Systematic review of nephrotoxicity of drugs of abuse, 2005-2016.

BACKGROUND: The United States is faced with an unprecedented epidemic of drug abuse. Every year thousands of Americans visit the emergency departments all over the country with illicit drug related complaints. These drugs have been known to be associated with a range of renal pathologies, from reversible acute kidney injuries to debilitating irreversible conditions like renal infarction. So far, no comprehensive study or systematic review has been published that includes the commonly used street drugs and designer drugs with potential nephrotoxic outcomes. METHODS: We conducted a systematic review of published case reports, case series, and cross sectional studies of nephrotoxicities related to drugs of abuse. Literature review was conducted using PubMed/Medline from January 1, 2005 -December 31, 2016 to search for publications related to drug abuse with a defined renal outcome. Publications which reported renal injury in relation to the use of illicit drugs were selected, specifically those cases with raised creatinine levels, clinically symptomatic patients, for instance those with oliguria and proven renal biopsies. RESULTS: A total of 4798 publications were reviewed during the search process and PRISMA flow chart and Moose protocol regarding systematic reviews were followed. 110 articles were shortlisted for the review. A total of 169 cases from case reports and case series, and 14 case studies were analyzed. Renal manifestations of specific illicit drug abuse were included in this review. CONCLUSION: Based on the evidence presented, a wide range of renal manifestations were found to be associated with drug abuse. If the trend of increasing use of illicit drug use continues, it will put a significant percentage of the population at an elevated risk for poor renal outcomes. This study is limited by the nature of the literature reviewed being primarily case reports and case series.

Protein Carbonylation of an Amino Acid Residue of the Na/K-ATPase α1 Subunit Determines Na/K-ATPase Signaling and Sodium Transport in Renal Proximal Tubular Cells.

BACKGROUND: We have demonstrated that cardiotonic steroids, such as ouabain, signaling through the Na/K-ATPase, regulate sodium reabsorption in the renal proximal tubule. By direct carbonylation modification of the Pro222 residue in the actuator (A) domain of pig Na/K-ATPase α1 subunit, reactive oxygen species are required for ouabain-stimulated Na/K-ATPase/c-Src signaling and subsequent regulation of active transepithelial (22)Na(+) transport. In the present study we sought to determine the functional role of Pro222 carbonylation in Na/K-ATPase signaling and sodium handling. METHODS AND RESULTS: Stable pig α1 knockdown LLC-PK1-originated PY-17 cells were rescued by expressing wild-type rat α1 and rat α1 with a single mutation of Pro224 (corresponding to pig Pro222) to Ala. This mutation does not affect ouabain-induced inhibition of Na/K-ATPase activity, but abolishes the effects of ouabain on Na/K-ATPase/c-Src signaling, protein carbonylation, Na/K-ATPase endocytosis, and active transepithelial (22)Na(+) transport. CONCLUSIONS: Direct carbonylation modification of Pro224 in the rat α1 subunit determines ouabain-mediated Na/K-ATPase signal transduction and subsequent regulation of renal proximal tubule sodium transport.

Involvement of reactive oxygen species in a feed-forward mechanism of Na/K-ATPase-mediated signaling transduction.

Cardiotonic steroids (such as ouabain) signaling through Na/K-ATPase regulate sodium reabsorption in the renal proximal tubule. We report here that reactive oxygen species are required to initiate ouabain-stimulated Na/K-ATPase·c-Src signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine prevented ouabain-stimulated Na/K-ATPase·c-Src signaling, protein carbonylation, redistribution of Na/K-ATPase and sodium/proton exchanger isoform 3, and inhibition of active transepithelial (22)Na(+) transport. Disruption of the Na/K-ATPase·c-Src signaling complex attenuated ouabain-stimulated protein carbonylation. Ouabain-stimulated protein carbonylation is reversed after removal of ouabain, and this reversibility is largely independent of de novo protein synthesis and degradation by either the lysosome or the proteasome pathways. Furthermore, ouabain stimulated direct carbonylation of two amino acid residues in the actuator domain of the Na/K-ATPase α1 subunit. Taken together, the data indicate that carbonylation modification of the Na/K-ATPase α1 subunit is involved in a feed-forward mechanism of regulation of ouabain-mediated renal proximal tubule Na/K-ATPase signal transduction and subsequent sodium transport.

Effects of cardiotonic steroids on dermal collagen synthesis and wound healing.

We previously reported that cardiotonic steroids stimulate collagen synthesis by cardiac fibroblasts in a process that involves signaling through the Na-K-ATPase pathway (Elkareh et al. Hypertension 49: 215-224, 2007). In this study, we examined the effect of cardiotonic steroids on dermal fibroblasts collagen synthesis and on wound healing. Increased collagen expression by human dermal fibroblasts was noted in response to the cardiotonic steroid marinobufagenin in a dose- and time-dependent fashion. An eightfold increase in collagen synthesis was noted when cells were exposed to 10 nM marinobufagenin for 24 h (P < 0.01). Similar increases in proline incorporation were seen following treatment with digoxin, ouabain, and marinobufagenin (10 nM x 24 h, all results P < 0.01 vs. control). The coadministration of the Src inhibitor PP2 or N-acetylcysteine completely prevented collagen stimulation by marinobufagenin. Next, we examined the effect of digoxin, ouabain, and marinobufagenin on the rate of wound closure in an in vitro model where human dermal fibroblasts cultures were wounded with a pipette tip and monitored by digital microscopy. Finally, we administered digoxin in an in vivo wound healing model. Olive oil was chosen as the digoxin carrier because of a favorable partition coefficient observed for labeled digoxin with saline. This application significantly accelerated in vivo wound healing in rats wounded with an 8-mm biopsy cut. Increased collagen accumulation was noted 9 days after wounding (both P < 0.01). The data suggest that cardiotonic steroids induce increases in collagen synthesis by dermal fibroblasts, as could potentially be exploited to accelerate wound healing.

Partial nephrectomy as a model for uremic cardiomyopathy in the mouse.

Because of the plethora of genetic manipulations available in the mouse, we performed a partial nephrectomy in the mouse and examined whether the phenotypical features of uremic cardiomyopathy described in humans and rats were also present in the murine model. A 5/6 nephrectomy was performed using a combination of electrocautory to decrease renal mass on the left kidney and right surgical nephrectomy. This procedure produced substantial and persistent hypertension as well as increases in circulating concentrations of marinobufagenin. Invasive physiological measurements of cardiac function demonstrated that the 5/6 nephrectomy resulted in impairment of both active and passive left ventricular relaxation at 4 wk whereas tissue Doppler imaging detected changes in diastolic function after 6 wk. Morphologically, hearts demonstrated enlargement and progressive fibrosis, and biochemical measurements demonstrated downregulation of the sarcoplasmic reticulum calcium ATPase as well as increases in collagen-1, fibronectin, and vimentin expression. Our results suggest that partial nephrectomy in the mouse establishes a model of uremic cardiomyopathy which shares phenotypical features with the rat model as well as patients with chronic renal failure.