Hypertensive nephropathy is associated with an increased risk of myeloma, skin, and renal cancer.

Previous studies suggest an increased cancer risk in hypertension. Patients with hypertensive nephropathy have not been studied. A national registry study was performed to assess the presence and size of this association. Clinical data and cancer diagnoses for all patients with biopsy-proven hypertensive nephropathy between 1985 and 2015 in Denmark were extracted from four national registries and compared with age- and sex-adjusted national cancer rates. The risk of cancer was twice the background population. It was raised for renal cancer (odds ratio 10.4), myeloma (13.2), skin cancer (7.9), and other/unspecified (1.8). No increase in incidence was seen until 1 year before renal biopsy and then rose rapidly. It was again normal 5 years after biopsy. Hypertensive nephropathy is associated with an increased risk of myeloma, skin, renal, and other cancers. Screening of patients with hypertensive nephropathy, in the presence of reduced renal function or significant proteinuria, may be indicated.

[A retrospective clinical analysis of 16 patients with scleroderma renal crisis].

OBJECTIVE: To analyze the clinical features, laboratory tests, treatments and outcome of patients with scleroderma renal crisis (SRC). METHODS: We retrospectively reviewed the clinical and laboratory data of 16 patients with scleroderma renal crisis in Peking Union Medical College Hospital from May 2004 to May 2013. The treatment and outcome of SRC patients were also retrospectively analyzed. RESULTS: There were a total of 16 SRC patients including 5 male patients and 11 females. The median age at SRC onset was (49.9 ± 12.3) years. It usually took 3.2 years from the diagnosis of systemic sclerosis (SSc) to SRC attack. Ten SRC patients belonged to diffuse cutaneous systemic sclerosis (dcSSc), and 6 patients were limited cutaneous systemic sclerosis (lcSSc). Among SRC patients, 16/16 were negative of anti-centromere antibodies (ACAs). All these 16 patients had hypertension and renal insufficiency, including 8 dialysis dependent after the onset of SRC and 7 with thrombotic microangiopathy. There were 3 patients receiving renal biopsy. The pathological findings were mainly summarized as intimal thickening and stenosis of renal arterioles. Among 13 patients with long-term followed-up, 11 patients received angiotensin converting enzyme inhibitors (ACEI), 5 patients died, 2 patients were dialysis dependent. Only 1 patient stopped dialysis after the combination treatment of ACEI and endothelin receptor antagonist. Another 5 patients didn't need dialysis. CONCLUSION: SRC usually occurred at the early course of SSc. dcSSc was more frequent than lcSSc. ACAs were rarely found in SRC patients. The immediate and sufficient use of ACEIs was still the cornerstone of SRC treatment. Future studies are needed to evaluate the efficacy of endothelin receptor antagonist in the treatment of SRC.

Burden and predictors of hypertension in India: results of SEEK (Screening and Early Evaluation of Kidney Disease) study.

BACKGROUND: Hypertension (HTN) is one of the major causes of cardiovascular morbidity and mortality. The objective of the study was to investigate the burden and predictors of HTN in India. METHODS: 6120 subjects participated in the Screening and Early Evaluation of Kidney disease (SEEK), a community-based screening program in 53 camps in 13 representative geographic locations in India. Of these, 5929 had recorded blood pressure (BP) measurements. Potential predictors of HTN were collected using a structured questionnaire for SEEK study. RESULTS: HTN was observed in 43.5% of our cohort. After adjusting for center variation (p < 0.0001), predictors of a higher prevalence of HTN were older age ≥ 40 years (p < 0.0001), BMI of ≥ 23 Kg/M2 (p < 0.0004), larger waist circumference (p < 0.0001), working in sedentary occupation (p < 0.0001), having diabetes mellitus (p < 0.0001), having proteinuria (p < 0.0016), and increased serum creatinine (p < 0.0001). High school/some college education (p = 0.0016), versus less than 9th grade education, was related with lower prevalence of HTN. Of note, proteinuria and CKD were observed in 19% and 23.5% of HTN subjects. About half (54%) of the hypertensive subjects were aware of their hypertension status. CONCLUSIONS: HTN was common in this cohort from India. Older age, BMI ≥ 23 Kg/M2, waist circumference, sedentary occupation, education less, diabetes mellitus, presence of proteinuria, and raised serum creatinine were significant predictors of hypertension. Our data suggest that HTN is a major public health problem in India with low awareness, and requires aggressive community-based screening and education to improve health.

Avosentan is protective in hypertensive nephropathy at doses not causing fluid retention.

Multiple studies indicate that endothelin antagonism may have a protective effect for chronic kidney disease. Despite that, clinical studies using avosentan have been halted due to adverse effects including fluid overload. Therefore, we aimed at investigating whether avosentan may have protective effects against hypertensive nephropathy at doses below those inducing fluid-retention. We used double transgenic rats (dTGR), overexpressing both the human renin and angiotensinogen gene, which develop malignant hypertension. Effects of avosentan alone or in combination with low-dose of valsartan (angiotensin AT1 receptor antagonist) on end-organ damage were studied. Avosentan induced a decrease of diuresis (18.3%) with a consequent decrease in hematocrit (8.3%) only at the highest dose investigated (100mg/kg). Treatment with the combination of avosentan and valsartan (10 and 0.1mg/kg, once daily by gavage, respectively) decreased albuminuria to a greater extent than each compound given alone (avosentan: 19.6mg/24h; valsartan: 12.9mg/24h; avosentan+valsartan: 1.7mg/24h, data are median values). Histological severity score also showed a drastic reduction of kidney damage. Furthermore, avosentan alone or in combination therapy dramatically decreased mortality compared to the 100% in untreated animals. These data support a therapeutic effect of avosentan at doses below those inducing fluid overload.

Causes of death in peritoneal dialysis patients with different kidney diseases and comorbidities: a retrospective clinical analysis in a Chinese center.

OBJECTIVES: The objective of the study is to identify and compare the different causes of death among peritoneal dialysis (PD) patients varying in baseline characteristics, including gender, age, primary diseases, and comorbidities and to assess risk factors for first-year death. METHODS: The clinical data of 179 PD patients who were regularly followed up in our hospital and died between January 2006 and February 2011 were retrospectively reviewed. RESULTS: Median age at PD catheter implantation was 73 years. The most common primary diseases leading to ESRD were diabetic nephropathy (DN; 26.3 %), chronic glomerulonephritis (CGN; 24.6 %), and hypertensive nephropathy (HN; 21.8 %). The main causes of death in the DN and CGN groups were infections (42.6 %) and cardiocerebrovascular accidents (34.1 %), respectively. Patients with systemic vasculitis (SV) had the highest mortality rate from infection (71.4 %). Cox regression model showed that, compared with patients with CGN, those who had primary disease of DN, renal amyloidosis, multiple myeloma, or vasculitis were at higher risk of first-year death. Cerebrovascular disease, chronic heart failure, and/or lower serum albumin at baseline were also risk factors for first-year death. CONCLUSIONS: The main causes of death in PD patients with DN and CGN were infections and cardiocerebrovascular accidents, respectively. Risk factors for first-year death included the primary diseases, cerebrovascular diseases, chronic heart failure, and lower serum albumin at baseline.

Oncological and functional outcomes after radical nephrectomy for renal cell carcinoma: a comprehensive analysis of prognostic factors.

OBJECTIVES: To investigate mortality rates and to comprehensively analyze prognostic indicators after radical nephrectomy for renal cell carcinoma. METHODS: Data were collected from 147 patients who underwent potentially curative radical nephrectomy for renal cell carcinoma. The following data were analyzed: tumor pathology, patient demographics and clinical parameters, such as pre- and postoperative estimated glomerular filtration rate, as well as the cause of death. Cause-specific survival rates were calculated including deaths caused by renal cell carcinoma and cardiovascular disease. A Cox proportional hazard model was used for statistical analysis. RESULTS: A univariate analysis showed that age at surgery (≥70 years), postoperative estimated glomerular filtration rate (<45 mL/min/1.73 m(2)), pathological high T stage, grade and venous invasion were significant poor prognostic indicators. The multivariate analysis provided evidence that pathological venous invasion was a significant poor prognostic indicator, whereas age at surgery (≥70 years), pre- (<65 mL/min/1.73 m(2)) or postoperative (<45 mL/min/1.73 m(2)) estimated glomerular filtration rate and pathological high grade were significant poor prognostic indicators in T1 tumor cases. CONCLUSIONS: Post-radical nephrectomy renal function insufficiency can lead to a poor prognostic outcome, especially in patients with T1 renal cell carcinoma. Physicians should consider a comprehensive follow up focusing on possible causes of death, including those related to both renal cell carcinoma and cardiovascular disease events after radical nephrectomy.

Prognostic value of 48-hour ambulatory blood pressure measurement and cardiovascular mortality in hemodialysis patients.

BACKGROUND: Hypertension is common and contributes to high cardiovascular morbidity and mortality in hemodialysis (HD) patients. It is unknown which blood pressure (BP) better defines the influence on cardiovascular mortality. The purpose of our study was to analyze the relationship between various BP measurements, traditional risk factors, markers of asymptomatic atherosclerosis [left ventricular mass (LVM), carotid intima media thickness (IMT)], and cardiovascular mortality in HD patients. METHODS: Seventy-three patients (44 males and 29 females; mean age: 54.2 years) were included. BP was measured before and after HD and 48-hour ambulatory blood pressure monitoring (ABPM) was performed. Using sonography, the LVM index and carotid IMT were measured. RESULTS: During a follow-up period up to 3,664 days, 28 patients died - 16 of them from cardiovascular causes. In a Cox regression model, which included age, gender, smoking, diabetes, sensitive C-reactive protein, albumin, hemoglobin, troponin T, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, calcium, phosphorus, carotid IMT, and LVM index, only 48-hour systolic ABPM (p = 0.037) and 48-hour diastolic ABPM (p = 0.006) turned out to be independent predictors of cardiovascular death. CONCLUSION: Only 48-hour ABPM and not single BP measurements before or after HD were associated with cardiovascular mortality in HD patients.

The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats.

BACKGROUND: Activation of glucagon-like peptide-1 (GLP-1) receptors improves insulin sensitivity and induces vasodilatation and diuresis. AC3174 is a peptide analogue with pharmacologic properties similar to the GLP-1 receptor agonist, exenatide. Hypothetically, chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS) rats. METHODS: DSS rats were fed low salt (LS, 0.3% NaCl) or high salt (HS, 8% NaCl) diets. HS rats were treated with vehicle, AC3174 (1.7 pmol/kg/min), or GLP-1 (25 pmol/kg/min) for 4 weeks via subcutaneous infusion. Other HS rats received captopril (150 mg/kg/day) or AC3174 plus captopril. RESULTS: HS rat survival was improved by all treatments except GLP-1. Systolic blood pressure (SBP) was lower in LS rats and in GLP-1, AC3174, captopril, or AC3174 plus captopril HS rats than in vehicle HS rats (p < 0.05). AC3174 plus captopril attenuated the deleterious effects of high salt on posterior wall thickness, LV mass, and the ratio of LV mass to body weight (P < or = 0.05). In contrast, GLP-1 had no effect on these cardiovascular parameters. All treatments reduced LV wall stress. GLP-1, AC3174, captopril, or AC3174 plus captopril normalized fasting insulin and HOMA-IR (P < or = 0.05). AC3174, captopril, or AC3174 plus captopril improved renal function (P < or = 0.05). Renal morphology in HS rats was associated with extensive sclerosis. Monotherapy with AC3174, captopril, or GLP-1 attenuated renal damage. However, AC3174 plus captopril produced the most effective improvement. CONCLUSIONS: Thus, AC3174 had antihypertensive, cardioprotective, insulin-sensitizing, and renoprotective effects in the DSS hypertensive rat model. Furthermore, AC3174 improved animal survival, an effect not observed with GLP-1.

Effect of pioglitazone on survival and renal function in a mouse model of polycystic kidney disease.

BACKGROUND/AIMS: Cystic epithelia in polycystic kidney disease display features similar to malignant cells. Thiazolidinediones have been shown to have anti-neoplastic properties, therefore we tested the hypothesis that pioglitazone reduces cyst formation, improves renal function, and prolongs survival in a mouse model of polycystic kidney disease. METHODS: PC-Pkd1-KO mice, which have homozygous mutations of the Pkd1 gene in principal cells, were used. On the day after giving birth, mothers were fed standard mouse chow with or without pioglitazone (30 mg/kg chow). After weaning, the assigned diet was continued. At 1 month of age, blood pressure was measured and animals were sacrificed to determine kidney weight, body weight, and serum urea. Kidneys were evaluated for proliferation using Ki-67, apoptosis using TUNEL analysis, and cyst number using MRI. Survival was observed. RESULTS: Pioglitazone did not alter renal function, cell proliferation, apoptosis, or cyst formation in animals with polycystic kidney disease, however it did increase survival. Pioglitazone reduced blood pressure in PC-Pkd1-KO, but not in controls. CONCLUSION: These findings suggest that pioglitazone may have a unique antihypertensive effect in polycystic kidney disease, and that such an effect may promote improved survival.

Clinical outcome of children with chronic kidney disease in a pre-dialysis interdisciplinary program.

The purpose of this retrospective cohort study was to describe the outcome of 107 patients with chronic kidney disease (CKD) admitted to a pre-dialysis interdisciplinary management program from 1990 to 2006. The events of interest were progression to CKD stage 5 (renal survival), patient survival, hypertension, and somatic growth. Survival was studied by the Kaplan-Meier method. Patients were classified into four groups according to their primary renal disease: congenital nephro-uropathies; glomerular diseases; cystic disease, and miscellaneous. Median follow-up time was 94 months [Interquartile (IQ) range 38-145]. The probability of reaching CKD stage 5 was estimated to be 36% by 5 years after admission. As a whole, the mean estimated glomerular filtration rate (GFR) decrease per year was 5.8 ml/min per 1.73 m(2) body surface area [standard deviation (SD) 12.4]. The glomerular diseases group showed a median rate of GFR deterioration of 10 ml/min per 1.73 m(2) per year (IQ range -24 to -5.7), whereas the median rate of GFR deterioration for the groups with cystic diseases, congenital nephro-uropathies, and miscellanea were 2.5 ml/min (IQ range -10 to +0.34), 2.2 ml/min (IQ range -5.0 to -0.52), and 0.36 ml/min (IQ range -2.5 to +2.6), respectively (P < 0.001). The results of this study support the view that children and adolescents with glomerular diseases present a faster deterioration of renal function. Therefore, patients with glomerular diseases need to be referred early to a pediatric nephrology center so that suboptimal pre-dialysis care might possibly be avoided.

Operative mortality for renal artery bypass in the United States: Results from the National Inpatient Sample.

BACKGROUND: The mortality rate for renal artery bypass grafting (RABG) is reported to be 0% to 4% for patients with renovascular hypertension and 4% to 7% for patients with ischemic nephropathy. However, these data come from high-volume referral centers known for their expertise in treating these conditions. Because of the relative infrequency of these operations in most vascular surgery practices, the nationwide outcomes for RABG are not known. The purpose of this study was to define the operative mortality rate for RABG in the United States and to identify risk factors for perioperative mortality. METHODS: The National Inpatient Sample was analyzed to identify patients undergoing RABG for the years 2000 to 2004. Categoric data were analyzed using chi(2) and the Cochran-Armitage trend tests. Multivariate logistic regression analyses were performed to identify risk factors for perioperative mortality after RABG. RESULTS: During the study period, 6608 patients underwent RABG, representing a frequency of 3.51 operations per 100,000 discharges. More than two-thirds were performed at teaching hospitals (4564 vs 2,044; P < .0001). The frequency of RABG decreased by 30.7% between 2000 and 2004 (4.28 vs 2.96 RABGs per 100,000 discharges; P for trend < .0001). The in-hospital mortality for RABG was 10.0%. On univariate analysis, in-hospital mortality after RABG varied with increasing age, race, region of the country, and a preoperative history of chronic renal failure, congestive heart failure, or chronic lung disease. Logistic regression models identified advanced age (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.44-1.72], female gender (OR, 1.20; 95% CI, 1.02-1.41), and a history of chronic renal failure (OR, 2.21; 95% CI, 1.75-2.78), congestive heart failure (OR, 1.94; 95% CI, 1.44-2.62), or chronic lung disease (OR, 1.40; 95% CI, 1.18-1.67) as independent markers of risk-adjusted, in-hospital mortality (P < .0001 for each of these five variables). CONCLUSIONS: Nationwide in-hospital mortality after RABG is higher than predicted by prior reports from high-volume referral centers. Advanced age, female gender, and a history of chronic renal failure, congestive heart failure, or chronic lung disease were predictive of perioperative death. For the typical vascular practice, these data may provide a rationale for lower risk alternatives, such as renal artery stenting or referral to high-volume referral centers for RABG.

[Can the progression of chronic renal failure be delayed?]. / Kann man die Progression der chronischen Niereninsuffizienz verzögern?

Chronic renal failure does not only involve the risk for the patient of becoming dependent on hemodialysis, but also increases the risk of premature death due to cardiovascular events. In most renal diseases, progressive chronic loss of renal function develops once a critical extent of renal damage has occurred, independent of the course of the underlying renal disease. The key factors driving the progressive loss of renal function are, apart from the underlying nephrological disease, arterial hypertension and diabetes mellitus. The loss of renal function is also promoted by other factors, such as increased intake of dietary proteins, chronic inflammation, smoking, and anemia. With the help of a multimodal therapeutic concept, the progression of chronic renal failure can be delayed effectively. This approach comprises strict blood pressure control with a target blood pressure of 130/80 mmHg in patients with micro-albuminuria and of 120/75 mmHg in patients with proteinuria of >1 g/d. The preferred drugs for the treatment of hypertension are ACE inhibitors and angiotensin receptor blockers. In diabetics with renal insufficiency, target HbA1c levels below 7% are to be aimed for. Dietary protein intake should be restricted to 0.8-1 g/kg body weight/d. Additional therapeutic targets include nicotine abstinence, early treatment of renal anemia, weight reduction, and, if indicated, lipid-lowering therapy.

Mortality and risk factors of scleroderma renal crisis: a French retrospective study of 50 patients.

OBJECTIVES: To describe presentation and outcome of patients with scleroderma renal crisis (SRC). METHODS: SRC was defined as rapidly progressive oliguric renal insufficiency and/or rapidly progressive arterial hypertension occurring during the course of systemic sclerosis (SSc). Chronic dialysis-free survival was analysed using multivariate Cox proportional hazards regression models. The risk for developing SRC associated with corticosteroid (CS) exposure during the preceding 1- or 3-month periods was analysed according to a case-crossover design. RESULTS: A total of 50 SSc patients aged 53.3 (14.5) (mean (SD)) years were included in the study. SRC occurred between 1979 and 2003, after a mean (SD) disease duration of 27.7 (49.1) months. A total of 43 (86%) patients had diffuse SSc, 5 (10%) had limited cutaneous SSc and 2 (4%) had SSc sine scleroderma. At the time of SRC, 10 (20%) patients were taking angiotensin converting enzyme inhibitors, and mean creatininaemia was 468 (293) micromol/l. A total of 28 (56%) patients required haemodialysis. In all, 11 patients underwent a renal biopsy, all of them had specific vascular lesions of SRC. Multivariate analyses retained age >53 years and normal blood pressure as independent predictors of decreased dialysis-free survival. Exposure to CS prior to SRC was identified in 30 (60%) patients. The odds ratios for developing SRC associated with CS exposure during the preceding 1- or 3-month periods were 24.1 (95% CI 3.0-193.8) and 17.4 (95% CI 2.1-144.0), respectively. CONCLUSION: SRC remains associated with severe morbidity and mortality. CS might increase the risk of developing SRC. Further studies are needed to confirm these results.

Early prediction of IgA nephropathy progression: proteinuria and AOPP are strong prognostic markers.

BACKGROUND: Inflammation and oxidative stress have been incriminated in the pathogenesis of IgA nephropathy (IgAN). The aim of the present study was to assess whether markers reflecting these pathophysiologic processes, namely C-reactive protein (CRP) and advanced oxidation protein products (AOPP), would allow-in conjunction with clinical and histopathologic parameters-to predict disease progression. METHODS: Between 1994 and 1997, 120 adult patients with biopsy-proven IgAN were included in a prospective cohort study, and followed until the end of 2002 or start of dialysis. In every patient, we determined plasma levels of CRP and AOPP. These parameters were included, together with clinical data, in a multivariate Cox proportional hazard regression analysis, with halving of baseline creatinine clearance as the primary renal end point. RESULTS: A total of 51 patients reached the renal end point, including 30 who had to start dialysis. With multivariate analysis, the most potent independent risk factors of poor renal outcome were proteinuria > or =1 g/day [proportional hazard risk (HR) = 23.7, P= 0.0001], hypertension (HR = 8.13, P= 0.008), and AOPP plasma level (HR = 1.09 per 10 micromol/L, P= 0.042), whereas angiotensin II inhibitors were protective (HR = 0.19, P= 0.001). CONCLUSION: Our data support the role of oxidative stress in the pathogenesis of IgAN and suggest that patients with proteinuria > or =1 g/day should be eligible for early implemented antioxidant and/or anti-inflammatory therapeutic strategies, with AOPP plasma level as a surrogate marker to evaluate their effects.

Blockade of endothelin receptors attenuates end-organ damage in homozygous hypertensive ren-2 transgenic rats.

BACKGROUND/AIMS: A growing body of evidence suggests that the interplay between the endothelin (ET) and the renin-angiotensin systems (RAS) plays an important role in the development of the malignant phase of hypertension. The present study was performed to evaluate the role of an interaction between ET and RAS in the development of hypertension and hypertension-associated end-organ damage in homozygous male transgenic rats harboring the mouse Ren-2 renin gene (TGRs) under conditions of normal-salt (NS, 0.45% NaCl) and high-salt (HS, 2% NaCl) intake. METHODS: Twenty-eight-day-old homozygous male TGRs and age-matched transgene-negative male normotensive Hannover Sprague-Dawley (HanSD) rats were randomly assigned to groups with NS or HS intake. Nonselective ET(A/B) receptor blockade was achieved with bosentan (100 mg/kg/day). Systolic blood pressure (BP) was measured in conscious animals by tail plethysmography. Rats were placed into metabolic cages to determine proteinuria and clearance of endogenous creatinine. At the end of the experiment the final arterial BP was measured directly in anesthetized rats. Kidneys were taken for morphological examination. RESULTS: All male HanSD fed either the NS or HS diet exhibited a 100% survival rate until 180 days of age (end of experiment). The survival rate in untreated homozygous male TGRs fed the NS diet was 41%, which was markedly improved by treatment with bosentan to 88%. The HS diet reduced the survival rate in homozygous male TGRs to 10%. The survival rate in homozygous male TGRs on the HS diet was significantly improved by bosentan to 69%. Treatment with bosentan did not influence either the course of hypertension or the final levels of BP in any of the experimental groups of HanSD rats or TGRs. Although the ET-1 content in the renal cortex did not differ between HanSD rats and TGRs, ET-1 in the left heart ventricle of TGRs fed the HS diet was significantly higher compared with all other groups. Administration of bosentan to homozygous male TGRs fed either the NS or HS diet markedly reduced proteinuria, glomerulosclerosis and attenuated the development of cardiac hypertrophy compared with untreated TGR. CONCLUSIONS: Our data show that nonselective ET(A/B) receptor blockade markedly improves the survival rate and ameliorates end-organ damage in homozygous male TGRs without significantly lowering BP.

Temporary losartan or captopril in young SHR induces malignant hypertension despite initial normotension.

BACKGROUND: Exposure of normotensive rats to angiotensin-converting enzyme (ACE) inhibitors in early life causes hypertrophy of intrarenal arteries. Similar defects have been found in knockout mice lacking angiotensinogen, ACE, or angiotensin II type 1 (AT1) receptors. On the other hand, transient inhibition of the renin-angiotensin system from 2 weeks of age in spontaneously hypertensive rats (SHR), either with ACE inhibitors or with AT1 receptor antagonists partially prevents the increase in blood pressure. However, permanent treatment of SHR from conception onwards with ACE inhibitors completely prevents hypertension. Although these studies demonstrated protection from hypertension-induced changes in the heart and large arteries, renal arteries were not studied and follow-up did not extend beyond 6 months of age. We postulated that while brief exposure to ACE inhibitors or AT1 receptor antagonists in young SHR would temporarily decrease blood pressure, it would also be associated with development of intrarenal arterial malformation, and ultimately have deleterious effects. METHODS: Direct effects on intrarenal arterial morphology of an ACE inhibitor (captopril, 100 mg/kg/day) and an AT1 receptor antagonist (losartan, 50 mg/kg/day), administered from the last week of gestation until 8 weeks of age were examined in SHR. After stopping treatment at 8 weeks, we continued to monitor blood pressure until spontaneous death. RESULTS: Systolic blood pressure at 8 weeks was normalized by captopril and losartan (SHR control 187 +/- 8 mm Hg; captopril 118 +/- 5 mm Hg; and losartan 120 +/- 9 mm Hg). However, by 30 weeks, blood pressure had increased to control SHR levels. At 4 weeks, the media of renal arteries and arterioles was hypertrophied. Marked smooth muscle cell hyperplasia of cortical arteries resulted in significantly increased wall thickness by 8 weeks, despite similar external diameter. Arterial wall structure was disrupted, with fragmentation of elastic fibers and irregular distribution of collagen type I fibers. After stopping treatment, the rats gradually began to show poor health and all had died by 1 year of age, while all 1-year-old control SHR females were in good health. The cause of morbidity and mortality in the rats treated in early life was clearly malignant hypertension. Severe hypertrophy of renal arterioles was found, as well as cerebral hemorrhage. CONCLUSION: Despite initial normalization of blood pressure interference with the renin-angiotensin system during a crucial stage of development in SHR can initiate marked smooth muscle cell hyperplasia and disruption of the wall structure of the intrarenal arteries. Subsequent progression of this intrarenal process after cessation of treatment suggests an independent process that eventually results in malignant hypertension and early death.

Beneficial and adverse renal and vascular effects of the vasopeptidase inhibitor omapatrilat in renovascular hypertensive rats.

BACKGROUND: Vasopeptidase inhibitors are a new class of compounds that inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase. This study determined whether treatment with the vasopeptidase inhibitor omapatrilat (OMA) produced different effects on renal and cardiovascular structure compared with inhibition of ACE by enalapril (ENP) in rats with two-kidney, one clip hypertension (2K1C). METHODS: Hypertensive 2K1C rats were randomized into four groups and studied for another 8 weeks: no treatment, OMA, ENP or ENP combined with the diuretic hydrochlorothiazide (ENP + HCTZ). Albuminuria, vascular and renal histology as well as glomerular expression of transforming growth factor-beta (TGF-beta) were determined at the end of the experiment. RESULTS: OMA decreased blood pressure slightly better than ENP. However, combination of ENP with a diuretic lowered blood pressure equally effective as OMA. OMA was numerically more efficient in reducing cardiovascular and renal hypertensive changes compared with ENP. In contrast, the combination of ENP + HCTZ was as efficient as OMA. However, OMA lowered overexpression of TGF-beta in the non-clipped kidney better than ENP or ENP +HCTZ. Antihypertensive therapy surprisingly decreased renal function as shown by increased plasma creatinine and urea and decreased creatinine clearance. CONCLUSION: OMA is marginally more potent compared with ENP alone in lowering blood pressure and preventing cardiovascular and renal injury. This effect may be due to slightly better blood pressure reduction because addition of HCTZ enhances the cardio- and nephroprotective capacity of ENP. In contrast, OMA reduces TGF-beta overexpression in the non-clipped kidney better than ENP or ENP + HCTZ. Therefore, vasopeptidase inhibition is not superior to ACE inhibition in the prevention of cardiovascular and renal damage Goldblatt hypertension.

Reduction in natural death and renal failure from a systematic screening and treatment program in an Australian Aboriginal community.

BACKGROUND: Australian Aborigines in remote areas are experiencing an epidemic of renal and cardiovascular disease. In November 1995, we introduced a renal and cardiovascular treatment program into the Tiwi community, which has a three- to fivefold increase in death rates and a recent annual incidence of treated end-stage renal disease (ESRD) of 2760 per million. Our previous study described an estimated 50% reduction in renal failure and all-cause natural deaths in the treatment group through December 31, 1998. We now describe a reduction in these events through mid 2000. METHODS: People eligible for treatment were those with confirmed hypertension, diabetics with microalbuminuria or overt albuminuria, and people with overt albuminuria, regardless of blood pressure and diabetes. Treatment centered around the use of perindopril (Coversyl, Servier), with additional agents as needed to reach defined blood pressure goals, attempts at control of glucose and lipid levels, and health education. Two hundred and sixty-seven people, or 30% of the adult population, have been enrolled, with mean follow up of 3.39 years. Rates of terminal endpoints were compared on an intention-to-treat basis with those of 327 historical controls matched for baseline disease severity, who were followed for a mean of 3.18 years in the pre-treatment program era, against a background of no treatment or inconsistent changing treatment. RESULTS: Terminal events occurred in 38 controls and 23 people in the treatment group. The estimated rate of natural deaths in the treatment group was 50% that of the controls, (P=0.012); the rate of renal deaths was 47% (P=0.038) and the rate of non-renal deaths was 54% that of controls (P=0.085). Survival benefit in the treatment group was observed at all levels of overt albuminuria, in non-diabetics and diabetics, in normotensive as well as hypertensive people, and in people who had been taking angiotensin converting enzyme-inhibitors (ACEi) in the pre-program era, as well as those who had not. Benefit was absent among the low death rates of people without overt albuminuria, and questionable among people with glomerular filtration rates (GFRs) <60 mL/min. The number of people needed to treat (NNT) to avoid one terminal event of natural causes was calculated at only 11.6. CONCLUSIONS: Falling rates of deaths and renal failure in the whole community support marked benefit of the program. Millions of dollars have been saved, based on avoidance of dialysis alone, but the reduction in premature death is the greater benefit. Chronic disease programs like this are enormously effective, and should be introduced into to all high-risk communities as a matter of urgency.

Successful renovascular reconstruction for renal allografts with multiple renal arteries.

BACKGROUND: Kidney grafts with multiple renal arteries have been considered a relative contraindication because of the increased risk of complications. In the present study, we retrospectively reviewed multiple renal artery reconstruction in kidney transplantation to elucidate the usefulness of these grafts. METHODS: From January 1997 until August 2001, 431 recipients underwent kidney transplantation at our institution; 393 patients are reviewed. The surgical techniques of vascular reconstruction and short-term outcome are reported. The living kidney transplant recipients were divided into vascular reconstructed and nonreconstructed groups, and mean serum creatine levels, warm and total ischemic times, and incidences of acute rejection and posttransplantation hypertension were compared. RESULTS: We noted multiple renal arteries in 96 (24.4%) of the 393 grafts. Arterial reconstruction was performed on 53 (13.5%) grafts, whereas 43 (10.9%) small polar arteries were simply ligated. Surgical management of the multiple arteries was variable. The most common reconstruction was conjoined anastomosis (17 cases) between two arteries of equal size and end-to-side anastomosis (14 cases) of smaller arteries to larger arteries. In nine cases, autogenous hypogastric or epigastric artery grafts were used to reconstruct multiple renal arteries. Multiple anastomosis was performed in six cases. In seven cases, complicated surgical vascular reconstruction was performed. The mean total ischemic times in the reconstructed and nonreconstructed groups were 102.6 and 71.0 min, respectively (P<0.01). The incidences of posttransplantation hypertension in the reconstructed and nonreconstructed groups were 68.2% (30/44) and 48.6% (141/290), respectively (P<0.05). There was no significant difference between the reconstructed and nonreconstructed groups in mean warm ischemic times, mean creatinine levels, and incidences of acute rejection. CONCLUSIONS: Allografts with multiple renal arteries can be used successfully in kidney transplantation.

Trends in the pathophysiological characteristics of malignant hypertension.

The aim of the present study is to investigate the pathophysiological characteristics of a number of recent cases of malignant hypertension (MHT) and to compare them to the characteristics of earlier cases. Patients with MHT (age 25-76, mean 44+/-2 years) who were admitted to our hospital from 1984-1999 were retrospectively studied. All of the patients had either grade III or IV retinopathy and diastolic blood pressure levels higher than 120 mmHg. The observations in this study were compared to previously reported findings regarding 59 MHT patients who were admitted from 1971-1983. Of the 37 recent MHT patients, 20 had essential hypertension (EHT) as the underlying disease, 13 had chronic glomerulonephritis (CGN), and the remaining 4 presented with other diseases including pyelonephritis and renovascular hypertension. A positive family history of hypertension was more prevalent in the EHT patients than in other patients, and persistent proteinuria, microhematuria, and anemia were more prevalent in the CGN patients. These characteristics were similar between the recent and previous cases. Within 4 weeks after admission, hemodialysis was initiated in 3 of the 13 patients (23%) with CGN and 2 of the 20 (10%) patients with EHT. The prevalence of renal death at 1 year after admission was 30%, which was lower than the prevalence in the previous cases (42%). Grade IV retinopathy was seen in 45% of the patients admitted from 1984-1999, significantly less than in the patients admitted from 1971-1983 (66%, p<0.05). In addition, left ventricular hypertrophy was less frequently observed on electrocardiogram in the recent cases (67%) than in the previous cases (88%, p<0.05). Our results suggest that the recent cases of MHT demonstrate less severe organ damage.