Adverse effects of left ventricular hypertrophy in the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study.

AIMS/HYPOTHESIS: We explored the impact of baseline left ventricular hypertrophy (LVH) and losartan treatment on renal and cardiovascular (CV) events in 1,513 patients from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, which studied the effects of losartan on the progression of renal disease and/or death in patients with type 2 diabetes and nephropathy. MATERIALS AND METHODS: LVH was assessed using ECG criteria (Cornell product and/or Sokolow-Lyon voltage). The risk of renal or CV events was determined by a proportional hazards model fit with treatment allocation and presence of LVH. Covariates at baseline included age, sex, systolic BP, mean arterial pressure, pulse, proteinuria, serum creatinine, albumin and haemoglobin. RESULTS: A total of 187 subjects (12%) had LVH at baseline. Treatment with losartan resulted in a significant decrease in the Cornell product (-6.2%) and Sokolow-Lyon voltage (-6.3%). LVH was shown to be significantly associated with the primary endpoint, which was a composite of doubling of serum creatinine (DSCR), endstage renal disease (ESRD) or death (hazard ratio [HR]=1.44, p=0.011), as well as with the composite renal endpoint of DSCR/ESRD (HR=1.42, p=0.031) and CV events (HR=1.68, p=0.001). Losartan treatment of patients with LVH decreased the CV as well as renal risk to a level similar to that of patients without LVH. CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes and nephropathy, LVH is associated with significantly increased risk of CV events and the progression of kidney disease. Importantly, in patients with LVH, losartan reduced the CV as well as the renal risk to a level similar to that seen in subjects without LVH.

Dual blockade of the renin-angiotensin system in diabetic nephropathy.

The presence of inadequately controlled hypertension in a diabetic patient with clinical signs of renal involvement portends a poor prognosis. Initial assessment should include ruling out factors which may exacerbate the hypertension and careful assessment of the stage of hypertension, renal function and amount of proteinuria. Intensive treatment requires finding a combination of medications which will reduce not only blood pressure but also proteinuria. It is suggested that treatment should be started with an ACE inhibitor or an AT1 receptor blocker often in a fixed combination with a low-dose thiazide diuretic. Calcium channel blockers and beta-blockers may be added if required as second or third-line agents. In patients not responding to this combination, the dosages of the ACE inhibitor or AT1 blocker should be titrated upwards in order to obtain the maximal therapeutic effect. However, if this is still insufficient, dual blockade of the RAS should be considered and even an aldosterone receptor blocker may need to be added to the therapeutic regimen. It should be remembered that such a patient requires close monitoring in order to be sure that he is compliant with respect to the prescribed treatment and that there are no side-effects such as hyperkalaemia.

Management of diabetic nephropathy: epidemiology, pathogenesis of nephropathy and factors influencing progression.

Diabetes mellitus is a major scourge of the modern world and the complications of this disease are important causes of morbidity and mortality. It is expected that the prevalence of this disease will increase several fold in all regions of the world over the coming decades. The prevalence of type 2 diabetes (initial resistance to endogenous insulin, usually found in obese adults) is about nine times greater than that of type 1 diabetes (absence of insulin, usually found in children and young adults) and thus the burden of this disease is mainly of patients with type 2 diabetes. The many complications of diabetes mellitus include cardiovascular disease, retinopathy, nephropathy, peripheral neuropathy and peripheral vascular disease. These complications appear in patients with either type of diabetes. This monograph will be devoted to the discussion of diabetic nephropathy (DN).

The effects of an ACE inhibitor and a calcium antagonist on the progression of renal disease: the Nephros Study.

BACKGROUND: The renoprotective effect of ACE inhibition in chronic renal disease is well established but the studies on effects of calcium antagonists on progression of renal disease and on proteinuria have given varying results. METHODS: We conducted an open long-term randomized prospective multi-centre study comparing the combination of ramipril and felodipine ER (F) with either drug alone in non-diabetic renal disease. Included were patients with uncontrolled hypertension (diastolic blood pressure (DBP)) > or =95 mmHg on treatment with a diuretic and a beta-blocker. Fifty-one patients received the combination of R and F, 54 patients R, and 53 patients F. The treatment goal was a DBP <90 mmHg and a similar BP reduction in the three groups. Mean doses at the last visit were 5+5, 10 and 9 mg, respectively, after a mean treatment time of nearly 2 years. The progression of renal impairment was studied by serial measurements of serum creatinine, iohexol clearance, and albuminuria. RESULTS: The reduction in supine systolic (S) BP and DBP expressed as median values were -19.0/-14.5,-14.3/-15.0 and -13.5/-13.3 mmHg in the R+F, R, and F groups, respectively. There was no significant difference between the groups. When correction for the acute drug effect was performed the R+F group had a slower progression rate of the renal disease (loss of glomerular filtration rate (GFR) ml/min/year) compared with the F group (P<0.05) but not to the R group (P>0.20). There was a rise in albuminuria after 2 years in the F group (P<0.05), but no significant change was found in the other groups. CONCLUSIONS: In patients with non-diabetic renal disease the combination of an ACE inhibitor and a calcium antagonist in reduced doses used in addition to baseline therapy with beta-blockers and diuretics, tended to cause a better BP reduction as each drug per se. The R+F treatment also caused a slower progression of the renal disease compared with F alone. The combination treatment seems to afford better BP control and appears to be a favourable therapeutic option in patients with renal disease and hypertension.

A questionnaire for the assessment of pruritus: validation in uremic patients.

A questionnaire was constructed for the evaluation and measurement of pruritus. The questionnaire, based on the short form of the McGill Pain Questionnaire, was tested in 145 patients suffering from uremic pruritus and currently undergoing hemodialysis treatment in 3 centers. The newly developed questionnaire proved to be reliable and provided valid data on the sensory, affective and overall intensity of uremic pruritus. The data suggest that uremic pruritus tends to be prolonged, frequently intense and a major source of distress to the patient. Dialysis was not found to influence the pruritus. The questionnaire may also be useful in pruritus secondary to other causes.

Irbesartan normalises the deficiency in glomerular nephrin expression in a model of diabetes and hypertension.

AIMS/HYPOTHESIS: The location of nephrin has been identified as the slit-diaphragm of the glomerular podocyte. Recent evidence suggests that nephrin could play a key role in the function of the glomerular filtration barrier and the development of proteinuria but its status in long-term diabetes is still not understood. We studied the expression of nephrin in a hypertensive model of diabetic nephropathy and investigated the potential influence of angiotensin II blockade on nephrin gene and protein expression. METHODS: Streptozotocin-diabetic spontaneously hypertensive rats were given either no treatment or the angiotensin II antagonist, irbesartan, at a dose of 15 mg/kg per day by gavage for 32 weeks. Non-diabetic spontaneously hypertensive rats were used as a control group. Real time RT-PCR and immunohistochemistry were used to assess and quantify gene and protein expression of nephrin. RESULTS: Diabetic spontaneously hypertensive rats developed albuminuria and had a reduction in both gene and protein expression of nephrin when compared with control rats. Irbesartan treatment prevented the development of albuminuria and completely abrogated the down regulation of nephrin in diabetic rats. CONCLUSION/INTERPRETATION: Long-term diabetes in spontaneously hypertensive rats is associated with a reduction in both gene and protein expression of nephrin within the kidney. These changes in nephrin levels were completely prevented by angiotensin II antagonist treatment, suggesting a potential novel mechanism to explain the antiproteinuric effect of agents which interrupt the renin-angiotensin system.

Increased serum angiotensin-converting enzyme activity and plasma angiotensin II levels during pregnancy and postpartum in the diabetic rat.

OBJECTIVE: The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, electrolyte balance and renal function in normal human pregnancy. The present study was designed to assess various components of the RAS and renal function during pregnancy and immediately after pregnancy in the streptozotocin (STZ)-diabetic rat. METHODS: Pregnant Wistar rats were allocated to three groups: I-control, non-diabetic rats (n=24), II-STZ-diabetic rats (STZ 55 mg/kg body weight, i.v. on day 10 of pregnancy, n=24), III-diabetic rats, as above, treated with insulin (4 units/day, s.c. n=21). On days 17-18 of pregnancy, or within 24 hours after delivery, the rats were sacrificed and the various components of the RAS were determined. RESULTS: Urinary protein excretion (UP) and creatinine clearance(CCr) were greater in group II, four days after STZ, than in group I (UP: I-7.6+/-2.8, II-18.6+/-6.3 mg/24-hour, p<0.001, CCr: I-1.04+/-0.33, II-2.38+/-0.7 ml/minute, p<0.001). Mean (+/-SD) serum angiotensin-converting enzyme (ACE) activity and plasma angiotensin II(Ang II) levels at days 17-18 of pregnancy were greater in the untreated diabetic rats than in control pregnant rats (ACE: 163+/-18 vs. 111+/-21 nmol/ml/minute, p<0.001, Ang II: 115+/-45 vs. 43+/-10 pg/ml, p<0.005). Postpartum serum ACE activity and plasma Ang II levels were greater in group II (ACE: I-123+/-14, II-142+/-24, III-108+/-21 nmol/ml/minute, p<0.01, Ang II: I-56+/-38, II-148+/-62, III-38+/-17 pg/mI, p<0.001). ACE activity in the lung was greater, whereas the activity in the renal cortex was less, in group II than in group I. Kidney weight in untreated diabetic rats was greater than in the other two groups. CONCLUSION: Increased serum ACE activity during pregnancy and postpartum in the untreated diabetic rat is associated with enhanced serum Ang II levels, which may contribute to increased protein excretion and renal hypertrophy.

Prediction of pregnancy outcome in subgroups of women with renal disease.

BACKGROUND: The preconception and intraconception parameters that are relevant to outcome in women with underlying renal disease remain controversial. SUBJECTS, MATERIALS AND METHODS: We analyzed the types and frequencies of short- and long-term (2 years after delivery) maternal and neonatal complications in 38 patients with primary renal disease (46 pregnancies), 24 IDDM patients with diabetic nephropathy (24 pregnancies), and 27 patients with a functioning renal allograft (42 pregnancies), most of them with mild renal insufficiency. Logistic regression models were formulated to predict successful outcome. RESULTS: Successful pregnancy outcome (live, healthy infant without severe handicap 2 years after delivery) was observed in 98% of the patients with primary renal disease, 96% of the IDDM patients with diabetic nephropathy, and 89% of the patients with a functioning renal allograft. Factors found to be significantly predictive of successful outcome were absence of preexisting hypertension in all groups, in addition to low preconception serum uric acid level in the primary renal disease patients, and long interval from transplantation to conception and use of a low dose ofprednisone in the renal transplant patients. CONCLUSION: Most women with different subtypes of renal disease have a successful pregnancy outcome with proper prenatal care. Worse pregnancy outcome was observed in women with moderate or severe renal failure. Fitted logistic models may provide useful guidelines for counseling women with preexisting renal disease about their prospects for a successful pregnancy in terms of immediate and long-term maternal and neonatal outcome.

Should the use of short acting angiotensin-converting enzyme inhibitors be abandoned?

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACE-I) have different modes of action and different durations of inhibition. The effects of ACE-I on the various components of the renin-angiotensin system (RAS) at trough hours were studied in patients with diabetes mellitus receiving long-term ACE-I treatment. METHODS: Out of 86 Type 1 and 2 diabetic patients, 49 were untreated, 25 received captopril and 12 received enalapril as chronic treatment. Blood for the determination of plasma renin activity (PRA), serum ACE activity and plasma angiotensin II (Ang II) was drawn in the morning (0700-0900 hours) after an overnight fast, about 12 hours after the last dose. PRA and Ang II were measured by RIA and serum ACE activity was assayed by a radiometric assay using (3)H-hippuryl-glycyl-glycine as a substrate. RESULTS: Mean age was significantly greater in the enalapril-treated patients. Systolic and diastolic blood pressures were not different between the captopril-treated and untreated groups. Serum ACE activity in the captopril-treated diabetic patients was 101.5+/-42.5 nmol/mL/min, values obtained in untreated diabetic patients (101.4+/-25.2 nmol/mL/min). In contrast, ACE activity in the enalapril-treated patients was significantly reduced (5.5+/-7.5 nmol/mL/min) compared with untreated and captopril-treated patients (p<0.00001). PRA values in the ACE-I treated patients were significantly increased. Plasma Ang II levels were significantly increased in the captopril-treated vs. untreated patients (65.1+/-50.2 vs. 36.2+/-31.7 pg/mL, p=0.006), whereas the values in the enalapril-treated patient were slightly, but not significantly, reduced (23.8+/-21.4 pg/mL). CONCLUSIONS Trough serum ACE activity is not suppressed in diabetic patients receiving captopril, compared with those receiving enalapril and we thus question the use of short acting ACE-I in these patients.

White coat hypertension and pregnancy outcome.

The presence and outcome effect of white coat hypertension in pregnancy was determined with 24-h ambulatory blood pressure (BP) monitoring. Sixty women presenting with high clinic BP (>/=140/90 mm Hg) in the second trimester were included. Patients were divided into two groups based on daytime ambulatory BP findings: <135/85 mm Hg, white coat hypertension (n = 37); >/=135/85 mm Hg, 'true' hypertension (n = 23). Complicated pregnancy outcome was defined as the presence of pre-eclampsia and/or intrauterine growth restriction. Groups were compared for pregnancy outcome and for background and delivery factors. The predictive value of ambulatory BP measurements for pregnancy outcome was determined. Pregnancy outcome was better in the white coat hypertension group than in the true hypertension group: pre-eclampsia-3 (8.1%) vs 13 (56.5%) (P = 0.0046); intrauterine growth restriction-5 (13.5%) vs 10 (43.4%) (P = 0. 0139); and preterm delivery-11 (29.7%) vs 15 (65.2%) (P = 0.015). Night-time ambulatory BP measurements were the best predictor of complicated pregnancy, followed by daytime and 24-h measurements. We conclude that second trimester ambulatory BP monitoring can be used to differentiate patients who have white coat hypertension, which is associated with a better pregnancy outcome than true hypertension.

Microalbuminuria after pregnancy complicated by pre-eclampsia.

BACKGROUND: Microalbuminuria is an important risk factor for underlying vascular disease. Its detection after pregnancy complicated by pre-eclampsia may have predictive value for the later development of chronic hypertension or renal disease. METHOD: The study group consisted of 48 women in whom pregnancy had been complicated by pre-eclampsia. Urinary albumin excretion rate, blood pressure, and renal function parameters were assessed 2-4 months and 3-5 years after the pregnancy. Results were compared with those in 44 women after normal pregnancy. RESULTS: Mean urinary albumin excretion rate was significantly higher in the study group than in the controls both at 2-4 months after delivery (27.0 +/- 33 vs 6.1 +/- 3.3 mg/24 h) and at 3-5 years after delivery (23.5 +/- 26.8 vs 6.7 +/- 2.8 mg/24 h) (P = 0.001). The rate of occurrence of microalbuminuria was not significantly different between the early (58%) and late (42%) time-points within the study group or between the nulliparous and the multiparous women. CONCLUSIONS: A history of pregnancy complicated by pre-eclampsia is associated with a high occurrence of microalbuminuria. Whether the presence of microalbuminuria reflects a possible underlying vascular disease in affected patients needs to be further investigated in large-scale studies.

Acute and chronic effects of spirapril, alone or in combination with isradipine on kidney function and blood pressure in patients with reduced kidney function and hypertension.

In the present study we investigated the effect of a single dose, and 3 months of treatment with spirapril on kidney function, renin-angiotensin system, renal handling of sodium and blood pressure, in patients with reduced kidney function (serum creatinine 1.5-3 mg%) and hypertension. A single dose of 6 mg spirapril given at the beginning of the study did not affect glomerular filtration rate (GFR), renal plasma flow (RPF), angiotensin converting enzyme (ACE) activity, plasma renin activity (PRA) or renal handling of sodium. When the single dose of spirapril was given after 3 months of treatment with this agent, renal hemodynamics and PRA did not change. ACE activity, which was depressed by the previous spirapril treatment, decreased further (from 9.5 +/- 3.1 to 1.4 +/- 1.0 nmol/ml/min), (p < 0.05). Administration of 6 mg spirapril o.d. for 3 months did not have any effect on GFR or RPF. Serum ACE activity decreased from 92.1 +/- 8.0 to 5.1 +/- 2.6 nmol/ml/min (p < 0.05) and PRA increased from 1.4 +/- 1.2 to 4.1 +/- 3.6 ng/ml/min (p < 0.05). Plasma aldosterone did not change. Similar results were obtained when spirapril was combined with 5 mg isradipine in the initial and final single dose, or in the 3 months' treatment (5 mg o.d.). Blood pressure was normalized in 38% of the patients who received spirapril and in 71% of the patients who received spirapril and isradipine. Thus, (a) treatment with spirapril in patients with mild to moderate chronic renal insufficiency was not associated with deleterious effects on kidney function; (b) spirapril in a dose of 6 mg alone or in combination with 5 mg isradipine is effective in reducing blood pressure in hypertensive patients with reduced kidney function.

Diabetic nephropathy.

Renal involvement is one of the major microvascular complications of both type 1 and type 2 diabetes mellitus. Diabetic nephropathy is the major cause of end-stage renal failure in most Western nations and is associated with increased morbidity and mortality as compared to other causes of renal disease. The pathogenesis of renal involvement in diabetes is presumed to be the result of the interplay of metabolic and hemodynamic factors. Significant advances in the prevention and treatment of progression of diabetic nephropathy have been achieved with intensive glycemic control and the treatment of elevated blood pressure. Patients with diabetes should thus be screened regularly for the appearance of any of the risk factors for renal or other complications and treated intensively according to established guidelines for control of hyperglycemia and hypertension. Ancillary therapeutic measures include treatment of hyperlipidemia, low-protein diet, and the cessation of smoking.

DNA polymorphisms in the ACE gene, serum ACE activity and the risk of nephropathy in insulin-dependent diabetes mellitus.

BACKGROUND: To determine the relationship between DNA polymorphisms in the angiotensin I converting enzyme (ACE) gene, serum ACE activity and the risk of diabetic nephropathy. METHODS: A case-control study was carried out in a population of Jewish insulin-dependent diabetes mellitus (IDDM) patients. Cases (77 IDDM patients with diabetic nephropathy) and controls (89 IDDM patients with normoalbuminuria) were genotyped with PCR protocols for detecting two DNA polymorphisms in the ACE gene: one in intron 7 detected with the restriction enzyme PstI and the other in intron 16 identified as an insertion/deletion (I/D). RESULTS: The risk of nephropathy was increased only in patients homozygous for the allele with the PstI site. These homozygotes had a nephropathy risk that was 2.3 times (95% C.I.: 1.2-4.5) that of the other genotypes. Furthermore, these individuals did not have elevated serum ACE activity. CONCLUSIONS: The results of this study are evidence that the risk of diabetic nephropathy in IDDM is influenced by genetic variability at the ACE locus, but the responsible variant is not the I/D polymorphism in intron 16. Our findings require further studies in other populations.

Insulin treatment reduces the increased serum and lung angiotensin converting enzyme activity in streptozotocin-induced diabetic rats.

Serum and lung angiotensin-converting enzyme (ACE) activity is increased in the streptozotocin (STZ)-diabetic rat. In the present study, the effect of insulin treatment on this increased ACE activity in the STZ-diabetic rat was investigated. Serum and tissue ACE activity was determined by radiometric assay using [3H]-Hippuryl-glycyl-glycine as substrate. Fifteen days after onset of diabetes (n = 16), 8 rats received insulin daily (6-12 units/kg, s.c.) for 33 days, 8 diabetes rats remained untreated. Control, non-diabetic, rats (n = 8) received saline. The baseline serum ACE activity in the control group was 595 +/- 13 nmol/ml/min and did not change significantly throughout the study. However, serum ACE activity in the untreated diabetic rats increased significantly as of day 14 post-STZ (650 +/- 24 nmol/ml/min, p < 0.001) compared to the corresponding values of the control group and compared to baseline values. Insulin administration to diabetic rats starting on day 15 post-STZ caused a gradual reduction in serum ACE activity to basal values, being (527 +/- 22 nmol/ml/min) at day 47. ACE activity in lungs of untreated diabetic rats was increased by 46%, 47 days post-STZ. Insulin treatment reduced lung ACE activity to values similar to those observed in non-diabetic rats. These changes were associated with reduced kidney weight and urine volume. In summary, insulin administration to hyperglycaemic rats resulted in a reduction in the enhanced serum and lung ACE activity to values seen in non-diabetic rats. Normalizing the activity of the renin-angiotensin system may slow or prevent the glomerular hypertension, a major factor in the development of diabetic nephropathy.

Thromboxane production in human lung during cardiopulmonary bypass: beneficial effect of aspirin?

BACKGROUND: Increased systemic levels of thromboxane (Tx) during cardiopulmonary bypass (CPB) in humans have been reported. It is not known whether this reflects a general systemic response to the surgical procedure or an increased pulmonary production of Tx in response to ischemia and reperfusion. METHODS: Thromboxane B2 levels were measured in the right atrium and left atrium of 14 patients undergoing coronary artery bypass grafting for angina. Eight patients (group 1) were without aspirin for at least 15 days before operation, and 6 patients (group 2) were treated with aspirin (100 mg/day) for at least 1 month before operation. Levels of TxB2 were determined by enzyme immunoassay after lipid extraction and separation. RESULTS: Thromboxane B2 levels were elevated throughout CPB. In group 1, left atrial TxB2 levels were significantly higher (p < 0.05) than right atrial levels at all study points during CPB. After pulmonary reperfusion, TxB2 levels in both atria increased significantly (p < 0.02) compared with the levels before cross-clamping of the aorta, and there was an increasing gradient between the two atria (p < 0.05). Mean plasma TxB2 levels during CPB in group 2 were significantly reduced (p < 0.0001) in the right atrium (by 73%) and in the left atrium (by 69%) compared with levels in group 1. CONCLUSIONS: The rise in TxB2 levels in the left atrium after CPB in humans reflects production of Tx mainly in the lungs, most probably by ischemic pulmonary tissue and intravascular hematologic components. Aspirin markedly reduces Tx production during CPB, and it might play a major role in preventing pulmonary injury after operations with CPB in humans.