Biopsy-proven first dose of oxaliplatin-induced acute tubular necrosis leading to end-stage renal failure: a case report.

BACKGROUND: Oxaliplatin is an anticancer therapy for pancreatic, gastric, and colorectal cancers. It is also used in patients with carcinomas of unknown primary sites. Oxaliplatin is associated with less frequent renal dysfunction than other conventional platinum-based drugs such as cisplatin. Albeit, there have been several reports of acute kidney injury with frequent use. In all cases, renal dysfunction was temporary and did not require maintenance dialysis. There have been no previous reports of irreversible renal dysfunction after a single dose of oxaliplatin. CASE PRESENTATION: Previous reports of oxaliplatin-induced renal injury occurred after patients received multiples doses. In this study, a 75-year-old male with unknown primary cancer and underlying chronic kidney disease developed acute renal failure after receiving the first dose of oxaliplatin. Suspected of having drug-induced renal failure through an immunological mechanism, the patient was treated with steroids; however, treatment was ineffective. Renal biopsy ruled out interstitial nephritis and revealed acute tubular necrosis. Renal failure was irreversible, and the patient subsequently required maintenance hemodialysis. CONCLUSIONS: We provide the first report of pathology-confirmed acute tubular necrosis after the first dose of oxaliplatin which led to irreversible renal dysfunction and maintenance dialysis.

Activity and short-term outcomes of kidney transplantation during the COVID-19 pandemic. / Actividad y resultados a corto plazo del trasplante renal durante la pandemia COVID-19.

INTRODUCTION: During the COVID-19 pandemic, the national transplant activity has been reduced due to the overload of the health system and concern for patient safety in this situation. The aim of our work is to expose the activity of kidney transplantation in Cantabria during the state of alarm, as well as to assess the safety of the transplantation program. MATERIAL AND METHODS: Retrospective study of kidney transplants performed in our Center from the beginning of the state of alarm until the beginning of the lockdown easing in Cantabria. Descriptive analysis of the demographic data of recipients and their donors, intraoperative data and postoperative outcomes. Comparative analysis with the data of the same period in 2017-2019, by means of the χ2 for categorical variables, Student's T and Mann-Whitney U tests in case of quantitative variables of normal and non-normal distribution, respectively. RESULTS: Fifteen kidney transplants were performed in the period described. Delayed renal function (DRF) was seen in 7.5% of patients, and 26.6% showed data of acute rejection; no patient presented COVID-19 disease. Comparative analysis showed a remarkable increase in the number of transplants in comparison with previous periods (15 vs 5.6), at the expense of donors from outside Cantabria (93.3%). We found no statistically significant differences in terms of cold ischemia time (p=0.77), DRF (p=0.73), need for dialysis (p=0.54), or appearance of post-surgical complications (p=0.61). CONCLUSIONS: The evolution of the pandemic in our region, and the adoption of strict protective measures has allowed the early and safe resumption of the renal transplantation program, increasing the number of transplants performed compared to previous years and maintaining comparable early post-operative results.

Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis.

Intravascular hemolysis of any cause can induce acute kidney injury (AKI). Hemolysis-derived product heme activates the innate immune complement system and contributes to renal damage. Therefore, we explored the role of the master complement regulator Factor H (FH) in the kidney's resistance to hemolysis-mediated AKI. Acute systemic hemolysis was induced in mice lacking liver expression of FH (hepatoFH-/-, ~20% residual FH) and in WT controls, by phenylhydrazine injection. The impaired complement regulation in hepatoFH-/- mice resulted in a delayed but aggravated phenotype of hemolysis-related kidney injuries. Plasma urea as well as markers for tubular (NGAL, Kim-1) and vascular aggression peaked at day 1 in WT mice and normalized at day 2, while they increased more in hepatoFH-/- compared to the WT and still persisted at day 4. These were accompanied by exacerbated tubular dilatation and the appearance of tubular casts in the kidneys of hemolytic hepatoFH-/- mice. Complement activation in hemolytic mice occurred in the circulation and C3b/iC3b was deposited in glomeruli in both strains. Both genotypes presented with positive staining of FH in the glomeruli, but hepatoFH-/- mice had reduced staining in the tubular compartment. Despite the clear phenotype of tubular injury, no complement activation was detected in the tubulointerstitium of the phenylhydrazin-injected mice irrespective of the genotype. Nevertheless, phenylhydrazin triggered overexpression of C5aR1 in tubules, predominantly in hepatoFH-/- mice. Moreover, C5b-9 was deposited only in the glomeruli of the hemolytic hepatoFH-/- mice. Therefore, we hypothesize that C5a, generated in the glomeruli, could be filtered into the tubulointerstitium to activate C5aR1 expressed by tubular cells injured by hemolysis-derived products and will aggravate the tissue injury. Plasma-derived FH is critical for the tubular protection, since pre-treatment of the hemolytic hepatoFH-/- mice with purified FH attenuated the tubular injury. Worsening of acute tubular necrosis in the hepatoFH-/- mice was trigger-dependent, as it was also observed in LPS-induced septic AKI model but not in chemotherapy-induced AKI upon cisplatin injection. In conclusion, plasma FH plays a key role in protecting the kidneys, especially the tubules, against hemolysis-mediated injury. Thus, FH-based molecules might be explored as promising therapeutic agents in a context of AKI.

Acute kidney injury as the presenting complaint of ceftazidime-induced immune-mediated haemolysis.

We present the case of ceftazidime-induced immune-mediated haemolysis with associated acute kidney injury in a 43-year-old woman. The patient initially presented to the regional cystic fibrosis centre for treatment of an infective exacerbation of cystic fibrosis. After initiation of ceftazidime (a third-generation cephalosporin), renal function rapidly deteriorated and a fall in haemoglobin was noted. On transfer to our care, a haemolysis screen identified immune-mediated haemolysis, and renal biopsy confirmed the finding of acute tubular necrosis secondary to haem pigment. The patient's renal function deteriorated such that she required haemodialysis, although she subsequently recovered and is now dialysis-independent. Although acute haemolytic reactions are recognised with third-generation cephalosporins, this is the first reported case of ceftazidime-induced immune-mediated haemolysis with acute kidney injury. Given the increased frequency of cephalosporin usage, it is important for both nephrologists and general physicians to be aware of this rare but very serious complication.

Antiviral Drugs and Acute Kidney Injury (AKI).

The introduction of more efficient antiviral drugs are common cause drug-induced acute kidney injury (AKI). The true prevalence of antiviral drugs induced nephrotoxicity is hardly determined. It causes AKI by many mechanisms including acute tubular necrosis (ATN), allergic interstitial nephritis (AIN), and crystal nephropathy. ATN has been described with a few kinds of antiviral drugs such as cidofovir, adefovir and tenofovir with unique effects on transporter defects, apoptosis, and mitochondrial injury. AIN from atazanavir is a rapid onset of AKI and usually nonoliguric but dialytic therapy are needed because of severity. Additionally, crystal nephropathy from acyclovir, indinavir, and foscarnet can cause AKI due to intratubular obstruction. In this article, the mechanisms of antiviral drug-induced AKI were reviewed and strategies for preventing AKI were mentioned.

Unusual effects of common antibiotics.

Antibiotics are widely prescribed and have a generally favorable safety profile. Common adverse effects such as rash and diarrhea are well recognized, but less common ones may go unrecognized. This review highlights rare but potentially lethal complications associated with antibiotics.

Translational Assessment of Drug-Induced Proximal Tubule Injury Using a Kidney Microphysiological System.

Drug-induced kidney injury, a major cause of acute kidney injury, results in progressive kidney disease and is linked to increased mortality in hospitalized patients. Primary injury sites of drug-induced kidney injury are proximal tubules. Clinically, kidney injury molecule-1, an established tubule-specific biomarker, is monitored to assess the presence and progression of injury. The ability to accurately predict drug-related nephrotoxicity preclinically would reduce patient burden and drug attrition rates, yet state-of-the-art in vitro and animal models fail to do so. In this study, we demonstrate the use of kidney injury molecule-1 measurement in the kidney microphysiological system as a preclinical model for drug toxicity assessment. To show clinical relevance, we use quantitative systems pharmacology computational models for in vitro-in vivo translation of the experimental results and to identify favorable dosing regimens for one of the tested drugs.

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.

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.

Orlistat-induced oxalate nephropathy: an under-recognised cause of chronic kidney disease.

Two patients developed kidney failure due to oxalate deposition in the kidney while taking orlistat. Cessation of orlistat was followed by partial recovery of kidney function. The mechanism by which orlistat causes hyperoxaluria and the management of orlistat-induced oxalate nephropathy is reviewed. We suggest that all patients taking orlistat are at risk of this condition, which may develop insidiously and is easily overlooked. Monitoring of kidney function of patients taking orlistat is warranted.

Renal damage induced by pemetrexed causing drug discontinuation: a case report and review of the literature.

BACKGROUND: Pemetrexed maintenance therapy holds tremendous potential in improving the survival of patients with advanced pulmonary adenocarcinoma. Major side effects include myelosuppression and cutaneous reactions. However, little data are available on pemetrexed nephrotoxicity. Our case describes clinically relevant renal events leading to treatment discontinuation in routine practice. CASE PRESENTATION: We report a case of a 69-year-old Moroccan man treated for metastatic non-small cell lung cancer. He was not on any other medications and he did not receive any nephrotoxic agents. He was exposed to intravenously administered contrast from thoracoabdominal computed tomography in the week of his last pemetrexed treatment. He developed kidney disease related to pemetrexed. He was submitted to renal biopsy, which showed acute tubular damage and interstitial fibrosis. His kidney function remained impaired, but stable, after discontinuation of pemetrexed therapy. He died 5 months later. CONCLUSIONS: Medical oncologists should be aware of renal adverse events for patients with advanced non-small cell lung cancer eligible for pemetrexed maintenance therapy. Suggestions for mitigating the risk for renal toxicities (dehydration, non-steroidal anti-inflammatory drugs and zoledronic acid, radiocontrast agents) during pemetrexed maintenance should be followed to enable early detection and management of this adverse event.

Acute granulomatous interstitial nephritis and acute rejection in a kidney transplant recipient after zoledronic acid therapy - a case report and review of the literature.

BACKGROUND: Acute granulomatous interstitial nephritis (AGIN) in native kidneys is most commonly linked to drugs. In allografts, it is a rare complication, and it occurs mostly with infections. CASE PRESENTATION: Our case report presents AGIN with simultaneous acute cellular rejections and acute tubular necrosis in a kidney transplant patient 2 weeks after intravenous application of zoledronic acid. A kidney biopsy showed signs of destructive AGIN with acute cellular rejection. After treatment with methylprednisolone pulses and immunosuppressive therapy modification, rebiopsy confirmed complete regression of AGIN with less intense persistent acute cellular rejection and acute tubular necrosis. Kidney function improved after glucocorticoid and intravenous immunoglobulin G therapy. CONCLUSION: To our knowledge, this is the first case of AGIN related to bisphosphonate zoledronate in a kidney transplant patient with consequent acute cellular rejection. In using intravenous zoledronate infusion in a kidney transplant recipient, we should be aware that it could potentially induce acute granulomatous tubulointerstitial nephritis and acute rejection.
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Rhabdomyolysis with acute tubular necrosis following occupational inhalation of thinners.

Thinners are mixtures of organic solvents commonly containing toluene, xylene, acetone, hexane, benzene and methyl isobutyl ketone. This report describes a case of rhabdomyolysis with acute tubular necrosis and renal failure, most likely attributable to toluene, following occupational exposure to thinners while cleaning a steel water tank. These adverse health effects have previously been reported following acute poisoning or intentional inhalation by drug abusers, but rarely in the occupational setting. Poor working conditions, lack of health and safety training and delayed treatment contributed to the onset and severity of the patient's complications. This case emphasizes the need for strict control measures, including adequate ventilation, training on working in confined spaces, appropriate personal protective equipment and emergency rescue procedures in such settings. In addition, rhabdomyolysis, acute tubular necrosis and renal failure should be added to safety data material as possible complications of excessive inhalation of thinners.

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 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.

Ischemic Acute Tubular Necrosis due to Diltiazem Overdose.

Diltiazem overdose has a high mortality rate due to cardiotoxicity associated with bradycardia and hypotension. A previous article reported that this type of overdose can cause acute tubular necrosis, which was not pathologically, but rather clinically, diagnosed. We herein report the case of a 55-year-old man who sustained nonoliguric acute kidney injury after taking 60 diltiazem tablets. A kidney biopsy performed six days after admission showed ischemic, not toxic, acute tubular necrosis. The patient's kidney function improved spontaneously. In this case report, we clarify the cause of renal impairment caused by diltiazem overdose pathologically. Physicians should therefore consider ischemic acute tubular necrosis as a cause of kidney injury in patients with diltiazem overdose.

Isquemia fría y supervivencia del injerto. Diferencias entre el primer y segundo injerto de un mismo donante / Cold ischemia and renal graft survival: A paired analysis comparing first and second grafts from the same donor

OBJETIVO: Comparar las características, evolución y supervivencia de las parejas renales procedentes de un mismo donante, con especial interés en el tiempo de isquemia fría (TIF) como factor de riesgo de supervivencia del injerto. MÉTODOS: A partir de nuestra base de datos de trasplantados renales, realizada de forma prospectiva desde 1987 hasta 2015, seleccionamos aquellos injertos emparejados procedentes de un mismo donante cadáver y los dividimos en dos grupos según correspondieran al primer o al segundo injerto. RESULTADOS: Estudiamos un total de 860 riñones emparejados. El TIF medio del primer y segundo grupo fue de 15,12 y 19,16 horas respectivamente. En el segundo grupo se observó una mayor incidencia de necrosis tubular aguda (NTA) y función inicial retrasada del injerto (FRI) (59,9% vs 69,4%; y 54,9% vs 63,5%, respectivamente p < 0,001). No se observaron diferencias significativas entre ambos grupos en las cifras de aclaramiento de creatinina o en la tasa de paso a diálisis. En términos de supervivencia del injerto, no se encontraron diferencias entre el primer y el segundo grupo (18,4 vs 18,1 años respectivamente, Log-rank p = 0,667). Adicionalmente se estudio la isquemia fría del conjunto de injertos, sin apreciar diferencias según su TIF (<14, 14-17, 17-20, >20 horas), el cual no se comportó como un factor de riesgo de supervivencia del injerto (HR=1.014 (p = 0,312)). CONCLUSIONES: La proporción de NTA y FRI es mayor en los segundos trasplantados. Sin embargo, no existen diferencias en términos de supervivencia del injerto a largo plazo. No encontramos evidencia de que un TIF por debajo de 24h se comporte como un factor de riesgo de supervivencia del injerto

OBJECTIVE: To compare the characteristics, clinical course, and survival of pairs of renal grafts from the same donor, with special interest in cold ischemia times (CIT) as a risk factor for graft survival. METHODS: We retrospectively reviewed paired grafts originating from the same cadaver donor from our prospectively recorded database of kidney transplants, from 1987 to 2015. We selected and divided them into two groups depending on whether they corresponded to the first or second graft. RESULTS: We studied a total of 860 paired kidneys. Mean CIT for the first and second groups were 15.12 and 19.16 hours, respectively. In the second group we observed higher incidences of acute tubular necrosis and initial delayed graft function (59.9% vs. 69.4% and 54.9% vs. 63.5%, respectively; p20 hours). For the set of grafts studied, CIT did not act as a risk factor for graft survival (hazard ratio [HR]=1.014; p = 0.312). CONCLUSIONS: The proportion of ATN and DGF were greater in second transplants. However, there were no differences in long-term graft survival. Furthermore, we found no evidence that a CIT for less than 24 hours acted as a risk factor to graft survival