Additive antiproteinuric effect of enalapril and losartan in children with hemolytic uremic syndrome

Background

Angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers decrease postdiarrheal hemolytic uremic syndrome (D + HUS) sequelar proteinuria. However, proteinuria may persist in some patients. In nephropathies other than D + HUS, an additive antiproteinuric effect with coadministration of both drugs has been observed.

Methods

To assess such an effect in D + HUS, 17 proteinuric children were retrospectively studied. After a median period of 1 year post-acute stage (range 0.5–1.9) patients received enalapril alone for a median of 2.6 years (range 0.33–12.0) at a median dose of 0.4 mg/kg/day (range 0.2–0.56). As proteinuria persisted, losartan was added at a median dose of 1.0 mg/kg/day (range 0.5–1.5) during 2.1 years (range 0.5–5.0).

Results

The decrease in proteinuria with enalapril was 58.0 %, which was further reduced to 83.8 % from the initial value after losartan introduction. The percentage of reduction was significantly greater with the association of both drugs (p?=?0.0006) compared with the effect of enalapril exclusively (p?=?0.023). Serum potassium, glomerular filtration rate, and blood pressure remained unchanged.

Conclusions

Our results suggest that adding losartan to persisting proteinuric D + HUS children already on enalapril is safe and reduces proteinuria more effectively. Whereas this effect is associated with long-term kidney protection, it should be determined by prospective controlled studies.     

Renoprotective effect of small doses of losartan and enalapril in patients with primary glomerulonephritis. Short-term observation

BACKGROUND: The renin-angiotensin system is thought to be involved in progression of chronic renal diseases of both diabetic and nondiabetic origin. It is confirmed that angiotensin-converting enzyme inhibitors reduce urinary protein excretion (UPE) and attenuate the development of renal injury. The angiotensin II receptor blockers are an alternative class of drugs inhibiting the renin-angiotensin system activity with preliminarily confirmed renoprotective activity. However, there is lack of data concerning renoprotective action of very small doses of these drugs. METHODS: Prospective, randomized, 3-month study of the effects of losartan 25 mg (n = 17) vs. enalapril 10 mg (n = 17) vs. combination of losartan 25 mg and enalapril 10 mg (n = 15) on proteinuria, kidney function and metabolic profile in 51 patients with biopsy proven chronic glomerulonephritis with normal or slightly declined kidney function [creatinine clearance (CRCL) between 36 and 93 ml/min] was performed. Clinical evaluation and laboratory tests were estimated before treatment (basal), during the first week and after 3 months of therapy. RESULTS: Both, monotherpy with losartan and enalapril significantly reduced proteinuria by 25.35 and 45.07%, respectively. There was no significant difference between groups. Combined therapy induced a more remarkable reduction of proteinuria (65.96%) than either of the drugs administered alone. This antiproteinuric effect was significantly more pronounced only in comparison with the losartan group (p = 0.009). Decreasing of blood pressure was most pronounced in the combined group. In all groups, no correlation between fall of UPE and reducing the systolic or diastolic blood pressure was found. Significant decline in CRCL was observed with enalapril treatment just after 1 week of therapy (p = 0.039) and at the end of observation (p = 0.043). CRCL remained stable in losartan-treated subjects. No changes in serum creatinine level, metabolic profile and sodium excretion were observed during therapy in studied groups. CONCLUSIONS: These results indicated that even very small doses of losartan and enalapril reduce proteinuria in patients with primary glomerulonephritis. Combination of these drugs could cause significantly greater antiproteinuric effect than either of the agents in monotherapy. It is likely that the treatment with losartan, compared to enalapril, is associated with less risk of acute fall of glomerular filtration at the beginning of therapy.     

Effects of antihypertensive therapy on intrarenal angiotensin and bradykinin levels in experimental renal insufficiency

BACKGROUND: Whereas angiotensin converting enzyme inhibitors and angiotensin type 1 receptor antagonists have beneficial effects in the remnant model of renal failure, calcium channel blockers do not consistently improve renal disease in this model. This study examined whether these different means of blood pressure reduction have different effects on renal levels of angiotensin (Ang) and bradykinin peptides. METHODS: Rats subjected to five-sixths nephrectomy were divided into groups with similar hypertension and proteinuria at 4 to 5 weeks. They then received either no treatment, or enalapril, losartan or nifedipine for 2 weeks. Following repeat measurements of proteinuria and blood pressure, Ang II and bradykinin peptides were measured in the remnant kidney and renin, Ang II, and aldosterone were measured in the plasma. RESULTS: All three drugs had equivalent blood pressure-lowering effects. Enalapril and losartan reduced proteinuria but nifedipine did not. Reduction of proteinuria in rats treated with enalapril and losartan was associated with a reduction in Ang II levels in both the peri-infarct and intact portions of the remnant kidney. By contrast, nifedipine increased Ang II levels in the intact portion of the remnant kidney. Losartan reduced bradykinin levels in the peri-infarct portion of the remnant kidney while enalapril reduced bradykinin levels in the intact portion of the remnant kidney. Nifedipine had no effect on intrarenal bradykinin levels. CONCLUSIONS: The differential effects of enalapril, losartan and nifedipine on proteinuria and intrarenal Ang II and bradykinin levels suggest that the ability of an antihypertensive to decrease proteinuria may depend on its ability to decrease kidney Ang II and bradykinin levels.     

Losartan and enalapril are comparable in reducing proteinuria in children with Alport syndrome

Background

A previous subgroup analysis of a 12-week, double-blind study demonstrated that losartan significantly lowered proteinuria versus placebo and amlodipine and was well tolerated in children (1–17 years old) with proteinuria secondary to Alport syndrome. The present subgroup analysis of the open-label, extension phase of this study assessed the long-term efficacy and tolerability of losartan versus enalapril.

Methods

Patients who had completed the double-blind study were re-randomized to losartan or enalapril and followed for proteinuria and renal function for up to 3 years.

Results

Twenty-seven patients with Alport syndrome were randomized to losartan (0.44-2.23 mg/kg/day; n?=?15) or enalapril (0.07-0.72 mg/kg/day; n?=?12). The least-squares (LS) mean percent change from week 12 in urinary protein to creatinine ratio (UPr/Cr was +1.1 % in the losartan group versus a further 13.9 % reduction in the enalapril group (GMR [95 % CI]?=?1.2 [0.7, 2.0]); the LS mean change from week 12 in estimated glomerular filtration rate (eGFR) was ?6.4 ml/min/1.73 m² in the losartan group versus ?9.1 ml/min/1.73 m² in the enalapril group. The adverse event incidence was low and comparable in both treatment groups.

Conclusions

In children with proteinuria secondary to Alport syndrome, losartan maintained proteinuria reduction, and enalapril produced a further proteinuria reduction over the 3-year study period. Both agents were generally well tolerated.     

Renin inhibitors: novel agents for renoprotection or a better angiotensin receptor blocker for blood pressure lowering?

PURPOSE OF REVIEW: Direct renin inhibitors are the newest antihypertensive therapeutic class. The review describes their antihypertensive and antiproteinuric effects and possible renoprotective capabilities. RECENT FINDINGS: Clinical trials demonstrate direct renin inhibitors reduce systolic and diastolic blood pressure comparable with other commonly used antihypertensive drugs, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. They also reduce proteinuria and are renoprotective in experimental models of kidney disease. Direct renin inhibitors, when used with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, offer incremental blood pressure reduction far greater than that observed when an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker are used together. This suggests that renin inhibitors possess a unique and distinct mechanism of action compared with the other two therapeutic classes. SUMMARY: Direct renin inhibitors, due to their antihypertensive and antiproteinuric effects, and the unique mechanism of action resulting in reduction in plasma renin activity and suppression of angiotensin II levels, may offer a unique opportunity to facilitate blood pressure reduction with both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as well as other commonly used therapeutic classes. More effective blood pressure and proteinuria reduction coupled with a unique means of suppressing the renin angiotensin system may offer improved opportunity for renoprotection.     

Low-dose angiotensin II receptor antagonists and angiotensin II-converting enzyme inhibitors alone or in combination for treatment of primary glomerulonephritis

OBJECTIVE: The renin-angiotensin system is thought to be involved in the progression of chronic renal diseases of both diabetic and non-diabetic origin. It has been confirmed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) reduce urinary protein excretion and attenuate the development of renal injury. Clinical data comparing the renal effects of ACEIs and ARBs, either singly or in combination, are scarce and usually concern the use of standard or high doses. MATERIAL AND METHODS: This was a prospective, randomized, 9-month study of the effects of low doses of losartan (25 mg; n = 18) versus enalapril (10 mg; n = 18) versus the combination of losartan (25 mg) and enalapril (10 mg) (n = 16) on proteinuria, kidney function and metabolic profile in 54 patients with biopsy-proven chronic glomerulonephritis, hypertension and normal or slightly impaired kidney function. The clinical evaluation and laboratory tests were performed before treatment (baseline) and after 3 and 9 months of therapy. RESULTS: After 3 months, significant decreases in proteinuria were observed in all groups: losartan, 22.6% (p = 0.02); enalapril, 43% (p = 0.012); and combined therapy, 63% (p = 0.001). This anti-proteinuric effect was even greater after 9 months of therapy: losartan, 44.2% (p = 0.02); enalapril, 49.6% (p = 0.02); and combined therapy, 51% (p = 0.003). There was no significant difference between losartan and enalapril with respect to their impact on proteinuria level. Proteinuria reduction was significantly greater in patients receiving combined therapy in comparison with losartan treatment after 3 months of therapy (p = 0.02). Creatinine clearance and serum creatinine were stable during the entire study period in all patients. No significant changes in lipids, serum uric acid or protein levels were observed. CONCLUSIONS: These results indicate that proteinuria is reduced by low doses of losartan or enalapril. The combination of these drugs seems to be beneficial and may offer an additional renoprotective effect. This needs to be confirmed in a study with a larger sample size.     

Angiotensin converting enzyme inhibitors for reduction of proteinuria in children with steroid-resistant nephrotic syndrome

The effects of angiotensin converting enzyme inhibitors (ACEI) on proteinuria, renal function, and serum proteins were evaluated in six children with steroid-resistant nephrotic syndrome and proteinuria of 3–15 g/24h (277±47 mg/m² per hour). Following ACEI, proteinuria decreased from 7,408±2,385 (mean±SEM) to 3,746±1,395 mg/24 h (P<0.05). Creatinine clearance was 87.8±22.6 before and 96.4±23.6 ml/min per 1.73 m² after ACEI. In two patients, inulin and para-aminohippuric acid clearances were normal before and after ACEI, together with parallel reductions of urine protein of 50% and 46%. Clearance of total protein was reduced by 56% following ACEI, compared with reduction in the clearance of gamma globulin by 58% and albumin by 39.5%. No significant change was seen in blood pressure, serum albumin, or total protein following ACEI. After ACEI, diuretic doses were able to be reduced or eliminated in three patients. Reduction of proteinuria was sustained during a followup period of 11–20 months in three patients. ACEI may be of benefit in the clinical management of children with steroidresistant nephrotic syndromes, allowing reduction in diuretic requirements.     

Effects of nifedipine and enalapril on glomerular structure and function in uninephrectomized SHR

Spontaneously hypertensive rats (SHR) that underwent uninephrectomy (UNX) at six weeks of age were randomly assigned to receive no treatment, the calcium channel blocker, nifedipine, or the angiotensin converting enzyme inhibitor, enalapril. Both drugs reduced systemic blood pressure, however, blood pressure tended to be greater in rats given nifedipine than in those on enalapril. After six months, proteinuria and the relevance of glomerula sclerosis were significantly reduced in the two treated groups compared to values observed in untreated SHR. Kidney weight was also reduced by therapy, suggesting that both enalapril and nifedipine inhibited compensatory kidney growth. Micropuncture studies performed in similarly treated groups of rats, but at 11 weeks of age, revealed that PGC was elevated in untreated UNX SHR and reduced by both nifedipine and enalapril. These findings support the hypothesis that glomerular hypertension and renal hypertrophy are important risk factors for glomerular injury. They suggest that calcium blockers are as effective as angiotensin converting enzyme inhibitors in preventing progressive kidney damage.     

Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy

BACKGROUND: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. METHODS: A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM). The study consisted of five periods, each lasting two months. The patients received losartan 50 mg, losartan 100 mg, enalapril 10 mg, enalapril 20 mg, and placebo in random order. At the end of each period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined. RESULTS: Both doses of losartan and enalapril reduced albuminuria (P < 0.05) and mean arterial blood pressure (MABP; P < 0.05), whereas GFR remained stable. Albuminuria was reduced by 33% (95% CI, 12 to 51) on losartan 50 mg, 44% (95% CI, 26 to 57) on losartan 100 mg, 45% (95% CI, 23 to 61) on enalapril 10 mg, and 59% (95% CI, 39 to 72) on enalapril 20 mg, and MABP fell by 9 +/- 2, 8 +/- 2, 6 +/- 3, and 11 +/- 3 mm Hg (mean +/- SEM), respectively. No significant differences were found between the effects of losartan 100 mg and enalapril 20 mg. HbA1C and sodium intake remained unchanged throughout the study, whereas a significant rise in serum potassium occurred during ACE inhibition. CONCLUSION: The angiotensin II subtype 1 receptor antagonist, losartan, reduces albuminuria and MABP similar to the effect of ACE inhibition. These results indicate that the reduction in albuminuria and blood pressure during ACE inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy.     

Antiproteinuric effect of losartan in non-diabetic renal disease is not dependent on ACE insertion/deletion polymorphism

BACKGROUND: The antiproteinuric effect of angiotensin-converting enzyme (ACE) inhibitors appears to vary depending on the ACE insertion (I)/deletion (D) genotype in non-diabetic nephropathy. This interaction may be overcome by using an angiotensin II receptor blocker. We evaluated the short-term antiproteinuric effect of losartan according to the ACE I/D genotype in patients with non-diabetic proteinuric renal diseases. METHODS: Ninety-nine (II/ID/DD: 36/52/11) non-diabetic patients with overt proteinuria were enrolled. The patients received losartan 50 mg daily followed by 100 mg in two treatment periods each lasting 12 weeks. Clinical parameters including proteinuria were measured at baseline and at the end of each period. RESULTS: At baseline each genotype (II/ID/DD) had comparable mean arterial blood pressure (mean +/- SD) 103.2 +/- 11.1/102.7 +/- 10.6/104.1 +/- 15.3; proteinuria (geometric mean, 95% CI, mg/day) 1,839 (1,518-2,227)/1,998 (1,683-2,372)/1,613 (1,072-2,427), and creatinine clearance (ml/min/1.73 m(2)) 65.7 +/- 28.4/63.2 +/- 27.8/68.8 +/- 25.3, respectively. Both doses of losartan significantly lowered blood pressure and proteinuria (p < 0.05 vs. baseline), and losartan 100 mg was more effective than 50 mg in reducing proteinuria (52.5 +/- 29.0 vs. 40.5 +/- 30.8%, respectively, p = 0.001). No differences in the antiproteinuric effect of losartan was observed among the ACE I/D genotype. Losartan 100 mg demonstrated a comparable degree of mean arterial pressure (mean +/- SD, %) (II/ID/DD, 13.3 +/- 7.6/10.8 +/- 9.8/13.0 +/- 11.6, respectively, p = NS) and proteinuria reduction (mean, 95% CI) among the three genotypes (51.4% (40.3-62.5%)/53.4% (45.5-61.4%)/51.4% (40.0-63.8%), respectively, p = NS). CONCLUSION: Our data suggest that losartan provides a similar short-term antiproteinuric response for all three genotypes of ACE I/D genotype in non-diabetic proteinuric chronic renal disease.     

Beneficial effect of triple treatment plus immunoglobulin in experimental nephrotic syndrome

Combinations of antiproteinurics, including angiotensin I-converting enzyme inhibitors + angiotensin II receptor antagonist + statins, are promising choices in the treatment of steroid-resistant nephrotic syndrome. We aimed to investigate the effects of high doses of immunoglobulin in addition to these combinations in rats with adriamycin-induced nephrosis. The study included 40 rats allocated into five groups: control, nephrotic syndrome without treatment, dual therapy (DT) with enalapril + losartan, triple therapy (TT) with enalapril + losartan + simvastatin, and quadruple therapy (QT) with enalapril + losartan + simvastatin + a high dose of immunoglobulin. The proteinuria levels were not statistically different between DT, TT and QT groups at weeks 5, 8, 12 and 16. At week 16, serum creatinine levels in the QT group were significantly lower than those in the control, DT and TT groups. The glomerulosclerosis index in the DT group was significantly lower than in the TT and QT groups. The scores for interstitial fibrosis and TGF-β staining were similar among treatment groups. In conclusion, we showed that quadruple therapy including immunoglobulin had a beneficial effect on renal function in the late phase, but it had no additional effects in reducing proteinuria or in glomerulosclerosis score in experimental nephrotic syndrome. Further studies with angiotensin I-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists (AIIRAs) and immunoglobulin combinations would offer some benefits in the treatment of nephrotic syndrome.     

Aldosterone breakthrough during therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in proteinuric patients with immunoglobulin A nephropathy

BACKGROUND: We are investigating whether aldosterone breakthrough negatively impacts on the antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARB). METHODS: We examine the role of aldosterone breakthrough in 43 normotensive, proteinuric (0.7 +/- 0.3 g/day) outpatients (aged 41.5 +/- 10.9 years) with immunoglobulin A nephropathy (IgAN) accompanied by stable renal function (creatinine clearance >50 mL/min). The patients were treated with temocapril (1 mg; n = 14), losartan (12.5 mg; n = 16), or a combination therapy (n = 13) for 12 months. We prospectively evaluated blood pressure (BP), urinary protein excretion (UPE), biochemical parameters and the renin-angiotensin-aldosterone system before and after 12 months of treatment. RESULTS: Although the overall plasma aldosterone concentrations values did not change after any of the treatments administered for 12 months, they eventually increased in 23 (temocapril, seven patients; losartan, eight patients; combination, seven patients) of the 43 patients (53.4%; aldosterone breakthrough), and fell in the remainder (46.6%). Blood pressure and renal function did not differ among the three groups at 12 months. In contrast, UPE was significantly higher in patients with, than without aldosterone breakthrough during temocapril and losartan administration. However, combination therapy induced a more remarkable reduction in UPE regardless of aldosterone breakthrough. CONCLUSIONS: A combination of ACE inhibitors and ARB in normotensive patients with IgAN produces a more profound decrease in proteinuria than either monotherapy. This additive antiproteinuric effect is not dependent on aldosterone breakthrough. Additional larger, prospective, randomized studies will be needed for general acceptance of this strategy.     

The D-allele of the ACE gene polymorphism predicts a stronger antiproteinuric response to ACE inhibitors

SUMMARY: Angiotensin converting enzyme (ACE) inhibitors have additional renoprotective effects over other antihypertensive drugs in retarding the development and progression of diabetic and non-diabetic nephropathies. This additional beneficial effect has been attributed to their antiproteinuric action. However, individual antiproteinuric responses to ACE inhibitors vary considerably. the mechanism underlying the variable response is unresolved. the role of the insertion/deletion (I/D) polymorphism of the ACE gene in this response was examined. the case series consisted of 96 patients (69 males, median age 46.5 years) on ACE inhibitors with an initial proteinuria in excess of 1.0 g/24h. A control series consisted of 103 patients (43 males, median age 40 years) with autosomal polycystic kidney disease. A second control series consisted of 82 patients (52 males, median age 39 years) with a diagnosis of insulin-dependent diabetes mellitus (IDDM) without microalbuminuria after more than 15 years of IDDM. Angiotensin converting enzyme genotyping was performed by polymerase chain reaction (PCR) analysis of chromosomal DNA. the ACE genotype distribution (DD 44%, ID 28%, II 28%) in the case series was not in accordance with the Hardy-Weinberg equilibrium (χ²= 17.2, P<0.001), whereas it was in both control series. the difference in ACE genotype distribution between the case series and both control series combined was significant as a result of an overrepresentation of patients with the DD genotype (χ²=9.2, P=0.01). the allele frequencies were compared in patients with a reduction of proteinuria above and below the median value of 45%. the antiproteinuric effectiveness of ACEI therapy in the whole group was greater in the presence of the D-allele (OR 1.6, 95% CI 0.9-2.9). the effect of the D-allele was more pronounced in the subgroup of patients with an initial proteinuria in the non-nephrotic range (relative risk 2.8, 95%CI 1.0-8.0) and in patients not receiving diuretics (relative risk 2.3, 95% CI 1.1–4.5). In conclusion, the DD genotype seems to predispose the development of proteinuria in the presence of a kidney disorder. the presence of the D-allele predicts a stronger antiproteinuric efficacy of ACE inhibitor therapy in patients with an initial proteinuria in the non-nephrotic range and in the patients not requiring comedication with diuretics.     

Antiproteinuric efficacy of losartan in comparison with amlodipine in non-diabetic proteinuric renal diseases: a double-blind, randomized clinical trial.

BACKGROUND: Proteinuria is a significant independent determinant of the progression of chronic renal diseases. It induces an increased synthesis of angiotensin II, endothelin and profibrogenic growth factors, such as transforming growth factor-beta (TGF-beta), by mesangial and tubular cells. The antiproteinuric effect of angiotensin-converting enzyme inhibitors (ACEIs) in diabetic and non-diabetic nephropathies predicts long-term renoprotection afforded by these drugs. Angiotensin II receptor antagonists are renoprotective in patients with type 2 diabetes, but studies about their effect in non-diabetic proteinuric nephropathies are very scarce. METHODS: We randomly assigned 97 patients with non-diabetic nephropathies and proteinuria >1.5 g/24 h to treatment with losartan (50 mg daily) or amlodipine (5 mg daily) for 20 weeks. Doses of the study medications were titrated to achieve a target blood pressure <140/90 mmHg in both groups. Primary outcome was the decrease in the level of 24 h proteinuria. Secondary outcomes were changes in the plasma and urinary levels of TGF-beta. RESULTS: The baseline characteristics in both groups were similar. Proteinuria decreased by 32.4% (95% confidence interval -38.4 to -21.8%) after 4 weeks of treatment and by 50.4% (-58.9 to -40.2%) after 20 weeks in the losartan group, whereas no significant proteinuria changes were observed in the amlodipine group (P < 0.001). There was no significant correlation between the level of baseline proteinuria and the proteinuria decrease induced by losartan. Both losartan and amlodipine induced a similar and significant blood pressure reduction. Target blood pressure was achieved with the initial dose of study medication (50 mg daily) in 76% of losartan group patients and in 68% of the amlodipine group patients (5 mg daily). Urinary TGF-beta significantly decreased with losartan (-22.4% of the baseline values after 20 weeks of treatment), whereas it tended to increase with amlodipine (between-group difference P < 0.05). A significant correlation between proteinuria decrease and urinary TGF-beta reduction was found in the losartan group (r = 0.41, P < 0.005). Serum creatinine and serum potassium remained stable during the study in both groups. CONCLUSIONS: Losartan induced a drastic decrease in proteinuria accompanied by a reduction in urinary excretion of TGF-beta in patients with non-diabetic proteinuric renal diseases.     

Sickle cell nephropathy: challenging the conventional wisdom

This review explores the current model of sickle cell nephropathy and the limitations of the model. Renal abnormalities are common complications of sickle cell disease (SCD). Beginning in childhood, patients with SCD develop a urinary concentrating defect resulting in polyuria and a predisposition to nocturnal enuresis and dehydration. The current model of sickle cell nephropathy suggests that destruction of the renal medulla induces production of renal vasodilating substances that feedback to the glomerulus causing hyperfiltration. Hyperfiltration leads to glomerulosclerosis and proteinuria, with eventual reduction in kidney function. The crucial steps of vasodilating substance production and hyperfiltration in children with SCD have not been proven. Treatment of sickle cell nephropathy is aimed at the reduction of proteinuria with angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Hydroxyurea and chronic transfusion therapy may also alter the progression of sickle cell nephropathy in children. Further studies are needed to identify an accurate model and effective treatments for sickle cell nephropathy.     

Dual renin-angiotensin system blockade at optimal doses for proteinuria

BACKGROUND: The antiproteinuric effect of combining the angiotensin-converting enzyme (ACE) inhibitor lisinopril and the angiotensin II (Ang II) antagonist losartan was compared to that of the optimal antiproteinuric doses of monotherapy. METHODS: To this purpose, lisinopril and losartan were studied in 9 nondiabetic renal patients with median proteinuria 4.5 g/day (95% CI, 3.5, 6.4), creatinine clearance of 80 mL/min (95% CI, 66, 96), and mean arterial pressure (MAP) of 102 mm Hg (95% CI, 93, 112). First, in two protocols with six-week treatment periods per dose, the optimal antiproteinuric dose of each drug was established in each patient. Losartan and lisinopril were used in randomized order, each preceded by a baseline period without medication. The doses of losartan (mg/day) were 50, 100, 150, and again 50. The lisinopril doses were 10, 20, 40, and again 10. After the second protocol, patients were treated with a combination, using the optimal antiproteinuric doses established for the individual drugs. RESULTS: The antiproteinuric response by losartan was optimal at 100 mg (-46%; 95% CI, -60, -24%), being larger than at the 50 mg dose (-27%; 95% CI, -42, -4%, P < 0.05), but not different from the 150 mg dose (-46%; 95% CI, -58; -20%). Proteinuria decreased further at each up-titration step of lisinopril to -75% (95% CI, -85, -43%) at the 40 mg dose. Combination therapy reduced proteinuria more effectively (-85%; 95% CI, -96, -58) than monotherapy with losartan, and to a lesser extent than with lisinopril. Optimal blood pressure responses were obtained at similar doses. CONCLUSIONS: Dose-titration with a renin-angiotensin system blocker, followed by add-on therapy is highly effective in order to reduce proteinuria. The safety of this regimen needs to be addressed in future studies.     

Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan

There is large interindividual variability in the antiproteinuric response to blockade of the renin-angiotensin-aldosterone system (RAAS). A low-sodium diet or addition of diuretics enhances the effects of RAAS blockade on proteinuria and BP, but the efficacy of the combination of these interventions is unknown. Therefore, this randomized, double-blind, placebo-controlled trial to determine the separate and combined effects of a low-sodium diet and hydrochlorothiazide (HCT) on proteinuria and BP was performed. In 34 proteinuric patients without diabetes, mean baseline proteinuria was 3.8 g/d, and this was reduced by 22% by a low-sodium diet alone. Losartan monotherapy reduced proteinuria by 30%, and the addition of a low-sodium diet led to a total reduction by 55% and the addition of HCT to 56%. The combined addition of HCT and a low-sodium diet reduced proteinuria by 70% from baseline (all P < 0.05). Reductions in mean arterial pressure showed a similar pattern (all P < 0.05). In addition, individuals who did not demonstrate an antiproteinuric response to losartan monotherapy did respond when a low-sodium diet or a diuretic was added. In conclusion, a low-sodium diet and HCT are equally efficacious in reducing proteinuria and BP when added to a regimen containing losartan and especially seem to benefit individuals who are resistant to RAAS blockade. Combining these interventions in sodium status is an effective method to maximize the antiproteinuric efficacy of RAAS blockade.     

Association between peri‐operative angiotensin‐converting enzyme inhibitors and angiotensin‐2 receptor blockers and acute kidney injury in major elective non‐cardiac surgery: a multicentre,prospective cohort study

The peri‐operative use of angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers is thought to be associated with an increased risk of postoperative acute kidney injury. To reduce this risk, these agents are commonly withheld during the peri‐operative period. This study aimed to investigate if withholding angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers peri‐operatively reduces the risk of acute kidney injury following major non‐cardiac surgery. Patients undergoing elective major surgery on the gastrointestinal tract and/or the liver were eligible for inclusion in this prospective study. The primary outcome was the development of acute kidney injury within seven days of operation. Adjusted multi‐level models were used to account for centre‐level effects and propensity score matching was used to reduce the effects of selection bias between treatment groups. A total of 949 patients were included from 160 centres across the UK and Republic of Ireland. From this population, 573 (60.4%) patients had their angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers withheld during the peri‐operative period. One hundred and seventy‐five (18.4%) patients developed acute kidney injury; there was no difference in the incidence of acute kidney injury between patients who had their angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers continued or withheld (107 (18.7%) vs. 68 (18.1%), respectively; p = 0.914). Following propensity matching, withholding angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers did not demonstrate a protective effect against the development of postoperative acute kidney injury (OR (95%CI) 0.89 (0.58–1.34); p = 0.567).     

Angiotensin converting enzyme inhibitor-induced angioedema: a report of two cases

Angioedema is a rare but potentially fatal side effect of angiotensin converting enzyme (ACE) inhibitors. We report for the first time, two children with systemic lupus erythematosus who developed acute angioedema after the long-term use of enalapril. Prompt recognition and appropriate management of ACE-induced angioedema prevented life-threatening complications. This report highlights the potential risks of angioedema associated with the use of ACE inhibitors in children. Patients should be advised to seek medical treatment immediately if they experience swelling of the face, neck, or tongue, and especially if they have trouble breathing, speaking, or swallowing. Received: 12 March 1999 / Revised: 8 June 1999 / Accepted: 8 June 1999