Systematic review of nephrotoxicity of drugs of abuse, 2005–2016

The United States is stricken by an unparalleled crisis of a drug overdose epidemic. In 2011 the National Center for Health Statistics (NCHS) reported that drug overdose death rates were fivefold higher as compared to the 1980s [1]. A survey by the National Survey on Drug Use and Health (NSDUH) in 2011 reported that 24.6 million Americans of ages 12 or older had used illicit drugs over the past month. This represented approximately 9.4% of the population aged 12 or older [2]. Opioids are the most common cause for deaths related to drug overdose while Marijuana is the most common illicit drug used in the United States [2‐4].

According to the Drug Enforcement Agency (DEA), 17.2 billion units of opioids were dispensed at retail level during 2011 compared with 14.9 billion in 2015 [4]. A study estimated that the cost of opioid abuse can go as high as $53.4 billion to cover the legal cost, medical complications, criminal justice system and loss of productivity which is a major portion of the cost and amounts up to $ 42 billion [5]. New psychoactive drugs such as Synthetic Cathinones or Bath Salts are on the rise and patients with their toxicities are presenting to the EDs; they are derivatives of pyrrolidinopropiophenone [MDPV] or mephedrone [6]. They are not commonly tested for during drug screening and are available as various products not yet labeled as controlled substances, allowing a “legal high”. Thus they have a higher affinity for abusers as well as peddlers [4].

There is a wide range of renal manifestations in subjects exposed to elicit drugs ranging from prerenal azotemia to more severe functional and structural injuries. Rhabdomyolysis is a common cause of acute kidney injury (AKI) which is incited by a number of reasons such as prolonged immobilization as seen in opioid users [7]. Rhabdomyolysis is also evident in patients presenting with synthetic cannabinoids and synthetic cathinones abuse but these patients have rhabdomyolysis possibly due to exertional muscular breakdown [8‐10].One of the notable causes of renal injury in drug abusers is an increase in the sympathomimetic activity which leads to generalized vasoconstriction and ischemic renal injury; this scenario is usually witnessed in patients with cocaine and methamphetamine abuse [11‐13]. Newer opioids and methamphetamines can cause thrombotic microangiopathy (TMA) [14].

Direct renal injury due to illicit drugs have been suggested but most of the reported direct injury is by mode of glomerular immunoglobulin and amyloid deposition such as in heroin abusers [15, 16]. Adulterants such as levamisole which is used to cut cocaine is known for its immunomodulatory properties that can cause antineutrophil cytoplasmic antibodies (ANCA)-vasculitis [17, 18].

To our knowledge, there is no comprehensive report or systematic review that includes the commonly used street and designer drugs with potential nephrotoxic outcomes. In this review, we are summarizing the nephrotoxicities of common and emerging drugs of abuse.

A total of 2846 publications were reviewed during the search process through PubMed/Medline while 1952 number of publications were reviewed through the reference list of selected articles. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (Fig. 1 PRISMA) flow chart and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) protocol were followed. 110 articles were shortlisted for the review [19]. Two investigators independently screened all abstracts and assessed the studies for eligibility, then extracted data on specific drugs and their nephrotoxic effects. Selection of articles was based on the title and abstracts but in case of uncertainty, the entire text of an article was read. All literature was catalogued in Mendeley. The primary outcome assessed was the nephrotoxic effects of the abovementioned illicit drugs. A total of 169 cases from case reports and case series with clinical parameters and outcomes reported with or without kidney biopsy were included as shown in Table 1. Table 1 summarizes the different illicit drugs and their patient demographics, showing that a majority of the illicit drug users were male except for Levamisole adulterated cocaine cases. Cases came from a range of ages 2 years to 65 years. Cocaine and Synthetic Cannabinoids (SCB) abuse led to the highest systolic and diastolic blood pressures whereas in other cases there wasn’t such a marked increase or decrease. The pulse was raised with all drugs of abuse and cases mostly presented with gastrointestinal symptoms, hyperthermia, altered mental status or flank pain. Intravenous drug abuse was the most common route used. Where a renal biopsy was performed, the most common outcomes were acute/chronic interstitial nephritis and membranopoliferative glomerulonephritis (MPGN). Amphetamine, Cocaine and levamisole adulterated cocaine users were most likely to need dialysis and amphetamine users were most likely to succumb to death as compared to other illicit drug users.

Fourteen case studies and analyzed case series were identified as shown in Table 2. A case series based on 456 SCB users showed AKI and rhabdomyolysis as the outcomes when SCB were used solely. Heroin users had a high probability of developing amyloidosis, nephrotic syndrome and progression to end-stage renal disease (ESRD). They also had a higher chance of developing rhabdomyolysis as compared to non- Heroin users and were seen to be co-infected with hepatitis C virus (HCV) as well as Human Immunodeficiency Virus HIV. Controlled prescription drugs (CPD) opioids were significantly shown to lead to renal failure (p < 0.001) A post mortem case series on cocaine users showed hypertensive- ischemic nephropathy in most cocaine users. Levamisole adulterated cocaine users were prone to be anti-neutrophil cytoplasm antibodies (ANCA) positive after long term drug use with a 100% prevalence of anti-myeloperoxidase antibodies. Amphetamine case series showed varied effects such as rhabdomyolysis leading to renal failure, malignant hypertension with hypertensive changes on biopsy and in one case series, death of all the subjects due to AKI and rhabdomyolysis.

Seven cases of hyperemesis were gathered during the data search with their clinical parameters as shown in Table 3, while 6 cases of N-methyl-D-aspartate receptor (NMDA) receptor agonist from two studies were tabulated in as shown in Table 4. Renal biopsy findings in selected patients with drug abuse are shown in Fig. 2. Data presented are specified by type and route (if reported) of drug exposure. Units of laboratory values are all presented in SI units.

The use of illicit drugs continues to surge and is approaching epidemic proportions throughout the United States. With nearly 10% of the population older than 12 having taken drugs for nonprescription purposes in the last month (2), new synthetic substances being introduced into the market and increased ease of access there will undoubtedly be a continual increase in the negative medical, financial and societal outcomes. The pathophysiology underlying renal injury from drugs of abuse continues to be delineated as research into this condition develops. Studies performed to date have elucidated specific mechanisms of injury. However, many of the studies are confounded by multiple illicit substance or comorbid conditions such as HIV or hepatitis. Continued resources, education and research are needed to fully understand the myriad of renal insults related to drugs of abuse.