José Mauro Vieira

Effect of acute kidney injury on weaning from mechanical ventilation in critically ill patients.

Objectives: Acute kidney injury (AKI) worsens outcome in various scenarios. We sought to investigate whether the occurrence of AKI has any effect on weaning from mechanical ventilation. Design and Setting: Observational, retrospective study in a 23‐bed medical/surgical intensive care unit (ICU) in a cancer hospital from January to December 2003. Patients: The inclusion criterion was invasive mechanical ventilation for ≥48 hrs. AKI was defined as at least one measurement of serum creatinine of ≥1.5 mg/dL during the ICU stay. Patients were then separated into AKI and non‐AKI patients (control group). The criterion for weaning was the combination of positive end‐expiratory pressure of ≤8 cm H2O, pressure support of ≤10 cm H2O, and Fio2 of ≤0.4, with spontaneous breathing. The primary end point was duration of weaning and the secondary end points were rate of weaning failure, total length of mechanical ventilation, length of stay in the ICU, and ICU mortality. Results: A total of 140 patients were studied: 93 with AKI and 47 controls. The groups were similar in regard to age, sex, and type of tumor. Diagnosis of acute lung injury/acute respiratory distress syndrome as cause of respiratory failure and Simplified Acute Physiology Score II at admission did not differ between groups. During ICU stay, AKI patients had markers of more severe disease: increased occurrence of severe sepsis or septic shock, higher number of antibiotics, and longer use of vasoactive drugs. The median (interquartile range) duration of mechanical ventilation (10 [6–17] vs. 7 [2–12] days, p = .017) and duration of weaning from mechanical ventilation (41 [16–97] vs. 21 [7–33.5] hrs, p = .018) were longer in AKI patients compared with control patients. Cox regression analysis demonstrated that a ≥85% increase in baseline serum creatinine (hazard rate, 2.30; 95% confidence interval, 1.30–4.08), oliguria (hazard rate, 2.51; 95% confidence interval, 1.24–5.08), and the number of antibiotics (hazard rate, 2.64; 95% confidence interval, 1.51–4.63) predicted longer duration of weaning. The length of ICU stay and ICU mortality rate were significantly greater in the AKI patients. After adjusting for Simplified Acute Physiology Score II, oliguria (odds ratio, 30.8; 95% confidence interval, 7.7–123.0) remained as a strong risk factor for mortality. Conclusion: This study shows that renal dysfunction has serious consequences in the duration of mechanical ventilation, weaning from mechanical ventilation, and mortality in critically ill cancer patients.

Cyclosporine-induced interstitial fibrosis and arteriolar TGF-β expression with preserved renal blood flow

BACKGROUND Cyclosporine A (CsA)-induced chronic nephrotoxicity is characterized by interstitial fibrosis and afferent arteriole hyalinosis. CsA lesion has been linked to maintained renal vasoconstriction and narrowing of the afferent arteriole lumen diameter, leading to preglomerular ischemia. We investigated the role of renal hemodynamics in CsA-induced transforming growth factor (TGF-beta) expression and interstitial fibrosis. METHODS Groups of rats fed a low salt diet were given CsA 5 mg/kg/day (CsA) or the vehicle (olive oil, [VH]) s.c. and had the renal blood flow (RBF), glomerular filtration rate (GFR), mean arterial pressure, renal vascular resistance, renal histologic changes, and immunohistochemical features for macrophages and TGF-beta evaluated after 1, 2, and 8 weeks of treatment. RESULTS At week 1, despite normal renal hemodynamics and MAP, there was a significant macrophage interstitial influx in CsA-treated rats (70+/-16 vs. 29+/-4 cells+/0.5 mm2, in CsA vs. VH, P=0.02) that was progressive with treatment (80+/-13 vs. 32+/-8 cells+/0.5 mm2, P=0.016 and 197+/-36 vs. 23+/-3 cells+/0.5 mm2, P=0.0002, CsA vs. VH at 2 and 8 weeks, respectively). After 2 weeks of treatment, CsA animals developed a significant interstitial fibrosis, with preserved RBF, even when it was assessed 2 hr after CsA injection. There was a significant increase in the immunostaining for TGF-beta in the juxtaglomerular arterioles in CsA-treated rats (48.6+/-3.8 vs. 35.1+/-1.1%, CsA vs. VH at 2 weeks, P<0.05 and 59.0+/-3.2 vs. 37.0+/-2.1%, CsA vs. VH at 8 weeks, P=0.0001). A significant and progressive GFR decrease followed the renal structural injury of CsA treatment. Arteriolar and glomerular anatomic injury were not found throughout the study. CONCLUSIONS Low CsA doses might generate interstitial fibrosis without any decrease in RBF or structural arteriolar lesion evidence, possibly through early macrophage influx and increased TGF-beta expression. It clearly seems that CsA-induced ischemia and tubulointerstitial injury may occur independently, suggesting that chronic CsA nephrotoxicity may be very hard to prevent or even not be preventable at all.

Statin Monotherapy Attenuates Renal Injury in a Salt-Sensitive Hypertension Model of Renal Disease

Background: Several salutary biological effects of statins have been described. We sought to investigate more closely the anti-inflammatory and antiproliferative effects of simvastatin (SIMV) in a model of hypertension and progressive renal disease, as well as its effects on the cyclin-cdk inhibitors p21 and p27. Methods: Munich-Wistar rats received the nitric oxide (NO) synthase inhibitor L-NAME (25 mg/kg/day p.o.) for 20 days accompanied by a high-salt diet (HS, 3% Na) and then were kept on HS for 60 days. Animals were then divided into two groups: vehicle (VH) or SIMV 2 mg/kg/day p.o. Albuminuria and tail-cuff pressure were determined at 30 and 60 days. RT-PCR was done to assess renal expression of TGF-β1, collagen I and III, fibronectin, p27, p21 and monocyte chemoattractant protein-1 (MCP-1). Renal protein expression was assessed by Western blot (proliferating cell nuclear antigen (PCNA)) and immunostaining (macrophage, lymphocyte, PCNA). Results: SIMV did not prevent the development of severe hypertension or albuminuria. SIMV-treated animals had less severe renal interstitial inflammation and cell proliferation. MCP-1 expression was significantly diminished in the SIMV-treated animals (55.4 ± 7.3 vs. 84.4 ± 8.2 OD, p = 0.02). mRNA renal expression for p27 and TGF-β did not change between groups, but p21 mRNA renal expression, highly induced in this model, significantly decreased with SIMV treatment (31.6 ± 6.6 vs. 50.2 ± 5.8 OD, p < 0.05). The interstitial fibrosis score significantly decreased with SIMV (2.46 ± 0.40 vs. 4.07 ± 0.38%, p < 0.01), which was confirmed by a decrease in renal collagen I and fibronectin expression. Serum cholesterol level did not change with SIMV. Conclusion: SIMV attenuated interstitial fibrosis associated with this model of hypertensive renal disease. The mechanism involved MCP-1 downregulation. SIMV treatment was also associated with a p21 downregulation in the kidney, which might be involved in the protection of renal scarring.

Role of p21 and oxidative stress on renal tubular resistance after acute ischaemic injury

BACKGROUND Subsequent ischaemic episodes may induce renal resistance. P21 is a cell cycle inhibitor that may be induced by oxygen-free radicals and may have a protective effect in ischaemic acute kidney injury (AKI). This study aimed at evaluating the role of oxidative stress and p21 on tubular resistance in a model of acquired resistance after renal ischaemia and in isolated renal tubules. METHODS Wistar rats were divided into: Group 1--sham; Group 2--sham operated and after 2 days submitted to 45-min ischaemia; and Group 3--45-min ischaemia followed after 2 days by a second 45-min ischaemia. Plasma urea was evaluated on Days 0, 2 and 4. Serum creatinine, creatinine clearance and oxidants (thiobarbituric acid-reactive substances) were determined 48 h after the second procedure (Day 4). Histology, immunohistochemistry for lymphocytes (CD3), macrophages (ED1), proliferation (PCNA) and apoptosis (TUNEL) were also evaluated. Rat proximal tubules (PTs) were isolated by collagenase digestion and Percoll gradient from control rats and rats previously subjected to 35 min of ischaemia. PTs were submitted to 15-min hypoxia followed by 45-min reoxygenation. Cell injury was assessed by lactate dehydrogenase release and hydroperoxide production (xylenol orange). RESULTS Ischaemia induced AKI in Group 2 and 3 rats. Subsequent ischaemia did not aggravate renal injury, demonstrating renal resistance (Group 3). Renal function recovery was similar in Group 2 and 3. Plasma and urine oxidants were similar among in Group 2 and 3. Histology disclosed acute tubular necrosis in Group 2 and 3. Lymphocyte infiltrates were similar among all groups whereas macrophages infiltrate was greater in Group 3. Cell proliferation was greater in Group 2 compared with Group 3. Apoptosis was similar in groups 2 and 3. The p21 expression was increased only in Group 3 whereas it was similar in groups 1 and 2. PTs from the ischaemia group were sensitive to hypoxia but resistant to reoxygenation injury which was followed by lower hydroperoxide production compared to control PT. CONCLUSION Renal resistance induced by ischaemia was associated with cell mechanism mediators involving oxidative stress and increased p21 expression.

Early Brief Treatment with Losartan plus Mycophenolate Mofetil Provides Lasting Renoprotection in a Renal Ablation Model

Background: Inflammatory events antecede established renal injury in rats with 5/6 renal ablation (Nx), as indicated by the beneficial effects of early, uninterrupted treatment with mycophenolate mofetil (MMF). Angiotensin II also exerts a major pathogenic role at this initial phase. We investigated whether losartan (L) or L+MMF treatment, started early, and L+MMF treatment, started late, would exert lasting renoprotection in Nx even after being discontinued. Methods: Adult male Munich-Wistar rats underwent Nx and were divided into three groups: Nx (untreated), NxL (given L), and NxLMMF (given L and MMF). Protocol 1: treatments began on day 1, and ceased on day 30, after Nx. Protocol 2: L+MMF treatment began on day 30 and ceased on day 60. Results: Protocol 1: on day 30, hypertension, albuminuria and renal injury were strongly attenuated in Groups NxL and NxLMMF. On day 120, these abnormalities were still attenuated in group NxLMMF. Protocol 2: on day 120, all parameters were similar between this late NxLMMF group and untreated Nx. Conclusion: In Nx, temporary suppression of early, transitory hemodynamic/inflammatory phenomena affords relatively durable renoprotection even after treatment discontinuation. This effect is not obtained with similar temporary treatment initiated later in the course of renal disease.

Acute effects of intermittent hemodialysis and sustained low-efficiency hemodialysis (SLED) on the pulmonary function of patients under mechanical ventilation.

The effects of hemodialysis (HD) on pulmonary function are still controversial. The objective of this study was to evaluate the effect of intermittent hemodialysis (IHD) and sustained low-efficiency dialysis (SLED) on the respiratory mechanics of ICU patients under invasive mechanical ventilation. We prospectively studied 31 patients. Laboratory and respiratory evaluation (static and dynamic compliance and resistance) was performed pre- and post-HD. Forty HD sessions were studied and grouped in: SLED (n = 17; Qa = 200–250 mL/min, Qd = 300 mL/min) and IHD (n = 23; Qa = 250–300 mL/min, Qd = 500 mL/min). There was no difference between the groups according to age, gender, comorbidities, APACHE II, and cause of mechanical ventilation, but pre-HD, patients in the IHD group had higher levels of plasma creatinine (5.4 ± 2.0 vs. 4.2 ± 1.3 mg/dL, p = 0.048) and platelets (286 ± 186 vs. 174 ± 95 103/mm2, p = 0.032) and lower arterial pH (7.37 ± 0.07 vs. 7.42 ± 0.05, p = 0.02). The efficiency of the treatment was similar (p > 0.05) with both types of HD regarding fluid removal, urea reduction rate, and decrease in plasma creatinine. Pre-HD, the ventilatory conditions of both groups were similar (p > 0.05) except for pressure support ventilation and airflow resistance. There were no changes (pre- versus post-HD p > 0.05) induced either by IHD or SLED in the ratio PaO2/FiO2 or in any measured ventilatory parameter. In conclusion, neither IHD nor SLED modifies the pulmonary function of patients under mechanical ventilation.