Assessment of extended urine protein monitoring frequency in patients receiving bevacizumab.

PURPOSE: Proteinuria monitoring is required for patients receiving bevacizumab. Nonetheless, the frequency of monitoring is not specified in the package insert. A 2014 quality improvement study performed at Yale New Haven Health System (YNHHS) found that proteinuria occurred in 15% (all grade) of the 162 patients evaluated. These results led to decreasing the frequency of proteinuria monitoring from every treatment to every other treatment. The objective of this study is to assess the safety of the extended interval for urine protein (UP) monitoring. METHODS: Patients receiving at least four bevacizumab treatments at YNHHS from January to June 2017 were randomly selected and retrospectively reviewed. The following data were collected: baseline patient characteristics, comorbidities, medication history, and proteinuria monitoring. The grade, prevalence and management of proteinuria were evaluated. The minimum necessary sample size was determined to be 384 treatments to achieve a 95% confidence interval. RESULTS: Fifty-five patients and 388 bevacizumab treatments were evaluated. Urine protein was assessed in 52.5% of treatments. The incidence of proteinuria among patients was 7.2% (grade 2) and 0% (grade 3). Cumulative dose and the number of total bevacizumab doses did not affect the timing for onset or severity of proteinuria. Two patients with UP ≥ 2+ were further monitored using a 24-h urine collection test with negative results. No treatments were held due to proteinuria. CONCLUSION: Monitoring proteinuria every other treatment does not increase the frequency of adverse events. Urine protein is now monitored prior to every third bevacizumab treatment, reducing unnecessary labs and chair time.

Urinalysis by combination of the dipstick test and urine protein-creatinine ratio (UPCR) assessment can prevent unnecessary lenvatinib interruption in patients with thyroid cancer.

BACKGROUND: Proteinuria induced by lenvatinib is a class effect that occurs secondary to VEGFR suppression. Withholding of lenvatinib is required in cases with severe proteinuria. Urine protein-creatinine ratio (UPCR, g/gCre) has recently attracted attention as an alternative to 24-h urine collection for assessing proteinuria. The aim of this study was to examine the correlation between the results of proteinuria assessed by the dipstick test and UPCR, and to investigate the influence of proteinuria grading with UPCR on lenvatinib dose adjustment compared to that with only the dipstick test. METHOD: Three hundred and ten urine samples from 63 patients with advanced thyroid cancer under treatment with lenvatinib, which were tested by both the dipstick test and UPCR were analyzed. Lenvatinib was withheld when there was evidence of CTCAE grade 3 proteinuria, and restarted when it resolved. The frequency of proteinuria, correlation between the results of the dipstick test and UPCR test, and the effect of dose withholding in cases with results of 3 + in the dipstick test were calculated. RESULTS: Proteinuria was seen in 56 (88.9%) patients. Of the 154 dipstick 3 + samples, only 56 (36.4%) were judged as more than 3.5 g/gCre by UPCR (grade 3 proteinuria), although none of the 1 + and only 3.7% of 2 + samples were judged as grade 3 proteinuria. We were able to prevent unnecessary lenvatinib interruption due to proteinuria in 63.6% of dipstick 3 + samples by assessment of UPCR. CONCLUSIONS: Urinalysis by combination of the dipstick test and UPCR assessment might be a better strategy for preventing unnecessary interruption of lenvatinib.

Assessment of urinary angiotensinogen as a marker of podocyte injury in proteinuric nephropathies.

Urinary protein (UP) is widely used as a clinical marker for podocyte injury; however, not all proteinuric nephropathies fit this model. We previously described the elevation of urinary angiotensinogen (AGT) accompanied by AGT expression by injured podocytes in a nitric oxide inhibition rat model (Eriguchi M, Tsuruya K, Haruyama N, Yamada S, Tanaka S, Suehiro T, Noguchi H, Masutani K, Torisu K, Kitazono T. Kidney Int 87: 116-127, 2015). In this report, we performed the human and animal studies to examine the significance and origin of urinary AGT. In the human study, focal segmental glomerulosclerosis (FSGS) patients presented with higher levels of urinary AGT, corrected by UP, than minimal-change disease (MCD) patients. Furthermore, AGT was evident in podocin-negative glomerular segmental lesions. We also tested two different nephrotic models induced by puromycin aminonucleoside in Wistar rats. The urinary AGT/UP ratio and AGT protein and mRNA expression in sieved glomeruli from FSGS rats were significantly higher than in MCD rats. The presence of AGT at injured podocytes in FSGS rats was detected by immunohistochemistry and immunoelectron microscopy. Finally, we observed the renal tissue and urinary metabolism of exogenous injected human recombinant AGT (which is not cleaved by rodent renin) in FSGS and control rats. Significant amounts of human AGT were detected in the urine of FSGS rats, but not of control rats. Immunostaining for rat and human AGT identified that only rat AGT was detected in injured podocytes, and filtered human AGT was seen in superficial proximal tubules, but not in injured podocytes, suggesting AGT generation by injured podocytes. In conclusion, the urinary AGT/UP ratio represents a novel specific marker of podocyte injury.

Non-clinical safety assessment of Hwangryunhaedok-tang: 13-week toxicity in Crl:CD Sprague Dawley rats.

Hwangryunhaedok-tang (Huang-Lian-Jie-Du-Tang in Chinese, Oren-gedoku-to in Japanese) is a traditional herbal medicine with a long history of use for anti-inflammatory purposes. In this study, subchronic toxicity of daily oral administration of a Hwangryunhaedok-tang water extract (HHT) at 0, 250, 750, and 2000mg/kg for 13weeks was examined in rats. Mortality, clinical signs, and changes in body weight, food consumption, clinical signs, ophthalmological examination, urinalysis, hematology, serum biochemistry, gross observation, organ weight, and histopathology were monitored in accordance with Good Laboratory Practice and OECD guidelines. We found no mortality or abnormality in clinical signs, body weight, serum biochemistry, or organ weight in HHT-treated groups in either sex. However, there were significant changes in glucose, bilirubin, urobilinogen, protein (only male) in urine after 2000mg/kg/day HHT treatment for both sexes. In hematological examinations, we found a significant decreased number of red blood cells (RBC), whereas, an increased the mean corpuscular volume, number of platelets, and rate of reticulocyte (RET) after 2000mg/kg/day HHT treatment of male rats. In male and female rats, 750 and 2000mg/kg/day HHT treatment decreased the number of RBC and increased RET. Histopathological examinations revealed stomach mucosal erosion in female rats (2000mg/kg/day). No-observed-adverse-effect levels were established for 750mg/kg HHT in rats under the conditions of this study. However, other toxicological studies are necessary to evaluate the safety of HHT fully.

Proteinuria and hypertension in patients treated with inhibitors of the VEGF signalling pathway--incidence, mechanisms and management.

Anti-VEGF therapy dramatically improved the outcome of patients with renal cancer and other advanced malignancies, but may be complicated by proteinuria and hypertension. VEGF is indispensable for the normal development of glomerulus and preservation of glomerular filtration barrier. Interference with its action may result in damage to glomerular endothelial cells and (in severe cases) in renal thrombotic microangiopathy. Blood pressure and proteinuria (using dipstick) should be assessed in all patients before starting anti-VEGF therapy and regularly monitored during the treatment. Patients with severe proteinuria and/or impaired renal function should be referred to the nephrologist for further work-up. Hypertension caused by anti-VEGF therapy can be effectively treated; progression of proteinuria and/or renal dysfunction may require tapering, or even withdrawal of anti-VEGF treatment.

Model-based treatment optimization of a novel VEGFR inhibitor.

AIM: To evaluate dosing and intervention strategies for the phase II programme of a VEGF receptor inhibitor using PK-PD modelling and simulation, with the aim of maximizing (i) the number of patients on treatment and (ii) the average dose level during treatment. METHODS: A previously developed PK-PD model for lenvatinib (E7080) was updated and parameters were re-estimated (141 patients, once daily and twice daily regimens). Treatment of lenvatinib was simulated for 16 weeks, initiated at 25 mg once daily. Outcome measures included the number of patients on treatment and overall drug exposure. A hypertension intervention design proposed for phase II studies was evaluated, including antihypertensive treatment and dose de-escalation. Additionally, a within-patient dose escalation was investigated, titrating up to 50 mg once daily unless unacceptable toxicity occurred. RESULTS: Using the proposed antihypertension intervention design, 82% of patients could remain on treatment, and the mean dose administered was 21.5 mg day⁻¹. The adverse event (AE) guided dose titration increased the average dose by 4.6 mg day⁻¹, while only marginally increasing the percentage of patients dropping out due to toxicity (from 18% to 20.8%). CONCLUSIONS: The proposed hypertension intervention design is expected to be effective in maintaining patients on treatment with lenvatinib. The AE-guided dose titration with blood pressure as a biomarker yielded a higher overall dose level, without relevant increases in toxicity. Since increased exposure to lenvatinib seems correlated with increased treatment efficacy, the adaptive treatment design may thus be a valid approach to improve treatment outcome.

Bevacizumab and ovarian cancer.

PURPOSE OF REVIEW: Vascular endothelial growth factor (VEGF), one of the major pathways involved in tumor angiogenesis, is often overexpressed in epithelial ovarian cancer (EOC), and therefore an attractive target for therapy. This review aims to evaluate the rationale for targeting angiogenic pathways by the usage of the anti-VEGF agent bevacizumab in EOC. RECENT FINDINGS: Bevacizumab monotherapy has been shown to be effective in the treatment of EOC with response rate of 16-21% in phase II trials. In phase III trials, patients with advanced EOC who received combination chemotherapy (paclitaxel + carboplatin) plus bevacizumab with maintenance bevacizumab had significantly longer progression-free survival than those who received chemotherapy alone, but did not prolong overall survival. The most common grade 3/4 adverse events of bevacizumab monotherapy include hypertension and proteinuria, while heavily pretreated patients were at increased risk of bowel perforation. The addition of bevacizumab to the standard chemotherapy in patients with advanced EOC may not be cost-effective. SUMMARY: Bevacizumab has significant activity and is the most promising drug in EOC. However, understanding of its unique adverse events and identification of predictive biomarkers of bevacizumab response are necessary in order to select patients most likely to benefit from this therapy.

Assessment of the extent of oxidative stress induced by intravenous ferumoxytol, ferric carboxymaltose, iron sucrose and iron dextran in a nonclinical model.

Intravenous (i.v.) iron is associated with a risk of oxidative stress. The effects of ferumoxytol, a recently approved i.v. iron preparation, were compared with those of ferric carboxymaltose, low molecular weight iron dextran and iron sucrose in the liver, kidneys and heart of normal rats. In contrast to iron sucrose and ferric carboxymaltose, low molecular weight iron dextran and ferumoxytol caused renal and hepatic damage as demonstrated by proteinuria and increased liver enzyme levels. Higher levels of oxidative stress in these tissues were also indicated, by significantly higher levels of malondialdehyde, significantly increased antioxidant enzyme activities, and a significant reduction in the reduced to oxidized glutathione ratio. Inflammatory markers were also significantly higher with ferumoxytol and low molecular weight iron dextran rats than iron sucrose and ferric carboxymaltose. Polarographic analysis suggested that ferumoxytol contains a component with a more positive reduction potential, which may facilitate iron-catalyzed formation of reactive oxygen species and thus be responsible for the observed effects. Only low molecular weight iron dextran induced oxidative stress and inflammation in the heart.

Confounders in the assessment of the renal effects associated with low-level urinary cadmium: an analysis in industrial workers.

BACKGROUND: Associations of proteinuria with low-level urinary cadmium (Cd) are currently interpreted as the sign of renal dysfunction induced by Cd. Few studies have considered the possibility that these associations might be non causal and arise from confounding by factors influencing the renal excretion of Cd and proteins. METHODS: We examined 184 healthy male workers (mean age, 39.5 years) from a zinc smelter (n = 132) or a blanket factory (n = 52). We measured the concentrations of Cd in blood (B-Cd) and the urinary excretion of Cd (U-Cd), retinol-binding protein (RBP), protein HC and albumin. Associations between biomarkers of metal exposure and urinary proteins were assessed by simple and multiple regression analyses. RESULTS: The medians (interquartile range) of B-Cd (µg/l) and U-Cd (µg/g creatinine) were 0.80 (0.45-1.16) and 0.70 (0.40-1.3) in smelter workers and 0.66 (0.47-0.87) and 0.55 (0.40-0.90) in blanket factory workers, respectively. Occupation had no influence on these values, which varied mainly with smoking habits. In univariate analysis, concentrations of RBP and protein HC in urine were significantly correlated with both U-Cd and B-Cd but these associations were substantially weakened by the adjustment for current smoking and the residual influence of diuresis after correction for urinary creatinine. Albumin in urine did not correlate with B-Cd but was consistently associated with U-Cd through a relationship, which was unaffected by smoking or diuresis. Further analyses showed that RBP and albumin in urine mutually distort their associations with U-Cd and that the relationship between RBP and Cd in urine was almost the replicate of that linking RBP to albumin CONCLUSIONS: Associations between proteinuria and low-level urinary Cd should be interpreted with caution as they appear to be largely driven by diuresis, current smoking and probably also the co-excretion of Cd with plasma proteins.

The threshold level of urinary cadmium associated with increased urinary excretion of retinol-binding protein and beta 2-microglobulin: a re-assessment in a large cohort of nickel-cadmium battery workers.

OBJECTIVE: To evaluate the threshold value of urinary cadmium (CdU) for renal dysfunction on the basis of relationships unconfounded by protein degradation, diuresis and the renal effects associated with chronic smoking. Methods We studied 599 workers (451 men, mean age 45.4 years) who were employed in four nickel-cadmium battery plants for 18.8 years on average. After adjustment for covariates by multiple regression, the CdU threshold values for increased concentrations of retinol-binding protein (RBPU) and b(2)-microglobulin (b(2)-mU) were assessed by logistic regression and benchmark dose analyses using as referents workers with CdU<1 µg/g creatinine. Results Relationships between urinary proteins and CdU (µg/g creatinine) were influenced by sex, age, diuresis and especially smoking. When considering all workers, odds for abnormal RBPU and b(2)-mU were significantly increased from CdU of 6-10 and >10, respectively. The benchmark dose (BMD5) and the benchmark dose lower limit (BMDL5) for a 5% excess in the background prevalence of abnormal RBPU and b(2)-mU were estimated at 5.1/3.0 and 9.6/5.9. When excluding ever smokers, odds for abnormal RBPU and b(2)-mU were both increased only among workers with CdU>10 (OR, 21.8, 95% CI, 6.4-74.4 and OR, 15.1, 95% CI, 3.6-63.1, respectively). In never smokers, these BMD5/BMDL5 of CdU were estimated at 12.6/6.6 and 12.2/5.5 while in ever smokers they were 6.2/4.9 and 4.3/3.5. Conclusions On the basis of associations undistorted by smoking and adjusted for covariates, the BMDL5 of CdU for low-molecular-weight proteinuria induced by occupational exposure to Cd can be reliably estimated between 5.5 and 6.6 µg/g creatinine.

Targeted therapies: a new generation of cancer treatments.

Targeted therapies, which include monoclonal antibodies and small molecule inhibitors, have significantly changed the treatment of cancer over the past 10 years. These drugs are now a component of therapy for many common malignancies, including breast, colorectal, lung, and pancreatic cancers, as well as lymphoma, leukemia, and multiple myeloma. The mechanisms of action and toxicities of targeted therapies differ from those of traditional cytotoxic chemotherapy. Targeted therapies are generally better tolerated than traditional chemotherapy, but they are associated with several adverse effects, such as acneiform rash, cardiac dysfunction, thrombosis, hypertension, and proteinuria. Small molecule inhibitors are metabolized by cytochrome P450 enzymes and are subject to multiple drug interactions. Targeted therapy has raised new questions about the tailoring of cancer treatment to an individual patient's tumor, the assessment of drug effectiveness and toxicity, and the economics of cancer care. As more persons are diagnosed with cancer and as these patients live longer, primary care physicians will increasingly provide care for patients who have received targeted cancer therapy.

Statin safety: an overview and assessment of the data--2005.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statin drugs, have been studied in numerous controlled human research trials involving hundreds of thousands of study participants. Statins have been prescribed for millions of patients. Based on this vast research and clinical experience, statins have been shown to improve lipid blood levels and reduce atherosclerotic coronary artery disease (CAD) risk, resulting in reduced CAD morbidity and mortality, and in several studies, reduced overall ("all-cause") mortality. From a safety perspective, both research trial evidence and clinical practice experience have demonstrated that statins are generally well tolerated. However, as with all pharmaceuticals, safety considerations exist with both monotherapy and combination statin therapy, mainly involving potential adverse effects on muscle, liver, kidney, and the nervous system. The evidence supporting statin-related potential adverse experiences on these organ systems is sometimes strong and based on clear clinical trial evidence (such as the increased risk of muscle enzyme elevation with higher statin doses). The evidence is at other times more speculative, being based on case reports and inconclusive clinical trial data (such as possible favorable or unfavorable effects of statins on cognition). Because the use of statins is so widespread, it is useful for the clinician to understand statin safety issues and the level of available evidence supporting the contention that various adverse effects are caused by statins. This review presents an assessment of statin safety based on an overview of the current statin safety data and their clinical implications.

An assessment of statin safety by nephrologists.

Recently, concerns regarding potential adverse effects of the statins on the kidney have been raised. The Kidney Expert Panel of the National Lipid Association's (NLA) Safety Task Force, made up of 3 nephrologists, was convened to review all of the currently available evidence pertinent to determining whether statins cause kidney injury, independent of the known, rare mechanisms of rhabdomyolysis and allergic, drug-induced, interstitial nephritis. The Panel reviewed published and unpublished evidence and found none that suggested that statins, when used in doses currently approved by the US Food and Drug Administration (FDA), cause kidney injury.

Comparison of renal function parameters in the assessment of cis-platin induced nephrotoxicity.

The early renal function parameters (RFP), i.e. urinary alanine aminopeptidase (AAP), beta-galactosidase (beta GAL), N-acetyl-beta-D-glucosaminidase (NAG), retinol-binding protein (RBP), albumin (ALB), total protein (TP) and the conventional RFP plasma creatinine were assessed in 8 patients before and during treatment with the nephrotoxic antitumor agent cis-platin. Plasma creatinine increased during treatment with cis-platin. In all patients, acute tubular damage was revealed by early RFP. Albumin and total protein excretion patterns suggested alterations in glomerular function. The cumulative change in RBP excretion was related to plasma creatinine concentrations following cis-platin administration. The present study demonstrates that urinary RBP is a valuable parameter for the early assessment of cis-platin-induced nephrotoxicity.

Assessment of the causality of the cadmium--protein relationships in the urine of the general population with reference to the Cadmibel study.

The assessment of acceptable exposure levels to cadmium in the work or general environment frequently relies on the analysis of the relationships between urinary cadmium (an indicator of the body burden) and proteins used as markers of nephrotoxicity. A possibility which cannot be excluded a priori is that the relationships between cadmium and proteins in urine might sometimes result from renal dysfunction unrelated to cadmium toxicity. To test this hypothesis, we have measured cadmium in the urine of 114 pregnant women of whom about 20% had developed a reversible tubular proteinuria. Cadmium excretion was correlated significantly with age but not with duration of pregnancy nor with low molecular weight urinary proteins. This indicates that tubular dysfunction unrelated to cadmium exposure does not necessarily increase cadmium excretion. Hence, these data support the conclusion of the recent Cadmibel Study on the renal tubular effects of cadmium on the general population of Belgium.

Renal toxicity of propyleneimine: assessment by non-invasive techniques in the rat.

The nephrotoxicity of three different dose levels of propyleneimine (10, 20 and 30 microliter/kg body wt) administered intraperitoneally to rats was studied and 20 microliters/kg body weight was found to be the most appropriate sublethal dose. Injection of propyleneimine (10 microliters/kg body wt) produced a small rise in N-acetyl-beta-D-glucosaminidase (NAG) activity, minor histological damage but no change in urine volume. Six rats were injected with 20 microliters/kg body weight, and urine was collected over the following 16 days. An immediate increase in urine volume, osmolality together with a concomitant decrease in specific gravity, was accompanied by a small increase in creatinine excretion and a more marked increase in the sodium and potassium content of urine after the administration of the nephrotoxin. NAG activity increased immediately and peaked on day 3, the activity remained elevated until day 12 when it fell to near normal levels. The activity of both beta-D-galactosidase and beta-D-glucosidase increased 9 days after administration of the nephrotoxin. In contrast, no consistent change was found in the excretion of the brush border marker enzymes, leucine aminopeptidase (LAP), alanine aminopeptidase (AAP) or alkaline phosphatase (ALP). Proteinuria increased sharply the day after injection and remained abnormal. Increased urinary albumin excretion and the predominance of low molecular weight proteins was demonstrated by sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis. Evidence is presented that propyleneimine exerts its early toxic effect on the renal papilla.

[Detection of drug-induced nephrotoxicity]. / Détection de la néphrotoxicité médicamenteuse.

This is a report of a round table organized during the second meeting of Clinical Pharmacology held in Giens (France) in September 1985. At the beginning of the meeting, the clinical aspects of drug-induced nephrotoxicity were reviewed. Thus we tried to precise the real interest of the studies of proteinuria, urinary cytology, enzymuria and fractional clearances of lithium or magnesium. The most interesting part of our discussions was to know the point of view of men working in drugs companies when a renal abnormality is found during a clinical trial of a drug and when previous experimental studies did not find any renal adverse effects of the drug. It was suggested in a such situation to do particular studies. Methods generally used to study renal physiology as autoradiography micropuncture, microinjection had to be performed to localize the action of the drug along the nephron. It was also discussed of the use of isolated perfused kidney as a tool in drug disposition and the use of renal cells culture. A better understanding of the mechanisms of direct renal toxicity of drugs was obtained from the results of experimental models. It is not so easy, at the present time, to know the mechanisms of immunological drug-induced nephrotoxicity. It seems necessary to develop new experimental models. The results obtained in animals with Cl2Hg or D. Penicillamine or gold salts afford to suspect some mechanisms for these types of nephropathies. This aspect of drug induced nephropathy is more complex because there is a large interindividual variation in susceptibility to these drugs.