Does calcium channel blockade have a role in prevention of expression of sepsis in renal transplant recipients?

Many antihypertensive agents have been demonstrated to assist in preservation of kidney function, among them those that modulate calcium channels. Calcium channel blockers may also be of value in protecting hemodialysis patients from complications of sepsis. In diabetic recipients of kidney transplant allografts treated with cyclosporine, calcium channel blockade has been retrospectively linked to improved graft preservation and to fewer episodes of sepsis. This brief review outlines clinical and experimental publications on potential protection from sepsis by addition of calcium channel blockers to standard antibiotic therapy in individuals who may or may not have normal kidney function, or in the presence or absence of immunosuppression. Such mechanisms include blockade of antibiotic cytosolic extrusion in the cases of Pneumococci, Mycobacterium tuberculosis, Plasmodium falciparum malaria, or Schistosoma mansoni; blockade of the calcineurin/calmodulin pathway (in immunosuppressed patients allowing for lower dosage of cyclosporine); stabilization of calcium movement at the level of sarcoplasmic reticulum by which shock (vasopressor instability) is prevented; or of cytosolic calcium influx and cell death (in the case of allograft acute tubular necrosis). Given the high cost of development of new antibiotics, a role for generic calcium channel blockade in sepsis prevention should be pursued by additional studies to investigate potential links between blockade of calcium channels and expression of sepsis in at-risk populations.

Cardiovascular-renal complications and the possible role of plasminogen activator inhibitor: a review.

Since angiotensin increases the expression of plasminogen activator inhibitor (PAI), mechanisms associated with an actively functioning renin-angiotensin-aldosterone system can be expected to be associated with increased PAI-1 expression. These mechanisms are present not only in common conditions resulting in glomerulosclerosis associated with aging, diabetes or genetic mutations, but also in autoimmune disease (like scleroderma and lupus), radiation injury, cyclosporine toxicity, allograft nephropathy and ureteral obstruction. While the renin-angiotensin-aldosterone system and growth factors, such as transforming growth factor-beta (TGF-ß), are almost always part of the process, there are rare experimental observations of PAI-1 expression without their interaction. Here we review the literature on PAI-1 and its role in vascular, fibrotic and oxidative injury as well as work suggesting potential areas of intervention in the pathogenesis of multiple disorders.

Do biologic markers predict cardiovascular end points in diabetic end-stage renal disease? A prospective longitudinal study.

BACKGROUND: Diabetic patients on hemodialysis are at high risk of death from cardiovascular disease, and research has suggested that various biologic markers of inflammation, oxidative stress and hemostasis may give added value to clinical information for predicting cardiovascular event (CVE)-free survival. This information could be particularly important in evaluating this population for renal transplant, given the scarcity of organs. We hypothesized that in diabetic patients undergoing renal replacement therapy (RRT) these biologic markers would prove useful in predicting event-free follow-up in a prospective study. METHODS: One hundred and fifty diabetic (76 type 1, 74 type 2) and 27 non-diabetic stable RRT patients were followed for 0.04-13.69 years for CVE (myocardial infarction, coronary arterial intervention, peripheral arterial bypass or amputation, cerebrovascular accident or carotid artery intervention), cardiac and all-cause mortality. Measured biologic markers of inflammation included the following: Il-6, C reactive protein, fibrinogen; of hemostasis: fibrinogen, plasminogen activator inhibitor (PAI), fibrinolytic activity, von Willebrand factor VII (vWF), platelet-selectin, viscosity and of oxidative stress: advanced glycated end products and antibody to oxidized low-density lipoprotein. For each, upper versus lower tertiles were compared for duration of event-free follow-up. RESULTS: Cardiovascular events prior to study entry occurred in 51.3% of DM1, 54.0% of DM2 and 25.9% of DM0 patients. Subsequent cardiovascular events were noted in 31.6% of DM1, 45.9% of DM2 and 11.1% of DM0 patients. All mean levels of biologic markers at baseline were abnormal (P < 0.05). CONCLUSIONS: In this RRT population, all biologic marker levels except PAI did not improve clinical prediction of events.

Diabetic microvascular complications: possible targets for improved macrovascular outcomes.

The results of recent outcome trials challenge hypotheses that tight control of both glycohemoglobin and blood pressure diminishes macrovascular events and survival among type 2 diabetic patients. Relevant questions exist regarding the adequacy of glycohemoglobin alone as a measure of diabetes control. Are we ignoring mechanisms of vasculotoxicity (profibrosis, altered angiogenesis, hypertrophy, hyperplasia, and endothelial injury) inherent in current antihyperglycemic medications? Is the polypharmacy for lowering cholesterol, triglyceride, glucose, and systolic blood pressure producing drug interactions that are too complex to be clinically identified? We review angiotensin-aldosterone mechanisms of tissue injury that magnify microvascular damage caused by hyperglycemia and hypertension. Many studies describe interruption of these mechanisms, without hemodynamic consequence, in the preservation of function in type 1 diabetes. Possible interactions between the renin-angiotensin-aldosterone system and physiologic glycemic control (through pulsatile insulin release) suggest opportunities for further clinical investigation.

Pulsatile intermittent intravenous insulin therapy for attenuation of retinopathy and nephropathy in type 1 diabetes mellitus.

Many hormones are secreted in a pulsatile fashion that is more efficient than continuous secretion when tested in vivo. A trial of multiple daily insulin doses with or without the addition of weekly pulsatile insulin infusion therapy was designed to determine if deterioration of renal and retinal function could be blunted. Sixty-five study subjects were evaluated prospectively in 7 centers. Thirty-six patients were randomly allocated to the infusion group and 29 to the standard therapy group. Mean serum creatinine was 1.6 mg/dL in both groups. Subjects were excluded if clearance was less than 30 mL/min. There were no significant differences between the groups with respect to age, duration of diabetes, sex distribution, glycohemoglobin, blood pressure, angiotensin-converting enzyme inhibitor use, proteinuria, or baseline diabetic retinopathy (DR) severity level (all eyes exhibited DR; 8 were deemed technically not amenable to evaluation). Progression of DR was noted in 31.6% of 57 patients (32.3% treated, 30.8% control; P = 1.0) with both eyes evaluable. For patients with 12 or more months of follow-up, 27.9% of 43 patients demonstrated progression of DR (32.0% treated, 22.2% control; P = .57). There were no significant differences between study groups with respect to progression or marked progression, nor was there any influence of duration of follow-up. Progression of DR was noted in 18.8% of 122 eyes that could be adequately evaluated (17.9% of 67 treated, 20% of 55 controls; P = .39). Serum creatinine increased to 1.7 mg/dL in the treatment group and to 1.9 mg/dL in the control group (P = .03). Statistically significant preservation of renal function by pulsatile insulin infusion was not matched by a statistically significant prevention of DR progression compared with standard diabetes care. Inadequate statistical power or duration of the study, or lack of further benefit of pulsatile insulin infusion on the retina in the presence of angiotensin-converting enzyme inhibition may be responsible.

Utilization of an abbreviated diabetes impact management scale to assess change in subjective disability during a trial of pulsatile insulin delivery demonstrates benefit.

A prospective interventional study of pulsatile intravenous insulin infusion therapy has demonstrated reduction of left ventricular mass and blunting of progression of diabetic nephropathy. We anticipated that improvements in objective parameters would be associated with similar improvement measurable by the self-administered Diabetes Impact Management Scale (DIMS). The DIMS was administered at baseline and 12 months for 19 participants randomized to receive either standard insulin treatment of 3 to 4 injections of insulin daily or insulin treatment plus an additional day per week of 3 intravenous pulses over an 8-hour period. For standard vs pulsed intravenous insulin therapy, mean baseline scores were similar for the 12 total questions as well as the groups of 7 questions with emotional content and 5 with physical (neurologic) content. Mean study group scores at 1 year and changes over 1 year were not significantly different for the 7 questions with emotional content (P = .3143, .7574). Score results for the 5 questions related to neurologic status at 1 year and changes over 1 year were significantly different between patients with standard and with pulsed insulin therapy (P = .0144, 0.0004). Pulsatile intravenous insulin, when added to standard multiple-dose insulin therapy, was demonstrated to improve subjective perception of neurologic disability on repeated use of an abbreviated form of the DIMS.

A pilot study to assess utility of changes in elements of the Diabetes Impact Management Scale in evaluating diabetic patients for progressive nephropathy.

A prospective study involving the use of the Diabetes Impact Management Scale (DIMS) in individuals with diabetic nephropathy as part of an interventional study of pulsatile intravenous insulin infusion therapy is used to define the utility of repeated subjective DIMS testing. We hypothesized that repeated use of such an evaluation would correlate well with other objective end points. The DIMS was administered at baseline and 12 months for 19 participants randomized to receive either standard insulin treatment of 3 to 4 injections of insulin daily or standard insulin treatment plus an additional day per week of 3 intravenous pulses over an 8-hour period. Measures of glycemic control, renal function, hemostatic factors, hemodynamics, left ventricular mass, and function were assessed at baseline and 12 months. Of 44 questions on impact of diabetes management, only 12 (5 reflecting physical and 7 reflecting emotional status) showed significant change from baseline to 1 year. Changes in the 5 physical questions related to neurologic status correlated with stable creatinine (P = .0001), stable creatinine clearance (P = .0001), and decrease in left ventricular hypertrophy (P =.0117). Repeated use of an abbreviated, standardized subjective instrument uncovered changes in quality of life that correlated with differences in renal function and left ventricular mass over 12 months. Further use of such an instrument may help us focus treatment for maximum impact.

A pilot study to test the effect of pulsatile insulin infusion on cardiovascular mechanisms that might contribute to attenuation of renal compromise in type 1 diabetes mellitus patients with proteinuria.

We hypothesized that correction of insulin deficiency by pulsatile intravenous insulin infusion in type 1 diabetes mellitus patients with nephropathy preserves renal function by mechanisms involving cardiac autonomic function, cardiac mass, or efficiency, or by hemostatic mechanisms. The control group (8 patients) received subcutaneous insulin (3-4 injections per day). The intravenous infusion group (10 patients) received three 1-hour courses of pulsed intravenous insulin infusion on a single day per week in addition to subcutaneous insulin. Laboratory measurements included 2-dimensional Doppler echocardiography, 24-hour ambulatory monitoring with heart rate variation analysis, platelet aggregation and adhesion, plasma fibrinogen, factor VII, von Willebrand factor, fibrinolytic activity, plasminogen activator inhibitor, and viscosity measured at baseline and 12 months. Blood pressure control was maintained preferentially with angiotensin-converting enzyme inhibitors. Ratio of carbon dioxide production to oxygen utilization was measured with each infusion and showed rapid increase from 0.8 to 0.9 (P = .005) at weekly treatments through 12 months. We observed an annualized decrease in creatinine clearance of 9.6 mL/min for controls vs 3.0 mL/min for infusion patients. Annualized fall in blood hemoglobin was 1.9 vs 0.8 g/dL, respectively (P = .013). There were no differences between the control and infusion group with respect to glycohemoglobin, advanced glycated end products, cholesterol, or triglycerides. No differences between the study groups for hemodynamic or hemostatic factors were evident. Blood pressures were not significantly different at baseline or 12 months. We conclude that although preservation of renal function with attenuation of loss of blood hemoglobin during 12 months of intravenous insulin infusion was associated with improvement in the efficiency of fuel oxidation as measured by respiratory quotient, this occurred without differences in metabolic/hemostatic factors, cardiac autonomic function, cardiac wall, or chamber size. Our hypothesis that preservation of renal function in type 1 diabetes mellitus patients with proteinuria by weekly pulsed insulin infusion involves mechanisms from the autonomic nervous system, cardiac size, and function, or elements of hemostasis was not confirmed.

Regression of left ventricular hypertrophy in diabetic nephropathy: loss of parasympathetic function predicts response to treatment.

Both left ventricular (LV) hypertrophy and decreased autonomic function are predictors of adverse cardiac events. Patients with diabetic nephropathy have an excess cardiovascular risk. The authors determined heart rate variability from 24-hour ambulatory electrocardiographic recordings and measures of LV mass with systolic and diastolic function from echocardiograms. Patients with diabetic nephropathy (n=16) were seen weekly for insulin and hypertension management. Glycohemoglobin decreased from 9.5+/-0.4% to 8.3+/-0.4% (p=0.01), and advanced glycated end products decreased from 12.1+/-2.2 to 7.4+/-1.2 units (p=0.03). Mean arterial pressure and body weight did not change. Serum creatinine increased (1.8+/-0.1 mg/dL to 2.0+/-0.2 mg/dL; p=0.03). The authors used a panel of markers of baseline heart rate variation to assess autonomic function. When covariance of the heart rate interval results were evaluated, the group below the median was found to have a significant decrease in LV mass, from 230 g to 184 g (p=0.013); the group above the median had an increase (182 g to 193 g; p=0.5329). Baseline covariance of the heart rate interval predicted 12-month changes in LV mass in 13 of 16 patients (predictive accuracy, 81%). Improvement in measures of heart rate variation correlated with a decrease in LV mass. Parallel improvement of LV mass and autonomic function suggests a common mechanism, allowing for prediction of LV mass improvement through analysis of baseline heart rate variation.

Risk factors for thromboembolic events in renal failure.

OBJECTIVES: To determine whether prior thromboembolic events (TE) influence current measures of hemostasis, inflammation and oxidative stress in a population at high cardiovascular risk. BACKGROUND: Renal failure patients demonstrate a remarkably elevated incidence of TE. METHODS: Relationships between plasma test results and prior TE history were studied in 78 diabetic and 23 non-diabetic patients with renal failure. TE were defined as myocardial infarction, stroke or vascular surgery. RESULTS: Markers for inflammation (interleukin (IL)-6, C reactive protein (CRP)), thrombosis (fibrinogen, low molecular weight (LMW) fibrinogen, factor VII, viscosity), fibrinolysis (fibrinolytic activity, plasminogen activator inhibitor (PAI)), endothelial/platelet activity (P-selectin, von Willebrand factor (vWf)) and oxidative stress (antibody to oxidized low-density lipoprotein (LDL), advanced glycated end products) were significantly different from a healthy control population. Dialysis patients with diabetes were twice as likely to have sustained a TE (58 vs. 30%, p = 0.032). Those patients in the total group with levels above the median for IL-6 (p = 0.045), and CRP (p < 0.017) were more likely to have sustained a TE than those with levels below the median. Those diabetic patients with levels above the median for CRP were more likely to have a prior history of TE (p < 0.021). For non-diabetic patients, levels above the median of IL-6 were associated with a prior history of TE (p = 0.027). Multiple correlations for factors of inflammation, hemostasis and oxidative stress indicate that these mechanisms are not independent of one another. CONCLUSION: Prior TE was associated with markers of inflammation a relationship that may influence the interpretation of these tests which are strongly interrelated in patients at high cardiovascular risk.

Left ventricular mass reduction in type 1 diabetic patients with nephropathy.

Left ventricular hypertrophy regression was postulated more likely to occur in diabetic patients when renal function was preserved. Seventeen type 1 diabetic patients followed for 12 months while receiving protocol-driven glycemic and blood pressure control had baseline and 12-month echocardiography. Despite identical treatment resulting in similar blood pressures, patients with better renal function (below the group mean, serum creatinine < or =1.7 mg/dL) demonstrated reduction in left ventricular mass and septal thickness as well as increase in left ventricular fractional fiber shortening not observed in those with worse renal function (above the group mean, serum creatinine >1.7 mg/dL). This latter group also did not experience the improvement in glycemic control observed in those with better renal function. Regression of left ventricular mass and functional improvement can be accomplished with improved glycemic control. In the presence of renal dysfunction, however, efforts to control glycemia and cardiac work are suboptimal. Aggressive glycemic and blood pressure targets to reduce cardiovascular morbidity in this high-risk population should be studied.