Prediction Of Nephrotoxicity Research Articles

A screen for apoptotic synergism between clinical relevant nephrotoxicant and the cytokine TNF-α

Nephrotoxicity remains one of the main reasons for post-market drug withdrawal. Tumour necrosis factor α (TNF-α) secretion has been shown to underlie the nephrotoxicity induced by some of these drugs. Yet, there is currently no reliable and sensitive in vitro assay available to screen for nephrotoxicants of which toxicity largely depends on TNF-α secretion. Therefore, we developed and applied a sensitive fluorescence-based in vitro assay for TNF-α-mediated nephrotoxicity screening using mouse immortalized proximal tubular epithelial cells (IM-PTECs). Our assay allows rapid evaluation of TNF-α-mediated toxicant-induced apoptosis and necrosis using fixed endpoint and live cell measurements. To evaluate our assay, sixteen nephrotoxicants and two control non-nephrotoxicants were used. Out of the sixteen nephrotoxicants, eight induced cell death, of which five induced apoptosis as well as necrosis. Moreover, TNF-α significantly enhanced apoptotic cell death induced by cisplatin, cyclosporine A, tacrolimus and azidothymidine. These nephrotoxicants are known to induce inflammation in vivo which has been linked to an enhancement of nephrotoxicity for cisplatin, cyclosporine A and tacrolimus, confirming the functionality of our assay. Overall, our assay allows rapid and sensitive measurement of apoptosis and necrosis induced by a combination of nephrotoxicants and inflammatory components such as TNF-α and can be used as an alternative assay for nephrotoxicity prediction in vitro.

An in vitro method for the prediction of renal proximal tubular toxicity in humans

The kidney is one of the major target organs for drug-induced toxicity. The renal proximal tubule is frequently affected due to its roles in drug transport and in concentrating the glomerular filtrate. Drug-induced kidney injury is associated with increased morbidity and mortality of patients. During drug development, nephrotoxicity is typically detected only late, which leads to high costs for the pharmaceutical industry. A central problem is the lack of pre-clinical models with high predictability. Regulatory accepted or validated in vitro models for the prediction of nephrotoxicity are not available. We developed a novel in vitro model for the prediction of renal proximal tubular toxicity in humans. It employs human primary renal proximal tubular cells and the expression levels of interleukin (IL)-6 and IL-8 were used as the endpoint. The model was evaluated with 41 well-characterized drugs and chemicals. The median values of the major performance metrics (balanced accuracy, sensitivity, specificity, positive predictive value, negative predictive value and area under the curve of the receiver operating characteristic curve) ranged between 0.76 and 0.85. This revealed that the predictability of the model is high and it would be expected that in ∼76%–85% of the cases where compounds were predicted as positives or negatives the predictions would be correct. Altogether, the data suggest that the model would allow the prediction of drug-induced proximal tubular toxicity at early pre-clinical stages during drug development. Future work will aim at further validating this model and adapting it to recently developed renal proximal tubular-like cells derived from human pluripotent stem cells. A new in vitro model for the prediction of human nephrotoxicity was developed. The model displays high predictability.

Novel human kidney cell lines for better prediction of nephrotoxicity

Novel human kidney cell lines for better prediction of nephrotoxicity

Prediction of nephrotoxicity induced by cisplatin combination chemotherapy in gastric cancer patients

To evaluate the treatment options for nephrotoxicity due to cisplatin combination chemotherapy. We retrospectively reviewed patients who had received cisplatin combination chemotherapy for gastric cancer between January 2002 and December 2008. We investigated patients who had shown acute renal failure (ARF), and examined their clinical characteristics, laboratory data, use of preventive measures, treatment cycles, the amount of cisplatin administered, recovery period, subsequent treatments, and renal status between the recovered and unrecovered groups. Forty-one of the 552 patients had serum creatinine (SCR) levels greater than 1.5 mg/dL. We found that pre-ARF SCR, ARF SCR, and ARF glomerular filtration rates were significantly associated with renal status post-ARF between the two groups (P = 0.008, 0.026, 0.026, respectively). On the receiver operating characteristic curve of these values, a 1.75 mg/dL ARF SCR value had 87.5% sensitivity and 84.8% specificity (P = 0.011). Cessation or reduction of chemotherapy should be considered for patients who have an elevation of SCR levels during cisplatin combination chemotherapy.

Discovery of Metabolomics Biomarkers for Early Detection of Nephrotoxicity

Drug-induced nephrotoxicity is a major concern, since many pharmacological compounds are filtered through the kidneys for excretion into urine. To discover biochemical biomarkers useful for early identification of nephrotoxicity, metabolomic experiments were performed on Sprague-Dawley Crl:CD (SD) rats treated with the nephrotoxins gentamicin, cisplatin, or tobramycin. Using a combination of gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS), a global, nontargeted metabolomics analysis was performed on urine and kidney samples collected after one, five, and twenty-eight dosing days. Increases in polyamines and amino acids were observed in urine from drug-treated rats after a single dose, and prior to observable histological kidney damage and conventional clinical chemistry indications of nephrotoxicity. Thus, these metabolites are potential biomarkers for the early detection of drug-induced nephrotoxicity. Upon prolonged dosing, nephrotoxin-induced changes included a progressive loss of amino acids in urine, concomitant with a decrease in amino acids and nucleosides in kidney tissue. A nephrotoxicity prediction model, based on the levels of branched-chain amino acids in urine, distinguished nephrotoxin-treated samples from vehicle-control samples, with 100%, 93%, and 70% accuracy at day 28, day 5, and day 1, respectively. Thus, this panel of biomarkers may provide a noninvasive method to detect kidney injury long before the onset of histopathological kidney damage.

Hyperuricemia and hypoalbuminemia predispose to cisplatin-induced nephrotoxicity.

The usefulness of pretreatment biochemical parameters in the prediction of nephrotoxicity associated with cisplatin treatment was studied. Twenty-two patients, who received 29 cycles of cisplatin, were evaluated. Cisplatin was given every 3-4 weeks with saline and mannitol. Azotemia occurred in almost all patients and was transient, peaking 1-2 weeks after therapy. The change in serum creatinine from baseline to peak correlated inversely with pretreatment serum albumin (r = -0.73; P less than 0.01) and with pretreatment uric acid (r = 0.76; P less than 0.01). Ten patients with uric acid levels of less than 6 mg/dl were receiving allopurinol. The competition between organic anions and cisplatin for excretion may, in part, explain the protective effects of hypouricemia. Hypoalbuminemia affects peritubular oncotic pressure and may in turn affect platinum excretion. Hypoalbuminemia also reduces the half-life of cisplatin, exposing the kidney to more of the unbound filterable drug.