Obstructive Protein Cast Nephropathy in Cynomolgus Monkeys Treated with Small Organic Molecules

2008 ◽  
Vol 45 (6) ◽  
pp. 945-948 ◽  
Author(s):  
R. E. Guzman ◽  
K. Datta ◽  
N. K. Khan
Keyword(s):  
Renal Toxicity ◽  
Obstructive Nephropathy ◽  
Drug Induced ◽  
Cast Material ◽  
Small Organic Molecules ◽  
Cynomolgus Monkeys ◽  
Cast Nephropathy ◽  
Cynomolgus Macaques ◽  
Species Specific ◽  
Tubular Dilatation

We have observed a renal toxicity consistent with an obstructive protein cast nephropathy in cynomolgus macaques but not in other species treated with different therapeutic candidates having a common carboxylic acid moiety, suggesting a species-specific sensitivity. Here, we present renal toxicity findings consistent with a protein cast nephropathy in a 2–week safety study in cynomolgus monkeys. Light microscopic changes consisted of intratubular cast formation, tubular dilatation, interstitial inflammation, and expansion of the medullary interstitium. Tubular cast material was identified as Tamm-Horsfall protein (THP) and, on ultrastructure, crystalloid material was present in vacuoles of tubular epithelium. It is hypothesized that microcrystal formation in the urinary tubular spaces induces aggregation of THP protein and cast formation in monkeys. Drug-induced obstructive nephropathy is not identified as a major problem in humans; thus, the clinical relevance of the above findings in monkeys is not clear.

In Silico Approaches to Study Drug-induced Renal Toxicity

Kidney ◽  
2013 ◽  
pp. 103-120
Author(s):  
Rajiv Govindaraj ◽  
Prasannavenkatesh Durai ◽  
Sangdun Choi
Keyword(s):  
In Silico ◽  
Renal Toxicity ◽  
Study Drug ◽  
Drug Induced ◽  
Approaches To Study

scholarly journals New Frontiers: Approaches to Understand the Mechanistic Basis of Renal Toxicity

2018 ◽  
Vol 46 (8) ◽  
pp. 1002-1005
Author(s):  
Mary B. Nabity ◽  
Joseph W. Polli ◽  
Vishal Vaidya ◽  
Andrzej Krolewski ◽  
Warren E. Glaab
Keyword(s):  
Renal Toxicity ◽  
Kidney Injury ◽  
Scientific Session ◽  
Diabetic Patients ◽  
Drug Induced ◽  
Research Areas ◽  
Novel Biomarkers ◽  
Mechanistic Basis ◽  
New Research

A scientific session entitled “New Frontiers: Approaches to Understand the Mechanistic Basis of Renal Toxicity” focused on novel biomarkers to monitor kidney injury both preclinically and clinically, as well as providing mechanistic insight of the induced injury. Further, the role and impact of kidney membrane transporters in drug-induced kidney toxicity provided additional considerations when understanding kidney injury and the complex role of drug transporters in either sensitivity or resistance to drug-induced injury. The onset of nephropathy in diabetic patients was also presented, focusing on the quest to discover novel biomarkers that would differentiate diabetic populations more susceptible to nephropathy and renal failure. The session highlighted exciting new research areas and novel biomarkers that will enhance our understanding of kidney injury and provide tools for ensuring patient safety clinically.

All That Glitters Yellow Is Not Gold: Presentation and Pathophysiology of Bile Cast Nephropathy

2017 ◽  
Vol 25 (7) ◽  
pp. 652-658 ◽  
Author(s):  
Mitchell Pitlick ◽  
Prerna Rastogi
Keyword(s):  
Liver Disease ◽  
Kidney Biopsy ◽  
Kidney Injury ◽  
Renal Tubules ◽  
Drug Induced ◽  
Underlying Liver Disease ◽  
Drug Induced Liver Injury ◽  
Tubular Necrosis ◽  
Cast Nephropathy ◽  
Severe Hyperbilirubinemia

Background. Acute kidney injury (AKI) often manifests in patients with liver disease because of a prerenal cause and presents as acute tubular necrosis or hepatorenal syndrome. Distinguishing between these entities is important for prognosis and treatment. Some patients may develop AKI related to their underlying liver disease: for example, membranoproliferative glomerulonephritis or IgA nephropathy. Bile cast nephropathy is an often ignored differential diagnosis of AKI in the setting of obstructive jaundice. It is characterized by the presence of bile casts in renal tubules, which can possibly cause tubular injury through obstructive and direct toxic effects. Thus, AKI in patients with liver disease may have a structural component in addition to a functional one. Methods. In this study, we describe 2 patients with severe hyperbilirubinemia who developed AKI and underwent a kidney biopsy that revealed bile casts in tubular lumens, consistent with bile cast nephropathy. Results. One patient was treated aggressively for alcoholic hepatitis and required hemodialysis for AKI. The second patient was treated conservatively for drug-induced liver injury and did not require dialysis. Both patients saw a reduction in their bilirubin and creatinine toward baseline. Conclusion. Bile cast nephropathy is an important pathological entity that may account for the renal dysfunction in some patients with liver disease. It requires kidney biopsy for diagnosis and may often be overlooked given the scarcity of kidney biopsy in this particular clinical setting. The etiology is multifactorial, and it is often difficult to predict without the aid of a renal biopsy.

scholarly journals Assessment of Biomarkers of Drug-Induced Kidney Injury in Cynomolgus Monkeys Treated with a Triple Reuptake Inhibitor

2011 ◽  
Vol 120 (2) ◽  
pp. 269-283 ◽  
Author(s):  
Mausumee Guha ◽  
Annabelle Heier ◽  
Sally Price ◽  
Margareta Bielenstein ◽  
Robert G. Caccese ◽  
...  
Keyword(s):  
Reuptake Inhibitor ◽  
Kidney Injury ◽  
Drug Induced ◽  
Cynomolgus Monkeys

scholarly journals Infection of cynomolgus macaques (Macaca fascicularis) and rhesus macaques (Macaca mulatta) with different wild-type measles viruses

2007 ◽  
Vol 88 (7) ◽  
pp. 2028-2034 ◽  
Author(s):  
H. Sittana El Mubarak ◽  
Selma Yüksel ◽  
Geert van Amerongen ◽  
Paul G. H. Mulder ◽  
Maowia M. Mukhtar ◽  
...  
Keyword(s):  
Measles Virus ◽  
Mononuclear Cells ◽  
Rhesus Macaques ◽  
Wild Type ◽  
Immunological Parameters ◽  
Peripheral Blood Mononuclear ◽  
Cynomolgus Monkeys ◽  
Cynomolgus Macaques ◽  
Measles Vaccination ◽  
Kinetics Of

Both rhesus and cynomolgus macaques have been used as animal models for measles vaccination and immunopathogenesis studies. A number of studies have suggested that experimental measles virus (MV) infection induces more-characteristic clinical features in rhesus than in cynomolgus monkeys. In the present study, both macaque species were infected with two different wild-type MV strains and clinical, virological and immunological parameters were compared. The viruses used were a genotype C2 virus isolated in The Netherlands in 1991 (MV-Bil) and a genotype B3 virus isolated from a severe measles case in Sudan in 1997 (MV-Sudan). Following infection, all rhesus monkeys developed a skin rash and conjunctivitis, which were less obvious in cynomolgus monkeys. Fever was either mild or absent in both species. Virus reisolation profiles from peripheral blood mononuclear cells and broncho-alveolar lavage cells and the kinetics of MV-specific IgM and IgG responses were largely identical in the two animal species. However, in animals infected with MV-Sudan, viraemia appeared earlier and lasted longer than in animals infected with MV-Bil. This was also reflected by the earlier appearance of MV-specific serum IgM antibodies after infection with MV-Sudan. Collectively, these data show that cynomolgus and rhesus macaques are equally susceptible to wild-type MV infection, although infection in the skin seems to follow a different course in rhesus macaques. MV-Sudan proved more pathogenic for non-human primates than MV-Bil, which may render it more suitable for use in future pathogenesis studies.

scholarly journals Cisplatin-Induced Nephrotoxicity and HIV Associated Nephropathy: Mimickers of Myeloma-Like Cast Nephropathy

2017 ◽  
Vol 2017 ◽  
pp. 1-5 ◽  
Author(s):  
Muhammad Siddique Khurram ◽  
Ahmed Alrajjal ◽  
Warda Ibrar ◽  
Jacob Edens ◽  
Umer Sheikh ◽  
...  
Keyword(s):  
Plasma Cell Dyscrasia ◽  
Renal Tubules ◽  
High Electron ◽  
Hiv Patients ◽  
Pneumocystis Jiroveci ◽  
The Third ◽  
Cast Nephropathy ◽  
Myeloma Cast Nephropathy ◽  
Foot Process ◽  
Tubular Dilatation

Myeloma cast nephropathy is an obstructing disorder of renal tubules, caused by precipitation of Bence Jones proteins. Myeloma-like cast nephropathy (MLCN) has been reported in the literature to occur in various primary renal and nonrenal diseases. We present a series of three rare cases of cast nephropathy, two of which are HIV patients, and the third patient is receiving cisplatin-based chemotherapy. However, in all three patients plasma cell dyscrasia has been ruled out. A 30-year-old male was admitted to the hospital with facial cellulitis. The second patient is a 31-year-old male who presented with Pneumocystis jiroveci pneumonia. The third patient was treated with cisplatin-based chemotherapy for carcinoma. First two cases revealed foci of diffuse tubular dilatation containing hyaline casts and interstitial inflammatory infiltrate, in addition to globally sclerotic glomeruli with ultrastructural foot process fusion and mesangium expansion. The third case showed acute tubular injury and cast formation of irregular casts composed of amorphous or granular material of low density admixed with scattered high electron-dense globules. Myeloma-like cast nephropathy and true myeloma cast nephropathy pose similar destructive effects on renal parenchyma. This new pattern of HIV-related nephropathy should be considered in HIV patients with MLCN, once monoclonal gammopathy is ruled out.

Drug-induced dyslipoproteinemia: a report of two cases.

1980 ◽  
Vol 26 (1) ◽  
pp. 163-168
Author(s):  
H K Naito ◽  
M C McHenry ◽  
L A Lewis
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serum Lipoproteins ◽  
Drug Induced ◽  
Drug Induction ◽  
Secondary Form ◽  
Species Specific

Abstract We describe two cases of atypical dyslipoproteinemia due to drug-induction. This secondary form of lipoprotein abnormality is unique because the newly available drug, miconazole, apparently directly delipidated the alpha-lipoproteins in the bloodstream. On closer study we found that the delipidation was caused by the vehicle rather than the fungicide--more specifically, only by the polyethoxylated castor oil in the vehicle. It affects serum lipoproteins both in vitro and in vivo, and the effect is species-specific. In vitro studies indicate that it preferentially delipidates high-density lipoprotein rather than low-density lipoprotein. Because its effects on the serum lipoproteins of rats resemble those on man, and because aortic lesions were produced in rats injected daily (90 mL/L) with this substance, caution is indicated in long-term use of drugs containing this chemical component in the vehicle.

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