Reduction of protein-bound uraemic toxins in plasma of chronic renal failure patients: A systematic review.

BACKGROUND: Protein-bound uraemic toxins (PBUTs) accumulate in patients with chronic kidney disease and impose detrimental effects on the vascular system. However, a unanimous consensus on the most optimum approach for the reduction of plasma PBUTs is still lacking. METHODS: In this systematic review, we aimed to identify the most efficient clinically available plasma PBUT reduction method reported in the literature between 1980 and 2020. The literature was screened for clinical studies describing approaches to reduce the plasma concentration of known uraemic toxins. There were no limits on the number of patients studied or on the duration or design of the studies. RESULTS: Out of 1274 identified publications, 101 studies describing therapeutic options aiming at the reduction of PBUTs in CKD patients were included in this review. We stratified the studies by the PBUTs and the duration of the analysis into acute (data from a single procedure) and longitudinal (several treatment interventions) trials. Reduction ratio (RR) was used as the measure of plasma PBUTs lowering efficiency. For indoxyl sulphate and p-cresyl sulphate, the highest RR in the acute studies was demonstrated for fractionated plasma separation, adsorption and dialysis system. In the longitudinal trials, supplementation of haemodialysis patients with AST-120 (Kremezin®) adsorbent showed the highest RR. However, no superior method for the reduction of all types of PBUTs was identified based on the published studies. CONCLUSIONS: Our study shows that there is presently no technique universally suitable for optimum reduction of all PBUTs. There is a clear need for further research in this field.

Hypophosphatemia after high-dose iron repletion with ferric carboxymaltose and ferric derisomaltose-the randomized controlled HOMe aFers study.

BACKGROUND: In patients with iron deficiency anemia, ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) allow high-dose iron repletion. While FCM is reported to induce hypophosphatemia, the frequency of hypophosphatemia after an equivalent dosage of FDI had not been assessed prospectively. METHODS: In the prospective, single-center, double-blind HOMe aFers study, 26 women with iron deficiency anemia (hemoglobin < 12 g/dL plus either plasma ferritin ≤ 100 ng/mL or a plasma ferritin ≤ 300 ng/mL and transferrin saturation (TSAT) ≤ 30%) were randomized to a single intravenous infusion of 20 mg/kg body weight (up to a maximum of 1000 mg) FCM or FDI. The primary endpoint was the incidence of hypophosphatemia (plasma phosphorus levels < 2.0 mg/dL at day 1, day 7 ± 2, and/or day 35 ± 2 after the infusion). In order to investigate potential skeletal and cardiovascular implications, we assessed changes in other components of mineral and bone metabolism, left ventricular function, and arrhythmias. RESULTS: Hypophosphatemia occurred more frequently in women treated with FCM (9 out of 12 [75%]) than in those treated with FDI (1 out of 13 [8%]; p = 0.001). Within 24 h after iron supplementation, women in the FCM group had significant higher plasma intact FGF23 (p < 0.001) and lower plasma 1.25-dihydroxyvitamin D (p < 0.001). As an indicator of urinary phosphorus losses, urinary fractional phosphorus excretion was higher in the FCM group (p = 0.021 at day 7 ± 2 after iron supplementation). We did not observe differences in skeletal and cardiovascular markers, potentially because of the limited number of participants. CONCLUSIONS: While both FCM and FDI provide efficient iron repletion in participants with iron deficiency anemia, FCM induced hypophosphatemia more often than FDI. TRIAL REGISTRATION: Clinical Trials.gov NCT02905539. Registered on 8 September 2016. 2015-004808-36 (EudraCT Number) U1111-1176-4563 (WHO Universal Trial Number) DRKS00010766 (Deutsches Register Klinischer Studien).

[Chronic kidney disease-a cardiovascular high-risk constellation]. / Chronische Nierenerkrankung ­ eine kardiovaskuläre Höchstrisikokonstellation.

Chronic kidney disease (CKD) is associated with substantial cardiovascular morbidity and mortality. This is mediated by the high prevalence of traditional cardiovascular risk factors in patients with CKD such as arterial hypertension and diabetes mellitus, but also by the presence of CKD-specific so-called nontraditional cardiovascular risk factors such as vascular calcification, uremic toxins, uremic dyslipidemia as well as inflammation and oxidative stress. Therefore, the primary and secondary prevention of cardiovascular disease represents an integral part of nephrology. This entails optimal control of blood pressure and diabetes, therapy of the uremic dyslipidemia as well as lifestyle-modifying factors such as weight reduction and smoking cessation.

[Anticoagulation in patients with chronic kidney disease : Recommendations from the working group "Heart-Kidney" of the German Cardiac Society and the German Society of Nephrology]. / Antikoagulation bei Patienten mit chronischer Niereninsuffizienz : Empfehlungen der Arbeitsgemeinschaft "Herz ­ Niere" der Deutschen Gesellschaft für Kardiologie ­ Herz- und Kreislaufforschung und der Deutschen Gesellschaft für Nephrologie.

Indications for anticoagulation are thromboembolic events, prosthetic heart valves, and atrial fibrillation with a corresponding risk score. Clinical trials have excluded patients with advanced chronic kidney disease and these data cannot be always generalized to patients with chronic kidney disease. Non-vitamin K antagonist oral anticoagulants (NOACs) are mostly not recommended or are contraindicated in advanced stages of chronic kidney disease. Observational studies have shown that dialysis patients with atrial fibrillation do not profit from coumarin anticoagulants; prospective studies are lacking.

BK polyomavirus-specific cellular immune responses are age-dependent and strongly correlate with phases of virus replication.

BK polyomavirus (BKPyV) infection is widespread and typically asymptomatic during childhood, but may cause nephropathy in kidney transplant recipients. However, there is only limited knowledge on BKPyV-specific immunity in children and adults, and its role in BKPyV-replication and disease posttransplant. We therefore characterized BKPyV-specific immunity from 122 immunocompetent individuals (1-84 years), 38 adult kidney recipients with (n = 14) and without BKPyV-associated complications (n = 24), and 25 hemodialysis (HD) patients. Blood samples were stimulated with overlapping peptides of BKPyV large-T antigen and VP1 followed by flow-cytometric analysis of activated CD4 T cells expressing interferon-γ, IL-2 and tumor necrosis factor-α. Antibody-levels were determined using enzyme-linked immunosorbent assay. Both BKPyV-IgG levels and BKPyV-specific CD4 T cell frequencies were age-dependent (p = 0.0059) with maximum levels between 20 and 30 years (0.042%, interquartile range 0.05%). Transplant recipients showed a significantly higher BKPyV-specific T cell prevalence (57.9%) compared to age-matched controls (21.7%) or HD patients (28%, p = 0.017). Clinically relevant BKPyV-replication was associated with elevated frequencies of BKPyV-specific T cells (p = 0.0002), but decreased percentage of cells expressing multiple cytokines (p = 0.009). In conclusion, BKPyV-specific cellular immunity reflects phases of active BKPyV-replication either after primary infection in childhood or during reactivation after transplantation. Combined analysis of BKPyV-specific T cell functionality and viral loads may improve individual risk assessment.

Dosing strategies for conversion of haemodialysis patients from short-acting erythropoiesis stimulating agents to once-monthly C.E.R.A.: experience from the MIRACEL study.

AIMS: To analyse the impact of dosing decisions for continuous erythropoietin receptor activator (C.E.R.A.), a continuous erythropoietin receptor activator. METHODS: This was a prospective, multicentre, single-arm study in haemodialysis patients receiving epoetin alfa/beta or darbepoetin alfa. After a 2-month screening phase, patients were converted to monthly C.E.R.A. using pre-filled syringes during a 5-month titration phase and a 2-month evaluation phase. RESULTS: Four hundred and twenty-four eligible patients were converted to C.E.R.A. Mean Hb were 11.7 ± 0.7, 11.7 ± 0.8 and 11.5 ± 0.8 g/dl during screening, titration and evaluation, respectively. C.E.R.A. starting dose was 125 µg (n = 311) or 200 µg (n = 106), with corresponding final doses of 129 ± 61 µg and 203 ± 58 µg. The mean number of C.E.R.A. dose decreases and increases were 0.9 ± 1.0 and 1.1 ± 1.0 per patient, respectively. Hb rarely exceeded 12.5 g/dl after a C.E.R.A. dose increase (< 8%) and remained ≥ 11 g/dl after a dose reduction on approximately three-quarters of occasions. Among the 53 occasions where Hb decreased ≥ 2 g/dl between two consecutive visits, the previous dose had been withheld (n = 9), concomitant blood loss, coagulopathy or infection was present (n = 13), or iron parameters were low (n = 17). There were 104 adverse events/month during screening, and 45/month during the titration/evaluation phases. Serious adverse events occurred in 18.0 and 21.0 patients/month during the screening and titration/evaluation phases, respectively. CONCLUSION: Switching haemodialysis patients from shorter-acting ESA to once-monthly C.E.R.A. using pre-filled syringes is straightforward, and Hb levels remain stable. Starting dose recommendations and dose changes correlated well with the clinical setting. Collateral factors such as infection or aggravating concomitant medical conditions should be taken into account.

Chronic erythropoietin treatment affects different molecular pathways of diabetic cardiomyopathy in mouse.

BACKGROUND: Recent studies in mice experimental models with acute ischaemic injury revealed that erythropoietin (EPO) has numerous tissue-protective effects in the heart, brain and kidneys. We therefore explored the tissue-protective properties of chronic EPO treatment in an experimental model of the db/db mouse with diabetic heart injury. MATERIAL AND METHODS: We randomly treated 11 db/db mice with placebo (saline), 0.4 microg of the continuous erythropoietin receptor activator (CERA) per week (n = 11) or 1.2 microg CERA per week (n = 11) for 14 weeks, and analysed cardiac tissue. The lower CERA dose was a non-haematologically effective dose, whereas the second increased the haematocrit. RESULTS: Compared with mice in the placebo group, CERA-treated mice had a reduction in TGF-beta(1) and collagen I expression in cardiac tissue (P < 0.01 vs. higher dose CERA). In addition, an increased expression of the pro-survival intracellular pathway p-AKT was observed (P < 0.05 vs. higher dose CERA). The values for the lower C.E.R.A had an intermediate nonsignificant effect. Furthermore, we were able to show that atrial natriuretic peptide (ANP) expression was increased in both CERA groups. CONCLUSIONS: Chronic treatment with CERA protects cardiac tissue in diabetic animals, i.e. it inhibits molecular pathways of cardiac fibrosis, and the effects are dose-dependent.

Erythropoietin and the endothelium - a promising link?

The major physiological function of erythropoietin (EPO) is thought to be the induction of erythropoiesis. However, a growing body of evidence indicates that EPO as well as recombinant human erythropoietin (rHuEPO) and its analogues have tissue-protective effects and prevent tissue damage during ischaemia. This mini review summarizes the present knowledge on protective vascular effects of EPO and discusses the potential underlying mechanisms.

A hibernating kidney - ischemic preconditioning in a renal transplant recipient with a proximal stenosis of the iliac artery.

Ischemic preconditioning has been first described by Murry and coworkers as the protection conferred to ischemic myocardium by preceding brief periods of sublethal ischemia separated by periods of reperfusion. Another phenomenon closely associated to IPC is hibernation and stunning. The hibernating myocardium refers to resting left ventricular dysfunction due to reduced coronary blood flow that can be partially or completely reversed by myocardial revascularization and/or by reducing myocardial oxygen demand. Similarly as for the myocardium, these effects are reproducible for other solid organs. Here we report a case of a renal transplant recipient with decompensated proximal transplant artery stenosis due to ACE inhibition resulting in acute renal failure. The transplant perfusion was strictly dependent on systemic arterial blood pressure leading to intermittent episodes of renal ischemia and reperfusion. Renal function was severely decreased (glomerular filtration rate approximately 8 ml/min) with the need of hemodialysis treatment over a period of 4 weeks after transplantation. After dilatation of the stenosis, the patient's renal function improved rapidly and achieved values better than ever before. Referring to the definition of hibernating myocardium, here we postulate a case of a hibernating kidney in context of ischemic preconditioning.

Erythropoiesis-stimulating agents: past and future.

Renal anemia is a well-recognized complication of chronic kidney disease (CKD), and the deficiency of erythropoietin (EPO) is the primary cause. Observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes, and renal failure, cardiac failure, and anemia all may interact to cause or worsen each other, the so-called cardio-renal anemia syndrome. Treatment of anemia can be successfully achieved with the use of erythropoiesis-stimulating agents (ESAs). From a mechanistic point of view, however, the therapeutic benefits of ESA could be far beyond the correction of anemia. ESA modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. A pleiotropic effect of EPO has been shown in the central nervous system, the cardiovascular system, and the kidney. While recent results of randomized controlled trials have established that there is little support for normalizing hemoglobin in CKD patients, the results of these studies do not negate renoprotective effects of EPO. A large number of patients with CKD will benefit from early recognition and appropriate correction of anemia with ESA.

Erythropoietin and progression of CKD.

In patients with primary as well as secondary chronic kidney disease (CKD), anemia has been identified as an independent risk factor for progression. In these patients anemia is thought to be a surrogate parameter for tissue hypoxia that perpetuates preexisting renal tissue injury, and treatment of anemia with recombinant human erythropoietin (rHuEPO) was therefore expected to retard progression. However, results of recently published large trials in patients with CKD did not fulfill these expectations. The reason for the discrepant findings may be distinct molecular pathways and/or EPO tissue receptor affinities that mediate the effect of EPO on erythropoiesis and tissue protection by EPO. A pivotal intracellular pathway is the activation of Akt (i.e., serine/threonine protein kinase B), but further potential pathways have been identified that may play an important role in tissue protection. In this study, we review data on the non-hematological effects of rHuEPO in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogue substances that are not related to anemia correction.

How can we improve prognosis in diabetic patients with end-stage renal disease?

Diabetes has become the single most important cause of end-stage renal failure, but survival of diabetic patients with renal replacement therapy continues to be poor. The major causes of death are cardiovascular complications. Most cardiovascular complications, particularly coronary atheroma, accumulate before patients enter renal replacement programs. This observation points to the need for improved patient care in pre-end-stage renal failure. In the diabetic patient, dialysis should be started earlier than in the nondiabetic patient, and prophylactic vascular access should be established when the glomerular filtration rate is approximately 20 ml/min. Proposals to improve prognosis of the diabetic patient with renal failure include interdisciplinary care for the patients with renal disease, strict normotension, administration of ACE inhibitors, administration of lipid-lowering agents, near-normalization of anemia using recombinant human erythropoietin, and improvement of diabetic foot care in the patient on renal replacement therapy.

Alloreactive T Cells to Identify Risk HLA Alleles for Retransplantation After Acute Accelerated Steroid-Resistant Rejection.

The risk of rejection by cellular alloreactivity to the transplant donor is not routinely assessed. Here we analyzed alloreactive T cells in kidney transplant recipients and report how their detection may have helped to prevent rejection of a second kidney graft in a patient with a history of acute accelerated steroid-resistant nonhumoral rejection. Alloreactive CD4 and CD8 T cells were quantified using a flow-cytometric mixed lymphocyte reaction assay based on interferon-γ induction. A group of 16 nonrejecting transplant recipients did not show any alloreactive T-cell immunity to their respective donors, whereas alloreactivity to third-party controls was detectable. In the patient with rejection, HLA-specific antibodies were not detectable before and shortly after rejection, but after transplantation the patient showed exceptionally high frequencies of alloreactive T cells against 2 of 11 HLA-typed controls (0.604% and 0.791% alloreactive CD4 T cells and 0.792% and 0.978% alloreactive CD8 T cells) who shared HLA alleles (HLA-A*24, -B*44, -C*02, -DQB1*5) with the kidney donor. These HLA alleles were subsequently excluded for allocation of a second graft. No alloreactive T cells were observed toward the second kidney donor, and this transplantation was performed successfully. Thus, shared HLA alleles between the donor and third-party controls may suggest that alloreactive T cells had contributed to rejection of the first graft. The rejecting patient highlights that determination of cellular alloreactivity before transplantation may be applied to identify unacceptable mismatches and to reduce the risk for acute cellular rejection episodes.

Changes in plasma phosphate levels influence insulin sensitivity under euglycemic conditions.

The euglycemic clamp technique is a useful tool to evaluate insulin-mediated glucose uptake. The plasma phosphate concentration decreases during euglycemic clamp studies. Because insulin-dependent glucose uptake is closely related to phosphate uptake, we investigated whether modulation of plasma phosphate levels in the range observed during clamp studies influences insulin sensitivity. We studied 11 healthy (phosphate-replete) male volunteers (mean age, 27.5 +/- 1.8 yr;, mean body mass index, 23.9 +/- 1.6 kg/m2) in a double blind placebo-controlled cross-over study. The volunteers received in random order on two occasions either an infusion of sodium chloride (sham infusion) or an infusion of sodium phosphate. Insulin sensitivity was assessed under euglycemic conditions (clamp technique). The mean plasma phosphate concentration decreased with sham infusion from 1.09 +/- 0.17 to 0.64 +/- 0.13 mmol/L, whereas it increased with phosphate infusion from 1.06 +/- 0.19 to 1.32 +/- 0.13 mmol/L. In all volunteers except one the glucose disposal rate (M-value) was higher after phosphate infusion (mean M-value, 10.4 +/- 1.5 mg/kg.min) than that after sham infusion (mean M-value, 9.4 +/- 1.5 mg/kg.min; P < 0.01, by Wilcoxon's test for paired samples). There were no significant differences in mean plasma glucose, sodium, insulin, or arterialized standard bicarbonate levels with the two infusion protocols. Mean plasma calcium, albumin-corrected calcium, and potassium levels, however, were all significantly (P < 0.05) lower after phosphate infusion than after sham infusion. The mean PTH level decreased with sham infusion from 28 +/- 9 to 20 +/- 6 ng/L, whereas it increased with phosphate infusion from 26 +/- 9 to 36 +/- 8 ng/L, whereas it increased with phosphate infusion from 26 +/- 9 to 36 +/- 8 ng/L. The difference between the two infusion protocols was statistically significant (P < 0.01). The data presented illustrate that plasma phosphate (and calcium) levels may be confounders that should be at least monitored, and possibly controlled for, when performing euglycemic clamp studies.

Angiotensin II affects basal, pulsatile, and glucose-stimulated insulin secretion in humans.

Angiotensin II (Ang II) modulates the tissue response to insulin (insulin sensitivity), but the effect of Ang II on the secretion of insulin has not been investigated thus far. Nineteen healthy volunteers (17 male; mean age, 26+/-1 years) were studied. In a double-blind, randomized, placebo-controlled study, seven volunteers were allocated on three occasions in random order after an overnight fast to three interventions: (1) solvent (placebo) infusion; (2) infusion of 1.0 ng Ang II x kg(-1) x min(-1) (subpressor dose); and (3) infusion of 5.0 ng Ang II x kg(-1) x min(-1) (pressor dose). Frequent blood samples (each minute) were obtained for estimation of plasma insulin concentrations over a period of 120 minutes to assess basal and pulsatile insulin secretion. In an ancillary study, plasma glucose and insulin levels were measured after an oral glucose tolerance test while solvent (placebo) or Ang II was infused in 12 fasting healthy volunteers. Plasma insulin concentrations were measured immunoenzymatically (enzyme-linked immunosorbent assay). Insulin secretion pulses were analyzed with the deconvolution technique, and the regularity of insulin secretion was analyzed with the approximate entropy technique. Plasma insulin half-life was assessed using the hyperinsulinemic euglycemic clamp method. The pressor dose of Ang II reduced total, basal, and pulsatile insulin secretion, and this effect was highly significant (P<.01). The subpressor dose tended to suppress insulin secretion. The burst frequency (number of peaks) and the regularity of insulin secretion were not affected by administration of Ang II. After the oral glucose load, the insulinemic response was significantly lower and plasma glucose concentrations were significantly higher with infusion of Ang II compared with placebo. Ang II affects both the basal (nonpulsatile) and the pulsatile component of spontaneous insulin secretion and the glucose-stimulated insulin secretion in humans. This observation is of potential interest with respect to the interaction of Ang II and insulin, eg, in the genesis of hyperinsulinemia and hypertension.

Effects of acute ACE inhibition on pulsatile renin and aldosterone secretion and their synchrony.

Pulsatile (burstlike) secretion of renin and aldosterone is positively coupled with a short time lag of about 10 to 20 minutes. We investigated how acute interruption of the renin-angiotensin-aldosterone axis, ie, acute angiotensin-converting enzyme (ACE) inhibition, alters the pattern of renin and aldosterone secretion. Eight healthy men (mean age, 22+/-1 years) were studied while on standardized salt intake. They were allocated on 2 occasions in random order to injection of placebo or 1.25 mg of the ACE inhibitor enalaprilat. Blood samples were obtained every 10 minutes for 24 hours for measurement of plasma renin and aldosterone concentrations. The hormone concentration profiles were analyzed using a multiparameter deconvolution technique; basal (tonic) and pulsatile hormone secretion was assessed. The regularity of pulsatile hormone secretion was analyzed using approximate entropy (ApEn). Cross-correlation and cross-ApEn analysis of renin and aldosterone secretion were performed to assess synchrony. Acute ACE inhibition caused an immediate burst of renin release and, in addition, significantly (P<0.01) increased 24-hour pulsatile and total renin secretion. It did not affect basal (nonpulsatile) renin secretion. The amplitude of renin bursts and the mass of hormone secreted per burst were significantly (P<0.01) increased, whereas the burst frequency (ie, number of secretory events) was unchanged. ApEn analysis revealed significantly (P<0.05) more regular renin secretion after ACE inhibition. In contrast, neither basal nor pulsatile aldosterone secretion was affected by administration of enalaprilat. Cross-ApEn analysis documented not only a maintained pattern of reproducibility (ie, synchrony) but also greater conditional regularity between pulsatile renin and aldosterone secretions with acute ACE inhibition. However, the quantitative strength of hormone coupling (assessed by cross-correlation analysis) was markedly diminished by enalaprilat treatment. The present findings suggest that the renin-angiotensin-aldosterone axis may not be completely uncoupled by acute ACE inhibition or that pulsatile renin and aldosterone secretion is driven by a common signal generator that is unaffected by ACE inhibition. In addition, a background basal and pulsatile aldosterone secretion not regulated by the renin-angiotensin axis may exist.

Angiotensin II enhances insulin sensitivity in healthy volunteers under euglycemic conditions.

OBJECTIVE: It has been postulated that vasoconstrictors cause insulin resistance. This effect has been documented for epinephrine but not for angiotensin II (Ang II). The aim of this study was to investigate the effect of the latter on insulin sensitivity. DESIGN: In order to study the influence of subpressor doses of Ang II on insulin-mediated glucose uptake under euglycemic conditions, eight healthy volunteers were allocated in random order to sham infusion or infusion of Ang II (first 0.75 ng/kg per min and subsequently 1.5 ng/kg per min). In addition, in seven of the subjects Ang II was infused after 3 days of indomethacin pretreatment (150 mg/day). METHODS: Insulin-mediated glucose uptake (expressed as M value) was measured with the euglycemic clamp technique. Insulin levels were measured enzymatically, plasma renin activity, Ang II, aldosterone and C-peptide levels by radioimmunoassay, blood pressure by Dinamap and muscle blood flow by plethysmography. RESULTS: The M value after sham infusion was 7.81 +/- 1.52 mg/kg per min and after 1.5 ng/kg Ang II per min was 9.76 +/- 1.26 mg/kg per min (P < 0.001). Indomethacin pretreatment did not abolish the Ang II-induced rise in the M value. Mean arterial blood pressure during the euglycemic clamp was unchanged with sham infusion and the low dose of Ang II. It increased slightly with the higher dose of Ang II. Inferior limb muscle perfusion was higher after infusion of Ang II than after sham infusion; this effect was not obliterated by indomethacin pretreatment. CONCLUSIONS: Ang II increases insulin-mediated glucose uptake: that is, it enhances insulin sensitivity by mechanisms independent of prostaglandins. The observations are of potential relevance to the changes in insulin sensitivity in some forms of hypertension.

Albuminuria in normotensive and hypertensive individuals attending offices of general practitioners.

OBJECTIVE: To investigate the rate of albumin excretion and the prevalence of albuminuria in hypertensive individuals relative to the normotensive population, and to clarify the quantitative importance of confounding variables. DESIGN AND METHODS: We examined the morning urines of all consecutive non-diabetic and diabetic hypertensive patients (n = 631; 371 women, 260 men) attending the offices of five general practitioners in a circumscribed geographical area during a 4-month period. To obtain a normotensive control population, all consecutive visitors (n = 375; 217 women, 158 men) were also examined. Urinary albumin excretion was assessed by kinetic nephrelometry in morning urine samples. RESULTS: The median albumin excretion rate was 4.3 micrograms/ml (range 1.9-112) in normotensive individuals; 3.4 micrograms/ml (1.9-1440) in hypertensive and 3.6 micrograms/ml (1.9-2790) in diabetic patients (n = 189; 115 women, 74 men). The overall prevalence of albuminuria above 20 micrograms/ml was 4% in normotensive individuals, 10% in hypertensive patients and 17% in diabetic patients. The proportion of patients with higher-grade albuminuria (> 50 micrograms/ml) was 1% among the normotensive subjects aged below 60 years and 2% in those aged above 60 years; the respective values in hypertensive patients were 3 and 6% and in diabetic patients 8 and 13%. The multivariate regression analysis showed a significant correlation between albuminuria and smoking (P < 0.0001), the presence of hypertension (P < 0.001), the current level of systolic blood pressure (P < 0.01) and age (0.031), but not sex or body mass index. CONCLUSIONS: The present study confirms a higher prevalence of albuminuria above 20 micrograms/ml in individuals with primary hypertension and diabetes mellitus compared with that in normotensive subjects, despite similar median albumin excretion rates. However, the excess of prevalence is moderate. Smoking, advanced age and current level of systolic blood pressure are the important determinants.

Altered action of angiotensin II in patients with type 2 diabetes mellitus of recent onset.

OBJECTIVE: Angiotensin II (Ang II) increases insulin sensitivity in healthy volunteers. This effect is thought to be mediated, at least in part, by an increase in skeletal muscle blood flow. In the past it had been documented that some biological actions of Ang II are altered in diabetes. We addressed the issue of whether this is also true for its action on insulin sensitivity. DESIGN AND METHODS: Twelve healthy volunteers (aged 43+/-9 years) and 15 patients with type 2 diabetes mellitus (NIDDM) of recent onset (aged 45+/-9 years) were allocated in random order in a double-blind placebo-controlled design to be administered a sham infusion or an infusion of 2 ng Ang II/kg per min. Insulin-stimulated glucose uptake (the M value) was measured with the euglycaemic clamp technique, leg muscle blood flow (MBF) with plethysmography, blood pressure with a Dinamap device, and glomerular filtration rate and effective renal plasma flow with the steady-state inulin (Cin) and p-aminohippurate (CPAH) clearance methods, respectively. RESULTS: In volunteers the mean M-value after Ang II infusion (10.1+/-1.5 mg/kg per min) was significantly higher (P < 0.01) than that after sham infusion (8.2+/-0.9 mg/kg per min). In contrast, in diabetic patients it was not significantly different with Ang II (6.1+/-1.3 mg/kg per min) and sham infusion (5.5+/-1.2 mg/kg per min). The difference in the mean absolute increase in the M value (deltaM) between groups was significant (P< 0.02). The Ang II-induced increase in MBF under euglycaemic conditions was attenuated in diabetic patients (from 15.0+/-3.5 to 15.5+/-3.9 ml/100 ml per min, NS) compared with volunteers (from 16.8+/-3.3 to 19.1+/-3.7 ml/100 ml per min, P< 0.01). Again, the difference between the mean absolute increases in MBF (deltaMBF) in the groups was significant (P < 0.01). A significant correlation was found between deltaMBF and deltaM (r= 0.62, P<0.01). The absolute acute increase in mean arterial blood pressure with Ang II was similar in diabetic patients and volunteers. Mean Cin, CPAH and fractional sodium excretion values were significantly lower and renal vascular resistances and filtration fractions higher during the Ang II than they were during the placebo clamp period. This was observed in patients as well as in healthy subjects, but the effects of Ang II on renal haemodynamics and sodium handling were more pronounced in diabetic patients. CONCLUSIONS: In patients with NIDDM of recent onset the stimulatory effect of Ang II on insulin sensitivity and on skeletal muscle blood flow is attenuated. In contrast, the effects of Ang II on renal perfusion and sodium handling are more pronounced in patients with NIDDM than they are in healthy subjects.

Serum cystatin C concentration as a marker of renal dysfunction in the elderly.

Serum cystatin C is a novel marker of renal function claimed to be superior to plasma creatinine. We assessed both parameters in young normotensive subjects (n = 12; 6 men; mean age, 25 +/- 2 years) and elderly normotensive and hypertensive subjects (n = 41; 19 men; mean age, 67 +/- 6 years). Glomerular filtration rate (GFR) was measured in all individuals using the inulin clearance (C(in)) technique. Compared with young subjects, mean GFR was modestly but significantly (P: < 0.001) less in elderly subjects (young, 119 +/- 11 mL/min/1.73 m(2) versus elderly, 104 +/- 12 mL/min/1.73 m(2)). Mean plasma creatinine concentration was identical in both groups (young, 0.93 +/- 0.11 mg/dL versus elderly, 0.93 +/- 0.10 mg/dL; P: < 0.90). Mean serum cystatin C concentration was significantly (P: < 0.001) greater in elderly subjects (0.84 +/- 0.10 mg/L) compared with young subjects (0.69 +/- 0.08 mg/L). In all but one elderly subject, plasma creatinine concentration was within the 95% confidence interval of plasma creatinine concentration in young subjects. Eleven of 41 elderly subjects (27%) had GFRs less than the lower 95% confidence interval, respectively, and 12 of 41 elderly subjects (29%) had a serum cystatin C concentration greater than the upper 95% confidence interval in young subjects. The correlation between serum cystatin C concentration and C(in) (r = -0.65; P: < 0.001) was considerably better than between plasma creatinine concentration and C(in) (r = -0.30; P: < 0.02). Serum cystatin C concentration is a better marker of renal dysfunction (ie, reduced GFR) than plasma creatinine concentration, at least in elderly subjects with plasma creatinine concentrations within the normal range.