mass ≥47 kg). Mean time posttransplant was 35.0 ± 23.3 months. Mean renal resistive index, left ventricular mass index, lean body mass, body mass index, and fat mass were 0.67 ± 0.1, 195.0 ± 118.5 g/m2, 47.3 ± 9.1 kg, 25.9 ± 5.0 kg, and 44.6±10.5 kg,respectively. Lean body mass was positively correlated to sex (r = 0.36, P = .03), body mass index (r = 0.04, P = .416),renalresistive index (r = 0.495, P = .01), and left ventricular mass index (r = 0.713, P = .02) but negatively correlated to serum albumin levels (r=-0.343, P=0.04). Lean body mass was significantly higher in males than in females (P = .03). Patients in group 2 had significantly higher left ventricular mass index (P = .01) and renal resistive index (P = .03). In multiple regression analysis, lean body mass (P = .01) and left ventricular mass index (P = .01) were predictors of renal resistive index. Lean body mass significantly influences left ventricular mass index and renal resistive index. Hence, body composition analysis could be an early predictor of graft function and cardiovascular outcomes in normotensive renal transplant recipients.

Conn´s syndrome after kidney transplantation.

Conn's syndrome, defined as unilateral aldosterone-producing adenoma, accounts for 35-40% of cases of primary hyperaldosteronism. Primary hyperaldosteronism typically occurs in younger patients with poorly controlled arterial hypertension due to extracellular fluid retention, in whom at least atriple combination of antihypertensives, including adiuretic, is needed to maintain normotension. The clinical picture of arterial hypertension may be complemented by symptoms associated with hypokalaemia, such as weakness, fatigue, palpitations, convulsions, polydipsia, or polyuria. In addition to arterial hypertension and hypokalaemia, the diagnosis of Conn's syndrome relies on examination of serum renin and aldosterone concentrations, plasma renin activity, exercise or furosemide stimulation tests, and imaging studies, preferably computed tomography. The method of treatment of Conn's syndrome is adrenalectomy. In patients with primary hyperaldosteronism with underlying bilateral adrenal cortical hyperplasia or patients contraindicated for surgery, mineralocorticoid receptor antagonists are administered in combination with antihypertensives targeted for optimal blood pressure control.In the group of patients after kidney transplantation, the exact incidence of primary hyperaldosteronism is unknown. Based on across-sectional study performed in 2020, it is estimated to be approximately 15% in the group of patients with unsatisfactorily compensated arterial hypertension; in the cohort of normotensive recipients, the incidence of primary hyperaldosteronism is not documented. Diagnosis of Conn's syndrome in patients in the early period after kidney transplantation is problematic, as the prevalence of arterial hypertension in transplanted patients is high (70-90%) according to the literature. Mineral abnormalities, including hypokalaemia, are also common in the early post-transplant period, mainly due to factors such as duration of cold ischaemia, onset of graft function, donor parameters, post-transplant tubulopathy, and diuretics, the effects of immunosuppressive drugs (especially calcineurin inhibitors and corticosteroids), and possibly potassium-restricted dietary habits that the patient brings from the pre-transplant period, which may mask the effect of hyperaldosteronism on potassium.We present the case of apatient who was diagnosed with Conn's syndrome 7 months after primary kidney transplantation from adeceased donor based on persistent hypokalaemia unresponsive to replacement therapy. At the time of the first manifestation of severe hypokalaemia, the patient was treated with adual combination of antihypertensives (amlodipine at adaily dose of 5 mg and carvedilol at adaily dose of 50 mg), without the need for adiuretics.We consider the case interesting because the spectrum of mineral and acid-base abnormalities in advanced renal failure and in the early post-transplant period, as well as acid-base and mineral imbalances, including hypokalaemia, and the high prevalence of arterial hypertension in the post-transplant period, may mask the picture of Conn's syndrome (Fig. 3, Ref. 19). Text in PDF www.elis.sk Keywords: kidney transplantation, primary hyperaldosteronism, hypokalaemia, metabolic alkalosis, secondary arterial hypertension.

AT1R BLOCKADE PROMOTES TRANSFER OF HYPERTENSION BY RENAL CD11C+F4/80+ MACROPHAGES

Objective: The immune system participates in arterial hypertension (AHT) induced by Angiotensin II (AngII). dendritic cells (DCs)-CD11c+ and macrophages (Mo) are abundant in the kidney. However, new subpopulations of CD11c+ cells with Mo characteristics have been described, presenting an F4/80+ phenotype. Additionally, recent studies have shown a controversial role of the type 1 AngII receptor (AT1R) in CD11c+ cells. In this context, it is unknown whether Mo CD11c+-F4/80+ modifies their phenotype during AngII-induced inflammatory kidney damage, and whether this promotes AHT in an AT1R-dependent manner. The goal was evaluate whether renal Mo CD11c+-F4/80+ (rMo) modify their phenotype in AHT by AngII and determine whether their transfer to normotensive animals promotes AHT in an AT1R-dependent manner. Design and method: Male C57BI/6 mice (8 - 10 weeks, n = 6) were infused with AngII (490 ng/kg/min), AngII+Losartan (LOS; 20mg/kg/day, in drinking water), or vehicle for 14 -days. Systolic blood pressure (SBP) was measured by photoplestimography, DCs-CD11c+-F4/80- and rMo infiltrate were evaluated in cortex and medulla by flow cytometry. These cells were isolated and transferred to normotensive recipients, whose SBP was measured for 7-days (n = 3 - 5). Finally, the rMo were stimulated in vitro with AngII (100nM-24h) to analyze the abundance of mRNAs (Nox2, Sgk1, ENaC and AT1R; qRT-PCR). The data correspond to the mean ± standard deviation. Results: AngII increased SBP (AngII 134.7 ± 6.9 vs. Vehicle (Vh) 114.5 ± 7.8mmHg;p &lt; 0.001) and promoted DCs-CD11c+F4/80- (AngII = 45.6 ± 11.9% vs. Vh = 31.7 ± 6.7%; p &lt; 0.05) and Mo-CD11c+F4/80+ (AngII = 66.1 ± 8.4% vs. Vh = 55.6 ± 5.1%; p &lt; 0.05) infiltration in renal medulla, and that was prevented by LOS (p &lt; 0.05). We did not observe statistical differences in cortex. Interestingly, rMo transfer from AngII animals did not induce AHT in healthy recipient animals after 24h (Basal = 106.8 ± 2.3 vs.112.4 ± 4.9 mmHg;ns), compared to DCs-CD11c+-F4/80- (Basal = 110.0 ± 8.3 vs.132.0 ± 14.3mmHg;p &lt; 0.05). However, the rMo of AngII+LOS animals increased SBP healthy recipients with respect to their baseline (basal = 109 ± 5.6 vs. 123 ± 8.0mmHg;p &lt; 0.05). The rMo and DCs of hypertensive animals showed an increase in the abundance of AT1R (p &lt; 0.05) compared to vehicle rMo. Conclusions: Pharmacological blockade of AT1R in vivo would have a differential effect on rMo, transferring AHT to normotensive animals. These findings suggest that subpopulations of renal CD11c+ cells have a differential role in AHT.

Influence of Butyrate on Impaired Gene Expression in Colon from Patients with High Blood Pressure.

Hypertension (HTN) is associated with gut dysbiosis and the depletion of butyrate-producing bacteria in animal models and people. Furthermore, fecal material transfer from donor hypertensive patients increases blood pressure in normotensive recipient animals and ameliorates HTN-associated pathophysiology. These observations have implications in the impaired interactions between the gut and gut microbiota in HTN. Although this concept is supported in animal models, little is known about human HTN. Therefore, our objective for this study was to compare gene expression with transcriptomics and its potential to influence microbiota in subjects with normal and high blood pressure (HBP). Colon samples from reference subjects with normal blood pressure (REF) and HBP were used for RNA-seq to analyze their transcriptomes. We observed the significant downregulation of gene sets governing immune responses (e.g., SGK1 and OASL), gut epithelial function (e.g., KRT20 and SLC9A3R1), gut microbiota (e.g., PPARG and CIDEC) and genes associated with cardiovascular and gut diseases (e.g., PLAUR and NLN) in HBP subjects; the expression of genes within these pathways correlated with blood pressure. Potential drug targets in the gut epithelium were identified using the Drug Gene International Database for possible use in HTN. They include peroxisome proliferator-activated receptor gamma (PPRG), active serum/glucocorticoid regulated kinase 1 (SGK1) and 3 beta-hydroxysteroid isomerase type II inhibitor (HSD3B). Finally, butyrate, a microbiota-derived short-chain fatty acid, restored the disrupted expression of certain functional genes in colonic organoids from HBP subjects. Patients with HBP exhibit a unique transcriptome that could underlie impaired gut-microbiota interactions. Targeting these interactions could provide a promising new therapeutic intervention for hypertension management.

SAT-326 ARTERIAL HYPERTENSION IN KIDNEY TRANSPLANT RECIPIENTS

Cardio vascular disease are known to be the first mortality cause in kidney transplantation (KT). Arterial hypertension (HT) is common in renal transplant recipients (RTRs) and it is reported to occur from 50% to 80 % of cases. We report here the prevalence of HT in RTRs in our kidney transplantation center and it’s predictive factors. Our study is about 78 RTRs from a living kidney donor in 97.5 % of cases in our kidney transplantation department from 2011 to 2018. Our report is about 78 KTR in one KT department (La Rabta Hospital Tunis Tunisia) from 2011 to 2018. We study here the prevalence of HT in KTR in our KT department. We performed a comparative study of 2 groups (HT recipients and normotensive recipients) in order to determine predictive factors for HT in KTR. This study is about 78 KTR from a living kidney donor in 97.5 % of cases and deceased donor in 2,5 % of cases and it is about 51 males and 27 females with a mean age of 34±7 years old. After KT, HT was noted in 46 patients (59.7 %) and 32 patients were normotensive (41%). Among normotensive patients, we noted that 6 patients (18%) had HT before KT which disappeared after KT. Among HT patients, HT was not controlled in 22% of cases (based on target blood pressure levels ≤ 130/80 mm Hg). All these patients had at least 2 or 3 anti-hypertensive medications. In our report of 78 KTR, some factors were noted: dyslipidaemia in 2% of cases, obesity and overweight in 24% of cases and donor HT in 4 % of cases. Delayed graft function was noted in 6 cases (8%) and immunosuppressive therapy was based on steroids in all cases (Prednisone 10 mg/day reached at the first month and maintained for all patients), ciclosporin in 14 patients (18%), sirolimus in 10 patients (12%) and tacrolimus in 70 % of cases. Our comparative study showed that many factors can be predictive of HT after KT such as HT before KT, diabetes, tabaco, delayed graft function, creatinine at 1 year after KT > 1.5 mg/dl, immunosuppressive medicament such ciclosporin use and donor factors (age donor > 50 years old). All these correlations are statistically significant. Our data show that HT had a high prevalence in kidney recipient (59.7%). Our comparative study showed that many factors can be significantly predictive of HT after KT such as HT before KT, diabetes, tabaco, delayed graft function, creatinine at 1 year after KT > 1.5 mg/dl, immunosuppressive medicament such ciclosporin use and donor factors (age donor > 50 years old). Most of these factors are reported by authors to be HT predictive factors in KTR. Some of these factors can be prevented in KTR in order to control HT prevalence after KT to reduce cardio-vascular mortality and to improve graft survival.

Abstract P1108: Serum Immunoglobulins are Not Necessary for Experimental Hypertension

The role of B cells and serum immunoglobulins (Ig) in hypertension is unclear. Elevated serum IgG has been observed in some hypertensive patients and in animal models of hypertension. Mice with a severe B cell deficiency due to lack of B cell activating factor receptor (BAFF-R) and mice lacking the cytokine interleukin 21 (IL21) - which is a potent inducer of B cell Ig class switching and high affinity Ig production - are protected from Ang II-induced hypertension and exhibit reduced serum IgG levels. Thus, we sought to determine whether hypertensive IgGs play a causative role in hypertension and end-organ dysfunction. First, we purified serum IgG from normotensive and hypertensive wild type (WT) mice and adoptively transferred equal amounts of IgG by intraperitoneal injection into normotensive recipient mice followed by infusion of a sub-pressor dose of angiotensin II (Ang II) for 2 weeks. Flow cytometric analysis of aortas revealed a modest increase in F4/80+ macrophages (p=0.04) and CD8+ T cells (p=0.02) in mice that received hypertensive IgG. However, there was no difference in endothelial dependent relaxation, renal inflammation, albuminuria, and blood pressure (BP) between the two groups. As an alternative method to investigate the role of class-switched high affinity Igs, we studied mice with genetic deletion of activation-induced deaminase (AID) which is an enzyme necessary for somatic hypermutation (to generate high affinity Igs) and isotype class switching. AID -/- mice exhibit undetectable IgG and higher levels of IgM in serum compared to WT mice. Ang II infusion for 4 weeks revealed no difference in BP, aortic inflammation, renal inflammation, and albuminuria. We also studied mice with deficiency of the IgM heavy chain (uMT). These mice exhibit undetectable levels of all immunoglobulins and are severely deficient in mature B cells. uMT-/- mice are also not protected from hypertension induced by Ang II infusion or deoxycorticosterone acetate (DOCA-salt) treatment. Together, these results demonstrate that while elevated serum immunoglobulins seen in hypertensive animals and humans may represent a biomarker of aberrant immune activation, they are likely not playing a causal role in hypertension pathophysiology.

Effects of in vitro culture at the preimplantation embryo stage on early development and hypertension in ISIAH rats

ABSTRACTObjective: The study investigates how IVC and ET affect hypertensive phenotype in ISIAH rats.Methods: ISIAH rats born as the result of ET and IVC were compared with naturally conceived controls.Results: Embryo transfer from hypertensive ISIAH rats to normotensive recipient dams caused lower SBP and DBP in the female offspring. When ET was accompanied with in vitro culture in R1ECM, not only the female offspring, but also males demonstrated alleviation of hypertension.Conclusions: IVC at the preimplantation embryo stage affected the manifestation of hypertension in the adult ISIAH offspring.

Hypertension‐associated dysbiosis leads to elevated sympathetic drive and alterations in neurotransmitter signaling in the nucleus of the solitary tract in WKY

IntroductionGut dysbiosis is linked to hypertension (HTN), and fecal microbiota transplantation (FMT) from hypertensive subjects to normotensive recipients induces high blood pressure (BP). Therefore, manipulation of gut microbiota is a potential therapeutic target in HTN. Here, we demonstrate a role for the central nervous system and particularly the nucleus of the solitary tract (NTS) in the dysbiosis‐mediated HTN in Wistar Kyoto (WKY) rats receiving cecal feces from the spontaneously hypertensive rats (SHR).Methods12 week‐old male WKY rats were orally gavaged with a combination of antibiotics (Vancomycin, Meropenem, and Omeprazole) at 50mg/kg/day for five days. Following two days of recovery, rats were given an oral cecal content suspension from either the male adult WKY (group WKY‐WKY, n=6), or age‐ and sex‐matched hypertensive SHR (group SHR‐WKY, n=6), initially every day for six days, and thereafter once a week for seven weeks. BP was measured by radio telemetry, and spectral analysis was performed on systolic BP (SBP) waveform signal (Ponemah) to derive autonomic variables. NTS was punched out from all rats at the end of study, and relative expression of genes associated with molecular signaling of several neurotransmitters and proinflammatory factors was measured by real time PCR, and normalized to GAPDH using the relative ΔΔCt method.ResultsFollowing FMT, a significant increase in SBP at night (6pm‐5am) was observed in SHR‐WKY vs WKY‐WKY group by week 6 (WKY‐WKY 134.8±1.34 mmHg vs SHR‐WKY 141.8±1.05 mmHg, P=0.0023), which continued through week 7 (WKY‐WKY 133.8±1.3 mmHg vs SHR‐WKY 139.1±2.16 mmHg, P=0.028). This was associated with a significant increase in low frequency (LF) of SBP (indicating vasomotor tone), and LF/high frequency (HF) ratio (indicating vasovagal balance) at night in the SHR‐WKY (LF: WKY‐WKY 1.21±0.014 vs SHR‐WKY 1.36±0.059, P=0.031; LF/HF: WKY‐WKY 1.433±0.75 vs SHR‐WKY 1.869±0.17, P=0.0485), suggesting elevated sympathetic drive at night in the SHR‐WKY group. Real time PCR revealed increased expression of pro‐inflammatory Tlr4 (WKY‐WKY 0.00267±0.000234 vs SHR‐WKY 0.00346±0.000197, P=0.0351) and Il1b (WKY‐WKY 0.000116±9.53e‐006 vs SHR‐WKY 0.000171±9.98e‐006, P=0.0119) in the NTS of SHR‐WKY rats. Moreover, relative expression levels of serotonin receptor subtype Htr1a (WKY‐WKY 0.00582±0.0011 vs SHR‐WKY 0.00372±0.00033, P=0.0608), as well as serotonin re‐uptake transporter (SERT) Slc6a4 (WKY‐WKY 0.0012±0.00028 vs SHR‐WKY 0.00028±3.82e‐005, P=0.0052) were reduced in the NTS of SHR‐WKY. Finally, relative expression levels of two major subunits of glutamate receptors, NR1 (WKY‐WKY 0.064±0.0015 vs SHR‐WKY 0.082±0.0042, P=0.009) and NR2A (WKY‐WKY 0.024±0.0014 vs SHR‐WKY 0.03224±0.0013, P=0.0042) were significantly increased in the NTS of SHR‐WKY rats.ConclusionsGut dysbiosis‐induced increase in BP is associated with significant elevation in the sympathetic drive, perturbations in neurotransmitter signaling and increased inflammatory markers in the NTS. These changes indicate a role for microbiota in regulation of the gut‐brain axis in HTN.Support or Funding InformationAHA Grant 14SDG18300010 to JZ and University of Florida College of Veterinary Medicine (UFCVM) Start Up Funds to JZ.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Renal amino acid transport systems and essential hypertension

Several clinical and animal studies suggest that "blood pressure goes with the kidney," that is, a normotensive recipient of a kidney genetically programmed for hypertension will develop hypertension. Intrarenal dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport. The candidate transport systems for L-DOPA, the source for dopamine, include the sodium-dependent systems B(0), B(0,+), and y(+)L, and the sodium-independent systems L (LAT1 and LAT2) and b(0,+). Renal LAT2 is overexpressed in the prehypertensive spontaneously hypertensive rat (SHR), which might contribute to enhanced L-DOPA uptake in the proximal tubule and increased dopamine production, as an attempt to overcome the defect in D1 receptor function. On the other hand, it has been recently reported that impaired arginine transport contributes to low renal nitric oxide bioavailability observed in the SHR renal medulla. Here we review the importance of renal amino acid transporters in the kidney and highlight pathophysiological changes in the expression and regulation of these transporters in essential hypertension. The study of the regulation of renal amino acid transporters may help to define the underlying mechanisms predisposing individuals to an increased risk for development of hypertension.

Low-grade albuminuria reduction with angiotensin II type 1 receptor blocker in renal transplant recipients

Microalbuminuria, defined as urine albumin to urine creatinine ratio of 30 to <300 mg/g, is an established risk factor for cardiovascular morbidity and mortality in the general population. Low-grade albuminuria (<30 mg/g) is considered a marker for subclinical vascular damage that predisposes to future cardiovascular diseases and death. Lowering urinary albumin excretion reduces the risk of cardiovascular disease. Our study was designed to evaluate the influence of angiotensin II type 1 receptor blocker (ARB) in normotensive renal transplant recipients with low-grade albuminuria. Our 6-month prospective observation study used a randomized control and open-label design as we examined the effects of an ARB (valsartan) on blood pressure, urinary albumin excretion, hematocrit, serum potassium and estimated glomerular filtration rate (eGFR) in normotensive recipients with allografts of more than 1 year. A total of 35 renal transplant recipients were enrolled in this study. Patients were randomly assigned to 2 groups: ARB group (n=18), receiving 40-80 mg valsartan daily for 6 months, and the control group (n=17). In the ARB group, urine albumin excretion was significantly reduced from 25.9 ± 19.1 mg/g to 12.0 ± 9.6 mg/g at 6 months after administration. eGFR decreased slightly at 6 months after administration. However, no patients undergoing treatment for adverse effects required discontinuation of ARB. This study reveals that ARB is safe and reduces low-grade albuminuria in normotensive renal transplant recipients. Thus, early treatment of ARB in recipients with low-grade albuminuria may prevent cardiovascular disease after renal transplantation.

Hypertension After Pediatric Heart Transplantation is Primarily Associated With Immunosuppressive Regimen

Hypertension is recognized as prevalent in pediatric cardiac transplant recipients. This study investigated risk factors for this complication and, in particular, the role of immunosuppression. Results of 24-hour ambulatory blood pressure monitoring of children surviving more than 1 year after cardiac transplantation were analyzed retrospectively. Subjects were designated either hypertensive or normotensive by comparison with published normal values. To identify factors associated with hypertension, clinical data contemporaneous with 24-hour ambulatory blood pressure monitoring were collected and compared between the groups. In the 51 children studied, the incidence of hypertension was 49%. Hypertensive and normotensive recipients were similar for sex, age at transplantation, time between transplantation and 24-hour ambulatory blood pressure results, and choice of calcineurin inhibitor. In contrast, hypertensive patients were taking significantly more immunosuppressive agents (2.92 vs 2.12 p < 0.01), had higher tacrolimus levels (10 vs 8.1 microg/liter, p = 0.03), and were more likely to be on maintenance prednisone therapy (64% vs 23%, p < 0.01) or regimens including sirolimus (40% vs 12%, p = 0.03). Multiple regression analysis controlling for tacrolimus level showed a combination of prednisone and sirolimus was more strongly associated with hypertension than either agent alone, with an odds ratio of 7.3 (95% confidence interval, 1.5-36.1) vs 4.1 (95% confidence interval, 0.85-26.3). Hypertension after pediatric cardiac transplantation is a common problem and primarily associated with immunosuppressive regimen.

The Kidney as a Determinant of Genetic Hypertension

Several lines of evidence suggest that the kidney plays an important role in the genesis of primary hypertension in humans and genetic hypertension in animals. Perhaps the most compelling evidence derives from clinical1–4 and experimental renal transplantation studies,5– 36 which have been performed over the last 3 decades. In virtually all of these studies, the genetic background of the donor kidney had a major impact on long-term blood pressure in the recipients. More specifically, renal grafts from genetically hypertensive donors increased blood pressure in genetically normotensive recipients, whereas renal grafts from genetically normotensive donors lowered blood pressure in genetically hypertensive recipients. In many but not all of the studies, blood pressure traveled with the kidney in both directions. Although these data clearly show that the kidney is an important determinant of long-term blood pressure in normotension and primary or genetic hypertension, several major problems still remain unresolved. These problems relate mainly to the interpretation of the data and to the potential mechanisms by which the kidney sets the level of long-term blood pressure. In this brief review, we discuss the results and implications of clinical and experimental renal transplantation studies in primary hypertension in humans and genetic hypertension in animals that have been published to date. In the mid-1980s, 3 studies1,2,4 on renal transplant patients were published that supported a major role for the kidney in human essential hypertension. The classical study by Curtis et al1 demonstrated the sustained remission of essential hypertension in 6 patients who had received kidney transplants from normotensive donors. Two other studies took the opposite approach by showing that grafts from donors with presumed hypertension4 or from donors with known family background of essential hypertension2 caused more severe hypertension and the need for more rigorous antihypertensive treatment in the …

The Effect of Combined Angiotensin-Converting Enzyme Inhibition and Calcium Antagonism on Allograft Coronary Vasculopathy Validated by Intravascular Ultrasound

Hypertension is a potential risk factor for allograft coronary vasculopathy. We evaluated the efficacy of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists, and their combined use, on the development of coronary vasculopathy in hypertensive heart transplant recipients. Eighty-two heart transplant recipients underwent serial intravascular ultrasound (IVUS) analysis at baseline (within 1 month) and at 1 year after transplantation and were evaluated for the development of coronary vasculopathy. Patients were divided into 4 groups. Nineteen normotensive recipients received no treatment, control (Group A). Hypertensive patients were treated with either ACE inhibitors (Group B, n = 37), calcium antagonists (Group C, n = 16), or both (Group D, n = 10). We found a significant reduction in IVUS indices of coronary vasculopathy in heart transplant recipients who used a combination of an ACE inhibitor and a calcium antagonist compared with recipients who used either drug alone (p < 0.05). This synergistic efficacy was independent of the baseline indices evaluated in a multivariate regression analysis model and was noted despite comparable mean arterial pressure among the 3 hypertensive groups at 1 year, thus suggesting the presence of a synergistic anti-proliferative effect beyond the anti-hypertensive efficacy. The combined use of an ACE inhibitor and a calcium antagonist is more effective than the individual use of either drug alone on the development of coronary vasculopathy in cardiac transplant recipients. Large randomized clinical trials are warranted to evaluate such a synergistic efficacy.

Sympatho‐renal interactions in the determination of arterial pressure: role in hypertension

Renal mechanisms and the sympathetic nervous system contribute to the development of arterial hypertension. Renal transplantation experiments in spontaneously hypertensive rats (SHRs) were performed to investigate how the sympathetic nervous system and the kidneys interact during the development and maintenance of hypertension. Our findings indicate that the rise in arterial pressure that occurs after transplantation of a kidney from a SHR into normotensive recipients is not mediated by elevations in sympathetic activity. However, chronic reductions in sympathetic tone reduce the rise in arterial pressure which can be induced by SHR renal grafts in normotensive recipients. Untreated SHRs transplanted with a kidney from sympathectomized donors have lower arterial pressure and reduced sodium sensitivity of arterial pressure compared to SHRs transplanted with a kidney from hydralazine-treated donors. It is concluded that chronic non-adapting changes in sympathetic activity modulate the degree to which renal mechanisms can cause hypertension in SHRs. Severe reduction in sympathetic tone during early ontogeny causes long-term changes in renal function that mitigate hypertension development in SHRs even when the extrarenal neuro-hormonal environment is restored.

Clinical characteristics of normotensive renal transplant recipients with microalbuminuria and effects of angiotensin II type I receptor antagonist on urinary albumin excretion.

Microalbuminuria is typically observed in renal transplant recipients with systemic hypertension. The effects of angiotensin II type 1 receptor antagonist (losartan) on the hypertensive recipients have been evaluated. However, the clinical background of normotensive recipients with microalbuminuria and the effect of losartan administration in those subjects have not been clarified. One of the two purposes for the present study was to investigate the clinical characteristics of normotensive recipients with microalbuminuria. The other was to evaluate the effect of losartan on urinary excretion of albumin in these patients. The clinical data and the change of the single kidney glomerular filtration rate (GFR) for the graft by radionuclide study were assessed in 13 normotensive recipients with microalbuminuria. These were compared with the data of 13 normotensive patients without microalbuminuria. The 13 recipients with microalbuminuria were treated with losartan for one year and urine excretion of albumin, N-acetyl-beta-D-glucosaminidase (NAG) and serum creatinine (S-Cr) levels were measured. The GFR of the grafts from donors to recipients significantly increased (30.9 to 55.2 mL/min) in microalbuminuric recipients, but did not significantly increase in the non-microalbuminuric recipients. Decreases of the urinary excretion rate of albumin (351 +/- 261 at baseline to 158 +/- 14 mg/gCr at 12 months), NAG (13 +/- 5 to 10 +/- 3 IU/gCr) and S-Cr (1.7 +/- 0.6 to 1.5 +/- 0.4 mg/DL) were observed in the microalbuminuric recipients with losartan administration. The present study suggests that an increased single kidney GFR of the graft from the donor in situ to the recipient might be a cause of microalbuminuria in normotensive recipients. The one-year effects of losartan were observed in terms of the decrease in urinary excretion of albumin, NAG and S-Cr levels.

Transplantation of enalapril-treated kidneys confers persistent lowering of arterial pressure in SHR.

The kidney plays a critical role in regulating the level of arterial pressure and in the pathogenesis of hypertension. Important evidence has come from studies in which hypertension is generated by transplanting kidneys from genetically hypertensive rats into normotensive recipients, suggesting that the level of blood pressure is strongly influenced by the genetic background of the kidney. We hypothesized that pharmacotherapy could modify specific properties intrinsic to the kidney such that after transplantation, there would be persistent changes in the level of arterial pressure. We determined that angiotensin-converting enzyme inhibitor treatment (enalapril) in spontaneously hypertensive rats induced both a persistent 17% reduction of mean arterial pressure and a persistent change in the kidney. This persistent change in the circulation could be completely transferred to untreated spontaneously hypertensive rats by kidney transplantation; ie, mean arterial pressure in untreated spontaneously hypertensive rat recipients was persistently lowered after transplantation of a kidney from a previously treated spontaneously hypertensive rat donor. In addition, the persistent lowering of mean arterial pressure after enalapril treatment could be completely abolished by implanting an untreated kidney, thereby revealing the importance of the kidney-specific changes. Furthermore, after within-group transplantations, there were no changes in the level of arterial pressure; ie, a 16% difference in mean arterial pressure remained between the 2 groups. The findings revealed that drug-induced changes specific to the kidney determined the level of arterial pressure, thereby suggesting the kidney should be a key therapeutic target for pharmacotherapy.

Kidney and hypertension

There is a unique relationship between the kidney and blood pressure (BP): on the one hand, renal dysfunction and particularly renal disease cause an increase in BP, while on the other hand, high BP accelerates loss of function of the diseased kidney. Transplantation studies, both in experimental animals and humans, documented that "blood pressure goes with the kidney," a normotensive recipient of a kidney genetically programmed for hypertension (HT) will develop HT, while conversely hypertensive patients with renal failure receiving the kidney of a normotensive donor may develop normotension. Family studies showed higher BP values and more frequent HT in first degree relatives of patients with primary glomerulonephritis or diabetic nephropathy, both type 1 and type 2. The notion that HT accelerates the loss of renal function has been proposed at the turn of the century, but definite evidence by observational and interventional studies has only been provided in the last two decades. The issue has been much confounded by the mistaken believe that damaged kidneys require higher BP values in order to function properly. The mechanisms of BP increase in renal disease comprise: salt retention, inappropriate activity of the renin-angiotensin system (RAS) and of the sympathetic nerve system as well as impaired endothelial cell-mediated vasodilatation. There is ample evidence both in primary renal disease (AIPRI and REIN trials) and in nephropathy of type 1 and type 2 diabetes (IDNT, RENAAL) that pharmacological blockade of the RAS by angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers has BP-independent renoprotective effects. More recently, it has also been shown that blockade of the sympathetic nerve system has BP-independent effects on albuminuria and on glomerulosclerosis.

Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock.

Anandamide, an endogenous cannabinoid ligand, binds to CB1 cannabinoid receptors in the brain and mimics the neurobehavioural actions of marijuana. Cannabinoids and anandamide also elicit hypotension mediated by peripheral CB1 receptors. Here we report that a selective CB1 receptor antagonist, SR141716A, elicits an increase in blood pressure in rats subjected to haemorrhagic shock, whereas similar treatment of normotensive rats or intracerebroventricular administration of the antagonist during shock do not affect blood pressure. Blood from haemorrhaged rats causes hypotension in normal rats, which can be prevented by SR141716A but not by inhibition of nitric oxide synthase in the recipient. Macrophages and platelets from haemorrhaged rats elicit CB1 receptor-mediated hypotension in normotensive recipients, and incorporate arachidonic acid or ethanolamine into a product that co-elutes with anandamide on reverse-phase high-performance liquid chromatography. Also, macrophages from control rats stimulated with ionomycin or bacterial phospholipase D produce anandamide, as identified by gas chromatography and mass spectrometry. These findings indicate that activation of peripheral CB1 cannabinoid receptors contributes to haemorrhagic hypotension, and anandamide produced by macrophages may be a mediator of this effect.

Kidneys from normotensive donors lower blood pressure in young transplanted spontaneously hypertensive rats.

Single transplanted kidneys from spontaneously hypertensive rats (SHR) have been shown to elicit hypertension in genetically normotensive recipients. This study was designed to investigate the effects of single transplanted kidneys from genetically normotensive donors [Biobreeding (BB)/Ottawa Karlsburg (OK) rats] on blood pressure in SHR recipients. The following groups were formed: group 1 (n = 11), SHR donors and SHR recipients; group 2 (n = 15), BB/OK donors and SHR recipients; and group 3 (n = 8), BB/OK donors and BB/OK recipients. Recipients received antihypertensive treatment (hydralazine) from weaning until renal transplantation at the age of 9 wk and immunosuppressive treatment (anti-CD4 antibody and cyclosporine A) for 3 wk starting on the day of transplantation. Six weeks after transplantation, intra-arterially measured blood pressure and heart weight-to-body weight ratio were highest in group 1, intermediate in group 2, and lowest in group 3. There were no significant differences with respect to plasma urea and creatinine concentrations among the three groups. These results support the hypothesis that hypertension in renal-transplanted SHR depends in part on the genetic background of the transplanted kidney.

Role of the native kidney in experimental post-transplantation hypertension.

In experimental renal transplantation studies using several animal models of primary hypertension, including stroke-prone spontaneously hypertensive rats (SHRSP) and their normotensive Wistar-Kyoto controls (WKY), single transplanted kidneys from genetically hypertensive but not normotensive donors elicited post-transplantation hypertension in bilaterally nephrectomized genetically normotensive recipients. The underlying mechanisms are presently unclear. The present study was designed to investigate the effects of a remaining native kidney on post-transplantation blood pressure, plasma renin activity and plasma angiotensin II concentration in (WKYxSHRSP) F1 hybrid recipients of a WKY or SHRSP kidney. The presence of a native kidney markedly reduced, but did not prevent, post-transplantation hypertension in recipients of an SHRSP kidney. WKY kidney grafts did not significantly alter blood pressure in bilaterally or unilaterally nephrectomized recipients. Plasma renin activity was lower in bilaterally than in unilaterally nephrectomized recipients, regardless of the source of the graft. The plasma angiotensin II concentration was similar in all groups. Renal graft function as assessed by 99mtechnetium-mercaptoacetyltriglycine scintigraphy was well preserved. These data suggest that post-transplantation hypertension in recipients of an SHRSP kidney may be partly due to the failure of the graft to eliminate a hypertensinogenic substance or to produce a blood pressure lowering agent.