Michael Lishner

Long-Term Stabilizing Effect of Angiotensin-Converting Enzyme Inhibition on Plasma Creatinine and on Proteinuria in Normotensive Type II Diabetic Patients

Diabetic nephropathy is the single most important cause of end-stage renal failure in the western world. It accounts for 15% to 25% of all renal failure in patients receiving chronic dialysis [1]. About 40% of type I and 20% of type II diabetics develop clinically important nephropathy [2-4]. However, the ratio of type II to type I diabetics is 10 to 1, and the number of patients with chronic renal failure due to type II disease exceeds that of type I [4-6]. Therefore, an obvious need exists to evaluate treatments that may delay the progress of nephropathy in type II diabetes. However, most studies of diabetic renal disease have hitherto focused on type I diabetes. Available data suggest that effective antihypertensive treatment is the best inhibitor of diabetic nephropathy [7-10]. Angiotensin-converting enzyme inhibitors have been found more effective than placebo and -adrenergic blocking agents in hypertensive as well as in normotensive diabetics with early and advanced nephropathy [11-15]. Some classes of calcium antagonists effectively decrease urinary protein excretion and may preserve renal function. However, analysis of several studies shows that, although the effects of angiotensin-converting enzyme inhibitors are consistent, those of calcium antagonists vary [16-18]. Short-term studies showed a clear antiproteinuric effect of captopril and of enalapril on the diabetic kidney, probably independent of the antihypertensive effect of these agents [14, 15, 19]. However, the outcome of long-term intervention and the possibility of a true alteration of the natural course of the disease were unknown. We did a relatively long-term, 5-year study of the effect of the angiotensin-converting enzyme inhibitor, enalapril, on the course of diabetic nephropathy in normotensive, type II diabetic patients with microalbuminuria and normal renal function. Our report describes a randomized, placebo-controlled, double-blind study on 94 diabetic patients. Methods Patients A total of 108 patients with type II diabetes mellitus, diagnosed according to World Health Organization criteria [20] who attended six clinics in the Tel Aviv area were recruited during 1986 and gave informed consent to participate in the study. The inclusion criteria were as follows: age less than 50 years; duration of diabetes mellitus of less than 10 years with no evidence of systemic, renal, cardiac, or hepatic diseases; body mass index less than 27 kg/m2; normal blood pressure values on two consecutive examinations (systolic, 140 mm Hg; diastolic, 90 mm Hg; mean blood pressure < 107 mm Hg); serum creatinine, < 123 mol/L (1.4 mg/dL); and microalbuminuria (urinary protein excretion of 30 to 300 mg/24 h) on two consecutive visits without evidence of urinary tract infection. Initially, there were 49 men and 59 women, ages 34 to 49 years (mean age [SD], 44 4 years). The duration of diabetes was 0.5 to 9.1 years (mean duration [SD], 6.7 1.6 years). Sixteen patients received insulin, 43 were taking oral hypoglycemic agents, and 49 were using diet to control their diabetes. Protocol The protocol was approved by the hospital review board. After a 2-month pretreatment period, the patients were randomly allocated to receive either 10 mg enalapril (Teva Pharmaceutical Industries, Ltd., Petach Tikwa, Israel) daily or placebo in a double-blind manner. The placebo tablets were similar but not identical to enalapril. Randomization was done using a table of random numbers [21]. The follow-up period was terminated, for each patient, exactly 5 years after his or her randomization, and the data were submitted for evaluation. The patients were seen by their family physicians approximately every 3 to 4 months. On these visits, fasting blood glucose, glycosylated hemoglobin, serum creatinine, serum electrolyte levels, and albuminuria in 24-hour urine samples were determined. Blood pressure was measured by mercury sphygmomanometers with the patients sitting after a 5-minute rest; the average of two determinations was recorded. The diastolic pressure was determined at Korotkoff phase V. If systolic blood pressure values of 145 mm Hg, or diastolic values of 95 mm Hg, were found on two consecutive occasions, treatment with long-acting nifedipine (Pressolate, Agis Industries Ltd., Yeruham, Israel) was initiated. Funduscopy was done yearly by an ophthalmologist, and the presence of diabetic retinopathy was recorded. Measurements Glucose and creatinine levels were determined by routine automated methods. Glycosylated hemoglobin levels were measured by affinity chromatography with a commercial kit (Isolab, Biochemical Methodology, Drower 4350, Akron, Ohio). The albumin excretion rate was measured on 24-hour urine samples by an automated immunoturbidimetric assay [22]. Sixteen to 20 fasting blood glucose determinations and 15 to 20 glycosylated hemoglobin values were available for each patient. For each patient, the correlation coefficients between fasting blood glucose and glycosylated hemoglobin levels were between 0.60 and 0.84. The mean blood pressure values were calculated for each patient (mean pressure defined as diastolic value plus one third of the pulse pressure). The reciprocal creatinine value (100/creatinine value) was calculated for each visit [23], and the decline in renal function was expressed as a percentage of the initial value. The course of renal function, of the mean blood pressure, and of urinary protein excretion were plotted against time (separately) for the enalapril and the placebo groups. Statistical Analysis All data were expressed as mean (SD) and ranges. Significance was defined as P < 0.05. To test for adequate randomization, the enalapril and placebo groups were compared with respect to mean age, mean duration of diabetes, as well as mean baseline values of albuminuria, serum creatinine, glycosylated hemoglobin, and mean blood pressure using pooled variance Student t-tests for independent groups as well as one-way analysis of variance. To compare the annual means of the various measurements between the two groups and within each group, one between-group factor and one repeated measures factor were used in analysis of variance. The rate of decrease of reciprocal creatinine levels and the rate of increase of albuminuria were calculated by linear regression analysis. Results Five patients, 2 taking enalapril and 3 taking placebo left the study during the first year. Six patients (4 taking enalapril and 2 taking placebo) developed a disturbing cough, and the treatment was discontinued. Three patients (1 on enalapril and 2 on placebo) were lost to follow-up during the third and fourth years. The final analysis was therefore done on 94 patients, of whom 49 received enalapril and 45 received placebo. Age, male/female ratio, duration of diabetes, and the other baseline data of the two groups are shown in Table 1. No statistically significant differences existed between the initial characteristics of the enalapril and the placebo groups. Table 1. Baseline Data from 94 Type II Diabetic Patients with Microalbuminuria* During the first year of treatment, the urinary albumin excretion in the enalapril group decreased from an initial mean of 143 mg/24 h to an annual mean of 122 mg/24 h. Values greater than 300 mg/24 h were recorded in only two patients. Subsequently, a minimal but steady increase occurred in mean daily albumin excretion of these patients, with a fourth-year mean of 136 mg/24 h and a fifth-year mean of 140 mg/24 h. In six patients, albuminuria exceeded 300 mg/24 h. In contrast, among the placebo-treated patients, a steady, gradual increase occurred in mean daily albuminuria. The initial albumin value was 123 mg/24 h, the first-year mean was 134 mg/24 h, and the fifth-year value was 310 mg/24 h. Albumin values were greater than 300 mg/24 h in 19 patients and greater than 1 mg/24 h in three patients. The difference between the mean values of daily albuminuria in the two groups became statistically significant after the first year. However, the difference in the rate of change in proteinuria from baseline was statistically significant at the end of the first year (P < 0.05). These data are shown in Figure 1 and are numerically detailed in the Appendix Table. If the development of overt proteinuria ( 300 mg/24 h) is considered clinically important, the risk for developing this degree of proteinuria within 5 years of follow-up was 19/45 (42%) in the placebo group compared with 6/49 (12%) in the enalapril group. Therefore, enalapril treatment resulted in an absolute risk reduction of 30 percentage points for the development of overt proteinuria (95% CI, 15% to 45%; P < 0.001) for a 5-year period. Appendix Table. Initial and Annual Averages of Blood Chemistry Values for the 5-Year Follow-up in the Enalapril- and Placebo-Treated Groups* Figure 1. Proteinuria during 5-year follow-up in diabetics treated with enalapril or placebo. P P P Renal function, expressed as reciprocal creatinine (100/cr) remained unchanged in the enalapril group during the first 2 years of follow-up. From the third year onward, a small, nonsignificant but systematic decrease was recorded. The decrease was 1% of the initial value during the 5 years. In the placebo-treated group, a gradual, steady decrease of about 2% occurred in renal function each year. The difference between the initial and mean fifth-year values was 13% (P < 0.05). The difference between the mean rate of decrease of reciprocal creatinine among the enalapril- and the placebo-treated groups became significant after the second year. These data are shown in Figure 2 and are outlined in the Appendix Table. Figure 2. Reciprocal creatinine (100/cr) levels expressed as percentage of initial value, during 5 years of follow-up in placebo-and enalapril-treated type II diabetics. P P The mean blood pressure in the enalapril-treated patients decreased slightly from an initial value of 99 mm Hg to 96 mm Hg during the first year

Spectral Analysis of Fluctuations in Heart Rate: An Objective Evaluation of Autonomic Nervous Control in Chronic Renal Failure

A quantitative, noninvasive method of assessing autonomic control, based on the spectral analysis of beat-to-beat fluctuations in heart rate (HR), was applied to patients with chronic renal failure (RF). Since the power spectrum of HR fluctuations measures the dynamic nervous control of HR, it can be used to quantitate a normal control system as opposed to a disturbed or depressed system. Indeed, in RF patients, a strong reduction in the HR power spectrum was observed in all frequency ranges, both sympathetically and parasympathetically mediated. A similar depression in autonomic control was demonstrated in patients on hemodialysis or peritoneal dialysis. RF patients not yet undergoing dialysis show a lesser degree of depression. Spectral analysis of HR fluctuations in RF patients makes it possible to quantitate autonomic dysfunction and to reliably measure its development as a function of time, and requires only a 10-min standard electrocardiogram recording.

Are platelet volume indices of clinical use? A multidisciplinary review

Abstract Platelet size correlates with platelet activity and can be assessed by platelet volume indices (PVI). The PVI, mean platelet volume (MPV), is universally available with routine blood counts by automated hemograms and therefore is an attractive index to study in clinical scenarios. PVI are useful in assessing the etiology of thrombocytopenia. In addition, a normal platelet distribution width in the setting of thrombocytosis is highly suggestive of a reactive etiology. Higher MPV is also associated with the presence of cardiovascular risk factors, chest pain due to acute coronary syndrome, and adverse outcome after acute coronary syndrome. Results from studies evaluating MPV in patients with peripheral artery disease, unprovoked deep vein thrombosis, and pulmonary embolism further advocate a potential role for MPV in identifying patients at high risk of thrombosis. Nevertheless, most of these data come from retrospective studies some of which have small study populations and confounding factors influencing platelet volume. Moreover, the cut-off values derived from these retrospective studies have not been validated prospectively. Despite the potential for clinical utility evident from these studies, the above-mentioned flaws together with technical problems in measuring MPV currently limit its clinical usefulness. Our review provides a perspective on PVIs potential clinical use.

Maternal and fetal outcome after invasive cervical cancer in pregnancy.

Invasive carcinoma of the cervix is the most common gynecologic malignancy to occur during the reproductive years. To analyze the effects of pregnancy on the course and survival of invasive cervical cancer, we compared 40 women with invasive cervical cancer to 89 nonpregnant controls matched for age, calendric year of diagnosis, stage, and tumor type. Additionally, we compared the distribution of invasive cervical cancer stages among the 40 pregnant women with that among the 1,963 cases of invasive cervical cancer treated during the same 30 years in women less than 45 years of age registered in the same hospital. To evaluate pregnancy outcome, we compared babies born to women with invasive cervical cancer to babies born of women matched for maternal age and not exposed to known teratogens or reproductive risks during pregnancy. Thirty-year survival of pregnant women with invasive cervical cancer was identical to that of their matched controls. Women having invasive cervical cancer were 3.1 times more likely to be diagnosed with stage I disease (95% confidence interval, 1.6 to 6.2). Additionally, they had a significantly lower chance of being diagnosed with stages III and IV (P = .02). Babies born to women with invasive cervical cancer were similar in gestational age and rates of prematurity but had a lower birth weight than the matched controls. There were two stillbirths among the 24 pregnancies that continued to term (8%), not statistically different from the 1.1% rate for Ontario. Our data suggest that pregnancy per se does not adversely affect the survival of women with invasive cervical cancer. However, this study provides evidence that pregnant women are more likely to present with early disease because of regular, pregnancy-related obstetric exams. Moreover, there is an increased risk for stillbirth, which should lead to follow-up of these patients by a high-risk perinatal unit.

Hair cortisol and the risk for acute myocardial infarction in adult men.

Acute stress is increasingly recognized as a precipitant of acute myocardial infarction (AMI). However, the role of chronic stress in developing AMI is less clear. We have developed a method to measure cortisol in hair, which allows longitudinal assessment of cortisol levels prior to an acute event. We aimed to evaluate the hypothesis that chronic stress, as assessed by hair cortisol content, is associated with the development of AMI. A prospective case–control study included 56 patients admitted to hospital with AMI and 56 control patients, admitted to internal medicine wards for other indications. An enzyme immunoassay technique was used to measure cortisol in the most proximal 3 cm of hair, considered to represent the most recent 3 months of exposure. Median hair cortisol contents (range) were 295.3 (105.4–809.3)ng/g in AMI patients and 224.9 (76.58–949.9)ng/g in controls (p = 0.006, Mann–Whitney U-test). After controlling for other risk factors for AMI using multiple logistic regression, log-transformed hair cortisol content remained the strongest predictor (OR 17.4, 95% CI 2.15–140.5; p = 0.007). We demonstrated elevated hair cortisol concentrations in patients with AMI. This suggests that chronic stress, as assessed by increased hair cortisol in the 3 months prior to the event, may be a contributing factor for AMI.

Reduced cardiotoxicity of doxorubicin by a 6‐hour infusion regimen. A prospective randomized evaluation

In order to evaluate the possible cardiosparing effect of a prolonged infusion of doxorubicin as compared with the standard mode of administration 62 consecutive patients with metastatic carcinoma of the breast or carcinoma of the ovary Stage III or IV were prospectively randomized to receive doxorubicin either as a rapid infusion over 15 to 20 minutes at 8 AM or as a continuous infusion over 6 hours, 8 AM to 2 PM. The remaining protocol was identical for the two groups. The cardiotoxic effect of doxorubicin was evaluated by history and physical examination and by the decline in resting ventricular ejection fraction (LVEF) as determined by gated pool radionuclide angiography with technetium 99m (99mTc) and by the decline in the height of the QRS complexes in the standard leads of the echocardiogram (ECG). Initially there were 31 patients in each group. The cumulative dose of doxorubicin, was 410 mg/m2 ± 42 SD in the standard infusion group and 428 mg/m2 ± 48 SD in the 6‐hour infusion group. The mean decline in LVEF after a cumulative doxorubicin dose of 300 mg/m2 was 17% in the first group and only 4.1% in the second. After 400 mg/m2 the mean fall in LVEF was 21% in the first group and 6% in the second. The mean decline in QRS voltage after 300 mg/m2 was 29% and 1.5%, respectively. Four patients, all in the standard infusion group, developed congestive heart failure. These data suggest that slow infusion of doxorubicin is associated with reduced cardiotoxicity.

Non‐steroidal anti‐inflammatory drugs for the prevention and treatment of cancer

Non‐steroidal anti‐inflammatory drugs (NSAIDs), both cyclooxygenase‐2 (COX‐2) selective and nonselective inhibitors, are amongst the most popular medications worldwide. Whilst their anti‐inflammatory effect is well known, recent studies have demonstrated an unexpected effect in both the prevention and treatment of several types of cancer. The anticancerous effect of NSAIDs is believed to be mainly due to the inhibition of COX‐2, which is overexpressed in many types of cancer and may play a major role in tumourigenesis. In this review, we will describe the possible mechanisms for NSAIDs anticancer effect and summarize the major clinical studies in cancer prevention and treatment. We will also discuss the effect of the recent reports of adverse cardiovascular effects on anticancer research of the selective COX‐2 inhibitors.

Cancer in pregnancy: Gaps, challenges and solutions

Cancer is the second leading cause of death during the reproductive years complicating between 0.02% and 0.1% of pregnancies. This incidence is expected to rise with the increase in age of childbearing. The relatively rare occurrence of pregnancy-associated cancer precludes conducting large, prospective studies to examine diagnostic, management and outcome issues. This article reviews the available data regarding the different aspects of the diagnosis and treatment of cancer during pregnancy as well as the effect of pregnancy on cancer prognosis. In pregnant patients diagnosed with cancer during the first trimester, treatment with multi-drug anti-cancer chemotherapy or radiotherapy (with fetal exposure >0.1-0.2 Gy) is associated with an increased risk of congenital malformations and therefore should follow a strong recommendation for pregnancy termination. The risk for malformation diminishes as pregnancy advances and when cancer is diagnosed during the second or third trimesters there is usually no clear indication for abortion. Treatment postponement, until achieving fetal maturity, while closely monitoring tumor growth may be considered in selected cases. According to the available experience it seems that non-obstetrical surgery may be performed during pregnancy without an increased risk for adverse outcomes. In most types of cancer, pregnancy has no effect on maternal prognosis when compared to non-pregnant patients matched by age, cancer stage and treatment.

Haematological cancers in pregnancy

Haematological cancer in pregnancy, although rare, poses a substantial risk to both mother and fetus. Hodgkins lymphoma is the most common, followed by non-Hodgkin lymphoma and acute leukaemia. Diagnosis of haematological cancers is challenged by an overlap of the disease and gestation-related symptoms and limitations of imaging studies in pregnancy. Data for safety and effectiveness of therapy are scarce and mostly retrospective. This report provides updated guidance for management, focusing on chemotherapy and biological agents. The primary goal of treatment is to preserve the mothers health; hence, pregnancy termination is often advisable at early stages, allowing delivery of adequate therapy. However, at later gestational stages treatment is often feasible. Pregnancy-related hypercoagulability, augmented by cancer, often necessitates thromboprophylaxis. The consequences and complex management of haematological cancer during pregnancy emphasise the need for collaborative research, focusing on basic mechanisms of disease and prospective epidemiological studies.

The treatment of Hodgkin's and non-Hodgkin's lymphoma in pregnancy

Lymphoma is the fourth most frequent malignancy diagnosed during pregnancy, occurring in approximately 1:6000 of deliveries. Its occurrence may increase due to the current trend to postpone pregnancy until later in life and the suggested high incidence of AIDS-related non-Hodgkins lymphoma in developing countries. The relatively rare occurrence of pregnancy-associated lymphoma precludes the conduction of large, prospective studies to examine diagnostic, management and outcome issues. Chemotherapy and radiotherapy during the first trimester are associated with increased risk of congenital malformations and this risk diminishes as pregnancy advances. In the vast majority of cases, when lymphoma is diagnosed during the first trimester, treatment with a standard chemotherapy regimen, following pregnancy termination should be recommended. In the rare patients at low risk, such as those with stage 1 Hodgkins lymphoma or indolent non-Hodgkins lymphoma, therapy can be delayed until the end of the first trimester and of embryogenesis while keeping the patients under close observation. When lymphoma is diagnosed during the second and third trimesters, evidence exists suggesting that full-dose chemotherapy can be administered safely without apparent increased risk of severe adverse fetal outcome.