Vitamin C Deficiency Causes Cell Type-Specific Epigenetic Reprogramming and Acute Tubular Necrosis in a Mouse Model.

BACKGROUND: Vitamin C deficiency is found in patients with variable kidney diseases. However, the role of vitamin C as an epigenetic regulator in renal homeostasis and pathogenesis remains largely unknown. METHODS: We showed that vitamin C deficiency leads to acute tubular necrosis (ATN) using a vitamin C-deficient mouse model (Gulo knock-out). DNA/RNA epigenetic modifications and injured S3 proximal tubule cells were identified in the vitamin C-deficient kidneys using whole-genome bisulfite sequencing, methylated RNA immunoprecipitation sequencing, and single-cell RNA sequencing. RESULTS: Integrated evidence suggested that epigenetic modifications affected the proximal tubule cells and fenestrated endothelial cells, leading to tubule injury and hypoxia through transcriptional regulation. Strikingly, loss of DNA hydroxymethylation and DNA hypermethylation in vitamin C-deficient kidneys preceded the histologic sign of tubule necrosis, indicating the causality of vitamin C-induced epigenetic modification in ATN. Consistently, prophylactic supplementation of an oxidation-resistant vitamin C derivative, ascorbyl phosphate magnesium, promoted DNA demethylation and prevented the progression of cisplatin-induced ATN. CONCLUSIONS: Vitamin C played a critical role in renal homeostasis and pathogenesis in a mouse model, suggesting vitamin supplementation may be an approach to lower the risk of kidney injury.

Oral acyclovir induced hypokalemia and acute tubular necrosis a case report.

BACKGROUND: Acyclovir is one of the most common prescribed antiviral drugs. Acyclovir nephrotoxicity occurs in approximately 12-48% of cases. It can present in clinical practice as acute kidney injury (AKI), crystal-induced nephropathy, acute tubulointerstitial nephritis, and rarely, as tubular dysfunction. Electrolytes abnormalities like hypokalemia, were previously described only when given intravenously. CASE PRESENTATION: A 54 year-old female presented with weakness and lower extremities paresis, nausea and vomiting after receiving oral acyclovir. Physical examination disclosed a decrease in the patellar osteotendinous reflexes (++ / ++++). Laboratory data showed a serum creatinine level of 2.1 mg/dL; serum potassium 2.1 mmol/L. Kidney biopsy was obtained; histological findings were consistent with acute tubular necrosis and acute tubulointerstitial nephritis. The patient was advised to stop the medications and to start with oral and intravenous potassium supplement, symptoms improved and continued until serum potassium levels were > 3.5 meq/L. CONCLUSIONS: The case reported in this vignette is unique since it is the first one to describe hypokalemia associated to acute tubular necrosis induced by oral acyclovir.

Rhabdomyolysis observed at forensic autopsy: a series of 52 cases.

Rhabdomyolysis is characterized by skeletal muscle injury resulting in the release of intracellular proteins (such as myoglobin) and electrolytes into the blood circulation, which cause acute kidney injury, myoglobinuria and electrolyte imbalances. Clinical diagnosis of rhabdomyolysis is made on the basis of biochemical analysis; however, for forensic autopsies, biochemical data are often not available, and it is necessary to diagnose rhabdomyolysis via histopathological examinations. This study analyzed 52 cases with rhabdomyolysis and applied myoglobin immunohistochemistry to kidney, urine and blood samples. We found that blunt force injuries were the most common cause of rhabdomyolysis across all age groups, and drugs were the second most common cause. The drugs included ketamines, amphetamines, synthetic cathinones, entheogens, benzodiazepines, opioid analgesics, and anesthesia. Less than 60% of our cases had biochemical data, including myoglobin (92.5~416,978 ng/mL), creatine kinase (220~774,015 U/L), potassium (1.6~10.3 meq/L), calcium (2.7~29.2 mg/dL), and phosphorus (2.6~14.2 mg/dL). In the kidney tissue sections, we found that 95% of the rhabdomyolysis cases were positive for myoglobin immunohistochemistry and that 96% were associated with acute tubular necrosis. Our findings describe the features of fatal rhabdomyolysis in a large series and suggest that myoglobin immunohistochemistry can be used in post-mortem blood and urine cell blocks to detect myoglobin.

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.

A Case of Oxalate Nephropathy: When a Single Cause Is Not Crystal Clear.

Hyperoxaluria can result in oxalate nephropathy with intratubular calcium oxalate crystallization and acute tubular injury. Primary inherited enzymatic deficiency or secondary causes such as excessive dietary intake, enteric increased absorption, or high doses of vitamin C, which is metabolized to oxalate, may underlie hyperoxaluria and oxalate nephropathy. We report a case of acute kidney injury due to oxalate nephropathy in a patient using chelating therapy with oral ethylenediamine tetra acetic acid (EDTA), intravenous supplementation with vitamin C, and chronic diarrhea and discuss the potential kidney damage these factors can cause in particular settings. To our knowledge, this is the first report suggesting an association between oral EDTA and oxalate nephropathy.

Renal Tubular Toxicity Associated With Rosuvastatin Therapy.

Preapproval clinical trials examining the safety and efficacy of rosuvastatin demonstrated an increased incidence of proteinuria, hematuria, rhabdomyolysis, and other acute kidney injury of unknown cause at high doses. The latter cases manifested with urine sediment findings and in some cases, renal histology, indicating renal tubular injury in the absence of rhabdomyolysis. Despite these provocative findings, there have been very few reports in the literature regarding non-rhabdomyolysis-mediated acute kidney injury associated with high-dose rosuvastatin since its widespread introduction more than a decade ago, suggesting that it is either a rare entity or systematically underdiagnosed and under-reported. We present a case of renal tubular toxicity attributable to the initiation of rosuvastatin treatment at a dose of 40mg in a patient with no prior evidence of kidney disease. Tubular toxicity should be considered in cases of unexplained kidney injury in the setting of exposure to a potent statin such as rosuvastatin, particularly at high dose. The limited evidence suggests a good kidney prognosis following withdrawal of the agent in these cases.

Acute tubular necrosis following transurethral resection of the Prostate using Glycine as irrigating fluid.

Transurethral resection of the prostate is currently the gold standard for the surgical treatment of the benign prostatic hyperplasia. This surgery may lead transurethral resection of the prostate (TURP) syndrome and in some cases, acute tubular necrosis can develop. We report a patient who developed hyponatremia, hemolysis and oliguric acute renal failure as a major complication following TURP using glycine as irrigating fluid.A 64-year-old man was admitted for a prostate resection procedure. Physical examination revealed a healthy elderly man. Preoperative laboratory data showed serum sodium 140 mEq/L, blood urea nitrogen (BUN) 0.6 g/L, creatinine 0.7 mg/dL and hemoglobin 12.9 g/dL. Few hours after, the patient becomes incoherent and developed oliguria, nausea and vomiting. The laboratory data revealed rapidly elevating BUN and creatinine levels (BUN 2.4 g/L; creatinine 6.1 mg/dL), the serum sodium concentration decreased by 14 meq/L. A decreased hemoglobin level (7.4 g/dL) with an elevated lactate dehydrogenase level (665 U/L) was observed. Renal ultrasonography was normal. The diagnosis of acute tubular necrosis complicating TURP syndrome was retained. The hyponatremia was slowly corrected to 132 mmol/L by diuresis and fluid restriction. The renal function recovered after four hemodialysis sessions. Using glycine as an irrigant for TURP may cause hyponatremia, hemolysis and also acute renal failure, especially in patients with longer resection time. It is necessary to carry out every effort to shorten resection time and avoid extravasation during surgery.

An unexpected cause of acute kidney injury in a patient with ANCA associated vasculitis.

Diagnostic kidney biopsies sometimes yield clinically unsuspected diagnoses. We present a case of a 69-year-old woman with established ANCA-associated vasculitis (AAV) of 4 years duration who was in clinical remission following cytotoxic therapy and was on maintenance immunosuppression. She presented to the hospital with acute kidney injury (AKI), symptoms suggestive of a systemic vasculitis, and in addition had hypercalcemia, metabolic alkalosis. A relapse in the AAV was suspected but a diagnostic kidney biopsy showed acute tubular necrosis, patchy interstitial inflammation, and calcium phosphate deposits. It was found that the patient recently started consuming large doses of over-the-counter calcium-containing antacids and vitamin Dcontaining multivitamin supplements. Cessation of these drugs led to improvement of renal function to baseline. This case highlights several teaching points: (1) the kidney biopsy can prove to be critically important even in cases where there appears to be a more obvious clinical diagnosis, (2) AK due to calcium-alkali syndrome has characteristic histopathological changes, and (3) that the triad of hypercalcemia, metabolic alkalosis, and AKI is exclusively associated with the ingestion of excessive quantities of calcium-containing antacids. The physician should keep this in mind, and pro-actively seek pertinent medication history from the patient. A brief review of calcium-alkali syndrome is given.

Effects of Schizolobium parahyba extract on experimental Bothrops venom-induced acute kidney injury.

BACKGROUND: Venom-induced acute kidney injury (AKI) is a frequent complication of Bothrops snakebite with relevant morbidity and mortality. The aim of this study was to assess the effects of Schizolobium parahyba (SP) extract, a natural medicine with presumed anti-Bothrops venom effects, in an experimental model of Bothrops jararaca venom (BV)-induced AKI. METHODOLOGY: Groups of 8 to 10 rats received infusions of 0.9% saline (control, C), SP 2 mg/kg, BV 0.25 mg/kg and BV immediately followed by SP (treatment, T) in the doses already described. After the respective infusions, animals were assessed for their glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Doppler), blood pressure (BP, intra-arterial transducer), renal vascular resistance (RVR), urinary osmolality (UO, freezing point), urinary neutrophil gelatinase-associated lipocalin (NGAL, enzyme-linked immunosorbent assay [ELISA]), lactate dehydrogenase (LDH, kinetic method), hematocrit (Hct, microhematocrit), fibrinogen (Fi, Klauss modified) and blinded renal histology (acute tubular necrosis score). PRINCIPAL FINDINGS: BV caused significant decreases in GFR, RBF, UO, HcT and Fi; significant increases in RVR, NGAL and LDH; and acute tubular necrosis. SP did not prevent these changes; instead, it caused a significant decrease in GFR when used alone. CONCLUSION: SP administered simultaneously with BV, in an approximate 10∶1 concentration, did not prevent BV-induced AKI, hemolysis and fibrinogen consumption. SP used alone caused a decrease in GFR.

Acute renal failure by ingestion of Euphorbia paralias.

Euphorbia paralias is known in traditional medicine as an anti-inflammatory agent, a purgative and for its local anesthetic property. To the best our knowledge, renal toxicity of this substance has not been previously reported. In this paper, we report the case of a 29-year-old male who developed renal damage following ingestion of Euphorbia paralias. He had been on follow-up for nephrotic syndrome since 1986, although irregularly, with several relapses but each responding well to steroid therapy. A kidney biopsy had not been performed earlier due to refusal by the patient. He was off steroids since April 2008 because the patient developed osteoporosis. He was admitted with general malaise and oliguria to our department in May 2009, following repeated vomiting and watery diarrhea for three days. On examination, he was edematous but had normal vital signs except for a pulse rate of 120/min. Hemoglobin was only 5.5 g/dL but with normal white cell and platelet counts. Blood biochemistry showed evidence of advanced renal failure with a serum creatinine level of 1835 µmol/L and urea at 44.6 mmol/L, sodium of 132 µmol/L and potassium at 4.3 mmol/L. He had features of nephrotic syndrome with severe hypoproteinamia and 24-h urinary protein of 10.45 g. Ultrasonography revealed enlarged kidneys with a reduced echogenecity of the medulla and the papillae. Subsequently, after hemodialysis with blood transfusion, a kidney biopsy was performed that showed focal segmental glomerulosclerosis associated with an acute tubular injury. On intensive interrogation, the patient gave a history of ingesting boiled Euphorbia paralias as a native treatment for edema, ten days prior to the onset of the current illness. A diagnosis of acute renal failure (ARF) resulting from the possible nephrotoxic effect of Euphorbia paralias poisoning was made. He was treated with intermittent hemodialysis and corticosteroids. Serum creatinine values improved after 48 days. At six months following the intoxication, serum creatinine of the patient was 240 µmol/L. In cases of unexplained ARF, a toxic mechanism should always be considered and acute renal failure caused by Euphorbia paralias should be included as a cause if renal toxicity is suspected in those places where it is being used as a native medicine.

Bisphophonates in CKD patients with low bone mineral density.

Patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) have a high risk of bone fracture because of low bone mineral density and poor bone quality. Osteoporosis also features low bone mass, disarranged microarchitecture, and skeletal fragility, and differentiating between osteoporosis and CKD-MBD in low bone mineral density is a challenge and usually achieved by bone biopsy. Bisphosphonates can be safe and beneficial for patients with a glomerular filtration rate of 30 mL/min or higher, but prescribing bisphosphonates in advanced CKD requires caution because of the increased possibility of low bone turnover disorders such as osteomalacia, mixed uremic osteodystrophy, and adynamic bone, even aggravating hyperparathyroidism. Therefore, bone biopsy in advanced CKD is an important consideration before prescribing bisphosphonates. Treatment also may induce hypocalcemia in CKD patients with secondary hyperparathyroidism, but vitamin D supplementation may ameliorate this effect. Bisphosphonate treatment can improve both bone mineral density and vascular calcification, but the latter becomes more unlikely in patients with stage 3-4 CKD with vascular calcification but no decreased bone mineral density. Using bisphosphonates requires considerable caution in advanced CKD, and the lack of adequate clinical investigation necessitates more studies regarding its effects on these patients.

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.

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.

Poscondicionamiento con ozono en un modelo de isquemia-reperfusión renal. Pruebas funcionales y morfológicas / Ozone postconditioning in renal ischaemia-reperfusion model. Functional and morphological evidences

Antecedentes: La isquemia-reperfusión es causa fundamental de complicaciones renales. La lesión más frecuente es la necrosis tubular aguda (NTA). En modelos de isquemia-reperfusión se ha demostrado que el precondicionamiento oxidativo con ozono ejerce un efecto modulador del estado redox de las células renales, al estimular los mecanismos antioxidantes endógenos. Trabajos más recientes, que han empleado el postcondicionamiento isquémico, han obtenido resultados similares. Objetivos: Evaluar el efecto del poscondicionamiento oxidativo con ozono sobre la morfología y la función renal en un modelo de isquemia-reperfusión en ratas. Métodos: Se utilizaron 40 ratas Wistar hembras con un peso entre 150 y 200 g, divididas al azar en cuatro grupos (control negativo, control positivo, oxígeno y ozono). Los grupos control positivo, oxígeno y ozono fueron sometidos a 60 minutos de isquemia y 10 días de reperfusión. Durante la reperfusión al grupo oxígeno se le administraron 26 mg/kg de peso corporal de oxígeno y al grupo ozono, 0,5 mg/kg de peso corporal de ozono, por vía rectal. Al final del experimento se tomaron muestras de orina y de sangre para las pruebas de función renal y se extrajeron los riñones para el estudio histológico. Resultados: El grupo ozono no mostró diferencias significativas en los valores de fracción de filtración y proteinuria con respecto al grupo control negativo. Los valores de intensidad de filtrado glomerular, flujo plasmático renal y creatinina mostraron una mejoría ligera en comparación con los grupos oxígeno y control positivo. El grupo ozono mostró de forma significativa un menor daño histológico global que los grupos control positivo y oxígeno. Conclusiones: El poscondicionamiento con ozono tuvo un efecto protector (AU)

Background: Ischaemia-reperfusion is one of the main causes of kidney complications. The most frequent lesion is acute tubular necrosis. Ozone oxidative preconditioning exerts a modulatory effect of redox state of renal cells in models of ischaemia-reperfusion, by stimulating endogenous antioxidant mechanisms. Similar results have been obtained in more recent studies using ischaemic postconditioning. Objectives: To evaluate the effect of ozone oxidative postconditioning on renal function and morphology in an ischaemia-reperfusion rat model. Methods: We used forty female Wistar rats weighing between 150g-200g randomly divided into 4 groups (negative control, positive control, oxygen and ozone). The groups: positive control, oxygen and ozone were subjected to 60 minutes of ischaemia and 10 days of reperfusion. During reperfusion, the oxygen group was given 26mg/kg body weight of oxygen, and the ozone group 0.5mg/kg body weight of ozone, rectally. At the end of the experiment urine and blood samples were taken for renal function tests and kidneys were removed for histological study. Results: The ozone group showed no significant differences for filtration fraction and proteinuria compared to the negative control group. The glomerular filtrate rate, renal plasma flow and creatinine showed a slight improvement in comparison with oxygen and positive control groups. The ozone group showed significantly less overall histological damage than the positive control and oxygen groups. Conclusions: Ozone postconditioning showed to have a protective effect in preserving renal function and morphology (AU)

Ozone postconditioning in renal ischaemia-reperfusion model. Functional and morphological evidences.

BACKGROUND: Ischaemia-reperfusion is one of the main causes of kidney complications. The most frequent lesion is acute tubular necrosis. Ozone oxidative preconditioning exerts a modulatory effect of redox state of renal cells in models of ischaemia-reperfusion, by stimulating endogenous antioxidant mechanisms. Similar results have been obtained in more recent studies using ischaemic postconditioning. OBJECTIVES: To evaluate the effect of ozone oxidative postconditioning on renal function and morphology in an ischaemia-reperfusion rat model. METHODS: We used forty female Wistar rats weighing between 150g-200g randomly divided into 4 groups (negative control, positive control, oxygen and ozone). The groups: positive control, oxygen and ozone were subjected to 60 minutes of ischaemia and 10 days of reperfusion. During reperfusion, the oxygen group was given 26mg/kg body weight of oxygen, and the ozone group 0.5mg/kg body weight of ozone, rectally. At the end of the experiment urine and blood samples were taken for renal function tests and kidneys were removed for histological study. RESULTS: The ozone group showed no significant differences for filtration fraction and proteinuria compared to the negative control group. The glomerular filtrate rate, renal plasma flow and creatinine showed a slight improvement in comparison with oxygen and positive control groups. The ozone group showed significantly less overall histological damage than the positive control and oxygen groups. CONCLUSIONS: Ozone postconditioning showed to have a protective effect in preserving renal function and morphology.

[Shedding light on the use of colistin: still gaps to be filled]. / Luces y sombras en el uso de colistina: falta mucho por conocer.

Colistin (polymyxin E), an old antibiotic replaced by other less toxic antibiotics in the 1970s, has been increasingly used over the last decade due to multidrug-resistance in Gram-negative bacteria and lack of new antibiotics. However, there is a dearth of information on the pharmacokinetics (PK), pharmacodynamics (PD) and toxicodynamics (TD) of colistin and its non-active prodrug colistimethate sodium (CMS). Optimised dose regimens have not been established for different types of patients. Additionally, most PK data available in the literature were obtained from concentrations derived from potentially misleading microbiological assays. Therefore, it is urgent to conduct prospective studies to optimise CMS/colistin use in patients, in particular the critically ill. This review summarises recent key clinical studies evaluating the efficacy, toxicity and PK/PD of colistin/CMS.

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.

[Clinical characteristics and long-term follow-up analysis of three cases with newborn aristolochic acid nephropathy].

OBJECTIVE: To summarize the clinical characteristics and prognosis of newborn aristolochic acid nephropathy induced by akebia. METHOD: Retrospective analysis of clinical manifestations, therapy and prognosis was made upon data of 3 newborn infants with renal function lesion induced by akebia. RESULT: Three infants who were fed with Chinese herbal medicines containing akebia trifoliate suffered from acute renal failure, renal glomerular and tubular injury, with symptoms of vomiting, diarrhea, and oliguria. Laboratory tests manifested hyperpotassemia, hyponatremia, elevation of serum creatinine and urea nitrogen, and metabolic acidosis. Renal glomerular lesion was mild, presented with proteinuria and increased serum ß(2) microglobin. Renal dysfunction was manifested with alkaline urine, glucosuria, positiveness of urine glucose, ketone and aminoaciduria, and increased urine ß(2) microglobin excretion. After symptomatic treatment for 3 to 4 weeks, the renal function of these infants recovered. Proteinuria, aminoaciduria and glucosuria turned negative within 5 to 8 months, 3 months to 1 year, and 9 months to 3 years, respectively. Urine pH decreased to 7.0 after 5.0 - 5.5 years. All cases took citric acid mixtures for 5.5 to 6 years. A 12-years follow-up demonstrated that serum creatinine of 3 cases were within normal range during the first 11 years of life, however recent follow-up showed increased serum creatinine of case 1 and case 2, except for serum creatinine of case 3 remained normal. The estimated glomerular filtration rate (eGFR) of all the 3 cases decreased. Among which, eGFR of case 1 and case 2 were lower than 90 [ml/(min·1.73 m(2))], and decreased 1.1 [ml/(min·1.73 m(2))] and 0.6 [ml/(min·1.73 m(2))] per year during recent six years, respectively. No obvious decrease of eGFR was observed in case 3. Blood gas analysis and urine routine were normal, yet blood and urine ß(2) microglobin excretion were still high. Urinary N-acetyl-ß-D-glucosaminidase increased again after having returned to normal. CONCLUSION: Newborn aristolochic acid nephropathy induced by akebia might induce acute renal failure and renal tubules injury. Renal function could recover after symptomatic treatment in short-term. Nevertheless, glomerular filtration rate presents a slow descending tendency and renal tubules lesion lasted for many years, which requires a long-term follow-up.