Effects of pre and post-treatments with dipyridamole in gentamicin-induced acute nephrotoxicity in the rat.

This study investigated the pretreatment and post-treatment effects of dipyridamole (20 mg/kg/day, p.o.) in gentamicin-induced acute nephrotoxicity in rats. Rats were administered gentamicin (100 mg/kg/day, i.p.) for 8 days. Gentamicin-administered rats exhibited renal structural and functional changes as assessed in terms of a significant increase in serum creatinine and urea and kidney weight to body weight ratio as compared to normal rats. Renal histopathological studies revealed a marked incidence of acute tubular necrosis in gentamicin-administered rats. These renal structural and functional abnormalities in gentamicin-administered rats were accompanied with elevated serum uric acid level, and renal inflammation as assessed in terms of decrease in interleukin-10 levels. Dipyridamole pretreatment in gentamicin-administered rats afforded a noticeable renoprotection by markedly preventing renal structural and functional abnormalities, renal inflammation and serum uric acid elevation. On the other hand, dipyridamole post-treatment did not significantly prevent uric acid elevation and renal inflammation, and resulted in comparatively less protection on renal function although it markedly reduced the incidence of tubular necrosis. In conclusion, uric acid elevation and renal inflammation could play key roles in gentamicin-nephrotoxicity. Dipyridamole pretreatment markedly prevented gentamicin-induced acute nephrotoxicity, while its post-treatment resulted in comparatively less renal functional protection.

Renal biopsy in patients over 75: 131 cases.

INTRODUCTION: Demographic analysis shows the ageing of the global population and the consequent increase in the age of hospitalized subjects and of patients starting dialysis. Hence, interest in the feasibility, safety, and usefulness of renal biopsy in elderly patients is growing. We examined the data of 131 patients over the age of 75 who underwent renal biopsy. We analyzed the safety of the procedure, treatment, and outcomes. RESULTS: Histological diagnoses included: membranous glomerulonephritis (GN) 20.6%, crescentic GN 12.9%, IgAGN 10.6%, focal segmental glomerulosclerosis 9.1%, acute GN 4.5%, amyloidosis 9.1%, and acute tubular necrosis 3.8%. Mean glomerular obsolescence was 28.9 Â ± 27.9%. Mean age of the patients was 78.7 Â ± 5.73 years. At the time of biopsy, serum creatinine (SCr) was 4.47 Â ± 2.56 mg/dL and proteinuria was 4.82 Â ± 6.78 g/day. Targeted treatment was given to 51.9% of patients, 52.9% of whom had a good clinical response. Eight patients had clinically non-relevant side effects (11.7%). A positive response (defined as a more than 50% reduction of SCr, or by partial or complete remission of proteinuria) was observed in 36 patients (52.9%). 76 patients were monitored for 57 Â ± 9.89 months: 18 patients were on dialysis (follow-up 2.56 Â ± 3.61 months), 15 died (follow-up 58.5 Â ± 13.43 months), and 52 remained under nephrologic observation for 36 Â ± 31 months (SCr was 2.56 Â ± 0.75 mg/dL and proteinuria was 4.82 Â ± 6.78 g/day). CONCLUSION: In our experience, renal biopsy is safe even in very elderly patients; it allowed targeted treatment in 51.9% of patients, 52.9% of whom had a good clinical response, possibly contributing to prolonged patient survival and improved quality of life.

Mannitol has no impact on renal function after open partial nephrectomy in solitary kidneys.

Mannitol has been administered during partial nephrectomy as a renal protective agent for ischemic damage. However, we do not have any high-level clinical evidence of its effectiveness. The aim of the present study was to evaluate the effect of mannitol during open partial nephrectomy by comparing the postoperative renal function of patients who received it and those who did not. We retrospectively reviewed the records of 55 patients who underwent open partial nephrectomy for renal cancer in a solitary kidney from January 1990 to December 2012, and who were followed up postoperatively for at least 6 months. Of the 55 patients, mannitol was given to 20 patients (group M+) and not to the other 35 patients (group M-). We compared not only the postoperative estimated glomerular filtration rate, but also its decrease rate and the incidence of acute kidney injury requiring dialysis in the two groups. There were no significant differences in perioperative patient characteristics between the two groups. Mannitol made no significant difference in both the postoperative estimated glomerular filtration rate and its decrease rate at any point within 6 months of the postoperative period. The incidence of acute kidney injury requiring dialysis was one (5.0%) in group M+ and two (5.7%) in group M-. These findings suggest that there might be no advantage from the administration of mannitol during open partial nephrectomy.

Identification of agents that reduce renal hypoxia-reoxygenation injury using cell-based screening: purine nucleosides are alternative energy sources in LLC-PK1 cells during hypoxia.

Acute tubular necrosis is a clinical problem that lacks specific therapy and is characterized by high mortality rate. The ischemic renal injury affects the proximal tubule cells causing dysfunction and cell death after severe hypoperfusion. We utilized a cell-based screening approach in a hypoxia-reoxygenation model of tubular injury to search for cytoprotective action using a library of pharmacologically active compounds. Oxygen-glucose deprivation (OGD) induced ATP depletion, suppressed aerobic and anaerobic metabolism, increased the permeability of the monolayer, caused poly(ADP-ribose) polymerase cleavage and caspase-dependent cell death. The only compound that proved cytoprotective either applied prior to the hypoxia induction or during the reoxygenation was adenosine. The protective effect of adenosine required the coordinated actions of adenosine deaminase and adenosine kinase, but did not requisite the purine receptors. Adenosine and inosine better preserved the cellular ATP content during ischemia than equimolar amount of glucose, and accelerated the restoration of the cellular ATP pool following the OGD. Our results suggest that radical changes occur in the cellular metabolism to respond to the energy demand during and following hypoxia, which include the use of nucleosides as an essential energy source. Thus purine nucleoside supplementation holds promise in the treatment of acute renal failure.

Protective and therapeutic effects of licorice in rats with acute tubular necrosis.

OBJECTIVES: Various protective and therapeutic effects such as antioxidant, anti-inflammatory, anticancer, antihistaminic, and antibacterial effects have been depicted for licorice. However, its biological effects in the kidney are still not clear. Therefore, we aimed to investigate the efficiency of licorice in rats with gentamicin (GM)-induced acute tubular necrosis. DESIGN AND METHODS: Rats were randomized into the control group (only saline for 12 days), licorice group (licorice for 12 days), GM group (GM for 12 days), GM + licorice group, and licorice-treated GM group (licorice for 12 days after taking GM for 12 days). Blood urea, creatinine, and uric acid levels were measured and histopathological analyses of the kidneys were performed. The oxidative side of oxidant-antioxidant balance was evaluated by detecting lipid peroxidation (LPO) and total peroxide levels, and antioxidative side was determined by measuring total antioxidant capacity (TAC) and reduced glutathione (GSH) levels in plasma and kidney tissues. RESULTS: The oxidant-antioxidant balance seemed to be shifted to the oxidative side in the GM group when compared with the control and GM + licorice groups. In GM group, biochemical profiles showed a remarkable increase in blood uric acid, urea, and creatinine levels, and depletion of renal tissue and plasma TAC and GSH levels. In addition, histopathologic studies revealed severe acute tubular necrosis, congestion, and hyaline casts, verifying GM-induced nephrotoxicity. Licorice was effective in reduction of blood urea, creatinine, and uric acid levels, and also effective in decreasing the tubular necrosis score. Licorice treatment also significantly reduced LPO and total peroxide levels, and increased TAC and GSH levels in both renal tissue and blood. Moreover, these changes in rats subjected to the combined therapy (GM + licorice) were significantly less than those of GM group. CONCLUSIONS: Licorice ameliorates GM-induced nephrotoxicity and oxidative damage by scavenging oxygen free radicals, decreasing LPO, and improving antioxidant defense.

Luteolin ameliorates cisplatin-induced acute kidney injury in mice by regulation of p53-dependent renal tubular apoptosis.

BACKGROUND: Cisplatin chemotherapy often causes acute kidney injury in cancer patients. The causative mechanisms of cisplatin-induced acute kidney injury include renal inflammation, activation of p53 tumour suppressor protein and tubular apoptosis. Luteolin, a flavone found in medicinal herbs and plants, has been reported to exhibit anti-inflammatory, antioxidant and anticarcinogenic activities. The purpose of this study was to investigate the anti-apoptotic effect of luteolin on cisplatin-induced acute kidney injury and the molecular mechanism. METHODS: C57BL/6 mice were treated with cisplatin (20 mg/kg) with or without treatment with luteolin (50 mg/kg for 3 days). Renal function, histological changes, degree of oxidative stress and tubular apoptosis were examined. The effects of luteolin on cisplatin-induced expression of renal p53, PUMA-α and Bcl-2 family proteins were evaluated. RESULTS: Treatment of mice with cisplatin resulted in renal damage, showing an increase in blood urea nitrogen and creatinine levels, tubular damage, oxidative stress and apoptosis. Treatment of cisplatin-treated mice with luteolin significantly improved renal dysfunction, reducing tubular cell damage, oxidative stress and apoptosis. Examination of molecules involving apoptosis of the kidney revealed that treatment of cisplatin increased the levels of p53 and its phosphorylation, PUMA-α, Bax and caspase-3 activity that were significantly decreased by treatment with luteolin. CONCLUSION: These results indicate that cisplatin induces acute kidney injury by regulation of p53-dependent renal tubular apoptosis and that luteolin ameliorates the cisplatin-mediated nephrotoxicity through down-regulation of p53-dependent apoptotic pathway in the kidney.

Low-dose darbepoetin alpha attenuates progression of a mouse model of aristolochic acid nephropathy through early tubular protection.

BACKGROUND/AIM: Aristolochic acid (AA) nephropathy, first reported as Chinese herbs nephropathy, is a rapidly progressive tubulointerstitial nephropathy that results in severe anemia, interstitial fibrosis and end-stage renal disease. Tubulointerstitial injury was studied in a mouse model of AA nephropathy to determine whether low-dose darbepoetin alpha (DPO) treatment prevents acute tubular necrosis and interstitial fibrosis. METHODS: AA was administered to C3H/He mice intraperitoneally and some mice were also treated with 0.1 microg/kg of DPO weekly starting on the day of AA administration or on day 28. At 28, 56 or 84 days, blood and urine samples were collected and mice were sacrificed for histological assessment of the kidneys. RESULTS: AA-treated mice developed anemia, elevation of serum creatinine, severe tubular injury similar to acute tubular necrosis and progressive interstitial fibrosis. Although early treatment with low-dose DPO had minimal effects on the hematocrit, it significantly ameliorated acute tubular injury and interstitial inflammation through increasing the survival of tubular cells. As a result, it contributed to preservation of peritubular capillaries and reduction of interstitial fibrosis. CONCLUSION: Low-dose DPO treatment conferred protection against acute tubular damage and attenuated interstitial fibrosis in a mouse model of AA nephropathy. Early administration of low-dose DPO may prevent the progression of acute tubular necrosis and the subsequent renal fibrosis in human AA nephropathy.

Atorvastatin prevents gentamicin-induced renal damage in rats through the inhibition of p38-MAPK and NF-kappaB pathways.

BACKGROUND AND AIMS: Gentamicin (GM) is still considered to be an important antibiotic against life-threatening, gram-negative bacterial infections despite its known nephrotoxic effects. We aimed to evaluate the potential protective effect of atorvastatin (ATO) against GM-induced nephrotoxicity in rats. MATERIALS AND METHODS: The rats were randomly divided into five groups of six animals each: control, GM (100 mg/kg/day), ATO (10 mg/kg/day), GM + ATO, and GM + Vehicle. Kidney function tests, tissue oxidative stress parameters, and histopathological and immunohistochemical studies clarified GM nephrotoxicity. RESULTS: GM caused a marked reduction in renal functions and increased oxidative stress parameters. Histopathological examination revealed tubular necrosis especially in the renal cortex in GM rats. On immunohistochemical evaluation, GM rat showed more intense expressions of mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-kappaB), and inducible nitric oxide synthase (iNOS) compared with control. Kidney function tests and tissue oxidative stress parameters were normalized in the GM + ATO group. Histopathological and immunohistochemical pictures were also greatly ameliorated. CONCLUSIONS: ATO acts in the kidney as a potent scavenger of free radicals to prevent the toxic effects of GM via the inhibition of MAPK and NF-kappaB signaling pathways and iNOS expression.

Angiopoietin-1 therapy enhances fibrosis and inflammation following folic acid-induced acute renal injury.

The loss of interstitial capillaries is a feature of several experimental models of renal disease and this contributes to secondary kidney injury. Angiopoietin-1 is a secreted growth factor which binds to Tie-2 present on endothelia to enhance cell survival thereby stabilizing capillary architecture in-vitro. Previous studies showed that angiopoietin-1 prevented renal capillary and interstitial lesions following experimental ureteric obstruction. We tested here the effect of angiopoietin-1 treatment on capillary loss and associated tubulointerstitial damage known to follow recovery from folic acid-induced tubular necrosis and acute renal injury. We found that delivery of angiopoietin-1 by adenoviral vectors stabilized peritubular capillaries in folic acid nephropathy but this was accompanied by profibrotic and inflammatory effects. These results suggest that the use of endothelial growth factor therapy for kidney disease may have varying outcomes that depend on the disease model tested.

[Wenyang Huoxue Recipe up-regulates the expression of angiopoietin-1 mRNA in rats with chronic aristolochic acid nephropathy].

OBJECTIVE: To investigate the effects of Wenyang Huoxue Recipe (WRHXR), a compound traditional Chinese herbal medicine for warming yang and promoting blood flow, on the expression of angiopoietin mRNA in rats with chronic aristolochic acid nephropathy induced by Caulis Aristolochia Manshuriensis (CAM) decoction, and to explore the protection mechanism of WYHXR against kidney damage. METHODS: Twenty-eight male SD rats were randomly divided into normal control group, CAM group and WYHXR-treated group. Rats in the normal control group (n=8) and CAM group (n=10) were intragastrically administered with normal saline 10 ml/(kg.d) or CAM decoction 10 ml/(kg.d) respectively. Rats in the WYHXR-treated group (n=10) were intragastrically administered with WYHXR 30 g/(kg.d) and CAM decoction 10 ml/(kg.d). The expressions of Ang-l and Ang-2 mRNAs were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) after 20-week treatment. RESULTS: Compared with the normal control group, the expression of Ang-l mRNA was significantly decreased, and the expression of Ang-2 mRNA was significantly increased in the CAM group (P<0.01). Compared with the CAM group, the expression of Ang-l mRNA was increased in the WYHXR-treated group (P<0.01). The expression of Ang-2 mRNA had no significant difference between the CAM group and the WYHXR-treated group (P>0.05). Renal pathology showed that renal damage in WYHXR-treated group was significantly reduced as compared with the CAM group. CONCLUSION: WYHXR can up-regulate the expression of Ang-l mRNA, which may be its action mechanism in protecting the kidneys.

Targeting of regulated necrosis in kidney disease.

The term acute tubular necrosis was thought to represent a misnomer derived from morphological studies of human necropsies and necrosis was thought to represent an unregulated passive form of cell death which was not amenable to therapeutic manipulation. Recent advances have improved our understanding of cell death in acute kidney injury. First, apoptosis results in cell loss, but does not trigger an inflammatory response. However, clumsy attempts at interfering with apoptosis (e.g. certain caspase inhibitors) may trigger necrosis and, thus, inflammation-mediated kidney injury. Second, and most revolutionary, the concept of regulated necrosis emerged. Several modalities of regulated necrosis were described, such as necroptosis, ferroptosis, pyroptosis and mitochondria permeability transition regulated necrosis. Similar to apoptosis, regulated necrosis is modulated by specific molecules that behave as therapeutic targets. Contrary to apoptosis, regulated necrosis may be extremely pro-inflammatory and, importantly for kidney transplantation, immunogenic. Furthermore, regulated necrosis may trigger synchronized necrosis, in which all cells within a given tubule die in a synchronized manner. We now review the different modalities of regulated necrosis, the evidence for a role in diverse forms of kidney injury and the new opportunities for therapeutic intervention.

Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury.

Several lines of evidence have demonstrated the anti-inflammatory and cytoprotective effects of alpha-1-antitrypsin (AAT), the major serum serine protease inhibitor. The aim of the present study was to investigate the effects of human AAT (hAAT) monotherapy during the early and recovery phase of ischemia-induced acute kidney injury. Mild renal ischemia-reperfusion (I/R) injury was induced in male C57Bl/6 mice by bilateral clamping of the renal artery and vein for 20 min. hAAT (80 mg/kg, Prolastin®) was administered daily intraperitoneally (i.p.) from day -1 until day 7 after surgery. Control animals received the same amount of human serum albumin (hAlb). Plasma, urine and kidneys were collected at 2h, 1, 2, 3, 8 and 15 days after reperfusion for histological and biochemical analysis. hAAT partially preserved renal function and tubular integrity after induction of bilateral kidney I/R injury, which was accompanied with reduced renal influx of macrophages and a significant decrease of neutrophil gelatinase-associated lipocalin (NGAL) protein levels in urine and plasma. During the recovery phase, hAAT significantly decreased kidney injury molecule-1 (KIM-1) protein levels in urine but showed no significant effect on renal fibrosis. Although the observed effect size of hAAT administration was limited and therefore the clinical relevance of our findings should be evaluated carefully, these data support the potential of this natural protein to ameliorate ischemic and inflammatory conditions.

Ischemic acute tubular necrosis models and drug discovery: a focus on cellular inflammation.

Acute renal failure (ARF) is a common cause of mortality and morbidity in hospitalized patients. Ischemia is an important cause of ARF, and ARF caused by ischemic injury is referred to as ischemic acute tubular necrosis (ATN). There is growing evidence from models that ischemic ATN is associated with intrarenal inflammation. Consequently, intrarenal inflammation is an attractive target for the development of novel drug therapies for ARF. This review outlines ischemic ATN models, the pathophysiological roles of inflammatory cells such as T and B cells in ischemic ATN models, and effective T and B cell therapeutic reagents.

NF-κB transcriptional inhibition ameliorates cisplatin-induced acute kidney injury (AKI).

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) cell signaling pathway is important in inflammation and cell survival. Inflammation and cell death in the kidney are features of cisplatin-induced AKI. While it is known that cisplatin induces NF-κB signaling in the kidney, the NF-κB responsive genes and the effect of direct NF-κB transcriptional inhibition in cisplatin-induced AKI is not known. Mice injected with cisplatin, 25mg/kg, developed AKI, acute tubular necrosis (ATN) and apoptosis on day 3. Mice were treated with JSH-23 (20 or 40 mg/kg) which directly affects NF-κB transcriptional activity. Kidney function, tubular injury (ATN, serum neutrophil gelatinase-associated lipocalin [NGAL], but not apoptosis) and myeloperoxidase (MPO) activity were significantly improved by JSH-23 (40 mg/kg). Sixty one NF-κB responsive genes were increased by cisplatin of which 21 genes were decreased by JSH-23. Genes that were decreased by JSH-23 that are known to play a role in cisplatin-induced AKI were IL-10, IFN-γ, chemokine [C-C motif] ligand 2 (CCL2) and caspase-1. Another gene, caspase recruitment domain family, member 11 (CARD11), not previously known to play a role in AKI, was increased more than 20-fold and completely inhibited by JSH-23. CXCL1 and TNF-α, known mediators of cisplatin-induced AKI, were decreased by JSH-23. RIPK1 and 3, receptor-interacting serine/threonine-protein kinases, that play an important role in necroptosis, were decreased by JSH-23. In mouse proximal tubule cells in culture, JSH-23 resulted in an increase in apoptosis suggesting that the mechanism of protection against AKI by JSH-23 is not due to a direct effect on proximal tubules. In conclusion, NF-κB transcriptional inhibition in cisplatin-induced AKI ameliorates kidney function and ATN without a significant effect on apoptosis and is associated with a decrease pro-inflammatory mediators and CARD11.

Carnitine palmitoyltransferase II deficiency due to a novel gene variant in a patient with rhabdomyolysis and ARF.

Adult patients deficient in carnitine palmitoyltransferase II (CPT II) cannot generate sufficient amounts of energy, which results in rhabdomyolysis and acute renal failure (ARF). Its genetic basis has been recognized; but histopathologic changes, especially electron microscopic changes, have scarcely been described. The study subject is a patient with ARF caused by repetitive nontraumatic rhabdomyolysis. The acylcarnitine profile of serum and enzyme assay on skin fibroblasts confirmed the diagnosis of CPT II deficiency. Renal biopsy specimens were examined microscopically and immunohistochemically. The histological diagnosis was interstitial nephritis with acute tubular necrosis caused by rhabdomyolysis. Myoglobin in tubules was detected by means of immunohistochemistry and electron microscopy. The genetic structure of CPT II was analyzed in the patient and his family. Eight pairs of polymerase chain reaction (PCR) primers were designed to cover the coding region. Each PCR-amplified gene product was subjected to DNA sequencing, which unveiled heterozygosity at the CPT II locus consisting of a deletion of cytosine and thymine at codon 408, resulting in a stop signal at 420, as well as a mutation of arginine to cysteine at codon 631. The frame shift at 408 has never been described before. DNA sequencing of the family showed the deletion mutation from the mother and the point mutation from the father. We describe renopathological findings in a patient with CPT II deficiency associated with rhabdomyolysis, which suggested the pathological role of myoglobin casts in the development of tubular necrosis. Genetic analysis of the patient identified a novel variant of the CPT II gene.

Fenoldopam mesylate in early acute tubular necrosis: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Acute tubular necrosis (ATN) occurs commonly in critically ill patients and is associated with increased morbidity and mortality. Fenoldopam is a dopamine receptor alpha1-specific agonist that increases renal blood flow in patients with kidney failure. We hypothesized that administration of low-dose fenoldopam during early ATN would decrease the need for dialysis therapy and/or incidence of death at 21 days. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, clinical trial in 155 patients with early ATN. Patients were considered eligible for enrollment if serum creatinine level increased to 50% greater than admission levels within 24 hours and mean arterial pressure was greater than 70 mm Hg. Patients were randomly assigned to the administration of placebo or fenoldopam for 72 hours. RESULTS: Overall, 22 of 80 patients (27.5%) in the fenoldopam group reached the primary end point compared with 29 of 75 patients (38.7%) in the placebo group (P = 0.235). This 11% absolute reduction in the primary end point was not statistically significant (P = 0.23). Similarly, there was no difference in the incidence of dialysis therapy between patients randomly assigned to fenoldopam (13 of 80 patients; 16.25%) versus the placebo group (19 of 75 patients; 25.3%; P = 0.163). Moreover, there was no statistically significant difference in 21-day mortality rates between the 2 groups (fenoldopam, 13.8% versus placebo, 25.3%; P = 0.068). In secondary analyses, fenoldopam tended to reduce the primary end point in patients without diabetes and postoperative cardiothoracic surgery patients with early ATN (fenoldopam patients without diabetes, 14 of 54 patients [25.9%] versus placebo patients without diabetes, 23 of 52 patients [44.2%]; P = 0.048) and postoperative cardiothoracic patients (6 of 34 patients [17.6%] versus 14 of 36 patients [38.8%]; P = 0.049). Conversely, fenoldopam did not improve the primary end point in patients with diabetes or those with acute renal failure from other causes. A larger multicenter trial using separate randomizations for patients with and without diabetes will be needed to determine the efficacy of fenoldopam mesylate in specific subpopulations with ATN. CONCLUSION: Fenoldopam does not reduce the incidence of death or dialysis therapy in intensive care unit patients with early ATN.

Acetaminophen-induced anion gap metabolic acidosis and 5-oxoprolinuria (pyroglutamic aciduria) acquired in hospital.

A rare cause of high anion gap acidosis is 5-oxoproline (pyroglutamic acid), an organic acid intermediate of the gamma-glutamyl cycle. Acetaminophen and several other drugs have been implicated in the development of transient 5-oxoprolinemia in adults. We report the case of a patient with lymphoma who was admitted for salvage chemotherapy. The patient subsequently developed fever and neutropenia and was administered 20.8 g of acetaminophen during 10 days. During this time, anion gap increased from 14 to 30 mEq/L (14 to 30 mmol/L) and altered mental status developed. After usual causes of high anion gap acidosis were ruled out, a screen for urine organic acids showed 5-oxoproline levels elevated at 58-fold greater than normal values. Predisposing factors in this case included renal dysfunction and sepsis. Clinicians need to be aware of this unusual cause of anion gap acidosis because it may be more common than expected, early discontinuation of the offending agent is therapeutic, and administration of N -acetylcysteine could be beneficial.

Basiliximab (Simulect) in acute tubular necrosis high-risk kidney transplantation.

BACKGROUND: Basiliximab (Simulect) therapy reduces acute rejection episodes in renal transplantation. Posttransplant acute tubular necrosis (ATN) is a predisposing factor for acute rejection and reduced graft survival. Anti-lymphocyte antibodies have been used to delay the use of calcineurin antagonists in patients receiving cadaveric renal transplants and to prevent acute rejection episodes. The aim of our study was to learn about the effects of Simulect on ATN in high-risk cadaveric renal transplantation recipients. MATERIALS AND METHODS: We studied 93 patients including, 45 who received Simulect (20 mg before transplantation and 20 mg at day 4 posttransplant and 48 patients who did not receive Simulect. All patients received mycophenolate mofetil, steroids, and cyclosporine (46%) or tacrolimus (54%). We defined ATN as the need for dialysis during the first week after transplantation. Risk factors for ATN were: cold ischemia time, donor and recipient age, donor cause of death as stroke, HLA matching, and panel-reactive antibodies. RESULTS: Among 54 patients who experienced ATN, 44% were in the Simulect group and 71% in the other group (P = .01). In the regression analysis, Simulect was shown to be a protective factor: 0.19 (0.05 to 0.62). Presence of de novo diabetes was more frequent in the group that did not receive Simulect (16 [33%] vs 6 [13%]; P = .02). Acute rejection episodes were similar in both groups: 2.5% in the Simulect group versus 4% in the other group (P = .34). CMV infections occurred in 15 patients (33%) from the Simulect group and in 20 patients (42%) in the other group. Seven patients died in the Simulect group, and five patients died in the other group. In general, Simulect was well tolerated and the degree of complications was similar in both groups. CONCLUSION: Simulect reduced the incidence of ATN among patients receiving a high-risk renal graft. It was well tolerated and no adverse effects were observed. The use of Simulect should be considered for patients receiving renal grafts at high risk for ATN.

Cause of acute tubular necrosis affects its prognosis. The Auriculin Anaritide Acute Renal Failure Study Group.

BACKGROUND: Acute tubular necrosis (ATN) is the most common type of acute renal failure in hospitalized patients and is associated with a high morbidity and mortality. The cause of ATN can be divided into nephrotoxic, ischemic, or mixed. OBJECTIVE: To test the hypothesis that the cause of ATN affects its clinical outcome. METHODS: The study compares clinical outcomes of patients enrolled in the placebo arm of a multicenter, randomized, double-blinded, placebo-controlled trial of anaritide (Auriculin, synthetic atrial natriuretic peptide, Scios, Mountain View, Calif) in patients with well-defined ATN. Patients were divided prospectively into groups according to the cause of ATN: pure nephrotoxic, pure ischemic, or mixed nephrotoxic and ischemic. Outcomes of interest were dialysis-free survival and all-cause mortality on day 14 and day 21. The causal groups were compared with respect to the prevalence of several comorbidities suspected of affecting the clinical outcomes. RESULTS: Mortality was 10% in the nephrotoxic group and 30% in the ischemic group on day 21. Dialysis-free survival was 66% in the nephrotoxic group and 41% in the ischemic group on day 21. Outcomes in the mixed and ischemic groups were similar. Compared with the nephrotoxic group, there was a significantly higher prevalence of cardiogenic shock, hypotension, sepsis, and respiratory failure and a tendency toward a higher prevalence of acute hepatic dysfunction in the ischemic group. Diabetes mellitus was more prevalent in the nephrotoxic group. Among patients with ischemic ATN, dialysis-free survival improved significantly and mortality tended to decline with advancing age. CONCLUSIONS: Among patients with ATN, those in whom renal ischemia was causative had significantly higher mortality and lower dialysis-free survival than those whose ATN was purely nephrotoxic in origin. This difference in clinical outcomes was associated with a higher prevalence of serious commorbidities in the ischemic ATN group. Advancing age was associated with improved dialysis-free survival and a tendency toward reduced mortality in patients with ischemic ATN.

Renoprotective effects of gamma-aminobutyric acid on cisplatin-induced acute renal injury in rats.

To investigate the effect of gamma-aminobutyric acid (GABA) on acute renal injury (ARI), we used here a rat model of acute tubular necrosis induced by the anticancer drug cisplatin (CP). GABA was given orally (100 or 500 mg/kg/day for ten consecutive days), and on the 6th day, some of the treated rats were also injected intraperitoneally with either saline or CP (6 mg/kg). Four days after CP treatment, urine was collected from all rats, which were then anaesthetized for blood pressure and renal blood flow monitoring. This was followed by intravenous injection of norepinephrine for the assessment of renal vasoconstrictor responses. Thereafter, blood and kidneys were collected for measurement of several functional, biochemical and structural parameters. GABA treatment (at 500 but not 100 mg/kg) significantly mitigated all the measured physiological and biochemical indices. Sections from saline- and GABA-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with GABA (500 mg/kg). The concentration of platinum in the cortical tissues was not significantly altered by GABA treatment. The results suggested that GABA can ameliorate CP nephrotoxicity in rats. Pending further pharmacological and toxicological studies, GABA may be considered a potentially useful nephroprotective agent in CP-induced ARI.