Angiotensin-converting enzyme inhibition induces apoptosis in erythroid precursors and affects insulin-like growth factor-1 in posttransplantation erythrocytosis

A number of studies suggest that erythropoietin (Ep), angiotensin II, and insulin-like growth factor (IGF-1) are involved in the pathogenesis of posttransplantation erythrocytosis (PTE). Angiotensin-converting enzyme inhibitors (ACEI) are the treatment of choice in PTE, but their mechanism of action is unclear. It was shown previously that ACEI added directly to cultures of erythroid precursors from patients with PTE inhibit colony growth. In this report, the effect of ACEI on CD34+ erythroid precursor apoptosis was studied, as were hematocrit (Hct), Ep, IGF-1, and IGF-binding protein 3 (IGF-BP3) levels. Ten patients with PTE, 10 transplant control patients, and 7 normal control subjects were studied. Peripheral blood CD34+ cells were isolated, and apoptosis was assessed by annexin assay and DNA laddering before and during ACEI therapy. At the same time, Hct, Ep, IGF-1, and IGF-BP3 levels were measured. Baseline CD34+ cell number, CD34+ apoptosis, Ep, IGF-1, and IGF-BP3 levels were the same between PTE and transplant control subjects. ACEI therapy was associated with a striking increase in CD34+ cell apoptosis and a decrease in Hct in both groups. In contrast to control subjects, patients with PTE on ACEI showed a significant decrease in IGF-1 levels and a greater percentage decrease in Hct. In normal control subjects, ACEI therapy was associated with a fall in Hct but no change in CD34+ cell apoptosis. In PTE, ACEI-related increase in erythroid progenitor apoptosis may partially explain the ACEI-associated decrease in Hct. However, it is not clear that erythroid precursor apoptosis is related to changes in IGF-1 or IGF-BP3.     

Angiotensin-converting enzyme inhibitors after renal transplantation

The blockade of the renin-angiotensin-aldosterone system may limit the progression of graft dysfunction in patients receiving kidney transplantations.We retrospectively evaluated the safety and efficacy of angiotensin-converting enzyme inhibitors (ACEI) in renal allograft recipients. Fifty-seven cadaveric kidney recipients (58% of recipients), were prescribed an ACEI (lisinopril). The indications for ACEI were isolated proteinuria (1 patient), erythrocytosis (6 patients), and arterial hypertension (50 patients). The choice of an ACEI for blood pressure control was due to presence of left ventricular hypertrophy (2 patients), mild proteinuria (4 patients), and high hemoglobin (4 patients).There was a significant reduction in the mean arterial pressure after 1 month (P = .0004) and 1 year (P = .0002) of therapy. Overall, the estimated glomerular filtrate rate (eGFR), calculated using the Cockcroft-Gault equation, remained unchanged. Among patients who had serum creatinine values above 2.0 mg/dL at the beginning of ACEI therapy, there was a significant rise in eGFR from 39.3 ± 13.2 to 44.1 ± 16.8 mL/min after 6 months (P = .01), and 43.3 ± 17.3 mL/min after 1 year (P = .04). In patients with erythrocytosis, the hemoglobin showed a significant and sustained reduction after 1 month (P = .004) and 1 year (P = .001).Six patients suspended ACEI owing to adverse events: cough (n = 4), worsening of graft function (n = 1), and hypotension (n = 1). Six patients required erythropoiesis-stimulating agents. No patient suspended treatment owing to hyperkalemia.In conclusion, ACEI were well tolerated, safe, and effective antihypertensive agents in kidney graft recipients. They seemed to have some beneficial effect in preserving GFR in patients with worse graft function.     

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers after renal transplantation

Abstract:  Renin-angiotensin system blockade retards the progression of diabetic and non-diabetic chronic kidney disease of the native kidneys. Though most patients suffer from a significant renal insufficiency (chronic kidney disease stage III) and a concomitant heart disease after renal transplantation, there is up to now no evidence supporting the use of inhibitors of the renin-angiotensin system in these patients. We wish to summarize the available evidence on the use of inhibitors of the renin-angiotensin system after renal transplantation. We specifically discuss potential beneficial as well as adverse effects of a renin-angiotensin system blockade. In addition, we review their influence on morphologic and biochemical markers as well as on renal function, graft and patient survival after renal transplantation.     

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in chronic renal disease: safety issues

Reducing the actions of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) slows nephropathy progression in patients with or without diabetes. These drug classes have proven therapeutic benefits, particularly in patients with renal insufficiency (ie, serum creatinine level 133-265 micromol/L [1.5-3.0 mg/dL]). This class of drugs could also provide renoprotective effects that are nonblood pressure-dependent when used as part of combination antihypertensive therapy in patients with more advanced renal disease. Although many studies demonstrate the use of ACE inhibitors and ARBs to delay the decline in renal function and reduce proteinuria, many physicians fail to use these drug classes in patients with renal insufficiency for fear that either serum creatinine or potassium levels will rise. Thus, because of these issues, patients are deprived of known strategies that delay progression of renal disease. A strong association exists between acute increases in serum creatinine of up to 30% to 35% after initiating ACE inhibitor therapy and long-term preservation of renal function. This association is predominantly present in people with a baseline serum creatinine of up to 3 mg/dL and usually stablizes within 2 to 3 months of therapy given blood pressure is reduced to goal. Moreover, the appropriate use of diuretics mitigates against profound increases in serum potassium. Thus, withdrawal of an ACE inhibitor in such patients should occur only when the rise in creatinine exceeds this threshold over a shorter period of time or hyperkalemia develops, ie, serum potassium level of 5.6 mmol/L or greater.     

Angiotensin-converting enzyme inhibition and renal protection in nondiabetic patients: the data of the meta-analyses

ESRD represents a major health problem. The number of patients who enter kidney replacement programs has increased at an average of 7% per year in the past 10 yr. A large number of experimental and clinical studies have demonstrated that chronic nephropathies share common pathogenic mechanisms that contribute to renal disease progression, even independent of the original cause. Clinical studies found a significant correlation between the extent of urinary protein excretion and the rate of GFR decline in both diabetic and nondiabetic chronic nephropathies. Randomized trials, in particular the Ramipril Efficacy In Nephropathy (REIN) study, also showed that treatments that reduce proteinuria (namely angiotensin-converting enzyme [ACE] inhibitors) are renoprotective and limit progression to ESRD. Meta-analyses of randomized clinical trials also evaluated the role of proteinuria and of ACE inhibition therapy in chronic renal disease progression. Their findings were consistent with those of the REIN study and confirmed in larger series of patients the predictive value of proteinuria and the renoprotective effect of proteinuria reduction by ACE inhibition therapy. Thus, the meta-analyses may confirm and extend previous findings generated by randomized clinical trials. Conceivably, well-designed studies in properly selected and carefully monitored patients who are at increased risk continue to be the best approach to test novel hypotheses. The meta-analyses, however, represent a valuable tool to evaluate the consistency and generalizability of trial results to larger cohorts of patients.     

Angiotensin-converting enzyme activity in renal disorders: influence of disease pattern, hemodialysis and transplantation

Serum angiotensin-converting enzyme activity (s-ACE) was measured spectrophotometrically in a variety of renal disorders. In 111 renal patients not on dialysis, s-ACE was slightly lower (22.9 +/- 5.9 U/ml; mean +/- SD) than in 116 controls 24.4 +/- 6.2 U/ml). In 52 patients on chronic hemodialysis s-ACE was 24.1 +/- 4.7 U/ml; serial analyses done before initiation of chronic dialysis showed a significant increase in s-ACE levels towards normal values. In 38 renal allograft recipients s-ACE was relatively low (22.0 +/- 5.0 U/ml); a significant decrease in s-ACE was observed in patients followed from the time of transplantation (24.6 +/- 6.4 U/ml) to two weeks after transplantation (20.2 +/- 4.5 U/ml). S-ACE was also depressed (17.4 +/- 2.6 U/ml) in 12 patients with acute renal failure, and it increased in parallel with normalization of renal function. S-ACE was normal (24.4 +/- 5.7 U/ml) in 14 patients with essential hypertension. Elevated s-ACE (above mean of controls + 2 SD) was observed in only one patient of the total series. We could not confirm previous reports on elevated s-ACE in dialysis patients, but several factors invalidate a direct comparison between series. Thus, the deviations in s-ACE in renal disorders seem to be discrete: depressed levels in acute renal failure and a relative depression in undialyzed patients with chronic renal disorders. The low activity after transplantation may be secondary to the immunosuppressive treatment.     

Angiotensin-converting enzyme inhibition attenuates renal platelet-derived growth factor gene expression and cell proliferation in subtotal nephrectomy

Cell proliferation, matrix accumulation and cell infiltration are characteristic features of progressive glomerulosclerosis and tubulointerstitial fibrosis. Platelet‐derived growth factor (PDGF), a cytokine which has proliferative, prosclerotic and chemokine properties, has been shown to be upregulated in the rat remnant kidney model. Inhibition of the renin–angiotensin system by angiotensin‐converting enzyme (ACE) inhibitors has a beneficial effect on renal function and morphology, but the effect of ACE inhibition on PDGF gene expression and PDGF‐mediated cellular proliferation in subtotal nephrectomy has not been studied in detail. Twelve rats were subtotally nephrectomized (STNx) and received either the ACE inhibitor perindopril or a placebo for 12 weeks. Five sham‐operated rats served as controls. Subtotal nephrectomy was associated with hypertension, proteinuria, elevated plasma creatinine and increased kidney weight. After 12 weeks, PDGF B‐chain mRNA was significantly upregulated in the glomeruli and tubulointerstitium of subtotally nephrectomized rats. ACE inhibition attenuated PDGF mRNA expression in association with a reduction in tubular and glomerular proliferation, as assessed by staining for proliferating cell nuclear antigen. In the context of the known in vitro and in vivo effects of PDGF, it is postulated that the renoprotective action of ACE inhibitors may be partially related to PDGF‐mediated antiproliferative mechanisms.     

Microwave tissue coagulator induces renal apoptotic damage to preserved normal renal tissue following partial nephrectomy

Background  

We assessed the extent of apoptotic damage induced by the microwave tissue coagulator (MTC) in the preserved normal renal tissue following partial nephrectomy.     

Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation

Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers (ARB) reduce cardiovascular death in the general population, but data for renal transplant recipients remain elusive. Similarly, ACEI/ARB have been shown to reduce proteinuria, but data on graft survival are lacking. Therefore a retrospective open cohort study was conducted of 2031 patients who received their first renal allograft at the Medical University of Vienna between 1990 and 2003 and survived at least 3 mo. Patient and graft survival was compared between patients with versus without ACEI and/or ARB therapy. Data were analyzed with and without propensity score models for ACEI/ARB therapy. Medication and comorbidities were analyzed as time-dependent variables in the Cox regression analyses. Ten-year survival rates were 74% in the ACEI/ARB group but only 53% in the noACEI/ARB group (P<0.001). The hazard ratio (HR) of ACEI/ARB use for mortality was 0.57 (95% confidence interval [CI] 0.40 to 0.81) compared with nonuse. Ten-year actual graft survival rate was 59% in ACEI/ARB patients but only 41% in nonusers (P=0.002). The HR of actual graft failure for ACEI/ARB recipients was 0.55 (95% CI 0.43 to 0.70) compared with nonusers; the HR of functional graft survival was 0.56 (95% CI 0.40 to 0.78). Ten-year unadjusted functional graft survival rates were 76% among ACEI/ARB patients and 71% in noACEI/ARB recipients (P=0.57). In summary, the use of ACEI/ARB therapy was associated with longer patient and graft survival after renal transplantation. More frequent use of these medications may reduce the high incidence of death and renal allograft failure in these patients.     

Angiotensin-converting enzyme inhibition but not angiotensin II receptor blockade regulates matrix metalloproteinase activity in patients with glomerulonephritis

Equivalent long-term effects on the kidney are attributed to angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB). Nevertheless, it is unknown to which degree effects of these compounds on individual inflammatory mediators, including matrix metalloproteinases (MMP), are comparable. On the basis of structural and functional differences, it was hypothesized that ACEI and ARB differentially regulate MMP activity. In a randomized, prospective crossover trial, the effect of an ACEI (fosinopril; 20 mg/d) and of an ARB (irbesartan; 150 mg/d) on MMP activity was evaluated. Ten hypertensive patients with glomerulonephritis and normal or mildly reduced creatinine clearance were studied. MMP activity and tissue inhibitors of metalloproteinase (TIMP) levels were analyzed in serum and urine: without therapy, with ACEI, with ARB, and with both agents combined. Treatment periods continued for 6 wk separated by periods of 4 wk each without therapy. Untreated patients with glomerulonephritis displayed distinctively higher serum levels of MMP-2 but much lower MMP-1/-8/-9 concentrations compared with healthy control subjects. Immunohistology of MMP-2 and MMP-9 in kidney biopsy specimen was accordingly. However, these patients excreted higher amounts of MMP-2 and MMP-9 in urine than healthy control subjects, possibly reflecting ongoing glomerular inflammation. In patients with glomerulonephritis, ACEI significantly reduced overall MMP serum activity to 25%, whereas ARB did not show any effect. Activities of MMP-1/-2/-8/-9 were also significantly inhibited by fosinopril but not by irbesartan. Levels of TIMP-1/-2 remained unaffected. In conclusion, ACEI and ARB differentially regulate MMP activity, which may ultimately have consequences in certain types of MMP-dependent glomerulonephritis.     

Angiotensin-converting enzyme inhibition and angiotensin II antagonism in nondiabetic chronic nephropathies

Angiotensin II (A II), the main effector of the renin angiotensin system (RAS), plays a central role in the hemodynamic and nonhemodynamic mechanisms of chronic renal disease and is currently the main target of interventions aimed to prevent the onset and progression of chronic nephropathies to end-stage renal disease (ESRD). In addition, to ameliorate glomerular hyperfiltration and size selectivity, reduce protein traffic and prevent glomerular and tubulointerstitial toxicity of ultrafiltered proteins, RAS inhibitors also limit the direct nephrotoxic effects of A II. Thus, both angiotension-converting enzyme (ACE) inhibitors (ACEi) and A II antagonists (ATA) exert a specific nephroprotective effect in both experimental and human chronic renal disease. This effect is time-dependent and is observed across degrees of renal insufficiency. Forced ACEi or ATA uptitration above doses recommended to control arterial hypertension and combined treatment with both agents allow optimization of A II inhibition and maximization of renoprotection. Multifactorial interventions combining RAS inhibition to treatments targeted also to non-RAS mechanisms could even achieve regression of glomerulosclerosis and chronic tubulointerstitial injury. Studies are needed to assess whether renal damage can be reverted to such a point that renal function could be fully prevented from worsening, and possibly improvement. The economic impact of even a partial improvement would be enormous. Moreover, chronic renal insufficiency is an independent risk factor for cardiovascular disease, and effective nephroprotection could also decrease the excess cardiovascular morbidity and mortality associated with chronic nephropathies. In patients with renal insufficiency, ACEi are even more cardioprotective than in those without and are well tolerated. Thus, RAS inhibitor therapy should be offered to all renal patients without specific contraindications, including those closer to renal replacement therapy.     

Effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on apoptotic changes in contralateral testis following unilateral testicular torsion

Objectives  In this experimental study, our aim was to determine whether angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 (AT1) receptor blockade affect the apoptotic changes in contralateral testis following unilateral testicular torsion (UTT). Methods  Study groups consisted of 30 adult male Wistar rats. The rats were randomly separated into five groups. Group 1 was maintained as control without manipulation. Group 2 underwent the sham operation. Torsion was created by rotating the left testis 720° clockwise for 4 h and maintained by fixing the testis to the scrotum in the other groups. Group 3 underwent torsion and detorsion, with saline administration after detorsion. In group 4, the same surgical procedure was done as in the detorsion group, but AT1 receptor blocker (losartan 30 mg/kg) was injected intraperitoneally for 60 min before detorsion. In group 5, the same surgical procedure was done as in the detorsion group, but ACE inhibitor (lisinopril 50 mg/kg) was injected intraperitoneally for 60 min before detorsion. Bilateral testes were removed from each rat 24 h after surgery. Apoptosis was assessed in paraffin-embedded sections stained for TUNEL method. Reticulum staining was performed to evaluate the extracellular changes semiquantitatively. Testicular biopsy score counts were performed on these sections according to Johnsen. Results  The mean apoptotic scores of group 1, group 2 and group 3 were significantly higher than that of the other groups. There was no difference between the apoptotic scores of groups 1, 2, 4 and 5. Reticulum stain was increased in group 3 as compared to other groups. The mean Johnsen biopsy score of group 3 was significantly lower than that of the other groups. Conclusion  ACE inhibition and AT1 receptor blockade reduced the tubular damage and apoptosis in the contralateral testes after UTT. The beneficial effect of these drugs may arise from inhibition of ischemic process resulting from increased sympathetic activity and elimination of insults subsequent to dysregulation of RAS. These results suggest that ACE inhibitors and AT1 receptor blockers may be of potential value in patients with UTT.     

Angiotensin-converting enzyme inhibitors in pregnancy may result in neonatal renal failure

Oligohydramnios and neonatal renal failure is reported in a premature infant whose mother had used enalapril in weeks 32-35 of her pregnancy. The infant recovered adequate renal function after peritoneal dialysis. Review of the literature supports our view that angiotensin-converting enzyme inhibitors should not be used in pregnancy; if they are, both mother and fetus should be monitored with extreme care.     

Angiotensin-converting enzyme inhibitors versus AT1 receptor antagonist in cardiovascular and renal protection: the case for AT1 receptor antagonist

The development of pharmacologic agents that directly inhibit the angiotensin II receptor (angiotensin receptor blocker [ARB]) has provided clinicians with an alternative to the previously available angiotensin-converting enzyme inhibitors (ACEI) to downregulate the renin-angiotensin system. This review focuses on the available data that can guide the clinician to the use of these two classes of agents vis à vis their ability to provide cardiovascular (CV) and renal protection. Although the CV protective effect of ACEI in high-risk populations is widely appreciated, whether such an effect is entirely BP independent can be questioned. Most head-to-head comparisons between ACEI and ARB have yielded comparable CV protective effects, with ARB being associated with fewer adverse effects. Likewise, several-but not all-studies have demonstrated a CV protective effect of ACEI when compared with other active agents in patients with type 2 diabetes. One study demonstrated a similar protection with ARB when compared with a beta blocker. In terms of renal protection, there are ample data to support a role for both ACEI and ARB to prevent the progression from microalbuminuria to overt albuminuria in both type 1 and type 2 diabetes. However, when progression of renal disease is used as an end point, protection has been demonstrated with ACEI only for type 1 but not type 2 diabetes. In this latter group, only ARB have been shown to slow progression to ESRD.     

Angiotensin-converting enzyme inhibition in experimental in-situ immune complex glomerulonephritis: influence on renal function, proteinuria, and morphology

BACKGROUND: Converting enzyme inhibition (CEI) ameliorates progressive lossof function in non-immune-mediated renal diseases and experimentalhypertension. Little, however, is known on the potential roleof CEI in established experimental chronic glomerular immuneinjury. We therefore studied the effect of the CEI ramiprilon renal function and morphology in a model of immune mediatedglomerular injury. METHODS: The immune complex glomerulonephritis was induced in uninephrectomizedrats by intrarenal perfusion with the cationized antigen followedby an intravenous application of the antibody. This diseaseis characterized by the development of progressive albuminuriaand a nephrotic syndrome (albuminuria: immune complex glomerulonephritis342±58, control 76±18 mg/24 h; P<0.001). TheCEI by ramipril, dissolved in the drinking water, was given28 weeks after induction of the disease and treatment was continuedfor 12 weeks. RESULTS: In these experiments ramipril significantly reduced albuminexcretion (immune complex glomerulonephritis+CEI 109±16mg/24 h; P<0.01) when compared with untreated nephritic rats.Ramipril, however, did not significantly change inulin clearances(immune complex glomerulonephritis 224±67, immune complexglomerulonephritis+CEI 278±48 µ1/min/100 g bw).Glomerular structural damage expressed as glomerular damageindex was significantly greater in rats with immune complexglomerulonephritis when compared with controls (immune complexglomerulonephritis 0.91±0.13; control 0.60±0.08;P<0.05), but was uneffected by the treatment with the CEI(immune complex glomerulonephritis+CEI 1.02±0.26; control+CEI0.63±0.11). CONCLUSIONS: These data demonstrate that ramipril reduced albuminuna in amodel of immune complex glomerulonephritis; however, it failedto alter GFR and glomerular damage index. The study suggeststhat ramipril ameliorates proteinuria independently of obviousglomerular histological changes. The reduction of proteinuriais, however, associated with a significant decrease in filtrationfraction and therefore is at least partially haemodynamicallymediated.     

Angiotensin-converting enzyme activity as a prognostic factor in acute renal failure.

We evaluated serum angiotensin-converting enzyme (ACE) activity and thyroid function to determine the importance as prognostic factors in acute renal failure (ARF). Among 37 ARF patients, 24 survived (recovered group) and 13 died (lethal group). Both serum thyroxine (T4) level and ACE activity were lower in ARF as a whole group (n = 37) than normal control group (n = 27, p less than 0.01). Both serum T4 level and ACE activity in lethal group (n = 13) were significantly lower than those of the recovered group (n = 24, p less than 0.01). Serum ACE activity but not serum T4 level was significantly related to the prognosis of ARF (p less than 0.02, Mantel-Haenszel analysis). This suggests that lowered serum T4 levels are not a specific indicator of ARF, but lowered ACE activity is significantly related to the prognosis of the patient in ARF. Serum ACE activity seems to be one of several clinically useful prognostic indicators in ARF.