de Dick Zeeuw

Sodium intake affects urinary albumin excretion especially in overweight subjects

Objectives.  To examine the relationship between sodium intake and urinary albumin excretion, being an established risk marker for later cardiovascular morbidity and mortality.

Angiotensin-(1–7) Is a Modulator of the Human Renin-Angiotensin System

The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1-7) to angiotensin-(1-5) and can lead to elevation of angiotensin-(1-7) levels in plasma and tissue. In animal models, angiotensin-(1-7) itself causes or enhances vasodilation and inhibits vascular contractions to angiotensin II. The function of angiotensin-(1-5) is unknown. We investigated whether angiotensin-(1-7) and angiotensin-(1-5) inhibit ACE or antagonize angiotensin-induced vasoconstrictions in humans. ACE activity in plasma and atrial tissue was inhibited by angiotensin-(1-7) up to 100%, with an IC(50) of 3.0 and 4.0 micromol/L, respectively. In human internal mammary arteries, contractions induced by angiotensin I and II and the non-ACE-specific substrate [Pro(11),D-Ala(12)]-angiotensin I were antagonized by angiotensin-(1-7) (10(-5) mol/L) in a noncompetitive way, with a 60% inhibition of the maximal response to angiotensin II. Contractions to ACE-specific substrate [Pro(10)]-angiotensin I were also inhibited, an effect only partly accounted for by antagonism of angiotensin II. Angiotensin-(1-5) inhibited plasma ACE activity with a potency equal to that of angiotensin I but had no effect on arterial contractions. In conclusion, angiotensin-(1-7) blocks angiotensin II-induced vasoconstriction and inhibits ACE in human cardiovascular tissues. Angiotensin-(1-5) only inhibits ACE. These results show that angiotensin-(1-7) may be an important modulator of the human renin-angiotensin system.

Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition : the CATS randomized trial

AIMS Information regarding the cardiorenal axis in patients after a myocardial infarction (MI) is limited. We examined the change in renal function after a first MI, the protective effect of angiotensin converting enzyme (ACE) inhibition and the prognostic value of baseline renal function. METHODS AND RESULTS The study population consisted of 298 patients with a first anterior wall MI who were randomized to the ACE inhibitor captopril or placebo after completion of streptokinase infusion. Renal function, by means of glomerular filtration rate (GFR), was calculated using the Cockroft-Gault equation (GFR(c)). In the placebo group, renal function (GFR(c)) declined by 5.5 min(-1)within 1 year, vs only 0.5 ml min(-1)in the ACE inhibitor group (P<0.05). This beneficial effect of captopril was most pronounced in patients with the most compromised renal function at baseline. The incidence of chronic heart failure (CHF) within 1 year increased significantly with decreasing GFR(c)(divided into tertiles: 24.0, 28.9, and 41.2%; P<0.01). The risk-ratio for GFR(c)<81 ml min(-1)vs >103 mL min(-1)was 1.86 (95% CI 1.11-3.13; P=0.019). CONCLUSIONS Renal function markedly deteriorates after a first MI, but is significantly preserved by ACE inhibition. Furthermore, an impaired baseline renal function adds to the prognostic risk of developing CHF in patients after a first anterior MI.

Long-term renal outcome after lung transplantation is predicted by the 1-month postoperative renal function loss

BACKGROUND Progressive renal function loss is common after lung transplantation. To facilitate the design of renoprotective strategies, identification of early predictors for long-term renal function loss would be useful. METHODS We prospectively analyzed renal function [glomerular filtration rate (GFR); 125I-iothalamate clearance] in a closely monitored cohort (minimum 24-month follow-up) of 57 patients who received lung transplants between November 1990 and September 1996 in our center. The analyzed end points were the slope of the GFR from 6 months posttransplant onward and the GFR at 24 months after transplantation. RESULTS Before transplantation, the GFR was 100 ml/min (median, range 59-163). It decreased to 67 ml/min (29-123) at 6 months, 53 ml/min (17-116) at 24 months, and 51 ml/min (20-87) at 36 months after transplantation. The magnitude of the loss of GFR 1 month post-transplantation was the only factor significantly correlated with absolute GFR at 24 months after transplantation. Pulmonary diagnosis was significantly associated with long-term rate of renal function loss. Median loss of GFR was greatest in patients with cystic fibrosis (-10 ml/min/year, range -14 to -6 ml/min/year), preserved in pulmonary hypertension (-1 ml/min/year, range -6 to +7 ml/min/year), and in between in emphysema (-6 ml/min/year, range -27 to +12 ml/min/year). No other factors could be identified. CONCLUSIONS In lung transplant recipients, the 1-month postoperative loss of GFR is an early marker for long-term renal prognosis. Pulmonary diagnosis appears to be a relevant predictor as well. These factors may guide further research and the development of preventive strategies.

ADDITIVE ANTIPROTEINURIC EFFECT OF THE NSAID INDOMETHACIN AND THE ACE INHIBITOR LISINOPRIL

Both angiotensin-converting enzyme (ACE) inhibitors like lisinopril and nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin have been shown to lower urinary protein excretion in renal disease. If this effect is caused by different mechanisms of action, the combination of these agents could have an additive antiproteinuric effect. We studied the effects of lisinopril and indomethacin separately and in combination in 10 patients with the nephrotic syndrome. Proteinuria was lowered from 10.5 +/- 1.8 g/24 h in the control period to 4.5 +/- 1.1 g/24 h on indomethacin, 4.3 +/- 1.0 g/24 h on lisinopril and to 2.4 +/- 0.8 g/24 h on the combination. Glomerular filtration rate (GFR) fell on either monotherapy, but particularly on the combination of drugs. The renal hemodynamic changes suggested a preglomerular vasoconstriction by indomethacin and a postglomerular vasodilation by lisinopril. Severe hyperkalemia occurred in 3 patients on the combination therapy. We conclude that the combination of indomethacin and lisinopril has an additive antiproteinuric effect. This, as well as the more pronounced fall in GFR on the combination, may suggest that both drugs lower proteinuria by decreasing intraglomerular capillary pressure but via different mechanisms. Combining these drugs may be useful in the symptomatic treatment of nephrotic syndrome, but renal function and serum potassium should be monitored carefully.

ACE Inhibition Preserves Heparan Sulfate Proteoglycans in the Glomerular Basement Membrane of Rats with Established Adriamycin Nephropathy

The gradual onset of the antiproteinuric effects of ACE inhibition suggests that structural effects on the glomerular basement membrane (GBM) may be involved in their renoprotective action. To test this hypothesis, we studied the effects of lisinopril (5 mg/kg/24 h) on proteinuria, focal glomerulosclerosis (FGS) and glomerular heparan sulfate (HS) proteoglycan (HSPG) GBM staining in rats with established Adriamycin nephrosis. Treatment was started 6 weeks after disease induction. As expected, lisinopril reduced blood pressure, proteinuria and the FGS score. In control rats, Adriamycin nephrosis was associated with significantly impaired GBM staining for both HSPG core protein (assessed from BL-31 staining) and HS staining (assessed from JM-403 staining) 12 weeks after disease induction. In rats treated with lisinopril (5 mg/kg/24 h) GBM stianing was significantly better preserved for HS as well as for HSPG core protein. These data suggest that structural effects on the GBM, improving glomerular permselectivity, may be involved in the renoprotective effects of ACE inhibition in proteinuria-induced renal damage.

Systemic gene therapy with interleukin-13 attenuates renal ischemia–reperfusion injury

Ischemia-reperfusion injury is a leading cause of acute renal failure and a major determinant in the outcome of kidney transplantation. Here we explored systemic gene therapy with a modified adenovirus expressing Interleukin (IL)-13, a cytokine with strong anti-inflammatory and cytoprotective properties. When ischemia was induced we found that the IL-13 receptor is expressed in both the normal and experimental kidneys. Prior to the induction of ischemia, rats received adenovirus-IL-13, control adenovirus or saline. IL-13 plasma levels increased more than 50-fold in adenovirus-IL-13 treated animals, confirming successful IL-13 gene delivery. Histological analysis showed decreased tubular epithelial cell damage with adenovirus-IL-13 therapy, accompanied by reduced kidney injury molecule-1 expression. Interstitial infiltration by neutrophils and macrophages was reduced by half as was interstitial fibrosis and expression of alpha-smooth muscle actin. IL-13 treatment significantly diminished the expression of E-selectin, IL-8, MIP-2, TNF-alpha and MCP-1 mRNA. These results suggest that the use of systemic IL-13 gene therapy may be useful in reducing renal tubulointerstitial damage and inflammation caused by ischemia-reperfusion.

Proteinuria and progression of renal disease: Therapeutic implications

The relationship between proteinuria and progression of renal disease has long been an issue of debate. The present review deals with some of the recent publications on this topic. New concepts are emphasized: the possible causal role of proteinuria in the pathophysiology of progressive renal function loss, and the decrease in urinary protein loss at the beginning of renoprotective therapy as a predictor of renal function outcome during this treatment.

Altered myogenic constriction and endothelium-derived hyperpolarizing factor-mediated relaxation in small mesenteric arteries of hypertensive subtotally nephrectomized rats

Objectives Chronic renal failure (CRF) is associated with altered systemic arterial tone and hypertension. Myogenic constriction and endothelium-derived hyperpolarizing factor (EDHF)-dependent relaxation represent major vasoregulatory mechanisms in small systemic arteries. Elevated myogenic response and impaired EDHF might participate in the development of essential hypertension; however, their role in CRF-related hypertension is unknown. We investigated whether myogenic response and EDHF are altered in subtotally nephrectomized (sNX) rats and whether these changes are modifiable by chronic treatment with angiotensin-converting enzyme (ACE) inhibitor. Methods In a pressure arteriograph, myogenic constriction and EDHF-mediated relaxation were evaluated in small mesenteric arteries isolated from male Wistar rats 15 weeks after either sham operation (n = 7) (SHAM), sNX (n = 12) or sNX followed by 9 weeks of treatment with lisinopril (sNX + LIS, 2.5 mg/kg, n = 13). Results Surprisingly, myogenic response was reduced in hypertensive CRF rats (maximal myogenic tone: 37 ± 2 and 18 ± 4%, P < 0.01; peak myogenic index: −0.80 ± 0.08 and −0.40 ± 0.12%/mmHg, P < 0.05 in SHAM and sNX respectively). At the same time EDHF-mediated relaxation was also impaired (maximal response: 92 ± 2 and 77 ± 5%, P < 0.01; pD2: 6.5 ± 0.1 and 5.9 ± 0.1, P < 0.05). Both myogenic response and EDHF were inversely related to the severity of renal failure and restored by treatment with lisinopril to levels found in SHAM animals. Conclusion Major constrictive (myogenic) and dilatory (EDHF) mechanisms of small systemic arteries are impaired in hypertensive CRF rats. These alterations do not seem to participate in the development of hypertension, being rather directly related to the severity of renal impairment. Both systemic vascular changes might be restored by renoprotective treatment with ACE inhibitor.

Dose of doxorubicin determines severity of renal damage and responsiveness to ACE-inhibition in experimental nephrosis

Nephrosis induced by doxorubicin (adriamycin) is an experimental model of glomerulosclerosis with relative stable proteinuria which is commonly used for pharmacological intervention studies. It is induced by a single or a double dose of doxorubicin, with doses that vary considerably among investigators from 2 to 7.5 mg/kg. Intervention studies with ACE-inhibitors in this model have provided conflicting results. We hypothesized that these discrepancies might be due to different properties of the doxorubicin model, related to the dose of doxorubicin used to induce proteinuria. We tested this hypothesis by inducing doxorubicin nephrosis with 1, 2 and 3 mg/kg, and evaluating the response to intervention with lisinopril. The 1-mg/kg doxorubicin dose did not induce significant proteinuria. The 2- and the 3-mg/ kg dose resulted in a proteinuria of 684+/-215 mg/24 h and 736+/-277 mg/24 h 6 weeks after induction, respectively (Mean+/-SD). Treatment with lisinopril 2 mg/kg/day reduced proteinuria to 160+/-170 mg/24 h(p<0.01) in the 2-mg/kg doxorubicin group, whereas in the 3-mg/kg doxorubicin group, proteinuria did not respond to lisinopril (529+/-264 mg/24 h). In time control rats, proteinuria remained stable. Renal damage developed in both time control groups, with a glomerulosclerosis score of 29+/-22 in the 2-mg/kg group and 84+/-41 in the 3-mg/kg doxorubicin group. Lisinopril resulted in a significantly lower glomerulosclerosis score in the 2-mg/kg doxorubicin group only (16+/-15, p<0.05), whereas the 3-mg/kg group showed no significant reduction (56+/-29, NS). In conclusion, the dose of doxorubicin used to induce nephrosis is an important determinant not only of the severity of the ensuring renal damage, but also of the response to intervention by ACE-inhibition. These findings have an impact on the interpretation of intervention studies in this model.