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Toxic acute kidney injury
Clinical Queries: Nephrology 0101 (2012) 29–33
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Clinical Queries: Nephrology January–March 2012, Vol. 1/Issue 1
j o u r n a l h o m e p a g e : h t t p : / / w w w. e l s e v i e r. c o m / l o c a t e / c q n
ISSN No.: 2211-9477
Toxic acute kidney injury Dharmendra Bhadauria*, Nitin Agrawal† *Assistant Professor, †Senior Resident, Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow – 226014, India.
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Article history: Received 9 November 2011 Accepted 20 November 2011
Keywords: Acute kidney injury Drug-induced AKI Toxins-induced AKI
a b s t r a c t
The kidney is a major organ in the human body carrying out the essential metabolic functions. Metabolism and excretion of exogenously administered therapeutic and diagnostic agents as well as environmental exposures are other major functions of kidneys. Kidney is vulnerable to develop various form of injury via virtue of its role as the primary eliminator of exogenous drugs, and toxins. Toxic kidney injury is an important and relatively common category of kidney damage. Several classes of dissimilar toxicants target the kidney. Despite the widespread appreciation of the role of nephrotoxic agents in their contribution to acute kidney injury (AKI), these drugs continue to have an ongoing etiological role. Tubular injury initiated by toxins often results from a combination of acute renal vasoconstriction and direct cellular toxicity due to intracellular accumulation of the toxin, or, alternatively, may be mediated immunologically in case of interstitial nephritis. Patients with reduced renal functional reserve, cardiovascular co-morbidity, diabetes mellitus, and advanced age are at increased risk. Awareness of the range of toxins on the one hand and simple mea sures such as adequate pre-hydration of the patient and drug monitoring on the other hand may be sufficient to avoid drug-induced AKI or minimize its clinical severity in susceptible patients. Copyright © 2012, Reed Elsevier India Pvt. Ltd. All rights reserved.
Introduction The kidney is a major organ in the human body carrying out the essential functions like clearance of metabolic waste products, control of fluid volume status, maintenance of electrolyte and acid–base balance, and endocrinal function. Metabolism and excretion of exogenously administered therapeutic and diagnostic agents as well as environmental exposures are other major functions of kidneys. Kidney is vulnerable to develop various form of injury (Table 1) via virtue of its role as the primary eliminator of exogenous drugs and toxins. Toxic kidney injury is an important and relatively common category of kidney damage. They generally are reversible when detected early but they may be permanent, leading to chronic kidney disease (CKD). A primary reason for the susceptibility of the kidney to the toxic action of environmental chemicals is the large blood flow and the resulting high concentrations of toxicant delivery to the kidney; renal blood flow (RBF) comprises 20–25% of the cardiac output. The kidney also hosts a variety of organic solute and ion transporters, and xenobiotic metabolizing enzymes that can concentrate and metabolize toxic compounds and damage cells of the nephron. The ability of the kidney to concentrate urine can result in increased localized concentrations of toxicants and initiate renal dysfunction. Several classes of dissimilar toxicants target the kidney (Table 2). Among them are therapeutic agents such as antibiotics, antineoplastics, anesthetics, diuretics, immunosuppressant, radiocontrast agents, and non-steroidal anti-inflammatory drugs (NSAIDs). Other nephrotoxic compounds include heavy metals, halogenated aliphatic hydrocarbons, herbicides/fungicides, mycotoxins, plant alkaloids, organic
solvents, and volatile hydrocarbons such as petroleum fuels. Many of the latter classes of compounds exist as industrial pollutants and natural products. Despite the widespread appreciation of the role of nephrotoxic agents in their contribution to AKI, these drugs continue to have an ongoing etiological role. Potentially nephrotoxic drugs include nonsteroidal anti-inflammatory drugs, radio contrast agents; antimicrobial, cancer chemotherapeutic agents and anesthetic agents. Endogenous compounds such as myoglobin and hemoglobin may furthermore cause toxic nephropathy. Tubular injury initiated by toxins often results from a combination of acute renal vasoconstriction and direct cellular toxicity due to intracellular accumulation of the toxin, or, alternatively, may be mediated immunologically in case of interstitial nephritis. Patients with reduced renal functional reserve, cardiovascular co-morbidity, diabetes mellitus, and advanced age are at increased risk. Awareness of the range of toxins on the one hand and simple measures such as adequate pre-hydration of the patient and drug monitoring on the other hand Table 1 Acute kidney problems caused by nephrotoxins. ● ● ● ● ● ● ● ● ●
*Corresponding author. E-mail address: [email protected] ISSN: 2211-9477 Copyright © 2012. Reed Elsevier India Pvt. Ltd. All rights reserved. doi: 10.1016/S2211-9477(11)70004-8
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Prerenal azotemia Acute tubular necrosis Acute interstitial nephritis Acute glomerulonephritis Crystal nephropathy Obstructive nephropathy Renal tubular acidosis/Fanconi syndrome Sodium wasting (Bartter-like syndrome) Potassium wasting Distal renal tubular acidosis Nephrogenic diabetes insipidus
D. Bhadauria & N. Agrawal / Clinical Queries: Nephrology 0101 (2012) 29–33
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Table 2 Commonly encountered nephrotoxic agents and exposures. Drugs
Alternative medications
Diagnostic agents
Environmental agents
Antimicrobial
Herbal remedies
Radiocontrast
Heavy metals
High osmolar, low osmolar, iso-osmolar
Lead, mercury, uranium, bismuth
Aminoglycosides, anti-viral agents, amphotericin B, colistin, sulphadiazine, ciprofloxacin
Aristolochic acid, ephedra, glycyrrhiza sp., taxus celebica, uno degatta, cape aloes
Chemotherapy
Adulterants
Other agents
Solvents
Platins, ifosphamide, mitomycin, gemcitabine, methotrexate, pentostatin, interleukin-2, anti-angiogenesis agents
Mefenamic acid, melamine, cadmium, phenylbutazone, dichromate
Gadolinium (in high-dose), oral NaP solution (colonoscopy preparation)
Hydrocarbons
Analgesics
Other nephrotoxin Silicon, cadmium
NSAIDs, selective COX-2 inhibitors, phenacitin, analgesic combination
Immunosuppressive Sirolimus, calcineurin inhibitors Others ACEIs/ARBs, methoxyflurane, sucrose, hydroxyethyl starch, mannitol, pamidronate, zolendronate, topiramate, zonisamide, orlistat, statins, mesalamine ACEI: angiotensin converting enzyme inhibitor, ARB: angiotensin receptor blocker, COX-2: cyclooxygenase-2, NSAID: non-steroidal anti-inflammatory drugs. Table 3 Risk factors for toxic nephropathy. Kidney-specific factors ● ●
●
●
● ●
Hypoxic renal environment Concentration of drugs and toxin in renal medulla & interstitium High blood flow and drug delivery rate to the kidneys Generation of Reactive Oxygen Species causing oxidative stress Proximal tubular uptake of toxins High metabolic rate of tubular cells in the loop of Henle
Patient-specific factors ● ● ● ● ●
●
● ●
Drug-specific factors
Older age Female sex Nephrotic syndrome, cirrhosis, obstructive jaundice Acute or chronic kidney disease Metabolic disturbances – Hypokalemia, hypomagnesemia, hypocalcemia, hypercalcemia – Alkaline or acid urine pH True or effective circulating decline circulatory volume – Diminished glomerular filtration rate – Increased proximal tubular toxin reabsorption – Sluggish distal tubular urine flow rates Immune response genes Increased allergic reactions to drugs Pharmacogenetics favoring drug/toxin toxicity – Gene mutations in hepatic and renal cytochrome P450 enzyme systems – Gene mutations in transport proteins and renal transporters
may be sufficient to avoid drug-induced acute kidney injury (AKI) or minimize its clinical severity in susceptible patients. Risk factors for renal toxicity Susceptibility of a patient to nephrotoxicity from drugs or toxicant exposure is related to many factors. These are the how kidney hands drugs and toxins, underlying host characteristics and co-morbid conditions, and the inherent nephrotoxicity of the offending agent. Older age, female sex, diabetes mellitus, underlying kidney disease, hypertension, and congestive heart failure are some of examples of factors that have significant influence on the patient’s ability to tolerate and/ or recover from the toxic injury. There are three major categories of risk factors like kidney-specific factors, patient-specific factors and drug/toxin-related factors (Table 3). Each risk factor contributes to the increased development of nephrotoxicity. Generally, more than one risk factor is acting to cause various forms of kidney disease. These factors explain the variability and heterogeneity with drug- or toxin-induced nephrotoxicity.
Pathogenesis Nephrotoxic epithelial cell injury can result in AKI and can be mediated via a variety of mechanisms. After direct or indirect chemicalinduced injury, renal epithelial cells either repair and regenerate or die. If the degree of cell death is sufficient, then overall renal function declines and AKI results. Indirect chemical insults may decrease RBF, thereby causing renal ischemia and reperfusion-induced cell injury and death. Furthermore, recent studies demonstrate that the
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●
●
● ●
●
igh-dose of drug and toxin exposure and H prolonged course of therapy Insoluble drug or metabolite forms crystals within intratubular lumens Potent direct nephrotoxic effects of the drug or toxin Drug combinations enhance nephrotoxicity Competition between endogenous and exogenous toxins for renal tubular excretory transporters increase Intracellular toxin accumulation
T and B cells and, to a lesser extent, macrophages and neutrophils inhibit renal function in AKI.1,2 The role of inflammatory cells in AKI is likely secondary to the initial insult and occurs during the maintenance phase of AKI.3,4 These examples highlight the premise that multiple mechanisms are involved in the pathophysiology of nephrotoxic epithelial cell injury and AKI. A secondary effect of nephrotoxicant-induced cell death in AKI can be the generation of back leak after an insult, injured and dead epithelial cells release from the basement membrane and adhere via integrins to other released and attached epithelial cells.4–7 The cellular aggregates can form tubular casts that block the flow of filtrate and increase intraluminal pressure, decreasing the single nephron glomerular filtration rate (GFR).4 In addition, the loss of epithelial cells can leave gaps in the basement membrane allowing tubular filtrate to back leak into the circulation, further decreasing the apparent single nephron GFR as currently measured. Thus, back leak and the loss of epithelial cells contribute to the decreased renal function. The susceptibility of the kidney to various agents can be attributed to several functional properties of this organ. These properties include: (a) receiving 20–25% of the cardiac output, ensuring high levels of toxicant delivery over a period of time; (b) extensive reabsorptive capacity with specialized transporters promoting cellular uptake of the toxicant; (c) urinary concentrating capacity that results in high concentrations of toxicants in the medullary lumen and interstitium; (d) biotransformation enzymes resulting in the formation of toxic metabolites and reactive intermediates; (e) high metabolic rates and workload of renal cells resulting in increased sensitivity to toxicants; and (f) sensitivity of the kidney to vasoactive agents. Nephrotoxicants generally damage specific segments of the nephron, with the proximal tubule (PT) epithelial cell being the primary target. The PT is commonly injured by multiple exogenous toxins,
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causing the syndrome of acute tubular necrosis (ATN). A classic example of ATN in the PT is aminoglycoside nephrotoxicity while other nephrotoxins that affect this segment include Ifosfamide, cisplatin, zolendronate, and radiocontrast. Acyclic nucleotide phosphonates promote ATN. Heavy metal intoxication with lead, cadmium, and mercury cause proximal tubular injury and ATN. Osmotic proximal tubular injury occurs with various sugars (sucrose, dextran, and mannitol) and starches (hydroxyethyl starch). Furthermore, different segments of the PT (S1, S2, and S3) are targets for different Nephrotoxicants. For example, aminoglycoside antibiotics, chromate, cadmium chloride, and the mycotoxin citrinin primarily affect the S1 and S2 segments, whereas cyclosporine, HgCl2, uranyl nitrate, cisplatin, bromobenzene, and cysteine conjugates of halogenated hydrocarbons affect the S3 segment.8 In addition, interferon, gold, and penicillamine may target cells in the glomeruli, whereas NSAIDs and angiotensin convertising enzyme (ACE) inhibitors may target cells in renal vessels.9 The reasons for these segmental differences may include: (a) differences in toxicant delivery to a given segment; (b) differences in transport and uptake among segments; and (c) differences in biotransformation enzymes among segments. This paper will review the important nephrotoxins like aminoglycoside, Amphotericin B and cisplatin that causes AKI, in brief. Other important nephrotoxic injuries caused by NSAIDs and radio contrast will be discussed by other authors. The pathologic term ATN and the clinical term acute renal failure/AKI are often used interchangeably when referring to ischemic and nephrotoxic renal injury. Aminoglycoside-induced nephrotoxicity Aminoglycoside-induced nephrotoxicity is fairly common, reaching the incidence of 10–25% despite the accurate control and follow-up exercised on patients.10–12 In a survey it was shown that the average incidence of nephrotoxicity caused by specific aminoglycoside antibiotics varies i.e. gentamicin, 14%; tobramycin, 12.9%; amikacin, 9.4%; and netilmicin, 8.9%.13 This incidence is not uniform across the population and varies depending on the target population,14–16 which indicates that some individuals seem to be more sensitive than others. The risk factors for the aminoglycoside nephrotoxicity are summarized in Table 4.
Clinical presentation Aminoglycoside nephrotoxicity is slow in evolution. Depression of GFR typically does not occur before 5–7 days of therapy have been completed. Non-oliguric renal failure is a common expression of aminoglycoside nephrotoxicity.17,30 The urine sediment most commonly shows mild proteinuria, hyaline, and granular casts. Distal tubular dysfunction has two major manifestations are polyuria and hypomagnesemia.10,18 Electrolyte abnormalities include hypomagnesemia, hypokalemia, hypocalcemia, and hypophosphatemia are infrequently observed, secondary to the decrement in PT transport. A Fanconi-like syndrome can occur with glycosuria, aminoaciduria, phosphaturia, and uricosuria.
Clinical course The renal functions usually return to the prior baseline level within 21 days after cessation of therapy. However, resolution of the acute episode may be delayed if the patient remains hypovolemic, septic, or catabolic; in these settings, tubular regeneration cannot occur.19
Pathophysiology Classically, the nephrotoxicity of aminoglycosides has been considered as a tubulopathy. Aminoglycosides are freely filtered across the
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Table 4 The risk factors for the aminoglycoside nephrotoxicity. Patient-related ● ● ● ● ● ● ● ●
Treatment-related
● Older age Reduced renal function ● ● Pregnancy ● Dehydration Renal mass reduction ● Hypothyroidism Hepatic dysfunction Metabolic acidosis
Longer treatment Higher dosages Split dosages Type of aminoglycoside Elevated plasma drug concentrations
Concomitant drugs ● ● ● ● ● ● ● ●
NSAIDs Higher dosage diuretics Amphotericin Cisplatin Cyclosporin Iodide contrast media Vancomycin Cephalosporin
NSAID: non-steroidal anti-inflammatory drug.
glomerulus. It accumulates mainly in the proximal tubular and also in distal collecting epithelial cells due mainly to the giant endocytic complex formed by megalin and cubilin, which is restricted to the PT. These drugs then traffic through the endosomal compartment and accumulate mostly in lysosomes, the Golgi apparatus, and endoplasmic reticulum.20–22 Aminoglycosides binds to membrane phospholipids.23,24 Aminoglycoside containing endoplasmic reticulum ruptures and release its contents including aminoglycoside in the cytosol.25,26 Cytosolic aminoglycosides then acts on mitochondria directly and indirectly, and thus activates the intrinsic pathway of apoptosis, interrupts the respiratory chain, impairs adenosine triphosphate (ATP) production,27,28 and produces oxidative stress by increasing super oxide anions and hydroxyl radicals,29,30 which further contributes to cell death. The lysosomal content bears highly active proteases named cathepsins, which are capable of producing cell death. Tubular effects cannot solely explain the reduced glomerular filtration rate, in the absence of tubular obstruction. Tubular and glomerular mechanisms differentially contribute to the reduced GFR. Tubular dysfunction leads to the loss of fluid and electrolytes that swiftly fire the tubuloglomerular feedback (TGF) response, which reduces RBF and GFR to the appropriate level. However, TGF adapts within hours and its control over GFR is lost even in the presence of an increasing tubular incompetence. In these circumstances, a number of factors may hold GFR low in the absence of TGF-mediated control. Contracting factors produced by mesangial, vascular, and tubular cells, including reactive oxygen species (ROS), platelet-activating factor, angiotensin II, and endothelin-1 act in an autocrine and paracrine manner to induce contraction of glomerular vessels and mesangial cells, which reduce RBF and Kf, respectively, and lower GFR. Reduced GFR and RBF may contribute to aggravating gentamicininduced tubular damage, probably because they limit oxygen and nutrient availability to tubular cells and facilitate oxidative stress, as it has been demonstrated in the ischemic renal failure.
Prevention Clinical strategies that may minimize the potential for nephrotoxicity include: 1. Selection of the least toxic aminoglycoside when possible. 2. Correcting hypokalemia and hypomagnesemia prior to administering an aminoglycoside. 3. Avoid aminoglycosides in patients with reduced effective arterial volume, limiting the duration of therapy from 7 to 10 days, and minimizing concomitant nephrotoxic medications. 4. There is enough data to suggest that single daily dosing has probably less nephrotoxic potential that the same dose given in the divided schedule. 5. Dosing based on individualized drug pharmacokineticsderived from measurements of serum drug concentration would appear to be a rational approach especially in high-risk patients. Several agents have emerged as potential compounds to prevent aminoglycoside nephrotoxicity. Despite their potential, none have
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been adopted clinically for the prevention of aminoglycoside nephrotoxicity. Amphotericin B-induced nephrotoxicity Amphotericin B is an important drug for treatment of invasive fungal infections. An important and common complication is nephrotoxicity, occurring in 5–80% of cases.31–35 The clinical complications include renal insufficiency, urinary potassium and magnesium wasting and hypokalemia and hypomagnesaemia, metabolic acidosis due to type 1 (or distal) renal tubular acidosis, and polyuria due to nephrogenic diabetes insipidus.31–36 The net effect of renal insufficiency is an elevation in the plasma creatinine concentration of up to 2.5 mg/dL.31,34,35,37 Severe renal failure is rare due to Amphotericin B but can occur in presence of other insults to kidney like volume depletion or exposure to amino glycoside, cyclosporine, or foscarnet.34,35,38,39 The nephrotoxicity is dose-dependent and cumulative with the risk of renal dysfunction being relatively low at doses of < 0.5 mg/kg per day and a cumulative dose of < 600 mg.34,35,39 Additional risk factors include chronic renal insufficiency and the severity of the underlying illness.34,35 Both direct tubular injury and renal vasoconstriction are hypothesized to play an important role in pathogenesis of nephrotoxicity.40,41 Amphotericin B increases membrane permeability by creation of pores after insertion into cell membranes,30 possibly due to deoxycholate, a detergent used as a solubilizing agent for amphotericin B40 and TGF system gets activated31,38 due to the increase in membrane permeability in the macula densa cells to NaCl, entry into the cell; this may lead to afferent arteriolar vasoconstriction and a fall in GFR.31,38
Risk factors The risk factors for the occurrence of amphotericin B nephrotoxicity are high-dose and co-therapy with other nephrotoxic agents like aminoglycoside or cyclosporine.34,35 Two preventive measures are salt loading and the use of lipid formulations of Amphotericin B.
Hydration of patient Hydration by saline loading has shown to reduce sensitivity of TGF system due to volume expansion and can protect against or ameliorate the amphotericin B-induced decline in GFR in experimental studies31,32,38,42 but not the signs of other tubular dysfunction like urinary potassium and magnesium wasting.42 Saline loading by volume expansion also used to decreases the release of vasoconstrictors (angiotensin II and norepinephrine) and increases the secretion of the vasodilator atrial natriuretic peptide. These hormonal changes might modify the vasoconstrictive effect of amphotericin B.43
Lipid-based formulations There is enough experimental44 and human data both observational45–48 and randomized trials37 suggesting that the incidence and severity of nephrotoxicity can be minimized by use of amphotericin B in lipid-based formulations. Mechanism of renoprotection is incompletely understood but two theories have been proposed: (1) the liposomal preparation lacks deoxycholate which, is the cause of direct tubular toxicity30; (2) the liposomes may be preferentially distributed to the reticuloendothelial system, where amphotericin B can be transferred directly to trapped fungi, thereby diminishing its delivery to other cholesterol-containing cells such as those in the kidney. Amphotericin B-induced nephrotoxicity is usually reversible with discontinuation of therapy.38,48 It can cause recurrent renal dysfunction on reinstitution of therapy.48
Cisplatin-induced nephrotoxicity Cisplatin is a chemotherapeutic agent use to do renal tubular dysfunction and a cumulative impairment in renal function, as manifested by a decline in the GFR that can be dose-limiting sometime. The multiple mechanisms contribute to cause renal dysfunction following exposure to cisplatin includes tubular epithelial cell toxicity, vasoconstriction in the renal microvasculature, and proinflammatory effects. Cisplatin is a potent cell toxin, particularly in a low chloride environment, after entry into cells, chloride atoms in cisplatin are replaced by water molecules. This product of hydrolysis is said as the active species and reacts with glutathione in the cytoplasm and DNA in the nucleus.49 As this drug is mainly excreted in the urine in the first 24 hours following administration so the concentration of drug found in the renal cortex is several time more than that in plasma and other organs.50,51 Cisplatin primarily injures the S3 segment of the PT, causing a decrease in the GFR.52 Evidences suggest that basolateral drug transporters play a role in cisplatin uptake.53 Changes in expression of PT organic cation transporter-2 (OCT2) have been shown to mediate the accumulation of cisplatin in proximal tubular epithelial cells, which suggests a key role for OCT2 in the development of cisplatin-mediated nephrotoxicity.54–56 Vasoconstriction in the renal microcirculation appears to contribute to decreased RBF soon after cisplatin injection.57,58 Cisplatin increases the expression of proinflammatory cytokines, which promote the differentiation, maturation, and activation of inflammatory cells and their response59,60 also established in animal models of cisplatin-induced AKI. The PT cells are selectively injured by cisplatin, as manifested by both necrosis and apoptosis, even though non-proliferating cells are generally less sensitive to the toxicity of agents that damage DNA.60 Possible reasons for the observed nephrotoxicity of cisplatin include its enhanced renal uptake by organic transporters followed by cisplatin-mediated reduced expression and function of sodiumdependent glucose and amino acid transporters61; reduced expression and function of magnesium and water transporters, metabolism of cisplatin to glutathione and cysteinyl–glycine conjugates62; and the generation of ROS.63,64 The clinical manifestations of cisplatin nephrotoxicity are reduction in GFR, which can be progressive and thrombotic microangiopathy, hypomagnesemia, salt wasting, a Fanconi-like syndrome and anemia. The incidence of renal impairment varies, depending upon the dose and frequency of drug administration and the criteria used to define nephrotoxicity. More than 50% of cases of nephrotoxicity with cisplatin were observed in the initial studies of pre-hydration era.49 The incidence and severity of renal failure is progressive and can eventually become irreversible. These observations apply to the administration of conventional doses of platinum. Renal failure is usually non-oliguric and urine output typically remains above 1000 mL per day due to the induction of a concentrating defect unless renal failure is advanced. This defect may reflect drug-induced damage to the concentration apparatus, loop of Henle or to the collecting tubules, the site of action of antidiuretic hormone.65 Injury to the collecting tubules is associated with decreased expression of aquaporin water channels.66 Cisplatin nephrotoxicity also appears to be mediated by the organic cation transporter (hOCT2).67 An increasing risk of ARF is associated with higher doses of cisplatin that result in high peak plasma free platinum concentrations, previous exposure to cisplatin, pre-existing kidney damage, and the concomitant use of other nephrotoxic agents. The standard approach to prevent cisplatin-induced nephrotoxicity is the administration of lower doses of cisplatin compared with previous regimens in combination with hydration with saline. Although a number of pharmacologic agents like amifostine, sodium thiosulfate, N-acetylcystiene, theophylline and glycine have been evaluated to decrease nephrotoxicity, none has an established role. Treatment of renal failure as general approach to other renal dysfunction or failure and discontinuation of cisplatin. Long-term follow-up of patients exposed to cisplatin-induced nephrotoxicity either remains
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stable or improves over time in patients with a GFR > 60 mL/min per 1.73 m2 at the end of therapy,68,69 such improvement may reflects hyper functioning of remaining of nephrons although unclear.70,71 References 1. Friedewald JJ, Rabb H. Inflammatory cells in ischemic acute renal failure. Kidney Int 2004;66:486. 2. Kelly KJ, Williams WW Jr, Colvin RB, Bonventre JV. Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. Proc Natl Acad Sci USA 1994;91:812. 3. Goligorsky MS, DiBona GF. Pathogenetic role of Arg-Gly-Asp-recognizing integrins in cute renal failure. Proc Natl Acad Sci USA 1993;90:5700. 4. Noiri E, Gailit J, Sheth D, et al. Cyclic RGD peptides ameliorate ischemic acute renal failure in rats. Kidney Int 1994;46:1050. 5. Romanov V, Noiri E, Czerwinski G, Finsinger D, Kessler H, Goligorsky MS. Two novel probes reveal tubular and vascular Arg-Gly-Asp (RGD) binding sites in the ischemic rat kidney. Kidney Int 1997;52:93. 6. Yip KP, Marsh DJ. 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36. Barton CH, Pahl M, Vaziri ND, Cesario T. Renal magnesium wasting associated with Amphotericin B therapy. Am J Med 1984;77:471. 37. Heidemann HT, Gerkens JF, Spickard WA, et al. Amphotericin B nephrotoxicity in humans decreased by salt repletion. Am J Med 1983;75:476. 38. Walsh TJ, Finberg RW, Arndt C, et al. Liposomal Amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med 1999;340:764. 39. Fisher MA, Talbot GH, Maislin G, et al. Risk factors for Amphotericin B-associated nephrotoxicity. Am J Med 1989;87:547. 40. Zager RA, Bredl CR, Schimpf BA. Direct Amphotericin B-mediated tubular toxicity: assessments of selected cytoprotective agents. Kidney Int 1992;41:1588. 41. Heyman SN, Stillman IE, Brezis M, et al. Chronic Amphotericin nephropathy: morphometric, electron microscopic, and functional studies. J Am Soc Nephrol 1993;4:69. 42. Sawaya BP, Weihprecht H, Campbell WR, et al. Direct vasoconstriction as a possible cause for Amphotericin B-induced nephrotoxicity in rats. J Clin Invest 1991; 87:2097. 43. Dórea EL, Yu L, De Castro I, et al. Nephrotoxicity of Amphotericin B is attenuated by solubilizing with lipid emulsion. J Am Soc Nephrol 1997;8:1415. 44. Luke RG, Boyle JA. Renal effects of Amphotericin B lipid complex. Am J Kidney Dis 1998;31:780. 45. Alexander BD, Wingard JR. Study of renal safety in Amphotericin B lipid complextreated patients. Clin Infect Dis 2005;40(Suppl 6):S414. 46. White MH, Anaissie EJ, Kusne S, et al. Amphotericin B colloidal dispersion vs. Amphotericin B as therapy for invasive aspergillosis. Clin Infect Dis 1997;24: 635. 47. Wingard JR, White MH, Anaissie E, et al. A randomized, double-blind comparative trial evaluating the safety of liposomal Amphotericin B versus Amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group. Clin Infect Dis 2000;31:1155. 48. Sacks P, Fellner SK. Recurrent reversible acute renal failure from Amphotericin. Arch Intern Med 1987;147:593. 49. Boulikas T, Vougiouka M. Cisplatin and platinum drugs at the molecular level. (Review). Oncol Rep 2003;10:1663. 50. Litterst CL, Torres IJ, Guarino AM, et al. Plasma levels and organ distribution of platinum in the rat, dog, and dog fish following intravenous administration of cis-DDP (II). J Clin Hematol Oncol 1977;7:169. 51. Safirstein R, Miller P, Guttenplan JB. Uptake and metabolism of cisplatin by rat kidney. Kidney Int 1984;25:753. 52. Choi MK, Song IS. Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet 2008;23:243. 53. Luke DR, Vadiei K, Lopez-Berestein G. Role of vascular congestion in cisplatininduced acute renal failure in the rat. Nephrol Dial Transplant 1992;7:1. 54. Winston JA, Safirstein R. Reduced renal blood flow in early cisplatin-induced acute renal failure in the rat. Am J Physiol 1985;249:F490. 55. Ramesh G, Reeves WB. TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 2002;110:835. 56. Ramesh G, Reeves WB. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol 2005;289:F166. 57. Kelly KJ, Meehan SM, Colvin RB, et al. Protection from toxicant-mediated renal injury in the rat with anti-CD54 antibody. Kidney Int 1999;56:922. 58. Portilla D, Kaushal GP, Basnakian AG. Recent progress in the pathophysiology of acute renal failure. In: Principles of Molecular Medicine 2nd ed, Runge MS, Patterson C, eds. Totawa, NJ: Humana Press 2006:643–9. 59. Xu EY, Perlina A, Vu H, et al. Integrated pathway analysis of rat urine metabolic profiles and kidney transcriptomic profiles to elucidate the systems toxicology of model nephrotoxicants. Chem Res Toxicol 2008;21:1548. 60. Townsend DM, Deng M, Zhang L, et al. Metabolism of Cisplatin to a nephrotoxin in proximal tubule cells. J Am Soc Nephrol 2003;14:1. 61. Baliga R, Ueda N, Walker PD, Shah SV. Oxidant mechanisms in toxic acute renal failure. Drug Metab Rev 1999;31:971. 62. Davis CA, Nick HS, Agarwal A. Manganese superoxide dismutase attenuates Cisplatin-induced renal injury: importance of superoxide. J Am Soc Nephrol 2001; 12:2683. 63. Masuda H, Tanaka T, Takahama U. Cisplatin generates superoxide anion by interaction with DNA in a cell-free system. Biochem Biophys Res Commun 1994; 203:1175. 64. Tanaka-Kagawa T, Kitahara J, Seko Y, et al. Reduced sensitivity of HeLa cells to cisplatinum by simultaneous overexpression of copper, zinc-superoxide dismutase and catalase. Biochem Pharmacol 1999;57:545. 65. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders 5th ed. New York: McGraw-Hill 2001:120–35. 66. Kim SW, Lee JU, Nah MY, et al. Cisplatin decreases the abundance of aquaporin water channels in rat kidney. J Am Soc Nephrol 2001;12:875. 67. Ciarimboli G, Ludwig T, Lang D, et al. Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am J Pathol 2005;167: 1477. 68. Hansen SW, Groth S, Daugaard G, et al. Long-term effects on renal function and blood pressure of treatment with cisplatin, vinblastine, and bleomycin in patients with germ cell cancer. J Clin Oncol 1988;6:1728. 69. Brock PR, Koliouskas DE, Barratt TM, et al. Partial reversibility of cisplatin nephrotoxicity in children. J Pediatr 1991;118:531. 70. Georgaki-Angelaki HN, Steed DB, Chantler C, Haycock GB. Renal function following acute renal failure in childhood: a long term follow-up study. Kidney Int 1989; 35:84. 71. Brenner BM. Nephron adaptation to renal injury or ablation. Am J Physiol 1985; 249:F324.
Contents lists available at ScienceDirect
Clinical Queries: Nephrology January–March 2012, Vol. 1/Issue 1
j o u r n a l h o m e p a g e : h t t p : / / w w w. e l s e v i e r. c o m / l o c a t e / c q n
ISSN No.: 2211-9477
Toxic acute kidney injury Dharmendra Bhadauria*, Nitin Agrawal† *Assistant Professor, †Senior Resident, Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow – 226014, India.
a r t i c l e
i
n f o
Article history: Received 9 November 2011 Accepted 20 November 2011
Keywords: Acute kidney injury Drug-induced AKI Toxins-induced AKI
a b s t r a c t
The kidney is a major organ in the human body carrying out the essential metabolic functions. Metabolism and excretion of exogenously administered therapeutic and diagnostic agents as well as environmental exposures are other major functions of kidneys. Kidney is vulnerable to develop various form of injury via virtue of its role as the primary eliminator of exogenous drugs, and toxins. Toxic kidney injury is an important and relatively common category of kidney damage. Several classes of dissimilar toxicants target the kidney. Despite the widespread appreciation of the role of nephrotoxic agents in their contribution to acute kidney injury (AKI), these drugs continue to have an ongoing etiological role. Tubular injury initiated by toxins often results from a combination of acute renal vasoconstriction and direct cellular toxicity due to intracellular accumulation of the toxin, or, alternatively, may be mediated immunologically in case of interstitial nephritis. Patients with reduced renal functional reserve, cardiovascular co-morbidity, diabetes mellitus, and advanced age are at increased risk. Awareness of the range of toxins on the one hand and simple mea sures such as adequate pre-hydration of the patient and drug monitoring on the other hand may be sufficient to avoid drug-induced AKI or minimize its clinical severity in susceptible patients. Copyright © 2012, Reed Elsevier India Pvt. Ltd. All rights reserved.
Introduction The kidney is a major organ in the human body carrying out the essential functions like clearance of metabolic waste products, control of fluid volume status, maintenance of electrolyte and acid–base balance, and endocrinal function. Metabolism and excretion of exogenously administered therapeutic and diagnostic agents as well as environmental exposures are other major functions of kidneys. Kidney is vulnerable to develop various form of injury (Table 1) via virtue of its role as the primary eliminator of exogenous drugs and toxins. Toxic kidney injury is an important and relatively common category of kidney damage. They generally are reversible when detected early but they may be permanent, leading to chronic kidney disease (CKD). A primary reason for the susceptibility of the kidney to the toxic action of environmental chemicals is the large blood flow and the resulting high concentrations of toxicant delivery to the kidney; renal blood flow (RBF) comprises 20–25% of the cardiac output. The kidney also hosts a variety of organic solute and ion transporters, and xenobiotic metabolizing enzymes that can concentrate and metabolize toxic compounds and damage cells of the nephron. The ability of the kidney to concentrate urine can result in increased localized concentrations of toxicants and initiate renal dysfunction. Several classes of dissimilar toxicants target the kidney (Table 2). Among them are therapeutic agents such as antibiotics, antineoplastics, anesthetics, diuretics, immunosuppressant, radiocontrast agents, and non-steroidal anti-inflammatory drugs (NSAIDs). Other nephrotoxic compounds include heavy metals, halogenated aliphatic hydrocarbons, herbicides/fungicides, mycotoxins, plant alkaloids, organic
solvents, and volatile hydrocarbons such as petroleum fuels. Many of the latter classes of compounds exist as industrial pollutants and natural products. Despite the widespread appreciation of the role of nephrotoxic agents in their contribution to AKI, these drugs continue to have an ongoing etiological role. Potentially nephrotoxic drugs include nonsteroidal anti-inflammatory drugs, radio contrast agents; antimicrobial, cancer chemotherapeutic agents and anesthetic agents. Endogenous compounds such as myoglobin and hemoglobin may furthermore cause toxic nephropathy. Tubular injury initiated by toxins often results from a combination of acute renal vasoconstriction and direct cellular toxicity due to intracellular accumulation of the toxin, or, alternatively, may be mediated immunologically in case of interstitial nephritis. Patients with reduced renal functional reserve, cardiovascular co-morbidity, diabetes mellitus, and advanced age are at increased risk. Awareness of the range of toxins on the one hand and simple measures such as adequate pre-hydration of the patient and drug monitoring on the other hand Table 1 Acute kidney problems caused by nephrotoxins. ● ● ● ● ● ● ● ● ●
*Corresponding author. E-mail address: [email protected] ISSN: 2211-9477 Copyright © 2012. Reed Elsevier India Pvt. Ltd. All rights reserved. doi: 10.1016/S2211-9477(11)70004-8
● ●
Prerenal azotemia Acute tubular necrosis Acute interstitial nephritis Acute glomerulonephritis Crystal nephropathy Obstructive nephropathy Renal tubular acidosis/Fanconi syndrome Sodium wasting (Bartter-like syndrome) Potassium wasting Distal renal tubular acidosis Nephrogenic diabetes insipidus
D. Bhadauria & N. Agrawal / Clinical Queries: Nephrology 0101 (2012) 29–33
30
Table 2 Commonly encountered nephrotoxic agents and exposures. Drugs
Alternative medications
Diagnostic agents
Environmental agents
Antimicrobial
Herbal remedies
Radiocontrast
Heavy metals
High osmolar, low osmolar, iso-osmolar
Lead, mercury, uranium, bismuth
Aminoglycosides, anti-viral agents, amphotericin B, colistin, sulphadiazine, ciprofloxacin
Aristolochic acid, ephedra, glycyrrhiza sp., taxus celebica, uno degatta, cape aloes
Chemotherapy
Adulterants
Other agents
Solvents
Platins, ifosphamide, mitomycin, gemcitabine, methotrexate, pentostatin, interleukin-2, anti-angiogenesis agents
Mefenamic acid, melamine, cadmium, phenylbutazone, dichromate
Gadolinium (in high-dose), oral NaP solution (colonoscopy preparation)
Hydrocarbons
Analgesics
Other nephrotoxin Silicon, cadmium
NSAIDs, selective COX-2 inhibitors, phenacitin, analgesic combination
Immunosuppressive Sirolimus, calcineurin inhibitors Others ACEIs/ARBs, methoxyflurane, sucrose, hydroxyethyl starch, mannitol, pamidronate, zolendronate, topiramate, zonisamide, orlistat, statins, mesalamine ACEI: angiotensin converting enzyme inhibitor, ARB: angiotensin receptor blocker, COX-2: cyclooxygenase-2, NSAID: non-steroidal anti-inflammatory drugs. Table 3 Risk factors for toxic nephropathy. Kidney-specific factors ● ●
●
●
● ●
Hypoxic renal environment Concentration of drugs and toxin in renal medulla & interstitium High blood flow and drug delivery rate to the kidneys Generation of Reactive Oxygen Species causing oxidative stress Proximal tubular uptake of toxins High metabolic rate of tubular cells in the loop of Henle
Patient-specific factors ● ● ● ● ●
●
● ●
Drug-specific factors
Older age Female sex Nephrotic syndrome, cirrhosis, obstructive jaundice Acute or chronic kidney disease Metabolic disturbances – Hypokalemia, hypomagnesemia, hypocalcemia, hypercalcemia – Alkaline or acid urine pH True or effective circulating decline circulatory volume – Diminished glomerular filtration rate – Increased proximal tubular toxin reabsorption – Sluggish distal tubular urine flow rates Immune response genes Increased allergic reactions to drugs Pharmacogenetics favoring drug/toxin toxicity – Gene mutations in hepatic and renal cytochrome P450 enzyme systems – Gene mutations in transport proteins and renal transporters
may be sufficient to avoid drug-induced acute kidney injury (AKI) or minimize its clinical severity in susceptible patients. Risk factors for renal toxicity Susceptibility of a patient to nephrotoxicity from drugs or toxicant exposure is related to many factors. These are the how kidney hands drugs and toxins, underlying host characteristics and co-morbid conditions, and the inherent nephrotoxicity of the offending agent. Older age, female sex, diabetes mellitus, underlying kidney disease, hypertension, and congestive heart failure are some of examples of factors that have significant influence on the patient’s ability to tolerate and/ or recover from the toxic injury. There are three major categories of risk factors like kidney-specific factors, patient-specific factors and drug/toxin-related factors (Table 3). Each risk factor contributes to the increased development of nephrotoxicity. Generally, more than one risk factor is acting to cause various forms of kidney disease. These factors explain the variability and heterogeneity with drug- or toxin-induced nephrotoxicity.
Pathogenesis Nephrotoxic epithelial cell injury can result in AKI and can be mediated via a variety of mechanisms. After direct or indirect chemicalinduced injury, renal epithelial cells either repair and regenerate or die. If the degree of cell death is sufficient, then overall renal function declines and AKI results. Indirect chemical insults may decrease RBF, thereby causing renal ischemia and reperfusion-induced cell injury and death. Furthermore, recent studies demonstrate that the
●
●
●
● ●
●
igh-dose of drug and toxin exposure and H prolonged course of therapy Insoluble drug or metabolite forms crystals within intratubular lumens Potent direct nephrotoxic effects of the drug or toxin Drug combinations enhance nephrotoxicity Competition between endogenous and exogenous toxins for renal tubular excretory transporters increase Intracellular toxin accumulation
T and B cells and, to a lesser extent, macrophages and neutrophils inhibit renal function in AKI.1,2 The role of inflammatory cells in AKI is likely secondary to the initial insult and occurs during the maintenance phase of AKI.3,4 These examples highlight the premise that multiple mechanisms are involved in the pathophysiology of nephrotoxic epithelial cell injury and AKI. A secondary effect of nephrotoxicant-induced cell death in AKI can be the generation of back leak after an insult, injured and dead epithelial cells release from the basement membrane and adhere via integrins to other released and attached epithelial cells.4–7 The cellular aggregates can form tubular casts that block the flow of filtrate and increase intraluminal pressure, decreasing the single nephron glomerular filtration rate (GFR).4 In addition, the loss of epithelial cells can leave gaps in the basement membrane allowing tubular filtrate to back leak into the circulation, further decreasing the apparent single nephron GFR as currently measured. Thus, back leak and the loss of epithelial cells contribute to the decreased renal function. The susceptibility of the kidney to various agents can be attributed to several functional properties of this organ. These properties include: (a) receiving 20–25% of the cardiac output, ensuring high levels of toxicant delivery over a period of time; (b) extensive reabsorptive capacity with specialized transporters promoting cellular uptake of the toxicant; (c) urinary concentrating capacity that results in high concentrations of toxicants in the medullary lumen and interstitium; (d) biotransformation enzymes resulting in the formation of toxic metabolites and reactive intermediates; (e) high metabolic rates and workload of renal cells resulting in increased sensitivity to toxicants; and (f) sensitivity of the kidney to vasoactive agents. Nephrotoxicants generally damage specific segments of the nephron, with the proximal tubule (PT) epithelial cell being the primary target. The PT is commonly injured by multiple exogenous toxins,
D. Bhadauria & N. Agrawal / Clinical Queries: Nephrology 0101 (2012) 29–33
causing the syndrome of acute tubular necrosis (ATN). A classic example of ATN in the PT is aminoglycoside nephrotoxicity while other nephrotoxins that affect this segment include Ifosfamide, cisplatin, zolendronate, and radiocontrast. Acyclic nucleotide phosphonates promote ATN. Heavy metal intoxication with lead, cadmium, and mercury cause proximal tubular injury and ATN. Osmotic proximal tubular injury occurs with various sugars (sucrose, dextran, and mannitol) and starches (hydroxyethyl starch). Furthermore, different segments of the PT (S1, S2, and S3) are targets for different Nephrotoxicants. For example, aminoglycoside antibiotics, chromate, cadmium chloride, and the mycotoxin citrinin primarily affect the S1 and S2 segments, whereas cyclosporine, HgCl2, uranyl nitrate, cisplatin, bromobenzene, and cysteine conjugates of halogenated hydrocarbons affect the S3 segment.8 In addition, interferon, gold, and penicillamine may target cells in the glomeruli, whereas NSAIDs and angiotensin convertising enzyme (ACE) inhibitors may target cells in renal vessels.9 The reasons for these segmental differences may include: (a) differences in toxicant delivery to a given segment; (b) differences in transport and uptake among segments; and (c) differences in biotransformation enzymes among segments. This paper will review the important nephrotoxins like aminoglycoside, Amphotericin B and cisplatin that causes AKI, in brief. Other important nephrotoxic injuries caused by NSAIDs and radio contrast will be discussed by other authors. The pathologic term ATN and the clinical term acute renal failure/AKI are often used interchangeably when referring to ischemic and nephrotoxic renal injury. Aminoglycoside-induced nephrotoxicity Aminoglycoside-induced nephrotoxicity is fairly common, reaching the incidence of 10–25% despite the accurate control and follow-up exercised on patients.10–12 In a survey it was shown that the average incidence of nephrotoxicity caused by specific aminoglycoside antibiotics varies i.e. gentamicin, 14%; tobramycin, 12.9%; amikacin, 9.4%; and netilmicin, 8.9%.13 This incidence is not uniform across the population and varies depending on the target population,14–16 which indicates that some individuals seem to be more sensitive than others. The risk factors for the aminoglycoside nephrotoxicity are summarized in Table 4.
Clinical presentation Aminoglycoside nephrotoxicity is slow in evolution. Depression of GFR typically does not occur before 5–7 days of therapy have been completed. Non-oliguric renal failure is a common expression of aminoglycoside nephrotoxicity.17,30 The urine sediment most commonly shows mild proteinuria, hyaline, and granular casts. Distal tubular dysfunction has two major manifestations are polyuria and hypomagnesemia.10,18 Electrolyte abnormalities include hypomagnesemia, hypokalemia, hypocalcemia, and hypophosphatemia are infrequently observed, secondary to the decrement in PT transport. A Fanconi-like syndrome can occur with glycosuria, aminoaciduria, phosphaturia, and uricosuria.
Clinical course The renal functions usually return to the prior baseline level within 21 days after cessation of therapy. However, resolution of the acute episode may be delayed if the patient remains hypovolemic, septic, or catabolic; in these settings, tubular regeneration cannot occur.19
Pathophysiology Classically, the nephrotoxicity of aminoglycosides has been considered as a tubulopathy. Aminoglycosides are freely filtered across the
31
Table 4 The risk factors for the aminoglycoside nephrotoxicity. Patient-related ● ● ● ● ● ● ● ●
Treatment-related
● Older age Reduced renal function ● ● Pregnancy ● Dehydration Renal mass reduction ● Hypothyroidism Hepatic dysfunction Metabolic acidosis
Longer treatment Higher dosages Split dosages Type of aminoglycoside Elevated plasma drug concentrations
Concomitant drugs ● ● ● ● ● ● ● ●
NSAIDs Higher dosage diuretics Amphotericin Cisplatin Cyclosporin Iodide contrast media Vancomycin Cephalosporin
NSAID: non-steroidal anti-inflammatory drug.
glomerulus. It accumulates mainly in the proximal tubular and also in distal collecting epithelial cells due mainly to the giant endocytic complex formed by megalin and cubilin, which is restricted to the PT. These drugs then traffic through the endosomal compartment and accumulate mostly in lysosomes, the Golgi apparatus, and endoplasmic reticulum.20–22 Aminoglycosides binds to membrane phospholipids.23,24 Aminoglycoside containing endoplasmic reticulum ruptures and release its contents including aminoglycoside in the cytosol.25,26 Cytosolic aminoglycosides then acts on mitochondria directly and indirectly, and thus activates the intrinsic pathway of apoptosis, interrupts the respiratory chain, impairs adenosine triphosphate (ATP) production,27,28 and produces oxidative stress by increasing super oxide anions and hydroxyl radicals,29,30 which further contributes to cell death. The lysosomal content bears highly active proteases named cathepsins, which are capable of producing cell death. Tubular effects cannot solely explain the reduced glomerular filtration rate, in the absence of tubular obstruction. Tubular and glomerular mechanisms differentially contribute to the reduced GFR. Tubular dysfunction leads to the loss of fluid and electrolytes that swiftly fire the tubuloglomerular feedback (TGF) response, which reduces RBF and GFR to the appropriate level. However, TGF adapts within hours and its control over GFR is lost even in the presence of an increasing tubular incompetence. In these circumstances, a number of factors may hold GFR low in the absence of TGF-mediated control. Contracting factors produced by mesangial, vascular, and tubular cells, including reactive oxygen species (ROS), platelet-activating factor, angiotensin II, and endothelin-1 act in an autocrine and paracrine manner to induce contraction of glomerular vessels and mesangial cells, which reduce RBF and Kf, respectively, and lower GFR. Reduced GFR and RBF may contribute to aggravating gentamicininduced tubular damage, probably because they limit oxygen and nutrient availability to tubular cells and facilitate oxidative stress, as it has been demonstrated in the ischemic renal failure.
Prevention Clinical strategies that may minimize the potential for nephrotoxicity include: 1. Selection of the least toxic aminoglycoside when possible. 2. Correcting hypokalemia and hypomagnesemia prior to administering an aminoglycoside. 3. Avoid aminoglycosides in patients with reduced effective arterial volume, limiting the duration of therapy from 7 to 10 days, and minimizing concomitant nephrotoxic medications. 4. There is enough data to suggest that single daily dosing has probably less nephrotoxic potential that the same dose given in the divided schedule. 5. Dosing based on individualized drug pharmacokineticsderived from measurements of serum drug concentration would appear to be a rational approach especially in high-risk patients. Several agents have emerged as potential compounds to prevent aminoglycoside nephrotoxicity. Despite their potential, none have
32
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been adopted clinically for the prevention of aminoglycoside nephrotoxicity. Amphotericin B-induced nephrotoxicity Amphotericin B is an important drug for treatment of invasive fungal infections. An important and common complication is nephrotoxicity, occurring in 5–80% of cases.31–35 The clinical complications include renal insufficiency, urinary potassium and magnesium wasting and hypokalemia and hypomagnesaemia, metabolic acidosis due to type 1 (or distal) renal tubular acidosis, and polyuria due to nephrogenic diabetes insipidus.31–36 The net effect of renal insufficiency is an elevation in the plasma creatinine concentration of up to 2.5 mg/dL.31,34,35,37 Severe renal failure is rare due to Amphotericin B but can occur in presence of other insults to kidney like volume depletion or exposure to amino glycoside, cyclosporine, or foscarnet.34,35,38,39 The nephrotoxicity is dose-dependent and cumulative with the risk of renal dysfunction being relatively low at doses of < 0.5 mg/kg per day and a cumulative dose of < 600 mg.34,35,39 Additional risk factors include chronic renal insufficiency and the severity of the underlying illness.34,35 Both direct tubular injury and renal vasoconstriction are hypothesized to play an important role in pathogenesis of nephrotoxicity.40,41 Amphotericin B increases membrane permeability by creation of pores after insertion into cell membranes,30 possibly due to deoxycholate, a detergent used as a solubilizing agent for amphotericin B40 and TGF system gets activated31,38 due to the increase in membrane permeability in the macula densa cells to NaCl, entry into the cell; this may lead to afferent arteriolar vasoconstriction and a fall in GFR.31,38
Risk factors The risk factors for the occurrence of amphotericin B nephrotoxicity are high-dose and co-therapy with other nephrotoxic agents like aminoglycoside or cyclosporine.34,35 Two preventive measures are salt loading and the use of lipid formulations of Amphotericin B.
Hydration of patient Hydration by saline loading has shown to reduce sensitivity of TGF system due to volume expansion and can protect against or ameliorate the amphotericin B-induced decline in GFR in experimental studies31,32,38,42 but not the signs of other tubular dysfunction like urinary potassium and magnesium wasting.42 Saline loading by volume expansion also used to decreases the release of vasoconstrictors (angiotensin II and norepinephrine) and increases the secretion of the vasodilator atrial natriuretic peptide. These hormonal changes might modify the vasoconstrictive effect of amphotericin B.43
Lipid-based formulations There is enough experimental44 and human data both observational45–48 and randomized trials37 suggesting that the incidence and severity of nephrotoxicity can be minimized by use of amphotericin B in lipid-based formulations. Mechanism of renoprotection is incompletely understood but two theories have been proposed: (1) the liposomal preparation lacks deoxycholate which, is the cause of direct tubular toxicity30; (2) the liposomes may be preferentially distributed to the reticuloendothelial system, where amphotericin B can be transferred directly to trapped fungi, thereby diminishing its delivery to other cholesterol-containing cells such as those in the kidney. Amphotericin B-induced nephrotoxicity is usually reversible with discontinuation of therapy.38,48 It can cause recurrent renal dysfunction on reinstitution of therapy.48
Cisplatin-induced nephrotoxicity Cisplatin is a chemotherapeutic agent use to do renal tubular dysfunction and a cumulative impairment in renal function, as manifested by a decline in the GFR that can be dose-limiting sometime. The multiple mechanisms contribute to cause renal dysfunction following exposure to cisplatin includes tubular epithelial cell toxicity, vasoconstriction in the renal microvasculature, and proinflammatory effects. Cisplatin is a potent cell toxin, particularly in a low chloride environment, after entry into cells, chloride atoms in cisplatin are replaced by water molecules. This product of hydrolysis is said as the active species and reacts with glutathione in the cytoplasm and DNA in the nucleus.49 As this drug is mainly excreted in the urine in the first 24 hours following administration so the concentration of drug found in the renal cortex is several time more than that in plasma and other organs.50,51 Cisplatin primarily injures the S3 segment of the PT, causing a decrease in the GFR.52 Evidences suggest that basolateral drug transporters play a role in cisplatin uptake.53 Changes in expression of PT organic cation transporter-2 (OCT2) have been shown to mediate the accumulation of cisplatin in proximal tubular epithelial cells, which suggests a key role for OCT2 in the development of cisplatin-mediated nephrotoxicity.54–56 Vasoconstriction in the renal microcirculation appears to contribute to decreased RBF soon after cisplatin injection.57,58 Cisplatin increases the expression of proinflammatory cytokines, which promote the differentiation, maturation, and activation of inflammatory cells and their response59,60 also established in animal models of cisplatin-induced AKI. The PT cells are selectively injured by cisplatin, as manifested by both necrosis and apoptosis, even though non-proliferating cells are generally less sensitive to the toxicity of agents that damage DNA.60 Possible reasons for the observed nephrotoxicity of cisplatin include its enhanced renal uptake by organic transporters followed by cisplatin-mediated reduced expression and function of sodiumdependent glucose and amino acid transporters61; reduced expression and function of magnesium and water transporters, metabolism of cisplatin to glutathione and cysteinyl–glycine conjugates62; and the generation of ROS.63,64 The clinical manifestations of cisplatin nephrotoxicity are reduction in GFR, which can be progressive and thrombotic microangiopathy, hypomagnesemia, salt wasting, a Fanconi-like syndrome and anemia. The incidence of renal impairment varies, depending upon the dose and frequency of drug administration and the criteria used to define nephrotoxicity. More than 50% of cases of nephrotoxicity with cisplatin were observed in the initial studies of pre-hydration era.49 The incidence and severity of renal failure is progressive and can eventually become irreversible. These observations apply to the administration of conventional doses of platinum. Renal failure is usually non-oliguric and urine output typically remains above 1000 mL per day due to the induction of a concentrating defect unless renal failure is advanced. This defect may reflect drug-induced damage to the concentration apparatus, loop of Henle or to the collecting tubules, the site of action of antidiuretic hormone.65 Injury to the collecting tubules is associated with decreased expression of aquaporin water channels.66 Cisplatin nephrotoxicity also appears to be mediated by the organic cation transporter (hOCT2).67 An increasing risk of ARF is associated with higher doses of cisplatin that result in high peak plasma free platinum concentrations, previous exposure to cisplatin, pre-existing kidney damage, and the concomitant use of other nephrotoxic agents. The standard approach to prevent cisplatin-induced nephrotoxicity is the administration of lower doses of cisplatin compared with previous regimens in combination with hydration with saline. Although a number of pharmacologic agents like amifostine, sodium thiosulfate, N-acetylcystiene, theophylline and glycine have been evaluated to decrease nephrotoxicity, none has an established role. Treatment of renal failure as general approach to other renal dysfunction or failure and discontinuation of cisplatin. Long-term follow-up of patients exposed to cisplatin-induced nephrotoxicity either remains
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