Drud-induced nephrotoxicity: Bibliography from January 2003 to December 2005

Drug-induced kidney injury is a major side effect in clinical practice. Renal injury associated with drugs may involve several components of the kidney: glomerulus, tubules, interstitium, and blood vessels. Acute renal failure may occur as a major reaction to many drugs. Moreover, therapeutic agents may induce an allergic reaction leading to interstitial inflammation and tubular damage. In this article, we present an updated version of the bibliography containing the case reports of nephrotoxicity published in the international literature from January 2003 to December 2005.     

Drug-induced nephrotoxicity: bibliography from January 2003 to December 2004

Drug-induced kidney injury is a major side effect in clinical practice. Renal injury associated with drugs may involve several components of the kidney: glomerulus, tubules, interstitium and blood vessels. Acute renal failure may occur as a major reaction to many drugs. Moreover, therapeutic agents may induce an allergic reaction leading to interstitial inflammation and tubular damage. In this article, we present an updated version of the bibliography containing the case reports of nephrotoxicity published in the international literature from January 2003 to December 2004.     

Non-drug-induced nephrotoxicity

Several drugs and other compounds can induce acute and/or chronic nephrotoxicity. The goal of this study was to review clinical features of nephrotoxicity induced by ‘atypical’ or ‘unconventional’ agents, such as environmental agents (metals, minerals, animals), food agents (mushrooms, aristolochic acid, medicinal traditional herbals, dietary supplements, melamine), drugs, and other products (ethylene glycol). Nephrotoxicity varies according to local background, dependent on different food and cultural customs, as well as to differences in local fauna and flora. The incidence of such a phenomenon is not well known. Many different pathophysiological pathways are involved, and the spectrum of renal lesions is rather wide. ‘Epidemic nephrotoxicity’ may occur, as recently illustrated by the melamine epidemics in Chinese infants receiving powdered milk formulas; a rapid reaction to unusual increased frequency of acute kidney injury and nephrolithiasis in young children has led to a rapid analysis from international experts, with subsequent recommendations for diagnosis and care. Nephrotoxicity should be considered when there is any unexplained renal impairment, especially in children.     

Urinary levels of regenerating islet-derived protein III β and gelsolin differentiate gentamicin from cisplatin-induced acute kidney injury in rats

A key aspect for the clinical handling of acute kidney injury is an early diagnosis, for which a new generation of urine biomarkers is currently under development including kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin. A further diagnostic refinement is needed where one specific cause among several potentially nephrotoxic insults can be identified during the administration of multidrug therapies. In this study we identified increases in regenerating islet-derived protein III beta (reg IIIb) and gelsolin as potential differential urinary markers of gentamicin's nephrotoxicity. Indeed, urinary levels of both reg IIIb and gelsolin distinguish between the nephrotoxicity caused by gentamicin from that caused by cisplatin where these markers were not increased by the latter. Reg IIIb was found to be overexpressed in the kidneys of gentamicin-treated rats and excreted into the urine, whereas urinary gelsolin originated from the blood by glomerular filtration. Our results illustrate an etiological diagnosis of acute kidney injury through analysis of urine. Thus, our results raise the possibility of identifying the actual nephrotoxin in critically ill patients who are often treated with several nephrotoxic agents at the same time, thereby providing the potential for tailoring therapy to an individual patient, which is the aim of personalized medicine.     

Effects of gentamicin,lipopolysaccharide, and contrast media on immortalized proximal tubular cells

Aminoglycosides are widely used in the treatment of gram-negative bacterial infections. Gentamicin (GE) acts mainly in proximal tubular cells, where it is uptake via organic anion transport system and it induces a high incidence of nephrotoxicity, which is characterized by tubular necrosis leading to acute renal failure in 10 to 50% of patients. Gram-negative bacteria have lipopolysaccharide (LPS) which is an endotoxin that causes renal damage. Moreover, many patients are undergone exams using radiologic contrast, which is a risk factor to induce a hemodynamic change in the kidney and to develop acute renal failure. Intracellular calcium [Ca2+]i is involved in renal cellular injury and maybe mediate the effects provoked by these drugs. This study was performed to evaluate necrosis, apoptosis and intracellular calcium levels ([Ca2+]i) in LLC-PK1 (epithelial cell line from pig kidney) induced by GE associated with LPS and a low-osmolality media, Hexabrix (HE).     

Nephrotoxicity of recreational party drugs

N-benzylpiperazine (BZP) is the active ingredient in recreational 'party' pills with a stimulant, euphoric mechanism of action akin to that of 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). Many people (ab)use BZP-based party pills usually without any significant toxic effects. However, nephrotoxicity secondary to hyperthermia and rhabdomyolysis has been reported. Another serious renal-related side-effect is hyponatraemia with acute cerebral oedema. There is also evidence that these agents may have a specific toxic effect producing acute kidney injury. Thus, acute kidney injury either direct or secondary to the effects of BZP or MDMA need to be considered when any individual presents with symptoms of a recreational party drug overdose.     

Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity

BACKGROUND: Cisplatin is one of the most widely used chemotherapeutic agents, but the risk of nephrotoxicity frequently hinders the use of higher doses to maximize its antineoplastic effects. The lack of early biomarkers has impaired our ability to initiate potential therapeutic or preventive interventions in cisplatin nephrotoxicity in a timely manner. In this study, we have explored the expression and urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in a mouse model of cisplatin-induced nephrotoxic injury. METHODS: Mice were subjected to intraperitoneal injections of 20 mg/kg (high dose) or 5 mg/kg (low dose) cisplatin. The expression of NGAL was measured in the kidney and urine by Western analysis and immunofluorescence, and compared to changes in serum creatinine and urinary N-acetyl-beta-D-glucosaminidase (NAG). RESULTS: Cisplatin resulted in tubule cell necrosis and apoptosis following the high dose, but not the low dose. By Western analysis, NGAL protein was rapidly induced in the kidney within 3 h of high-dose cisplatin. By immunofluorescence, NGAL was induced predominantly in proximal tubule cells in a punctate cytoplasmic distribution, reminiscent of a secreted protein. NGAL was easily detected in the urine by Western analysis within 3 h of cisplatin administration in a dose- and duration-dependent manner. By comparison, changes in urinary NAG or serum creatinine were not evident until 96 h after cisplatin. Using defined concentrations of purified recombinant NGAL, urinary NGAL excretion following cisplatin administration was quantified to be in the 20-80 ng/ml range. CONCLUSION: The results indicate that NGAL represents an early and quantitative urinary biomarker for cisplatin nephrotoxicity.     

Condyloma. A new epidemic

Condyloma acuminatum of the anus is an increasingly frequent disease that may require a combination of therapies. Large bulky lesions can be reduced with topical freezing, cautery, or the scapel. Topical chemotherapy with podophyllum resin can be supplemented with cancer chemotherapeutic agents. Many of these drugs probably act, at least in part, by stimulating a strong local cellular immune reaction. Dinitrochlorobenzene was used to eradicate lesions that had been resistant to treatment with podophyllum resin. 5-Flourouracil was used as a control. All 23 patients studied were initially skin tested with both agents and randomized to either treatment group. All but one of the dinitrochlorobenzene-treated patients had excellent regressions. Immunotherapeutic agents, such as dinitrochlorobenzene, warrant further study as adjuvant therapeutic agents for this disease.     

Bisphosphonate nephrotoxicity

Bisphosphonates are valuable agents for the treatment of post-menopausal osteoporosis (PMO), hypercalcemia of malignancy, and osteolytic bone metastases. Oral bisphosphonates are used mainly to treat PMO and are not associated with significant nephrotoxicity. In contrast, nephrotoxicity is a significant potential limiting factor to the use of intravenous (IV) bisphosphonates, and the nephrotoxicity is both dose-dependent and infusion time-dependent. The two main IV bisphosphonates available to treat hypercalcemia of malignancy and osteolytic bone disease in the United States are zoledronate and pamidronate. Patterns of nephrotoxicity described with these agents include toxic acute tubular necrosis and collapsing focal segmental glomerulosclerosis, respectively. With both of these agents, severe nephrotoxicity can be largely avoided by stringent adherence to guidelines for monitoring serum creatinine prior to each treatment, temporarily withholding therapy in the setting of renal insufficiency, and adjusting doses in patients with pre-existing chronic kidney disease. In patients with PMO, zoledronate and pamidronate are associated with significantly less nephrotoxicity, which undoubtedly relates to the lower doses and longer dosing intervals employed for this indication. Ibandronate is approved in the US for treatment of PMO and in Europe for treatment of PMO and malignancy-associated bone disease. Available data suggest that ibandronate has a safe renal profile without evidence of nephrotoxicity, even in patients with abnormal baseline kidney function.     

Effects of gentamicin,lipopolysaccharide, and contrast media on immortalized proximal tubular cells

Aminoglycosides are widely used in the treatment of gram-negative bacterial infections. Gentamicin (GE) acts mainly in proximal tubular cells, where it is uptake via organic anion transport system and it induces a high incidence of nephrotoxicity, which is characterized by tubular necrosis [5] leading to acute renal failure in 10 to 50% of patients. Gram-negative bacteria has lipopolysaccharide (LPS) which is an endotoxin that cause renal damage. [1] Moreover, many patients are undergone exams using radiologic contrast, which is a risk factor to induce a hemodynamic change in the kidney and to develop acute renal failure. [6] Intracellular calcium [Ca2+]i is involved in renal cellular injury [7,3] and maybe mediate the effects provoked by these drugs. This study was performed to evaluate necrosis, apoptosis, and intracellular calcium levels ([Ca2+]i) in LLC-PK1 (epithelial cell line from pig kidney) induced by GE associated with LPS and a low-osmolality media, Hexabrix (HE).     

Comparison of the cytotoxic activities of chemotherapeutic drugs using a human bladder cancer cell line

Summary Many chemotherapeutic drugs have been used to treat patients with advanced bladder cancer, but few of these have been evaluated adequately in phase II clinical trials. Continuous cell lines provide one means for comparing the in vitro cytotoxicities of anticancer agents. In this study, a continuous cell line derived from a transitional cell cancer of the human bladder, which still produces tumours histologically similar to the tumour of origin on xenotransplantation, was used to measure the in vitro cytotoxicities of twelve chemotherapeutic drugs by clonogenic assay. The most cytotoxic agents tested were methotrexate, mitoxantrone, adriamycin, mitomycin C and cisplatin. These in vitro findings are compatible with the activity of these drugs given systemically as single agents in phase II clinical trials in patients with advanced bladder cancer.     

Acute interstitial nephritis associated with ulcerative colitis

Although drugs used in inflammatory bowel diseases (IBD) cause renal injury, glomerulopathies may also accompany IBD. We report a case with the rare association of ulcerative colitis (UC) and acute progressive interstitial nephritis. Although the kidney is acknowledged as a target organ for injury as a result of drug nephrotoxicity, our findings lend support to the novel recognition that the deranged autoimmune system emerging in UC causes interstitial nephritis as an extraintestinal manifestation. Overt renal failure due to interstitial nephritis has rarely been reported in UC patients. The case presented here therefore provides novel information on UC-associated nephropathy.     

Perioperative management of the patient with chronic kidney disease

The prevalence of chronic kidney disease (CKD) is increasing. Perioperative management of patients with CKD aims to control modifiable risk factors associated with acute kidney injury (AKI). AKI on the background of CKD may lead to dialysis dependency. CKD has widespread cardiovascular, endocrine, metabolic and haematological effects. Preoperative assessment and preparation require multidisciplinary input from the surgical, anaesthetic and nephrology teams. Perioperative care should ensure the correction of hypovolaemia, maintenance of renal blood flow and perfusion pressure, prevention of radiocontrast-induced nephrotoxicity, avoidance of nephrotoxic drugs and treatment of urinary tract obstruction.     

Ifosfamide toxicity in cultured proximal renal tubule cells

Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that ifosfamide metabolites, particularly chloroacetaldehyde, produced within the kidney contribute to nephrotoxicity. The present study examined the effects of ifosfamide and its metabolites, chloroacetaldehyde and acrolein, on rabbit proximal renal tubule cells in primary culture, using a transwell culture system that allows separate access to apical and basolateral cell surfaces. The ability of the uroprotectant medications sodium 2-mercaptoethanesulfonate (mesna) and amifostine to prevent chloroacetaldehyde-and acrolein-induced renal cell injury was also assessed. Ifosfamide (2,000–4,000 μM) did not affect transcellular inulin diffusion but caused a modest but significant impairment in organic ion transport; this impairment was greater when ifosfamide was added to the basolateral compartment of the transwell. Chloroacetaldehyde and acrolein (6.25–100 μM) produced dose-dependent impairments in transcellular inulin diffusion and organic ion transport. Chloroacetaldehyde was a more potent toxin than acrolein. Co-administration of mesna or amifostine prevented metabolite toxicity. Amifostine was only protective when added to the apical compartment of transwells. These results show that ifosfamide is taken up by renal tubule cells preferentially through their basolateral surfaces, and supports the hypothesis that chloroacetaldehyde is primarily responsible for ifosfamide-induced nephrotoxicity. The protective effect of mesna and amifostine in vitro contrasts with clinical experience showing that these medications do not eliminate ifosfamide nephrotoxicity in vivo.     

Nephrotoxic drugs

The nephrotoxic effects of cyclosporine, aminoglycoside antibiotics, cisplatin, amphotericin B, beta-lactam antibiotics and indomethacin are reviewed. These drugs were chosen because they are among the most frequent causes of renal injury in children. In addition, their nephrotoxicity is caused by different mechanisms. Several generalizations can be made, however. First, agents which cause tubular damage tend to be synergistic in their toxic effects. This synergism is seen when several nephrotoxic drugs are given simultaneously. In addition, the use of a nephrotoxic agent in a patient with pre-existing renal disease can result in severe tubular injury. Second, serum levels of the drug frequently fail to correlate with the degree of nephrotoxicity in individual patients. Third, early signs of renal injury can be subtle (e.g., minor changes in electrolyte excretion) or dramatic (e.g., acute renal failure). The sublte changes are particularly important, since they can be useful predictors of serious nephrotoxicity.     

Nephrotoxicity as a cause of acute kidney injury in children

Many different drugs and agents may cause nephrotoxic acute kidney injury (AKI) in children. Predisposing factors such as age, pharmacogenetics, underlying disease, the dosage of the toxin, and concomitant medication determine and influence the severity of nephrotoxic insult. In childhood AKI, incidence, prevalence, and etiology are not well defined. Pediatric retrospective studies have reported incidences of AKI in pediatric intensive care units (PICU) of between 8% and 30%. It is widely recognized that neonates have higher rates of AKI, especially following cardiac surgery, severe asphyxia, or premature birth. The only two prospective studies in children found incidence rates of 4.5% and 2.5% of AKI in children admitted to PICU, respectively. Nephrotoxic drugs account for about 16% of all AKIs most commonly associated with AKI in older children and adolescents. Nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, amphotericin B, antiviral agents, angiotensin-converting enzyme (ACE) inhibitors, calcineurin inhibitors, radiocontrast media, and cytostatics are the most important drugs to indicate AKI as significant risk factor in children. Direct pathophysiological mechanisms of nephrotoxicity include constriction of intrarenal vessels, acute tubular necrosis, acute interstitial nephritis, and-more infrequently-tubular obstruction. Furthermore, AKI may also be caused indirectly by rhabdomyolysis. Frequent therapeutic measures consist of avoiding dehydration and concomitant nephrotoxic medication, especially in children with preexisting impaired renal function.     

Nephrotoxicity of common drugs used by urologists

Many clinically popular drugs, such as aminoglycoside antibiotics, amphotericin B, radiographic contrast media, analgesics, platinum-based cancer chemotherapy, and cyclosporine, can cause deterioration of kidney function even when the dose has been adjusted properly for renal insufficiency. The authors review the pathophysiologic mechanisms of nephrotoxicity of these drugs and prevention and treatment strategies.     

Asymptomatic arsine nephrotoxicity. A case report

A completely asymptomatic patient with arsine nephrotoxicity is described. The light and electron microscopic appearances of the kidney biopsy specimen are documented. The pathogenesis of the lesions, the usual manifestations of arsine exposure, and how these differed from those seen in our patient, are discussed.     

Kidney Disease After Heart and Lung Transplantation

Kidney disease is a commonly recognized complication of heart and lung transplantation and is associated with increased morbidity and mortality. While the spectrum of kidney disease in this population is wide-ranging, studies indicate that between 3% and 10% of these patients will ultimately develop end-stage renal disease (ESRD). This review examines the risk factors for both acute and chronic kidney injury, with a particular emphasis on the role of calcineurin inhibitor-mediated nephrotoxicity in both these settings. Against the background of current National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, we have further considered and recommended appropriate strategies for long-term management of kidney disease-related manifestations in heart and lung transplant recipients. Specific aspects addressed include retarding progressive renal injury and minimizing nephrotoxicity, as well as treatment of hypertension, hyperlipidemia and anemia. Finally, for patients in this population with advanced kidney disease, renal replacement therapy options are discussed. Based on the impact of chronic kidney disease on outcomes in both heart and lung recipients, we advocate early referral to a nephrologist for patients displaying evidence of significant renal dysfunction.     

Potential Therapeutic Targets for Cisplatin-Induced Kidney Injury: Lessons from Other Models of AKI and Fibrosis

The effectiveness of cisplatin, a mainstay in the treatment of many solid organ cancers, is hindered by dose-limiting nephrotoxicity. Cisplatin causes AKI in 30% of patients. Patients who do not develop AKI by clinical standards during treatment are still at risk for long-term decline in kidney function and the development of CKD. The connection between AKI and CKD has become increasingly studied, with renal fibrosis a hallmark of CKD development. To prevent both the short- and long-term effects of cisplatin, researchers must use models that reflect both types of pathology. Although a lot is known about cisplatin-induced AKI, very little is known about the mechanisms by which repeated low levels of cisplatin lead to fibrosis development. In this review, strategies used in various rodent models to prevent kidney injury, its progression to fibrosis, or both, are examined to gain mechanistic insights and identify potential therapeutic targets for cisplatin-induced kidney pathologies. Reviewing the results from these models highlights the diverse and highly complex role of cell death, cell senescence, endoplasmic reticulum stress, autophagy, and immune cell activation in acute and chronic kidney injuries. The use of several models of kidney injury is needed for development of agents that will prevent all aspects of cisplatin-induced kidney injury.