Mechanism Of Acute Renal Failure Research Articles

POS-019 ACUTE KIDNEY INJURY IN ONCOLOGY AND TUMOR LYSIS SYNDROME

Acute kidney injury (AKI) is a common and serious complication in patients with neoplasia, it leads to a number of negative consequences, including length of hospitalization, denial of active cancer treatment, worsening of overall prognosis, and increase in costs. AKI may disturb the bioavailability and/or safety profile of many oncologic drugs, potentially leading to suboptimal treatments, or enhance risk for drug-induced toxicities. The aim of our work is to study the epidemiology, causes, therapeutics and prognosis of AKI in cancer patients. Retrospective study including all patients admitted to our university hospital for a period of 2 years from January 2018 to December 2019, known to be carriers of neoplastic disease and presenting acute renal injury selected according to the criteria of the Acute Kidney Injury Classification Network (AKIN). The patients were followed until their discharge or their death. 110 patients had an associated cancer pathology. The mean age was 44.46 ± 18.66 years, with a female predominance of 65%, a male / female sex ratio of 0.75. 41% of patients were admitted to medical services and 32% of patients hospitalized for surgery. The mean serum creatinine was 97.9 ± 63.6 mg / L. The mechanism of acute renal failure was dominated by the obstructive origin found in (56%) of cases, followed by myelomatous cylinder nephropathy (20%), nephrotoxicity of cancer chemotherapy (10%), syndrome. tumor lysis in (8%) and sepsis in (6%). The use of hemodialysis was necessary in 82% of cases. Only 18.68% recovered normal renal function. The death rate was 13.18%. AKI is a serious complication of cancer or of its treatments and is responsible for additional morbidity and mortality.

Two Rare Mechanisms for Acute Anuric Renal Failure in a Patient with Metastatic Malignant Melanoma - A Case Report

This case report examines two rare mechanisms of acute renal failure in a patient with metastatic melanoma treated with high-dose vitamin C. The first is oxalate nephropathy, which is an uncommon but known complication of high-dose vitamin C therapy in naturopathic medicine. The second is due to melanuria and renal melanosis, which has been described in metastatic melanoma; however, acute renal failure requiring renal replacement therapy has not been reported previously.

The potential protective effects of erythropoietin and estrogen on renal ischemia reperfusion injury in ovariectomized rats

BackgroundRenal ischemia–reperfusion (RIR) is an important etiopathological mechanism of acute renal failure (ARF). Erythropoietin (EPO) has been candidate as a nephroprotectant agent. However, its nephroprotective effect when it is accompanied with estrogen has not been studied in female. MethodsFifty-six female rats were divided into seven groups. Each formed of 8 rats. Group I: control group. Group II: Female rats exposed to RIR (named RIR group).Group III: Female rats exposed to RIR and pretreated with EPO (named RIR+EPO group). Group IV: ovariectomized rats exposed to RIR (named OVR+RIR group). Group V: ovariectomized rats received estrogen (E) then exposed to RIR (named OVR+RIR+E group). Group VI: ovariectomized rats received EPO before RIR (named OVR+RIR+EPO group). Group VII: ovariectomized rats received E then received EPO before RIR (named OVR+RIR+E+EPO group).Serum creatinine, blood urea nitrogen (BUN) and renal blood flow (RBF) were measured. Tumor necrosis factor-α (TNF-α), Myeloperoxidase activity (MPO), nitric oxide (NO), endothelin-1(ET-1) and EPO levels were assessed in the renal tissue. Histopathology was assessed to detect renal damage score. ResultsRIR significantly increased the serum levels of creatinine and BUN with decrease in RBF. In addition it significantly increased TNF-α, MPO and endothelin-1 levels with decrease in NO and EPO levels in renal tissue. However, these parameters significantly reversed by EPO except RBF. Combination of E and EPO leads to significant decrease in the protective effect of EPO. ConclusionIt seems that EPO could protect the kidney against RIR, while this protective effect was decreased when E was supplemented.

In-vitro renal epithelial cell infection reveals a viral kidney tropism as a potential mechanism for acute renal failure during Middle East Respiratory Syndrome (MERS) Coronavirus infection

BackgroundThe Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes symptoms similar to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), yet involving an additional component of acute renal failure (ARF) according to several published case reports. Impairment of the kidney is not typically seen in Coronavirus infections. The role of kidney infection in MERS is not understood.FindingsA systematic review of communicated and peer-reviewed case reports revealed differences in descriptions of kidney involvement in MERS versus SARS patients. In particular, ARF in MERS patients occurred considerably earlier after a median time to onset of 11 days (SD ±2,0 days) as opposed to 20 days for SARS, according to the literature. In-situ histological staining of the respective cellular receptors for MERS- and SARS-Coronavirus showed highly similar staining patterns with a focus of a receptor-specific signal in kidney epithelial cells. Comparative infection experiments with SARS- and MERS-CoV in primary human kidney cells versus primary human bronchial epithelial cells showed cytopathogenic infection only in kidney cells, and only if infected with MERS-CoV. Kidney epithelial cells produced almost 1000-fold more infectious MERS-CoV progeny than bronchial epithelial cells, while only a small difference was seen between cell types when infected with SARS-CoV.ConclusionEpidemiological studies should analyze kidney impairment and its characteristics in MERS-CoV. Virus replication in the kidney with potential shedding in urine might constitute a way of transmission, and could explain untraceable transmission chains leading to new cases. Individual patients might benefit from early induction of renoprotective treatment.

Possible role of mtDNA depletion and respiratory chain defects in aristolochic acid I-induced acute nephrotoxicity

This report describes an investigation of the pathological mechanism of acute renal failure caused by toxic tubular necrosis after treatment with aristolochic acid I (AAI) in Sprague–Dawley (SD) rats. The rats were gavaged with AAI at 0, 5, 20, or 80mg/kg/day for 7days. The pathologic examination of the kidneys showed severe acute tubular degenerative changes primarily affecting the proximal tubules. Supporting these results, we detected significantly increased concentrations of blood urea nitrogen (BUN) and creatinine (Cr) in the rats treated with AAI, indicating damage to the kidneys. Ultrastructural examination showed that proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Mitochondrial function analysis revealed that the two indicators for mitochondrial energy metabolism, the respiratory control ratio (RCR) and ATP content, were reduced in a dose-dependent manner after AAI treatment. The RCR in the presence of substrates for complex I was reduced more significantly than in the presence of substrates for complex II. In additional experiments, the activity of respiratory complex I, which is partly encoded by mitochondrial DNA (mtDNA), was more significantly impaired than that of respiratory complex II, which is completely encoded by nuclear DNA (nDNA). A real-time PCR assay revealed a marked reduction of mtDNA in the kidneys treated with AAI. Taken together, these results suggested that mtDNA depletion and respiratory chain defects play critical roles in the pathogenesis of kidney injury induced by AAI, and that the same processes might contribute to aristolochic acid-induced nephrotoxicity in humans.

Experimental Induction of Calcium Oxalate Nephrolithiasis in Mice

The availability of various transgenic and knockout mice provides an excellent opportunity to better understand the pathophysiology of calcium oxalate stone disease. However, attempts to produce calcium oxalate nephrolithiasis in mice have not been successful. We hypothesized that calcium oxalate nephrolithiasis in mice requires increasing urine calcium and oxalate excretion, and experimentally induced hyperoxaluria alone is not sufficient. To provide evidence we induced hyperoxaluria by administering hyperoxaluria inducing agents in normocalciuric and hypercalciuric mice, and investigating various aspects of nephrolithiasis. We administered ethylene glycol, glyoxylate or hydroxyl proline via diet in male and female normocalciuric B6 mice, and in hypercalciuric sodium phosphate co-transporter type 2 a -/- mice for 4 weeks. We collected 24-hour urine samples on days 0, 3, 7, 14, 21 and 28, and analyzed them for pH, creatinine, lactate dehydrogenase calcium and oxalate. Kidneys were examined using light microscopy. Urine was examined for crystals using light and scanning electron microscopy. Hypercalciuric mice on hydroxyl proline did not tolerate treatment and were sacrificed before 28 days. All mice on ethylene glycol, glyoxylate or hydroxyl proline became hyperoxaluric and showed calcium oxalate crystalluria. No female, normocalciuric or hypercalciuric mice showed renal calcium oxalate crystal deposits. Calcium oxalate nephrolithiasis developed in all mice on glyoxylate and in some on ethylene glycol. In all mice the kidneys showed epithelial injury. Male mice particularly on glyoxylate had more renal injury and inflammatory cell migration into the interstitium around the crystal deposits. Results confirm that hyperoxaluria induction alone is not sufficient to create calcium oxalate nephrolithiasis in mice. Hypercalciuria is also required. Kidneys in male mice are more prone to injury than those in female mice and are susceptible to calcium oxalate crystal deposition. Perhaps epithelial injury promotes crystal retention. Thus, calcium oxalate nephrolithiasis in mice is gender dependent, and requires hypercalciuria and hyperoxaluria.

Are calcium oxalate crystals involved in the mechanism of acute renal failure in ethylene glycol poisoning?

Introduction. Ethylene glycol (EG) poisoning often results in acute renal failure, particularly if treatment with fomepizole or ethanol is delayed because of late presentation or diagnosis. The mechanism has not been established but is thought to result from the production of a toxic metabolite. Methods. A literature review utilizing PubMed identified papers dealing with renal toxicity and EG or oxalate. The list of papers was culled to those relevant to the mechanism and treatment of the renal toxicity associated with either compound. Role of metabolites. Although the “aldehyde” metabolites of EG, glycolaldehyde, and glyoxalate, have been suggested as the metabolites responsible, recent studies have shown definitively that the accumulation of calcium oxalate monohydrate (COM) crystals in kidney tissue produces renal tubular necrosis that leads to kidney failure. In vivo studies in EG-dosed rats have correlated the severity of renal damage with the total accumulation of COM crystals in kidney tissue. Studies in cultured kidney cells, including human proximal tubule (HPT) cells, have demonstrated that only COM crystals, not the oxalate ion, glycolaldehyde, or glyoxylate, produce a necrotic cell death at toxicologically relevant concentrations. COM crystal accumulation. In EG poisoning, COM crystals accumulate to high concentrations in the kidney through a process involving adherence to tubular cell membranes, followed by internalization of the crystals. Mechanism of toxicity. COM crystals have been shown to alter membrane structure and function, to increase reactive oxygen species and to produce mitochondrial dysfunction. These processes are likely to be involved in the mechanism of cell death. Conclusions. Accumulation of COM crystals in the kidney is responsible for producing the renal toxicity associated with EG poisoning. The development of a pharmacological approach to reduce COM crystal adherence to tubular cells and its cellular interactions would be valuable as this would decrease the renal toxicity not only in late treated cases of EG poisoning, but also in other hyperoxaluric diseases such as primary hyperoxaluria and kidney stone formation.

A tribute to Franklin H. Epstein

A tribute to Franklin H. Epstein

Dimethyl sulphoxide administration decreases renal ischemic–reperfusion injury

Kidney ischemia is one of the mechanisms of acute renal failure and it is known that the free oxygen radicals play an important role in this type of injury. We tested the hypothesis that dimethyl sulphoxide (DMSO), a free radical scavenger, has a protective role in a renal ischemia–reperfusion animal model [1].

Trimetazidine reduces early and long-term effects of experimental renal warm ischemia: A dose effect study

Renal ischemia reperfusion (IR) injury (IRI) is an important mechanism of acute renal failure (ARF) and a crucial factor of tissue damage during vascular surgery. IR may lead to tissue destruction and influence the early and long-term outcome of organs. The anti-anginal medication trimetazidine (TMZ) is a drug, the protective effects of which have been already assessed during cold preservation and warm ischemia (WI). The objective of this dose-effect study was to assess the role of TMZ in severe renal WI model. We have used an established WI pig kidney model associated with a uninephrectomy condition and studied the dose-dependent role of TMZ (1, 5, and 10 mg/Kg, i.v. for 24 hours before WI) against deleterious effects of WI (60 minutes of WI followed by reperfusion) compared with sham-operated (control) and uninephrectomized animals (unif). Direct effect of TMZ was determined using different variables: renal function (creatinine clearance; C(cr)) and indirectly, the consequences on inflammation (cells infiltration), rate of apoptosis, fibrosis development, and renal epithelial cells change into myofibroblast, which defined epithelial to mesenchymal transition (alpha-smooth muscle actin [alpha-SMA] and vimentin expression). TMZ (5 or 10 mg/Kg) significantly increased C(cr) and reduced the inflammatory response prevalent in ischemic kidney injury and rate of apoptosis expression. In addition, the limitation of initial IRI was correlated with an earlier and greater expression of hypoxia-inducible transcription factor-1alpha (HIF-1alpha), which is a hypoxia marker during kidney regeneration. A reduction of the tubulointerstitial development of fibrosis and a limitation of the alpha-smooth muscle actin expression (alpha-SMA) was observed with TMZ treatment. At 3 months, vimentin expression was increased in WI groups without TMZ or low TMZ dose treatment compared with 5 or 10 mg/Kg treated groups. Collectively, these data suggest that TMZ made the warm ischemic kidneys more resistant to the deleterious impact of a single episode of IR and could have a role in preserving the ischemic kidney from long-term damage.

A patient with alcoholic liver failure referred for liver transplantation

A patient with alcoholic liver failure referred for liver transplantation

Reversible renal vasoconstriction in a patient with acute renal failure after exercise

Acute renal failure (ARF) with severe loin pain induced by anaerobic exercise is a rare condition that is accompanied by wedge-shaped contrast enhancement seen on computerized tomographic (CT) scan without evidence of rhabdomyolysis. An 18-year-old Korean male was transferred to our hospital for evaluation of mild azotemia, that developed after anaerobic exercise. The laboratory tests revealed that the serum creatinine was 2.1 mg/dl and the serum uric acid level was 1.6 mg/dl without any elevation of the serum myoglobin or creatine phosphokinase. Under the impression of exercise-induced ARF, we tried to determine the relationship between the occurrence of clinical symptoms, renal dysfunction and the characteristic CT findings by observing those changes prospectively before and after anaerobic exercise. After obtaining a written consent, the patient underwent a strenuous period of anaerobic exercise to induce the clinical symptoms. Before exercise, he was completely asymptomatic; his serum creatinine level was 0.9 mg/dl and CT scan of the kidneys showed no abnormalities. Loin pain developed 2 hours after exercise, and the serum creatinine level increased to 1.2 mg/dl 18 hours after the exercise. CT scan 18 hours after exercise showed multiple perfusion defects, and a 24-hour delayed CT scan showed multiple areas of wedge-shaped enhancement on both kidneys. These changes were completely resolved on the follow-up CT scan obtained 13 days after exercise with the return of a normal serum creatinine level. We conclude that reversible renal vasoconstriction is probably the main pathophysiologic mechanism of acute renal failure induced by anaerobic exercise.

Cellular and molecular mechanisms of sex differences in renal ischemia–reperfusion injury

Renal ischemia-reperfusion (I/R) is an important etiopathological mechanism of acute renal failure (ARF). Despite improvements in the treatment of ARF, it is associated with significant morbidity and mortality. I/R injury also occurs during renal transplantation and leads to reduced allograft survival. Sex differences have been found in I/R injury in many different organs including the kidney. Women have half the mortality of men in ARF. In animal models also, females are protected against renal I/R injury. The mechanisms by which sex affects the outcome to renal I/R injury are being actively investigated. This review will examine the evidence for gender differences in renal I/R injury and discuss the probable mechanisms by which sex affects the renal response to I/R injury.

Molecular Mechanisms of Acute Renal Failure following Ischemia/Reperfusion

Acute renal failure (ARF) necessitating renal replacement therapy is a common problem associated with high morbidity and mortality in the critically ill. Hypotension, followed by resuscitation, is the most common etiologic factor, mimicked by ischemia/reperfusion (I/R) in animal models. Although knowledge of the pathophysiology of ARF in the course of this condition is increasingly detailed, the intracellular and molecular mechanisms leading to ARF are still incompletely understood. This review aims at describing the role of cellular events and signals, including collapse of the cytoskeleton, mitochondrial and nuclear changes, in mediating cell dysfunction, programmed cell death (apoptosis), necrosis and others. Insight into the molecular pathways in the various elements of the kidney, such as vascular endothelium and smooth muscle and tubular epithelium leading to cell damage upon I/R will, hopefully, open new therapeutic modalities, to mitigate the development of ARF after hypotensive episodes and to promote repair and resumption of renal function once ARF has developed.

Cell cycle regulation: Repair and regeneration in acute renal failure

Research into mechanisms of acute renal failure has begun to reveal molecular targets for possible therapeutic intervention. Much useful knowledge into the causes and prevention of this syndrome has been gained by the study of animal models. Most recently, investigation of the effects on acute renal failure of selected gene knock-outs in mice has contributed to our recognition of many previously unappreciated molecular pathways. Particularly, experiments have revealed the protective nature of two highly induced genes whose functions are to inhibit and control the cell cycle after acute renal failure. By use of these models we have started to understand the role of increased cell cycle activity after renal stress, and the role of proteins induced by these stresses that limit this proliferation.

Cell cycle regulation: repair and regeneration in acute renal failure

Research into mechanisms of acute renal failure has begun to reveal molecular targets for possible therapeutic intervention. Much useful knowledge into the causes and prevention of this syndrome has been gained by the study of animal models. Most recently, investigation of the effects on acute renal failure of selected gene knock-outs in mice has contributed to our recognition of many previously unappreciated molecular pathways. Particularly, experiments have revealed the protective nature of 2 highly induced genes whose functions are to inhibit and control the cell cycle after acute renal failure. By use of these models we have started to understand the role of increased cell cycle activity after renal stress and the role of proteins induced by these stresses that limit this proliferation.

Haptoglobin reduces renal oxidative DNA and tissue damage during phenylhydrazine-induced hemolysis

Haptoglobin knockout (Hp-/-) mice are more sensitive to phenylhydrazine-induced hemolysis than Hp+/+ mice. Hemolysis was induced in Hp-/- and Hp+/+ mice using phenylhydrazine. Relative renal tissue damage and function were then assessed. Hp-/- mice had higher basal levels of renal lipid peroxidation, as evidenced by levels of malonaldehyde and 4-hydroxy-2(E)-nonenal (MDA/HNE). After the administration of phenylhydrazine, levels of 8-hydroxyguanine (but not other products of oxidative DNA damage) were significantly elevated in the renal DNA. There was also increased induction of heme oxygenase-1. The more severe renal damage in Hp-/- mice was also evident in the delayed erythropoietin gene expression and poorer renal clearance of 3H-inulin. This reduction in glomerular filtration function in Hp+/+ and Hp-/- mice could be restored to baseline by vasodilators (prazosin or diazoxide), implicating renal vasoconstriction as a major mechanism of acute renal failure during induced hemolysis. Precipitation of hemoglobin in the kidney was not increased in Hp-/- mice. Haptoglobin appears to play an important physiological role as an antioxidant, particularly during hemolysis.

Acute renal failure in patients over 80 years old: 25-years' experience.

To determine the epidemiological trends, spectrum of etiologies, morbidity and mortality of acute renal failure (ARF) in patients over 80 years old. Historical cohort analysis. Intensive care unit (ICU) of nephrology, Tenon Hospital, Paris. The criteria of inclusion was ARF, defined on the basis of a creatinine value over 120 mumol/l, in patients over 80 years of age admitted between October 1971 and September 1996. When moderate chronic nephropathy was pre-existing, ARF was defined by the increase of at least 50% over the basal creatininemia. Three hundred and eighty-one patients over 80 years of age were included. The etiology and mechanism of ARF are detailed. 29% of the patients received dialysis. Global mortality at the hospital was 40%. Factors significantly associated with a poor prognosis are identified. Mean survival after hospitalization was 19 months. The frequency of admission to ICUs for ARF in patients older than 80 years seems to be on the increase. Mortality is less severe than expected. These patients could benefit from the renal replacement therapy of modern intensive care medicine.

Apoptotic mechanisms in acute renal failure

It has been generally accepted that a catastrophic breakdown of regulated cellular homeostasis, known as necrosis, is the mode of cellular injury in various forms of acute renal failure. One of the major advances in our understanding of cell death has been the recognition that the pathways traditionally associated with apoptosis as described in the landmark study by Kerr, Wyllie, and Currie in 1972 may be very critical in the form of cell injury associated with necrosis. The pathway that is followed by the cell varies with both nature and severity of insults and may evolve from an apoptotic to a necrotic form of cell death. It is also likely that there are some common pathways that are shared and regulated in the two modes of cell death. In this review, we first describe evidence for the role of apoptotic pathways in ischemic acute renal failure, and then consider the potential mechanisms that may participate in this model of acute renal tubular injury. We then summarize the current information of apoptotic pathways related to other common causes of acute renal failure including endotoxin-induced, toxic acute renal failure and transplant rejection. A better understanding of the mechanisms of apoptosis could lead to safer and more specific therapeutic interventions for acute renal failure.

Severe renal vasoconstriction and anuria after intravenous urography in a patient with renal impairment

Acute renal failure caused by radiocontrast agents remains a severe problem, particularly in patients with risk factors. There is debate concerning the pathophysiology of contrast media-induced acute renal failure, including, but not limited to, renal ischemia or tubular damage. Vascular ischemia is considered a major contributor because consistent changes in renal hemodynamics have been recorded experimentally. We describe a patient who has a typical course of contrast-associated renal failure manifested by severe renal vasoconstriction and backflow of the contrast agent during renal angiography performed after 6 days of an intravenous urography. Such degree of renal vasoconstriction is noteworthy in that this particular case might serve as a model in delineation of the pathogenetic mechanisms of acute renal failure after contrast media administration.