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 Table of Contents  
Year : 2018  |  Volume : 5  |  Issue : 2  |  Page : 36-41

A review of drug-induced renal injury

1 Senior Consultant, Pediatric and Neonatal Intensive Care Unit, Thane, India
2 Sr. Resident, Jupiter Lifeline Hospitals Ltd, Thane, India
3 Chief, Advanced Pediatric Critical Care Centre & Head, Dept of Pediatrics, Wanless Hospital, Miraj, Wanless Hospital, Miraj, India

Date of Submission20-Mar-2018
Date of Acceptance10-Apr-2018
Date of Web Publication30-Apr-2018

Correspondence Address:
Paramanand Andankar
Department of Pediatrics, Jupiter Lifeline Hospitals Ltd. Eastern Express Highway, Service Rd, Next To Viviana Mall, Thane, 400601, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.21304/2018.0502.00371

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Drug- induced acute kidney injury is common in critically ill patients. Understanding the mechanism of drug induced renal damage helps to decide appropriate preventive strategies. Identifying at risk patients and avoidance of nephrotoxic agents is of key importance. Drug dose adjusted for renal function should be used in clinical practice.

Keywords: nephrotoxins, acute kidney injury, xenobiotics

How to cite this article:
Andankar P, Shah K, Patki V. A review of drug-induced renal injury. J Pediatr Crit Care 2018;5:36-41

How to cite this URL:
Andankar P, Shah K, Patki V. A review of drug-induced renal injury. J Pediatr Crit Care [serial online] 2018 [cited 2020 Mar 29];5:36-41. Available from: http://www.jpcc.org.in/text.asp?2018/5/2/36/281118

  Introduction Top

The kidney plays a major role in the excretion of drugs, hormones, and xenobiotics. It is therefore a common site of drug toxicity. The incidence of drug induced acute kidney injury (AKI) varies depending on the definition of AKI and the patient population being studied. In the intensive care unit (ICU), the etiology of AKI is often multifactorial. The use of nephrotoxic drugs has been implicated as a causative factor in up to twenty five percent of all cases of severe acute renal failure in critically ill patients. [1],[2] The purpose of this review is to describe the mechanisms of drug induced renal injury, the risk factors of nephrotoxicity and currently available strategies for its prevention.

[TAG:2]Vulnerability of the kidney[3][/TAG:2]

The susceptibility of the kidney to nephrotoxic injury has several reasons. The kidney receives twenty five percent of resting cardiac output, leading to high rate of drug delivery. The kidney has the greatest endothelial surface per gram of tissue and possesses the highest capillary hydrostatic pressure favoring trapping of circulating antigen and in situ immune complex formation. Tubular transport and other renal metabolic processes utilize considerable oxygen and hence susceptible to ischemic injury. The kidney is the only place where highly protein bound drugs dissociate, traverse the tubular cells and either accumulate within the proximal tubular epithelium and/or reach the tubular lumen. In the distal part of the nephron, urine is concentrated and the likelihood of crystalline precipitation increases substantially, particularly if urinary pH favors decreased solubility

  Metabolism of Xenobiotics Top

Xenobiotics are defined as chemicals or compounds to which an organism is exposed that are extrinsic or foreign to the normal metabolism of that organism[4]. The metabolism of drugs in liver and kidney cells has been described schematically in various phases[5]. Phase 0 for drug uptake and entry via transporter. Phases 1 and 2 for biotransformation exemplified by hydroxylation and glucuronidation. Phase 3 for transport of xenobiotics/metabolites towards excretion (transcellular translocation). Phase 4 for efflux into excreted fluids and/or backward into blood via transporter. (Figure 1)

The principle renal transport systems, which contribute to drug nephrotoxicity, reside in the proximal tubule. Organic anion transporters (OAT) and Organic cation transporters (OCT) are the solute carriers (SLC). OATs are present in both the brush border and basolateral membrane of the proximal tubule and are involved in transport of para-aminohippuric acid (PAH), methotrexate, NSAIDs and antiviral nucleoside analogues. OCTs are localized in the basolateral membrane of the proximal tubule and are primarily involved in tubular secretion of drugs like cimetidine, choline, dopamine, acyclovir and zidovudine. Multi-drug resistant transporter (MDR) also known as P-glycoprotein (P-gp) is located on the brush border of the proximal tubule and acts as an efflux transporter of drugs. Substrates for P-gp include anticancer drugs such as vincristine, vinblastine and doxorubicin, cyclosporine, verapamil, digoxin and steroids including aldosterone. Peptide transporters (PEPT1, PEPT2) are localized to the brush border of the proximal tubule where they facilitate the uptake of beta-lactams, ACE inhibitors, and valacyclovir.

  Patho-physiology of drug induced kidney injury Top

Drugs can have direct nephrotoxic effect by damaging the renal tubules or can be indirectly nephrotoxic by altering the intrarenal blood flow. Understanding various patterns of renal injury helps in providing effective preventive measures.

1Vasoconstriction: This is the main mechanism of acute nephrotoxicity for calcineurin inhibitors and vasopressors and contributes to the nephrotoxicity of amphotericin and contrast agents.

2Altered intraglomerular hemodynamics: This is responsible for the decline in renal function seen with nonsteroidal antiinflammatory drugs (NSAID), angiotensin converting enzyme inhibitors (ACEI), and angiotensin receptor blockers (ARB). In patients with hemodynamic instability and volume depletion, renal perfusion becomes prostaglandin- dependent, thus explaining the nephrotoxic effect of NSAID. Renal dysfunction that accompanies antihypertensive therapy is a result of excessively lowering of blood pressure. ACEI and ARB are more commonly associated with this complication, because any decline in intraglomerular pressure due to blood pressure lowering will be exaggerated by concomitant vasodilation of the efferent arteriole. And even without a decline in blood pressure, the decrease of efferent resistance may result in a lower glomerular filtration rate (GFR) in patients where constriction of the efferent arteriole serves to minimize the decline in GFR such as in patients with absolute or effective reduction in intravascular volume, in patients with obstructive renal vascular disease or in patients receiving drugs associated with afferent vasoconstriction.[6]

3Tubular cell toxicity: The role of the proximal tubule in concentrating and reabsorbing the glomerular filtrate renders it vulnerable to toxic injury. This involves the cellular transport systems mentioned previously and is thus dose dependent to a degree. The S3-segment of the proximal tubule has the highest rate of oxygen delivery/ oxygen consumption of all functional entities in the body and hence most susceptible to ishemia.[7] Tubular injury is associated with use of aminoglycosides, amphotericin, calcineurin inhibitors, cisplatin, methotrexate, antivirals such as foscarnet, cidofovir and antiretrovirals, pentamidine, cocaine, and contrast agents.

4.Interstitial nephritis: This is immunologically mediated event involving the activation of cytokines and occurs in an idiosyncratic and non-dose dependent manner. The onset after drug exposure ranges from 3 to 5 days with a second exposure up to several weeks with a first exposure. It has been associated with antibiotics (beta-lactams, quinolones (especially ciprofloxacin), rifampin, macrolides, sulfonamides, tetracyclines), most NSAID, diuretics (thiazides, loop diuretics, and triamterene), anticonvulsants (phenytoin), cimetidine and ranitidine, allopurinol, antivirals(acyclovir, indinavir), and cocaine. In humans, cell-mediated immunity is probably involved with most cases of drug-induced acute interstitial nephritis.[8]

5.Tubular obstruction: The precipitation of crystals in distal tubular lumens is mostly pH-dependent and explains the nephrotoxicity occurring with acyclovir, sulfonamide, methotrexate, indinavir, and triamterene.[9] Uric acid and calcium phosphate crystals occur in tumor lysis syndrome, most commonly observed following chemotherapy for high-grade lymphoproliferative malignancies.[10]

6.Drug-induced thrombotic microangiopathy:

This has been reported with mitomycin, cyclosporin, tacrolimus, OKT3, interferon, ticlopidine, clopidogrel, cocaine, indinavir and quinine.[9] Only a few cases of angiitis due to drugs have been reported, the most prominent being secondary to methamphetamine.[11]

7.Osmotic nephrosis: The alteration of glomerular filtration pressure caused by hyper-osmolar solution leads to decrease in GFR. The re-uptake of non- metabolized molecules like mannitol into proximal tubular cells by pinocytosis, generates an oncotic gradient, causing swelling and vacuolization of tubular cells. The use of hydroxyethylstarch for resuscitation of hypotensive patients has been associated with increased incidence of AKI.[12] The addition of sucrose to Intravenous immunoglobulin (IVIG) as a stabilizing agent helps decrease the constitutional symptoms of IVIG administration, but increases the risk of acute kidney injury.[13]

8. Rhabdomyolysis : Renal injury secondary to rhabdomyolysis occurs with use of high dose statin[14] and drugs of abuse like heroin, cocaine and methamphetamine.

Prevention of Drug induced Acute Kidney injury

A novel framework to approach drug induced nephrotoxicity focuses on Risk assessment, early Recognition, targeted Response, timely Renal support and Rehabilitation coupled with Research (The 6R approach).[15] [Table 1]

Identification of risk factors in the ICU

The risk factors for nephrotoxicity should be corrected prior to prescribing a potentially nephrotoxic drug, whenever possible. A risk-benefit analysis should be done in presence of non-modifiable risk factors.

  1. True intravascular volume depletion is a recognized risk factor for AKI, although the evidence in the literature is limited due to the difficulty in adequately assessing volume status.[9] The effective circulating volume depletion, in patients with heart failure, third spacing, and sepsis increases the risk of nephrotoxicity. Both true and effective volume depletion result in prostaglandin-dependent renal perfusion, explaining the increased risk of NSAID- induced nephrotoxicity,[16],[17],[18] and in reliance on efferent vasoconstriction for the maintenance of glomerular filtration pressure, explaining the decrease of GFR associated with the use of ACEI and ARB[19].
  2. Patients with sepsis have altered systemic and renal hemodynamics. The synergestic effect of endotoxin and exogeous toxins increases the risk of AKI.
  3. Ischemic and nephrotoxic injuries are induced more readily in sodium-depleted patients because of impaired renal hemodynamics and activation of the renin-angiotensin system.[20]
  4. The concomitant use of diuretics and other drugs (vancomycin, amphotericin B) increases nephrotoxicity, through their effect on circulating volume, through sodium depletion, and also possibly by a tendency to prescribe diuretics in patients developing renal dysfunction.
  5. Acid-base disturbances may exacerbate intrarenal crystal deposition.[21]
  6. Hypoalbuminemia has been shown to increase the risk for cisplatin [22] and aminoglycoside-induced nephropathy.[23]

Role of pharmacokinetics to reduce risk of renal damage

Pharmacokinetic principles do not differ for children versus adults, but the age-dependent variability oftotal body water, metabolic rates, renal tubular function, and protein-binding issues require specific attention. The alterations of pharmacokinetics induced by organ failure and critical illness should be considered and are particularly important for drugs with a small volume of distribution and/or high protein binding. When managing patients with renal impairment, drug doses should be adjusted taking into account all of the following:

  • the usual mechanism of clearance of the drug
  • the degree of renal failure
  • the potential nephrotoxicity of the drug
  • the degree of removal of the drug by renal replacement therapies, and
  • the severity of the condition being treated.

Prevention of aminoglycoside-related AKI

Aminoglycoside demonstrates concentration- dependent bactericidal activity, with a prolonged ‘‘postantibiotic effect’', thereby permitting extended interval dosing in an effort to optimize efficacy and minimize toxicity. When feasible in patients with normal and stable kidney function, once-daily (often referred to as extended-interval) dosing of aminoglycosides should be used to limit aminoglycoside nephrotoxicity. [24] Single-dose daily regimens are difficult to apply in patients with preexisting kidney disease, and patients with altered hemodynamics, such as critically ill patients in the ICU setting. The changing pharmacokinetics and pharmacodynamics of aminoglycosides in the critically ill patient, are such that the avoidance of single-daily dosing and application of frequent therapeutic drug monitoring is indicated.[25] Aminoglycoside drug levels should be monitored when treatment with multiple daily dosing is used for more than 24 hours or single-daily dosing is used for more than 48 hours.[24] The risk of AKI attributable to aminoglycosides is sufficiently high, hence they should no longer be used for standard empirical or directed treatment, unless no other suitable alternatives exist[26].

Prevention of amphotericin B-related AKI

The broad-spectrum, polyene, antifungal agent amphotericin B deoxycholate is the mainstay of treatment for systemic mycoses. Adverse events with amphotericin B includes thrombophlebitis, electrolyte disturbances, hypoplastic anemia, and systemic toxicity associated with fever, chills, hypotension, and cytokine release, but drug induced nephrotoxicity remains the prinicpal dose limiting toxicity.[27] Measures like adequate salt repletion,[28] potassium and magnesium replacement and continous 24 hours administration[29] have been used to reduce the risk of nephrotoxicity with amphotericin B deoxycholate. Liposomal amphotericin consists of amphotericin B complexed with hydrogenated soy phosphatidylcholine, distearoylphosphatidylcholine, and cholesterol.[30] Liposomal amphotericin is less nephrotoxic than conventional amphotericin, due to the size of the liposomes preventing interaction of amphotericin B with the cells of the distal tubules.

Prevention of Contrast media induced nephropathy

It is prudent to use either iso-osmolar or lowosmolar iodinated contrast media, rather than high-osmolar iodinated contrast media in patients at increased risk of Contrast media induced nephropathy(CMIN).[31] Extracellular volume expansion at the time of radiocontrast media administration may serve to counteract both the intrarenal hemodynamic alterations and the direct tubulotoxic effects that play a role in the pathophysiology of CMIN. Volume expansion may also directly reduce cellular damage by dilution of the contrast medium, particularly in the medullary tubular segments.

N-Acetylcysteine (NAC), a thiol-containing antioxidant has been used to ameliorate the toxic effects ischemia-reperfusion injury mediated by reactive oxygen species. IV hydration along with oral administration of NAC (12mg/kg) every 12 hours for four total doses is used for CMIN prevention. The prophylactic use of adenosine antagonist theophylline and dopamine agonist fenoldopam is not recommended for prevention of CMIN.[24] Radiological measures[24] to reduce CMIN include-

  • Adapt injection duration to scan duration when performing CT-angiography, so that the injection is not still running when the scan is finished.
  • Use a saline chaser to decrease the amount of contrast media, by using the contrast medium that otherwise would remain in the dead space of the arm veins; this may save 10-20 ml of contrast media.
  • Use 80 kVp; contrast-medium dose may be reduced by a factor of 1.5-1.7 compared to the dose used at 120 kVp since iodine attenuation increases, and combine with increased tube loading (mAs) to maintain signal-to-noise ratio.

Specific Reno-protective agents

Probenecid is a competitive inhibitor of the organic anion transporter, located on the basolateral membrane of proximal tubular cells. It decreases the cellular content of drugs and toxins using this transporter.[32] Probenecid has been administered to decrease the nephrotoxicity of cisplatin[33], sevoflurane,[34] and cidofovir.[35] It should, however, be remembered that probenecid also decreases the renal elimination of these drugs.

Amifostine, an organic thiophosphate that chelates cisplatin, has been demonstrated to be nephroprotective.[36] The protective effect also appears time dependent with maximal protection when administered in morning hours.[37]

Calcium channel blockers may decrease the renal hemodynamic effects of calcineurin inhibitors.[38]

  Conclusion Top

Drug related renal dysfunction is common in critically ill patients. Identificationt of patients with high risk of AKI and avoidance of nephrotoxic substances helps in decreasing such adverse events. Modifiable risk factors (such as volume or sodium depletion, use of diuretics, or the administration of other nephrotoxic drugs) should be corrected and dose adjusted with estimated GFR should be used in clinical practice. A clinical pharmacist should be involved in multidisciplinary critical care team to minimize medication errors.

Source of Funding - Nil

Conflict of Interest - Nil

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