Sulfate metabolism in the alloxan-diabetic rat: relationship of altered sulfate pools to proteoglycan sulfation in heart and other tissues

Summary The incorporation of [³⁵S]sulfate into heart proteoglycans has been studied in normal and alloxan-diabetic rats by perfusion and in vivo administration of the isotope; in the latter situation, comparison was also made of radiolabeled sulfate utilization by several other tissues (kidney, liver, lung, muscle, testes and skin). The radiolabeled products were characterized by sodium dodecylsulfate polyacrylamide gel electrophoresis and anion exchange chromatography, as well as by sizing of the glycosaminoglycan chains by gel filtration both before and after nitrous acid treatment. The most prominent band observed in the heart guanidine extract by electrophoresis had a molecular weight of 85,000 and minor components (M_r=360,000 and 170,000) were also detected; approximately 20% of the proteoglycan associated [³⁵S]sulfate was present in heparan sulfate chains. After perfusion the pattern, as well as the amount of radioactivity recovered from the diabetic heart, was similar to the normal heart. In contrast, after intraperitoneal injection of the [³⁵S]sulfate, a substantial reduction in incorporation was found not only in heart but in several other tissues studied, although no qualitative differences were noted in the macromolecules formed by the two groups of animals. Measurement of the serum sulfate concentration indicated that the level in the alloxan-diabetic rat (1.23 mmol/l) was significantly less (p<0.01) than that of the normal rat (1.67 mmol/l). Moreover, when serum specific activity curves were prepared between 10 min and 24 h after isotope injection, the decline in the diabetic curve was found to be much more rapid than that of the normal curve, with the area under the diabetic specific activity curve between 0 and 4 h being 0.61 that of normal (p<0.005). Since the amount of free [³⁵S]sulfate recovered in the tissues was also considerably lower in the diabetic animals, the specific activity differences of the precursor appear to account for the reduced incorporation of sulfate observed in vivo in contrast to perfusion, where pool sizes and specific activity can be controlled. Measurement of renal sulfate clearance indicated that it is enhanced in the alloxan-diabetic rats, suggesting that handling of sulfate in diabetes is similar to that previously described in this disease for inorganic phosphate.     

Exercise as a provocative test in early renal disease in Type 1 (insulin-dependent) diabetes: albuminuric,systemic and renal haemodynamic responses

Summary The value of exercise as a provocative test for early renal disease in Type 1 (insulin-dependent) diabetes was reevaluated. Three carefully characterized groups of males were studied: 10 non-diabetic controls, 16 diabetic patients (group 1) with normal urinary albumin excretion (< 15 g/min) and 14 Albustix-negative diabetics (group 2) with increased urinary albumin excretion (15–122 g/min). Assignment to a study group was made on the basis of three 24-h urine collections, and the groups were well matched for age, weight, height, and serum creatinine concentration. The two diabetic groups were similar with regard to duration of disease (13±6 versus 16±3 years), metabolic control (HbA_1c: 8.4±1.4 versus 8.7±1.3%) and degree of diabetic complications (beat-to-beat variation and retinopathy). An exercise protocol of 450 and 600 kpm/min workloads was employed. In the resting state group 2 patients had elevated systolic blood pressure compared with the normal subjects (132±13 versus 119±9 mmHg), and their glomerular filtration rate was significantly reduced compared with group 1 (123±19 versus 138±15ml/min per 1.73m², p < 0.05). During exercise the urinary albumin excretion rate increased significantly in all three groups (normal subjects: 6±0.7 to 8±1.3 (g/min); group 1: 6±0.6 to 9±1 g/min and group 2: 48±10 to 113±23 g/min), the relative increase being higher in group 2 (p < 0.01). The changes in systemic haemodynamics were similar in all three groups in spite of a reduced maximum working capacity in group 2 (949±249 versus group 1:1163±200 and normal subjects 1267±264 kpm/min (p < 0.05). The renal haemodynamic changes were qualitatively similar for the three groups, but the filtration fraction during exercise increased in groups 1 and 2 to almost identical values and were significantly higher than in normal subjects (group 1 + group 2: 0.29±0.02 versus normal subjects: 0.26±0.03, p < 0.02). These findings suggest that an elevated transcapillary pressure gradient, as obtained during moderate exercise, will not cause an abnormal increase in albumin excretion per se. A functional glomerular lesion, already recognisable at rest (elevated albumin excretion) must also be present.     

De novo development of antibodies to kidney‐associated self‐antigens angiotensin II receptor type I,collagen IV,and fibronectin occurs at early time points after kidney transplantation in children

Chronic rejection is the leading cause of graft loss following pediatric kidney transplantation. Our group and others have demonstrated an association between the development of Abs to self‐antigens and chronic rejection following adult lung and heart transplantation. The goal of this study was to determine whether Abs to kidney‐associated self‐antigens develop following pediatric renal transplantation. We investigated post‐transplant development of Abs to kidney‐associated self‐antigens angiotensin II receptor type I, Fn, and collagen IV in a pediatric cohort. Using ELISA, we measured Abs to kidney‐associated self‐antigens in serum. Our cohort included 29 subjects with samples collected pretransplant and for 12 months post‐transplant. No samples had Abs to kidney‐associated self‐antigen pretransplant. In contrast, 50% (10/20) of subjects developed Abs to one or more kidney‐associated self‐antigen post‐transplantation. The median time to antibody appearance and duration of persistence were 103 and 61 days, respectively. Development of Abs did not correlate with graft function. Half of subjects developed Abs to kidney‐associated self‐antigens angiotensin II receptor type I, Fn, or collagen IV in the first year after kidney transplantation—a higher rate of early antibody development than expected. In this small study, Abs did not correlate with worse clinical outcomes.     

Impact of calcium entry blockers on glomerular injury in experimental hypertension

Summary A major problem for patients with kidney disease and their physicians is that most chronic renal diseases progress to global glomerular sclerosis and end-stage renal failure. Studies in experimental models of hypertension and renal insufficiency have advanced our understanding of the pathogenesis of progressive kidney damage. In a number of settings, sclerosis has been related to the presence of intrarenal hypertension, a consequence of the hemodynamic adaptation to a reduction in the number of functioning nephrons. A growing body of evidence also supports the hypothesis that kidney and glomerular hypetrophy constitute an independent risk factor for glomerular sclerosis. Recent studies suggest that calcium antagonists can reduce glomerular injury in experimental hypertension. Renal protection may be related to the ability of these agents to inhibit compensatory renal growth.     

Comparison of two methods of determining renal perfusion with and without captopril pretreatment in groups of patients with left ventricular dysfunction

Methods of effective renal plasma flow measurement by ¹²⁵I-orthoiodohippurateelimination and para-aminohippurate clearance were comparedwith and without captopril pretreatment in 10 chronic heartfailure patients and in 20 patients after transmural myocardialinfarction. In the chronic heart failure group measurements of effectiverenal plasma flow by the two techniques were strongly correlated(r=0·92, P<0·00001), as was the captopril-mediatedchange in effective renal plasma flow by the two methods (r=0·85,P=0·002). However, in absolute terms para-aminohippurateclearance significantly exceeded ¹²⁵I-orthoiodohippurate clearanceby a mean (± SD) of 24·8 ± 43·7ml. min^–1 (P<0·05) so that only using the formertechnique was a signifincant in renal perfusion observed inresponse to converting enzyme inhibition. In the post-myocardial infarction group, correlations betweenthe two methods were variable and much poorer than in the chronicheart failure group (r=0·54, P=0·01 and r=0·74,P=0·002 on consecutive days). Furthermore, captoprilmediatedincrements in effective renal plasma flow by the two techniqueswere unrelated (r= – 0·19, P=0·59). In thisgroup ¹²⁵I-orthoiodohippurate elimination significantly exceededpara-aminohippurate clearance (P<0·05). This reversedassociation and the weaker relationships between methods inpost-infarction as compared to chronic heart failure patientsmay be related to interference by thrombolytic or aspirin treatments.     

心脏术后急性肾功能衰竭的替代治疗

目的　评估肾脏替代治疗对心脏术后急性肾功能衰竭的效果。方法　 1995年 1月至 2 0 0 3年 7月 ,5 4例心脏术后因急性肾功能衰竭接受了肾脏替代治疗 ,其中腹膜透析 2 0例 ,血液透析 15例 ,连续性肾脏替代治疗 19例。结果　 14例患者肾功能恢复出院 ,6例病情好转后自动出院 ,34例死亡。结论　肾脏替代治疗是心脏术后急性肾功能衰竭的一种有效治疗手段 ,应尽早实施。     

Worsening or ‘pseudo-worsening’ renal function? The prognostic value of hemoconcentration in patients admitted with acute heart failure

Introduction

Renal insufficiency, as evidenced by an increase in creatinine, is associated with higher mortality in patients with acute heart failure (AHF). Conversely, hemoconcentration (HC) in AHF is associated with lower mortality, but can also cause an increase in creatinine. Our aim was to assess the prognosis of HC in patients hospitalized for AHF presenting with or without worsening renal function (WRF).

Renal Denervation in High-Risk Patients With Hypertension

BackgroundRenal denervation (RDN) is under investigation for treatment of uncontrolled hypertension and might represent an attractive treatment for patients with high cardiovascular (CV) risk. It is important to determine whether baseline CV risk affects the efficacy of RDN.ObjectivesThe purpose of this study was to assess blood pressure (BP) reduction and event rates after RDN in patients with various comorbidities, testing the hypothesis that RDN is effective and durable in these high-risk populations.MethodsBP reduction and adverse events over 3 years were evaluated for several high-risk subgroups in the GSR (Global proSpective registrY for syMPathetic renaL denervatIon in seleCted IndicatIons Through 3 Years Registry), an international registry of RDN in patients with uncontrolled hypertension (n = 2,652). Comparisons were made for patients age ≥65 years versus age <65 years, with versus without isolated systolic hypertension, with versus without atrial fibrillation, and with versus without diabetes mellitus. Baseline cardiovascular risk was estimated using the American Heart Association (AHA)/American College of Cardiology (ACC) atherosclerosis cardiovascular disease (ASCVD) risk score.ResultsReduction in 24-h systolic BP at 3 years was −8.9 ± 20.1 mm Hg for the overall cohort, and for high-risk subgroups, BP reduction was −10.4 ± 21.0 mm Hg for resistant hypertension, −8.7 ± 17.4 mm Hg in patients age ≥65 years, −10.2 ± 17.9 mm Hg in patients with diabetes, −8.6 ± 18.7 mm Hg in isolated systolic hypertension, −10.1 ± 20.3 mm Hg in chronic kidney disease, and −10.0 ± 19.1 mm Hg in atrial fibrillation (p < 0.0001 compared with baseline for all). BP reduction in patients with measurements at 6, 12, 24, and 36 months showed similar reductions in office and 24-h BP for patients with varying baseline ASCVD risk scores, which was sustained to 3 years. Adverse event rates at 3 years were higher for patients with higher baseline CV risk.ConclusionsBP reduction after RDN was similar for patients with varying high-risk comorbidities and across the range of ASCVD risk scores. The impact of baseline risk on clinical event reduction by RDN-induced BP changes could be evaluated in further studies. (Global proSpective registrY for syMPathetic renaL denervatIon in seleCted IndicatIons Through 3 Years Registry; NCT01534299)     

Absence of effects of ketanserin on renal prostacyclin and thromboxane A2 in essential hypertension

The anti-hypertensive effect of ketanserin, a new antagonist of 5-HT2-serotonergic receptors, was evaluated in 10 patients with uncomplicated essential hypertension. At the end of 2 weeks of placebo wash-out and following 2 and 4 weeks of treatment with ketanserin (20 mg twice daily), blood pressure and heart rate were measured both in the supine and standing position. In addition, before and at the end of treatment, plasma renin activity (PRA), plasma concentration of aldosterone and the nocturnal urinary excretion of 6-keto-PGF1 alpha and TXB2, the two metabolites that largely reflect the renal synthesis of prostacyclin and thromboxane, respectively, were determined. The study was carried out in a metabolic ward where the intake of sodium was adjusted to 100-120 mmol day-1. Ketanserin significantly reduced blood pressure both in the supine and standing position with no significant change of heart rate. The treatment did not produce any variation of PRA, aldosterone, urinary excretion of 6-keto-PGF1 alpha or TXB2. These results indicate that ketanserin reduces blood pressure without interfering with the renin-angiotensin-aldosterone system or the renal synthesis of prostacyclin and thromboxane.