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Adverse effects of drugs on the kidney

Published:December 22, 2015DOI:https://doi.org/10.1016/j.ejim.2015.12.001

      Highlights

      • Drug reactions offending the kidney are frequent.
      • Herbal remedies and over-the counter medications are unsuspected offending agents.
      • Drug misuse is frequent with analgesics, leading to unrecognized adverse consequences.

      Abstract

      The number of drugs presently marketed is countless, their prescription is relentlessly growing, such that the likelihood of adverse effects is strikingly increasing. As many drugs are cleared by the body through kidney excretion, renal adverse events are likely. In this review we shall concisely describe the pathophysiologic mechanisms of renal damage by drugs, the different clinical presentations outlining renal toxicity in the course of pharmacologic treatment, and the main offending agents.

      Keywords

      1. Introduction

      The entire population is presently exposed to a number of different pharmacologic agents, most of which are noxious and taken with no scientific justification. An even larger amount of drugs is taken inadvertently, with food, herbal remedies and over-the-counter medications, and without any medical control and prescription. This causes a widespread toxicity that is difficult to detect, often unsuspected and potentially very dangerous. As most drugs are excreted by the kidney, it is reasonable to assume that the kidney itself could be a privileged target of their toxic actions. In this paper, we shall review the renal effect of the use, misuse and abuse of pharmacologic agents. The kidney alterations will be presented according to their pathophysiologic mechanisms, i.e. immuno-related toxic effects, analgesic nephropathy, drug-induced glomerular disease, direct toxic effects of drugs, nephrogenic systemic fibrosis, selective toxic effects, herbal medications, renal hemodynamics-related renal failure and crystalline nephropathy. Table 1 displays a glossary of the abbreviations used.
      • 1.1
        Immunologic reactions caused by drugs involving the kidney
        We recognize immunocomplex diseases and hapten-mediated mechanisms.
        • A.
          IC disease caused by drugs.
          • Drugs can be contained in IC, causing drug-mediated IC renal disease, AGN or AIN usually secondary to a spillover mechanism: the excess IC which does not bind to glomerular structures “spills over” into the interstitial microcirculation, binding to tubular BM, triggering interstitial inflammation [
            • Border W.A.
            • Lehman D.H.
            • Egan J.D.
            • Sass H.J.
            • Glode J.E.
            • Wilson C.B.
            Antitubular basement-membrane antibodies in methicillin-associated interstitial nephritis.
            ]. This recalls Goodpasture syndrome, when the excess Ab spills over into the interstitium, causing AIN beside AGN.
          • Drugs can cause systemic immunologic reactions, causing micro-angiopathic vasculitis, which can injure the kidney. The most typical is HITP, where progressive renal failure with an elusive urinary sediment (accounted for by a pathogenic micro-thrombotic reaction affecting arterioles and interstitium, while mostly sparing the glomerulus) is the hallmark of the disease [
            • McCrae K.R.
            • Bussel J.B.
            • Mannucci P.M.
            • Remuzzi G.
            • Cines D.B.
            Platelets: an update on diagnosis and management of thrombocytopenic disorders.
            ]. The picture can occur with clopidogrel and congeners, and when the conversion of macro- into micro-aggregates of von Willebrand factor is blocked [
            • McCrae K.R.
            • Bussel J.B.
            • Mannucci P.M.
            • Remuzzi G.
            • Cines D.B.
            Platelets: an update on diagnosis and management of thrombocytopenic disorders.
            ].
          • Drugs primarily affecting the immune system cause almost exclusively glomerular disease and, to a minor extent, interstitial disease. They trigger a lupus-like syndrome [
            • Katz U.
            • Zandman-Goddard G.
            Drug-induced lupus: an update.
            ], reported with alpha-methyl-dopa, d-penicillamine, interferon, levamisole [
            • Carlson A.Q.
            • Tuot D.S.
            • Jen K.Y.
            • Butcher B.
            • Graf J.
            • Sam R.
            • et al.
            Pauci-immune glomerulonephritis in individuals with disease associated with levamisole-adulterated cocaine: a series of 4 cases.
            ], procainamide and many other substances exerting blockade of immune recognition [
            • Flax M.H.
            Editorial: drug-induced autoimmunity.
            ].
        • B.
          Hapten-mediated disease.
          • Pathophysiology
            Haptens are epitopes represented by drugs, part of drug molecules, or biologic substances transformed into immunogenic epitopes by drugs or other processes. The immunologic reaction to haptens causes disease by the inflammatory effect of Ab-hapten interaction. This occurs mainly in the renal interstitium, where haptens bind to tubular BMs or interstitial matrix, leading to AIN. The disease can subside after discontinuation of the offending agent, with prednisone treatment, or proceed to chronic interstitial nephritis ending in CRF [
            • Jahnukainen T.
            • Saarela V.
            • Arikoski P.
            • Ylinen E.
            • Rönnholm K.
            • Ala-Houhala M.
            • et al.
            Prednisone in the treatment of tubulointerstitial nephritis in children.
            ]. In many circumstances, the reaction is IgE or IgG4 mediated, with eosinophils infiltrating the interstitium, attended by eosinophiluria: this is called “allergic” AIN, even though the Ag is not an “allergen”, as it could be a hapten or a non-allergic, immunogenic epitope. This “allergy” is called type B idiosyncratic non-immunoglobulin-E-mediated immune reaction marked by cell-mediated immune injury to the renal tubule-interstitium, carried out by CD4+ T-lymphocytes [
            • Krishnan N.
            • Perazella M.A.
            Drug-induced acute interstitial nephritis: pathology, pathogenesis, and treatment.
            ,
            • Joh K.
            • Shibasaki T.
            • Azuma T.
            • Kobayashi A.
            • Miyahara T.
            • Aizawa S.
            • et al.
            Experimental drug-induced allergic nephritis mediated by antihapten antibody.
            ]. The drug becomes immunogenic through antigen mimicry, haptenization, or neo-antigen formation. Dendritic cells of renal interstitium, and tubular epithelial cells can transform the injury into a chronic process. Thus, acute drug-induced AIN can progress to a chronic form attended by fibroblast activation, ending in interstitial fibrosis, tubular atrophy and, finally, ESRD [
            • Joh K.
            • Shibasaki T.
            • Azuma T.
            • Kobayashi A.
            • Miyahara T.
            • Aizawa S.
            • et al.
            Experimental drug-induced allergic nephritis mediated by antihapten antibody.
            ,
            • Tanaka T.
            • Nangaku M.
            Pathogenesis of tubular interstitial nephritis.
            ]. The recruitment of T-lymphocyte immunity represents the hallmark of evolution into chronically progressive interstitial disease [
            • Joh K.
            • Aizawa S.
            • Yamaguchi Y.
            • Inomata I.
            • Shibasaki T.
            • Sakai O.
            • et al.
            Drug-induced hypersensitivity nephritis: lymphocyte stimulation testing and renal biopsy in 10 cases.
            ]. It is almost always caused by T-cell activation, CD4 and CD8+, which, in turn, can recruit either an IgE or IgG4-mediated pathway. The data indicate that drug-specific T cells activated locally release different cytokines responsible for renal damage [
            • Spanou Z.
            • Keller M.
            • Britschgi M.
            • Yawalkar N.
            • Fehr T.
            • Neuweiler J.
            • et al.
            Involvement of drug-specific T cells in acute drug-induced interstitial nephritis.
            ].
            • Known haptens. Methicillin nephritis was named by the initial cases reported, although all penicillins and cephalosporins can cause this through haptenic mechanisms. It is a typical interstitial nephritis [
              • Muriithi A.K.
              • Leung N.
              • Valeri A.M.
              • Cornell L.D.
              • Sethi S.
              • Fidler M.E.
              • et al.
              Biopsy-proven acute interstitial nephritis, 1993–2011: a case series.
              ,
              • Silverstein R.L.
              • Eigenbrodt E.H.
              • McPhaul Jr., J.J.
              Interstitial nephritis caused by methicillin. Studies in a case complicating staphylococcal sepsis with acute glomerulonephritis.
              ], accounting for 49% of all instances [
              • Muriithi A.K.
              • Leung N.
              • Valeri A.M.
              • Cornell L.D.
              • Sethi S.
              • Fidler M.E.
              • et al.
              Biopsy-proven acute interstitial nephritis, 1993–2011: a case series.
              ]. Methicillin-specific anti-tubular BM antibody diseases have been reported [
              • Border W.A.
              • Lehman D.H.
              • Egan J.D.
              • Sass H.J.
              • Glode J.E.
              • Wilson C.B.
              Antitubular basement-membrane antibodies in methicillin-associated interstitial nephritis.
              ].
            • Other haptens causing AIN are NSAIDS [
              • Henao J.
              • Hisamuddin I.
              • Nzerue C.M.
              • Vasandani G.
              • Hewan-Lowe K.
              Celecoxib-induced acute interstitial nephritis.
              ,
              • Kleinknecht D.
              Interstitial nephritis, the nephrotic syndrome, and chronic renal failure secondary to nonsteroidal anti-inflammatory drugs.
              ,
              • Markowitz G.S.
              • Falkowitz D.C.
              • Isom R.
              • Zaki M.
              • Imaizumi S.
              • Appel G.B.
              • et al.
              Membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib.
              ], accounting for a further 11% [
              • Muriithi A.K.
              • Leung N.
              • Valeri A.M.
              • Cornell L.D.
              • Sethi S.
              • Fidler M.E.
              • et al.
              Biopsy-proven acute interstitial nephritis, 1993–2011: a case series.
              ], hydrogen-ion pump inhibitors [
              • Geevasinga N.
              • Coleman P.L.
              • Webster A.C.
              • Roger S.D.
              Proton pump inhibitors and acute interstitial nephritis.
              ,
              • Nadri Q.
              • Althaf M.M.
              Granulomatous tubulointerstitial nephritis secondary to omeprazole.
              ,
              • Magalhães-Costa P.
              • Matos L.
              • Chagas C.
              Chronic tubulointerstitial nephritis induced by 5-aminosalicylate in an ulcerative colitis patient: a rare but serious adverse event.
              ] for some 14% [
              • Muriithi A.K.
              • Leung N.
              • Valeri A.M.
              • Cornell L.D.
              • Sethi S.
              • Fidler M.E.
              • et al.
              Biopsy-proven acute interstitial nephritis, 1993–2011: a case series.
              ], plus a number of miscellaneous other substances [
              • Vikrant S.
              • Gupta D.
              • Kaushal S.S.
              Sodium stibogluconate-associated acute interstitial nephritis in a patient treated for visceral leishmaniasis.
              ,
              • Argirov M.
              • Ricken G.
              • Zecher D.
              • Fischereder M.
              Acute interstitial nephritis associated with moxifloxacin use.
              ,
              • Xie H.
              • Chen H.
              • Hu Y.
              • Xu S.
              • He Q.
              • Liu J.
              • et al.
              Clindamycin-induced acute kidney injury: large biopsy case series.
              ,
              • Lomax A.J.
              • Hill P.A.
              • Ashley D.M.
              Case report of interstitial nephritis induced by bevacizumab therapy for glioblastoma multiforme.
              ,
              • Nandakoban H.
              • Furlong T.J.
              • Flack J.R.
              Acute tubulointerstitial nephritis following treatment with exenatide.
              ], to quote only a few.
            • Clinical symptoms. Interstitial nephritis is characterized by back pain, caused by renal swelling, which distends the capsula, while the kidney outline remains smooth. Plasma creatinine concentration (PCr) rises slowly and progressively, urine output increases initially despite the fall in GFR, an important clue to the diagnosis. Sterile pyuria, low-grade proteinuria made up by “tubular” protein, namely, short peptides and tubular enzymes, renal tubular cell casts and leukocyte casts are observed. Eosinophiluria can be found in allergic nephritis. Urine specific gravity is low and isostenuric in advanced disease. Fever relapsing during antibiotic treatment after an initial resolution constitutes an additional clue and is more suggestive if associated with peripheral eosinophilia. The urine sediment may disclose additional findings, according to concomitant glomerular involvement, vascular and endothelial lesions, and tubular damage. The disease, if unrecognized, can progress to CRF.
              These symptoms point to interstitial involvement, as this affects the epithelial peritubular side facing the tubular BM, thus damaging transport systems. Therefore, phosphate reabsorption is impaired, resulting in increased phosphaturia. Hydrogen ion secretion is hampered, delivering more bicarbonate to the distal nephron, overwhelming its reabsorption mechanism: the excretion of alkaline urine and RTA ensue. Other PT functions, as PT accounts for the majority of peritubular sites exposed to the interstitium, are deranged, like AA and glucose resorption. PT reclamation of low molecular weight peptides is hampered, causing “tubular proteinuria”, which is easily distinguished from glomerular proteinuria made up by albumin or immunoglobulins not retained by the glomerular sieve. As the countercurrent mechanism is critically dependent upon the integrity of renal medullary and papillary interstitium, urine concentration is preferentially lost in AIN with respect to AGN: polyuria occurs even in the face of reduced GFR, until its fall does not reach a point beyond which even the increased fraction of urine flow over that of filtration cannot afford a normal urine volume.
            • Diagnosis. Recognition of AIN requires awareness of the disease, accurate follow-up of patients during drug treatment, continuous review of the drugs administered, knowledge of the potential offending agents, appropriate questioning of patients about symptoms, sequential PCr measurement and urinalysis with careful examination of urinary sediment.
              Diagnosis can be reached clinically on the grounds of the above symptoms, and confirmed, when necessary, by renal biopsy. This can be avoided in most circumstances by prompt drug withdrawal, prednisone administration [
              • González E.
              • Gutiérrez E.
              • Galeano C.
              • Chevia C.
              • de Sequera P.
              • Bernis C.
              • et al.
              Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis.
              ], continuous follow-up of renal function and clinical conditions.
            • Treatment. Treatment consists of PDN administration, 1 mg/kg either i.v. or p.o. at 8 am for 7–20 days according to response, with tapering in a variable time, from one up to six months, guided by the evaluation of remission versus persistent disease [
              • González E.
              • Gutiérrez E.
              • Galeano C.
              • Chevia C.
              • de Sequera P.
              • Bernis C.
              • et al.
              Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis.
              ]. There are patients requiring dialysis for ARF or CRF. PDN is given as 50% of the total at breakfast, 25% at lunch and at 5 p.m. Tapering is accomplished by withdrawing the afternoon and lunch administrations. After one month, a double daily dose should be given every other day.
      • 1.2
        Analgesic nephropathy
        This is a chronic process which leads slowly over many years to CRF by causing an interstitial nephropathy [
        • Buckalew Jr., V.M.
        • Schey H.M.
        Renal disease from habitual antipyretic analgesic consumption: an assessment of the epidemiologic evidence.
        ]. The toxic effect is dose related, and requires the continuous daily intake of analgesics for decades. In many circumstances, the interstitial changes disrupt the vascular system, causing ischemic alterations that contribute to scarring and fibrosis, ending in papillary necrosis, impairing urine concentration by damaging the countercurrent mechanism. The urine changes are unrevealing for years, the increase in PCr slow and undetected for a long time. The disease can be suspected for an acute episode, like papillary necrosis or infection, or because of imaging that detects shrunken kidneys with an irregular outline, distorted pelvis and papillary calcifications. The entity, formerly attributed to phenacetin abuse, can be due to any analgesic.
      • 1.3
        Drug-induced glomerular disease
        Drugs can exert a direct toxic effect on the glomerulus, either on endothelium, or podocytes, or mesangium. Bisphosphonates, antiplatelet agents, NSAIDs, interferons and anti-angiogenesis drugs have been implicated. This poorly defined entity, recently reported, will undergo deeper investigation in the future [
        • Markowitz G.S.
        • Bomback A.S.
        • Perazella M.A.
        Drug-induced glomerular disease:direct cellular injury.
        ]. Puromycin can cause minimal change disease, and it is used in animals to provoke proteinuria in experimental studies [
        • de Mik S.M.
        • Hoogduijn M.J.
        • de Bruin R.W.
        • Dor F.J.
        Pathophysiology and treatment of focal segmental glomerulosclerosis: the role of animal models.
        ].
      • 1.4
        Direct toxic effects of drugs on the kidney
        AIN can be due to the direct toxic effects of pharmacologic agents on tubular epithelial cells. There is evidence indicating that the damaged tubular cell releases cytokines, activating T-cell-mediated immunologic responses that cause fibroblast activation, interstitial fibrosis and, consequently, CRF [
        • Spanou Z.
        • Keller M.
        • Britschgi M.
        • Yawalkar N.
        • Fehr T.
        • Neuweiler J.
        • et al.
        Involvement of drug-specific T cells in acute drug-induced interstitial nephritis.
        ,
        • Eddy A.A.
        Experimental insights into the tubulointerstitial disease accompanying primary glomerular lesions.
        ,
        • Pohl M.
        • Fischer M.T.
        • Mader S.
        • Schanda K.
        • Kitic M.
        • Sharma R.
        • et al.
        Pathogenic T cell responses against aquaporin 4.
        ], which can be prevented by the prompt interruption of the offending drug. This toxicity can selectively affect specific transport mechanisms, leading to ATN, ARF, rapidly progressive interstitial fibrosis ending in subacute renal failure (gadolinium) and chronically progressive interstitial fibrosis ending in delayed onset of CRF (herb medications).
        • A.
          ATN can be produced by a number of offending drugs, such as clindamicin22, antiviral agents, substances that precipitate as microcrystalline aggregates into the tubular lumen, damaging the epithelium, X-ray contrast media.
        • B.
          ARF is the clinical counterpart of ATN in most circumstances. PCr rises rapidly, the patient becomes oliguric up to total anuria. The urine is isosthenuric, contains epithelial tubular casts, epithelial cells, leukocytes and leukocyte casts, scanty proteinuria, variable hematuria. The presence of muddy brown casts is typical, although it occurs also in rhabdomyolysis-induced renal failure. The anuric phase can progress to CRF directly, or recover variably, often completely, to progress slowly to CRF subsequently when repair processes recruit T-lymphocyte-mediated mechanisms that are not switched down at a proper time.
        • C.
          Contrast ARF has become the most common type of drug-induced renal failure.
          • “True” contrast ARF is characterized by a typical onset: the morning following the exposure, the patient tells the physician that he has not voided. PCr is increased; the urine, often obtained only through a catheter, shows the typical findings of ARF. The FENa is >0.025, almost unerringly >0.05. Anuria or extreme oliguria last, on average, 5–7 days, during which PCr continues to rise to levels compatible with complete interruption of filtration. When the urine output resumes, it becomes polyuric, to subsequently return to normal together with PCr. Dialysis may become necessary when anuria lasts long enough to cause uremic symptoms. When partial or complete recovery of renal function does not occur, CRF ensues.
            This “typical” picture was reported mostly after iopanoic acid administration, the contrast agent formerly used for colecystography [
            • Canales C.O.
            • Smith G.H.
            • Robinson J.C.
            • Remmers Jr., A.R.
            • Sarles H.E.
            Brief recordings. Acute renal failure after the administration of iopanoic acid as a cholecystographic agent.
            ]. Being uncommon, there is no animal model for it, such that its cause is presently unknown. As it reproduces the features of acute ischemic ARF, it may share common pathways with renal ischemia [
            • Tumlin J.
            • Stacul F.
            • Adam A.
            • Becker C.R.
            • Davidson C.
            • Lameire N.
            • et al.
            Pathophysiology of contrast-induced nephropathy.
            ]. The renal biopsy reveals foci of ATN.
          • The contrast-induced ARF reported in the recent literature displays a wide range of renal derangement, amounts of contrast agents administered, duration of the disease, evolution into CRF and recovery, clinical symptoms and response to treatment. Most authorities studying the disease define it as a rise in PCr > 25%, or an absolute change > 0.5 mg/dL, beginning within 48 or, at most, 96 h after exposure [
            • McCullough P.A.
            • Adam A.
            • Becker C.R.
            • Davidson C.
            • Lameire N.
            • Stacul F.
            • et al.
            Epidemiology and prognostic implications of contrast-induced nephropathy.
            ]. This includes a number of cases due to dehydration caused by the preparation of the X-ray procedure, to interference by the contrast agents on creatinine secretion, to their systemic hemodynamic effects combined with other drugs, to the procedures per se. The more dangerous intra-arterial contrast infusion is necessary for patients fraught with a number of severe conditions, usually heart failure due to CAD, myocardial infarction and/or other critical derangements, with comorbidities like DM and vascular disease. Therefore, this entity is nowadays called contrast-induced nephropathy (CIN), as ARF with anuria is very rare, while a variable worsening of renal function is common.
            Pathophysiology. Iodinated contrast agents induce intense and prolonged vasoconstriction at the corticomedullary junction of the kidney, and directly impair renal auto-regulatory capacity through loss of nitric oxide production. The viscosity of the media, which slows down the tubular fluid flow, favors the precipitation of poorly soluble components, including the dyes. These effects, coupled with direct tubular toxicity of contrast media, lead to overt ATN and CIN [
            • Tumlin J.
            • Stacul F.
            • Adam A.
            • Becker C.R.
            • Davidson C.
            • Lameire N.
            • et al.
            Pathophysiology of contrast-induced nephropathy.
            ]. Non-ionic contrast media are considered less toxic [
            • Rudnik M.R.
            • Goldfarb S.
            • Wexler L.
            • Ludbrook P.A.
            • Murphy M.J.
            • Halpern E.F.
            • et al.
            Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study.
            ,
            • Lautin E.M.
            • Freeman N.J.
            • Schoenfeld A.H.
            • et al.
            Radiocontrast-associated renal dysfunction: a comparison of lower-osmolality and conventional high-osmolality contrast media.
            ,
            • Barret B.J.
            • Carlisle E.J.
            Metanalysis of the relative nephrotoxicity of high- and low-osmolality iodate contrast media.
            ,
            • Schwab S.J.
            • Hlatky M.A.
            • Pieper K.S.
            • Davidson C.J.
            • Morris K.G.
            • Skelton T.N.
            • et al.
            Contrast nephrotoxicity: a randomized trial of a nonionic and an ionic radiographic contrast agent.
            ], such that ionic agents are no longer used, although impeccable trials showed no difference between them [
            • Barret B.J.
            • Carlisle E.J.
            Metanalysis of the relative nephrotoxicity of high- and low-osmolality iodate contrast media.
            ,
            • Kuhn M.J.
            • Chen N.
            • Sahani D.V.
            • Reimer D.
            • van Beek E.J.
            • Heiken J.P.
            • et al.
            The PREDICT study: a randomized double-blind comparison of contrast-induced nephropathy after low- or isoosmolar contrast agent exposure.
            ].
            Clinical evidence. The intra-arterial injection of large amounts of contrast, required in PTCA, is attended by a high incidence of CIN, as the agent spills over in the aorta and reaches dangerous concentrations in the blood perfusing the kidney [
            • Becker C.R.
            • Davidson C.
            • Lameire N.
            • McCullough P.A.
            • Stacul F.
            • Tumlin J.
            • et al.
            High-risk situations and procedures.
            ,
            • Mehran R.
            • Aymong E.D.
            • Nikolsky E.
            • Lasic Z.
            • Iakovou I.
            • Fahy M.
            • et al.
            A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation.
            ]. This is consistent with the low CIN occurrence in cerebral angiography [
            • Oleinik A.
            • Romero J.M.
            • Schwab K.
            • Lev M.H.
            • Jhawar N.
            • Delgado Almandoz J.E.
            • et al.
            CT angiography for intracerebral hemorrhage does not increase risk of acute nephropathy.
            ], as the amount of dye used is less, and it reaches the kidney via the venous route. The volume of non-ionic media infused is critical: to be safe, it must be <125 ml [
            • Davidson C.
            • Stacul F.
            • McCullough P.A.
            • Tumlin J.
            • Adam A.
            • Lameire N.
            • et al.
            Contrast medium use.
            ]. In the presence of comorbidities, renal toxicity is significantly more likely [
            • Rudnik M.R.
            • Goldfarb S.
            • Wexler L.
            • Ludbrook P.A.
            • Murphy M.J.
            • Halpern E.F.
            • et al.
            Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study.
            ], as even volumes <100 ml can be dangerous. The incidence of CIN is 0.15% [
            • Byrd L.
            • Sherman R.L.
            Radiocontrast-induced acute renal failure: a clinical and pathophysiologic review.
            ], 1.6% in selective clinical conditions [
            • Parfrey P.S.
            • Griffiths S.M.
            • Barrett B.J.
            • Paul M.D.
            • Genge M.
            • Withers J.
            • et al.
            Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency or both. A prospective controlled study.
            ], it reaches 12% in hospitalized patients [
            • Rich M.W.
            • Crecelius C.A.
            Incidence, risk factors, and clinical course of acute renal insufficiency after cardiac catheterization in patients 70 years of age or older. A prospective study.
            ], surging to 50% in high-risk situations, like in ICU patients [
            • Bouzas-Mosquera A.
            • Vázquez-Rodríguez M.J.
            • Calviño-Santos R.
            • Peteiro-Vázquez J.
            • Flores-Ríos X.
            • Marzoa-Rivas R.
            • et al.
            Contrast-induced nephropathy and acute renal failure following urgent cardiac catheterization: incidence, risk factors, and prognosis.
            ,
            • Al-Ghonaim M.
            Prevention and treatment of contrast-induced nephropathy.
            ,
            • Nash K.
            • Hafeez A.
            • Hou S.
            Hospital-acquired renal insufficiency.
            ]. The risk, proportional to the severity of pre-existing renal failure, is factored by age >70, hemodynamic instability, nephrotic syndrome and transplanted kidney [
            • Byrd L.
            • Sherman R.L.
            Radiocontrast-induced acute renal failure: a clinical and pathophysiologic review.
            ,
            • Parfrey P.S.
            • Griffiths S.M.
            • Barrett B.J.
            • Paul M.D.
            • Genge M.
            • Withers J.
            • et al.
            Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency or both. A prospective controlled study.
            ,
            • Rich M.W.
            • Crecelius C.A.
            Incidence, risk factors, and clinical course of acute renal insufficiency after cardiac catheterization in patients 70 years of age or older. A prospective study.
            ,
            • Bouzas-Mosquera A.
            • Vázquez-Rodríguez M.J.
            • Calviño-Santos R.
            • Peteiro-Vázquez J.
            • Flores-Ríos X.
            • Marzoa-Rivas R.
            • et al.
            Contrast-induced nephropathy and acute renal failure following urgent cardiac catheterization: incidence, risk factors, and prognosis.
            ,
            • Al-Ghonaim M.
            Prevention and treatment of contrast-induced nephropathy.
            ,
            • Nash K.
            • Hafeez A.
            • Hou S.
            Hospital-acquired renal insufficiency.
            ,
            • Pucelikova T.
            Contrast-induced nephropathy.
            ,
            • Cronin R.E.
            Southwestern Internal Medicine Conference: renal failure following radiologic procedures.
            ]. Multiple myeloma and diabetes mellitus are absolute contraindications to contrast procedures [
            • Byrd L.
            • Sherman R.L.
            Radiocontrast-induced acute renal failure: a clinical and pathophysiologic review.
            ]. The association between diabetes and PCr >6 mg/dL produces an incidence of ARF of 50%, dialysis being needed in 15% of instances [
            • Manske C.L.
            • Sprafka J.M.
            • Strony J.T.
            • Wang Y.
            Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography.
            ]. In myeloma, the contrast injection is possible with adequate prevention [
            • McCarthy C.S.
            • Becker J.A.
            Multiple myeloma and contrast media.
            ]; in diabetes, the high incidence of CAD imposes the execution of coronary angiography even though CAT is safer [
            • Rihal C.S.
            • Textor S.C.
            • Grill D.E.
            • Berger P.B.
            • Ting H.H.
            • Best P.J.
            • et al.
            Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention.
            ].
            There is evidence that ECV expansion before, and with maintenance infusion after injection of the dye, exerts a protective effect against CIN [
            • Stacul F.
            • Adam A.
            • Becker C.R.
            • Davidson C.
            • Lameire N.
            • McCullough P.A.
            • et al.
            Strategies to reduce the risk of contrast-induced nephropathy.
            ], which is clearly established in animal models of ARF [
            • Satta A.
            • Faedda R.
            • Turrini F.
            • Manca A.
            • Branca G.F.
            • Bartoli E.
            Prevention of acute renal failure by diuretics.
            ]. The volumes of isotonic saline solution used differ widely, probably because of concerns for pulmonary edema. We infuse 1.5% of BW as normal saline during the 6 h preceding, and an identical volume during, the 6 h following the contrast injection. A favorable effect of bicarbonate infusion is supported by some authors [
            • Navaneethan S.D.
            • Singh S.
            • Appasamy S.
            • Wing R.E.
            • Sehgal A.R.
            Sodium bicarbonate therapy for prevention of contrast-induced nephropathy: a systematic review and meta-analysis.
            ], and is considered ineffective by others [
            • Stacul F.
            • Adam A.
            • Becker C.R.
            • Davidson C.
            • Lameire N.
            • McCullough P.A.
            • et al.
            Strategies to reduce the risk of contrast-induced nephropathy.
            ]. Bicarbonate is given as a 154 mEq/L solution at 3 mL/kg/h i.v. for 1 h before, then 1 mL/kg/h for 6 h after contrast [
            • Navaneethan S.D.
            • Singh S.
            • Appasamy S.
            • Wing R.E.
            • Sehgal A.R.
            Sodium bicarbonate therapy for prevention of contrast-induced nephropathy: a systematic review and meta-analysis.
            ], or as 1 mL/kg/h 6 h before and after contrast [
            • Ozcan E.E.
            • Guneri S.
            • Akdeniz B.
            • Akyildiz I.Z.
            • Senaslan O.
            • Baris N.
            • et al.
            Sodium bicarbonate, N-acetylcysteine, and saline for prevention of radiocontrast-induced nephropathy. A comparison of 3 regimens for protecting contrast-induced nephropathy in patients undergoing coronary procedures. A single-center prospective controlled trial.
            ]. Assuming a BW of 70 kg, volume expansion can be calculated [
            • Bartoli E.
            • Castello L.
            • Bergamasco L.
            • Sainaghi P.P.
            A new method to distinguish the hyponatremia of electrolyte loss from that due to pure solvent changes.
            ] from the above rates on the grounds of salt injected: saline infusion raised ECV from 14 to 15.5 before, and to 18 L after the procedure, attended by PNa of 148 and 163 mEq/L, respectively. The infusion rates of Ozcan yield 16.8 and 19.1 L, 155 and 171 mEq/L, respectively. These numbers represent maximum estimates obtained from the calculation algorithm used [
            • Bartoli E.
            • Castello L.
            • Bergamasco L.
            • Sainaghi P.P.
            A new method to distinguish the hyponatremia of electrolyte loss from that due to pure solvent changes.
            ]. Thus, bicarbonate has no magic property: it is simply very effective in expanding ECV. The lack of effectiveness in some studies can be explained by bicarbonate “dumping” into the urine, diffusion into cells because of metabolic acidosis, third space mechanism in patients with edema, adverse effects caused by the severe metabolic alkalosis produced (pH of 7.90 as calculated maximum). When bicarbonate is infused as isotonic solution, the expansion matches the volume infused.
            The evidence favoring acetylcysteine (600 mg i.v.) together with saline before the procedure, though still controversial [
            • Goldenberg I.
            • Shechter M.
            • Matetzky S.
            • Jonas M.
            • Adam M.
            • Pres H.
            • et al.
            Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography. A randomized controlled trial and review of the current literature.
            ], is more convincing [
            • Trivedi H.
            • Daram S.
            • Szabo A.
            • Bartorelli A.L.
            • Marenzi G.
            High-dose N-acetylcysteine for the prevention of contrast-induced nephropathy.
            ]. Furosemide, which is protective in experimental models of ARF [
            • Faedda R.
            • Satta A.
            • Branca G.F.
            • Turrini F.
            • Contu B.
            • Bartoli E.
            Diuretics in post-ischemic acute renal failure.
            ], is considered detrimental for CIN [
            • Kelly A.M.
            • Dwamena B.
            • Cronin P.
            • Bernstein S.J.
            • Carlos R.C.
            Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy.
            ,
            • Stacul F.
            • Adam A.
            • Becker C.R.
            • Davidson C.
            • Lameire N.
            • McCullough P.A.
            • et al.
            Strategies to reduce the risk of contrast-induced nephropathy.
            ], probably because of the dehydration induced in patients with pre-existing renal disease. Theophylline was found to be protective [
            • Kelly A.M.
            • Dwamena B.
            • Cronin P.
            • Bernstein S.J.
            • Carlos R.C.
            Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy.
            ] as well as ineffective [
            • Stacul F.
            • Adam A.
            • Becker C.R.
            • Davidson C.
            • Lameire N.
            • McCullough P.A.
            • et al.
            Strategies to reduce the risk of contrast-induced nephropathy.
            ].
            In conclusion, the cause of CIN is elusive. It is prevented by volume expansion before and after injection. There is no reason to induce a severe acute metabolic alkalosis with bicarbonate when saline expands the ECV of a volume equal to that infused without causing any significant acid–base derangement. Other prophylactic measures are probably ineffective, although N-acetylcysteine could be added to saline for its likely effectiveness, safety and low cost.
        • D.
          Final suggestions when requesting the execution of a contrast procedure.
          • Primum non nocere: do no harm. Do not order unnecessary procedures.
          • Use non-ionic hypo-osmolar contrast media, to avoid court litigations.
          • Provide the minimum volume of dye (<125 ml [
            • Rich M.W.
            • Crecelius C.A.
            Incidence, risk factors, and clinical course of acute renal insufficiency after cardiac catheterization in patients 70 years of age or older. A prospective study.
            ,
            • Cronin R.E.
            Southwestern Internal Medicine Conference: renal failure following radiologic procedures.
            ]) and the less risky venous route and CAT rather than intra-arterial injections [
            • Davidson C.
            • Stacul F.
            • McCullough P.A.
            • Tumlin J.
            • Adam A.
            • Lameire N.
            • et al.
            Contrast medium use.
            ], if possible.
          • Follow published protocols effective in minimizing the risk [
            • Mehran R.
            • Aymong E.D.
            • Nikolsky E.
            • Lasic Z.
            • Iakovou I.
            • Fahy M.
            • et al.
            A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation.
            ,
            • Stacul F.
            • Adam A.
            • Becker C.R.
            • Davidson C.
            • Lameire N.
            • McCullough P.A.
            • et al.
            Strategies to reduce the risk of contrast-induced nephropathy.
            ].
          • Weigh the risk: it carries a worse prognosis to skip a necessary coronary angiography than to face the possibility of CIN [
            • Inrig J.K.
            • Patel U.D.
            • et al.
            Mortality, kidney disease and cardiac procedures following acute coronary syndrome.
            ]. In these extreme circumstances, both preventive and post-exposure dialysis proved effective [
            • Lee P.T.
            • Chou K.J.
            • Liu C.P.
            • Mar G.Y.
            • Chen C.L.
            • Hsu C.Y.
            • et al.
            Renal protection for coronary angiography in advanced renal failure patients by prophylactic hemodialysis: a randomized controlled trial.
            ,
            • Marenzi G.
            • Marana I.
            • Lauri G.
            • Assanelli E.
            • Grazi M.
            • Campodonico J.
            • et al.
            The prevention of radiocontrast-agent-induced nephropathy by hemofiltration.
            ].
          • Provide prophylaxis with saline infusion 1.5% of BW 6 h before and after the exam, adding 600 mg of N-acetylcysteine to the last bottle before and after contrast infusion. The entity of expansion and its time course can be modulated according to the heart pump conditions.
          • Monitor the patient carefully, checking PCr, urine flow rate, uranalysis up to 96 h after the procedure.
      • 1.5
        Gadolinium renal failure
        Executing NMR with a gadolinium contrast in patients with pre-existing renal failure has caused a high incidence of the so-called “nephrogenic systemic fibrosis” (NSF) [
        • Broome D.R.
        Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting.
        ]. Gadidiamide is the riskiest gadolinium-based contrast [
        • Khawaja A.Z.
        • Cassidy D.B.
        • Al Shakarchi J.
        • McGrogan D.G.
        • Inston N.G.
        • Jones R.G.
        Revisiting the risks of MRI with gadolinium based contrast agents-review of literature and guidelines.
        ]. This entity is characterized by systemic fibroblast proliferation, similar to scleroderma, affecting the skin and internal organs. In the kidney, a progressive interstitial fibrosis occurs, leading to the rapid onset of irreversible ERSD [
        • Zou Z.
        • Ma L.
        Nephrogenic systemic fibrosis: review of 408 biopsy-confirmed cases.
        ]. As contrast-enhanced NMR has viable alternatives, NSF can be totally prevented by avoiding the procedure in patients with renal disease. Dialysis removes the toxic gadolinium compounds.
      • 1.6
        Selective toxic effect of drugs on the kidney
        • A.
          Cisplatin, iphosphamide and their congeners selectively damage tubular transport systems through intracellular hydroxyl radical formation. Polyuria and glycosuria occur initially; subsequently, oliguria occurs when renal failure worsens. Hypercalciuria, hyperphosphaturia and hypermagnesuria occur due to selective impairment of Ca, P and Mg transport systems, attended by their reduced serum concentrations. The biopsy reveals vacuolization and mitochondrial damage of PT, with foci of necrosis, triggering interstitial fibrosis and renal failure if the offending agents are not interrupted. Renal impairment is reversible upon early discontinuation of the offending drug [
          • Jones D.P.
          • Chesney R.W.
          Renal toxicity of cancer chemotherapeutic agents in children: ifosfamide and cisplatin.
          ]. Combination chemotherapy can enhance cisplatin and iphosphamide toxicity, as well as cause ARF due to thrombosis of renal vessels.
        • B.
          Aminoglycoside antibiotics are cleared from the body exclusively through glomerular filtration, their clearance being equal to GFR. They exert concentration-dependent renal toxicity [
          • Humes H.D.
          • Weinberg J.M.
          • Knauss T.C.
          Clinical and pathophysiologic aspects of aminoglycoside nephrotoxicity.
          ], which is maximal for colistin: the initial fall in GFR reduces their clearance, raising their plasma concentration: this begins a vicious circle that, enhancing the toxic effect, initiates progression to ARF. The renal biopsy discloses proximal tubular damage, loss of brush border, sloughing off of tubular cells, mitochondrial swelling and interstitial edema, leading to interstitial fibrosis, ARF and then CRF with continuing administration of the drug. The clinical picture is typical: the patient refers nocturia, heralding polyuria, due to the impairment of the countercurrent mechanism caused by interstitial edema and inflammation, plus NDI. Poliuria is quickly followed by normo-glycaemic glycosuria due to alteration of glucose transport. Initially, at the onset of polyuria and glycosuria, GFR is only slightly impaired, while it drops progressively with continuing administration of the antibiotic. Poliuria remains till the fall in GFR reaches important values. There is slight proteinuria and important enzymuria, a marker of tubular damage, associated with selective transport systems, and more frequently with potassium and magnesium wasting. ARF supervenes in two or more weeks, while it subsides following early recognition and treatment discontinuation. Aminoglycoside toxicity can be effectively avoided by proportioning the individual doses and/or their intervals to the estimated GFR. It is important to monitor diuresis by questioning the patient about the onset of nocturia, to recognize the onset of toxicity, confirmed by checking glycosuria and PCr. The initial renal failure fades away in a few days upon early discontinuation of the agent. Renal toxicity is related to ototoxicity. There no convincing evidence that once-daily aminoglycoside administration reduces nephrotoxicity while enhancing the bactericidal effect.
        • C.
          Amphotericin B displays a dose-related toxic effect characterized by rising creatinine, a short-lived polyuria followed by oliguric renal failure, RTA and magnesium wasting. Prevention, recognition and treatment are the same as those described for the previous drugs. Liposomal preparations are well-tolerated because of slow release of the agent [
          • White M.H.
          • Bowden R.A.
          • Sandler E.S.
          • Graham M.L.
          • Noskin G.A.
          • Wingard J.R.
          • et al.
          Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia.
          ].
      • 1.7
        Herb medications
        The advance of scientific medicine is attended by the stunning faith of many people on over-the-counter medications, sold without prescription, control or due experimentation. The same governments which enforce strong regulation on prescription drugs seem totally indifferent to, or unaware of these remedies. Among these, herbs, mostly oriental, are very popular. Some of them cause renal failure [
        • Allard T.
        • Wenner T.
        • Greten H.J.
        • Efferth T.
        Mechanisms of herb-induced nephrotoxicity.
        ], because of their content in aristolochic acid and tetrandrine [
        • Yuan S.Y.
        • Yang C.R.
        • Cheng C.L.
        • Hsu S.L.
        • Liao J.W.
        • Lin C.C.
        • et al.
        Comparative nephrotoxicity of aristolochic acid and tetrandrine in vitro and in vivo.
        ], producing progressive and asymptomatic interstitial fibrosis and apoptosis of renal tubules, ending in CRF. The clinical picture and the mechanism seem similar to that of Balkan nephropathy [
        • Bamias G.
        • Boletis J.
        Balkan nephropathy: evolution of our knowledge.
        ], and, in more severe and rapidly progressive instances, to the orellanus syndrome [
        • Esposito P.
        • La Porta E.
        • Calatroni M.
        • Bianzina S.
        • Libetta C.
        • Gregorini M.
        • et al.
        Renal involvement in mushroom poisoning: the case of Orellanus syndrome.
        ], which can also occur with the mushroom “hypholoma fasciculare”. They are extremely dangerous as they run asymptomatically till renal failure is no longer reversible. Many unexplained renal failures occurring without apparent cause can be retrospectively traced to the use of these uncontrolled teas, concoctions, leaves of unknown origin, “bush teas” and poisonous mushrooms.
      • 1.8
        Hemodynamic mechanisms
        • A.
          Cyclosporine A and congener drugs determine diffuse fibrosis and sclerosis of small size renal vessels, mesangial sclerosis, hyalinization of glomeruli and oliguric progressive renal failure. These effects are caused by vasoconstriction and platelet aggregation, related micro-thrombotic disease, and by decreased nitric acid production-increased expression of TGF-beta [
          • Olyaei A.J.
          • de Mattos A.M.
          • Bennett W.M.
          Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies.
          ]. The toxicity is heralded by malignant, drug refractory hypertension, attributed to endothelin activation [
          • Castello L.
          • Sainaghi P.P.
          • Bergamasco L.
          • Letizia C.
          • Bartoli E.
          Pathways of glomerular toxicity of cyclosporine-A: an “in vitro” study.
          ,
          • Cavarape A.
          • Endlich K.
          • Feletto F.
          • Parekh N.
          • Bartoli E.
          • Steinhausen M.
          Contribution of endothelin receptors in renal microvessels in acute cyclosporine-mediated vasoconstriction in rats.
          ]. The disease is avoided by close monitoring of plasma cyclosporine concentration, maintained within a safe range, as well as PCr and BP. The urinary sediment is unrevealing.
        • B.
          Oral contraceptives. By increasing renin substrate [
          • Laragh J.H.
          Oral contraceptives-induced hypertension—nine years later.
          ], they cause hypertension, which can progress into a malignant phase with mechanisms similar to those of cyclosporine A and TTP, ending in ESRD. BP should be monitored carefully during the six months following estro-progestins intake, as the adverse effect appears precociously.
        • C.
          PG inhibitors. Aspirin and practically all NSAIDs can cause a renal hemodynamics-induced renal failure [
          • Harris R.C.
          COX-2 and the kidney.
          ]. The glomerulus must have a stable hemodynamics in order to avoid undesired fluctuations of GFR. For this purpose, renal afferent and efferent arterioles are under complex control by agonist vasoconstrictors and antagonist vasodilators, including PG [
          • Cavarape A.
          • Bauer J.
          • Bartoli E.
          • Endlich K.
          • Parekh N.
          Effects of angiotensin II, arginine vasopressin and tromboxane A2 in renal vascular bed: role of rho-kinase.
          ,
          • Cavarape A.
          • Endlich N.
          • Assaloni R.
          • Bartoli E.
          • Steinhausen M.
          • Parekh N.
          • et al.
          Rho-kinase inhibition blunts renal vasoconstriction induced by distinct signaling pathways in vivo.
          ]. The stimulation of each system triggers a homeostatic response of the antagonist branch. When volume depletion and pump failure result in strong vasoconstriction of the glomerular arterioles, PG are maximally stimulated within the glomerular vasculature to maintain glomerular flow and filtration pressure. Their sudden inhibition by PG-blockers produces a sudden, unopposed vasoconstriction [
          • Cavarape A.
          • Endlich N.
          • Assaloni R.
          • Bartoli E.
          • Steinhausen M.
          • Parekh N.
          • et al.
          Rho-kinase inhibition blunts renal vasoconstriction induced by distinct signaling pathways in vivo.
          ,
          • Cavarape A.
          • Bartoli E.
          Effects of BQ-123 on systemic and renal hemodynamic responses to endothelin-1 in the rat split hydronephrotic kidney.
          ], that can result in a variable degree of renal failure, rarely ARF. This occurs more frequently in liver cirrhosis [
          • Bartoli E.
          Pathophysiology of Na and water retention in liver cirrhosis and its correction with vasoconstrictors and aquaretics.
          ] and congestive heart failure. The condition is usually reversible upon withdrawal of the offending agent and restoration of extracellular volume and systemic hemodynamics. Curiously, the angiotensin blockade in CRF and renal artery stenosis, where the peptide is maximally activated, can cause ARF by selectively lowering the resistance of the glomerular afferent arteriole [
          • Cavarape A.
          • Bartoli E.
          Effects of BQ-123 on systemic and renal hemodynamic responses to endothelin-1 in the rat split hydronephrotic kidney.
          ].
      • 1.9
        Crystalline nephropathy
        This is due to intraluminal precipitation of the offending drugs, because of pH-dependent solubility, interaction with other tubular fluid components and saturation concentration within the tubular fluid. The crystals can damage the epithelium, obstruct fluid, recruit other poorly soluble substances into the micro-aggregates and proceed to chronic calcification and interstitial damage. In addition, some of these agents can cause AIN.
        • Foscarnet causes renal failure clinically similar to that of aminoglycosides.
        • The drugs used for HAART treatment cause microcrystalline nephropathy [
          • Rho M.
          • Perazella M.A.
          Nephrotoxicity associated with antiretroviral therapy in HIV-infected patients.
          ]:
          • -
            Tefenovir produces Fanconi syndrome and metabolic acidosis
          • -
            Cidofovir and adefovir determine mitochondrial damage and Fanconi syndrome, which benefits from probenecid administration
          • -
            Acyclovir i.v. causes a pure microcrystalline disease, which is prevented by volume expansion
          • -
            Indinavir shows a more typical clinical picture, as its toxicity may be heralded by acute renal pain, mimicking stone disease, hematuria and pyuria. Occasionally, AIN has been reported
          • -
            Methotrexate and sulfadiazine precipitate at acid pH, an event prevented by HCO3 administration
        • Triamterene exerts toxic effects by microcrystalline disease, occasional AIN [
          • Nasr S.H.
          • Milliner D.S.
          • Wooldridge T.D.
          • Sethi S.
          Triamterene crystalline nephropathy.
          ].
        • Sulfonamides can cause AIN. Being cations, they reproduce the effects of amiloride and triamterene on the distal tubule, causing hyperkalemia, slight metabolic acidosis and distal RTA [
          • Perazella M.A.
          • Mahnensmith R.L.
          Trimethoprim-sulfamethoxazole: hyperkalemia is an important complication regardless of dose.
          ].
      • 1.10
        Miscellaneous entities with different mechanisms
        • Lithium, used as an anti-depressant, determines NDI when it reaches toxic concentrations in plasma, usually above 1.5 mEq/L. If unrecognized, this adverse effect can cause dehydration and renal failure. As lithium is excreted by the kidney, renal failure will reduce its excretion, resulting in higher and more toxic plasma concentrations, further impairing GFR. AIN and tubular necrosis have been reported when patients were exposed to very toxic concentrations for long times [
          • Raedler T.J.
          • Wiedemann K.
          Lithium-induced nephropathies.
          ]. Rare cases of nephrotic syndrome due to cortisone-sensitive minimal change disease have been described.
        • Aquaporins are essential constituents of tubular cell membranes. In animals models, an AIN was reported, caused by T-lymphocyte-dependent immune response to anti-aquaporin-2 antibodies [
          • Pohl M.
          • Fischer M.T.
          • Mader S.
          • Schanda K.
          • Kitic M.
          • Sharma R.
          • et al.
          Pathogenic T cell responses against aquaporin 4.
          ]. Although not used in humans, these antibodies suggest a possible enhancing mechanism in AIN following tubular necrosis, where antigenic aquaporins could be released.
        • Osmotic agents (dextran, mannitol and glycerol) are used to treat brain edema. ARF after massive administrations has been reported, denominated osmotic nephrosis [
          • Dickenmann M.
          • Oettl T.
          • Mihatsch M.J.
          Osmotic nephrosis: acute kidney injury with accumulation of proximal tubular lysosomes due to administration of exogenous solutes.
          ,
          • Pérez-Pérez A.J.
          • Pazos B.
          • Sobrado J.
          • Gonzalez L.
          • Gándara A.
          Acute renal failure following massive mannitol infusion.
          ]. Despite its name, it is not characterized by proteinuria >3 g/day. It is due to swelling of PT cells, with obstruction of the lumen and consequent fall in filtration rate. Any osmotic agent retained within the ECV causes hyponatremia, which causes cell swelling [
          • Bartoli E.
          • Sainaghi P.P.
          • Bergamasco L.
          • Castello L.
          Hyperosmolar coma due to exclusive glucose accumulation: recognition and computations.
          ,
          • Bartoli E.
          • Sainaghi P.P.
          • Bergamasco L.
          • Castello L.
          Computation of the excess glucose and Na deficit of hypo-osmolar hyponatremic hyperglycaemia.
          ], unopposed when the osmotically active substance is excreted. After the initial polyuria, oliguria and anuria ensue. Reversibility occurs after correcting the water–electrolyte derangement and the elimination, even by dialysis, of the osmotic substance [
          • Pérez-Pérez A.J.
          • Pazos B.
          • Sobrado J.
          • Gonzalez L.
          • Gándara A.
          Acute renal failure following massive mannitol infusion.
          ].
      Table 1The acronyms used and their explanation.
      Glossary
      AA = amino acids

      AGN = acute glomerulo-nephritis

      AIN = acute interstitial nephritis

      ARF = acute renal failure

      ATN = acute tubular necrosis

      BP = blood pressure

      BW = body weight

      BM = basement membrane

      CAT = computerized axial tomography

      CAD = coronary artery disease

      CHF = congestive heart failure

      CIN = contrast-induced nephropathy

      CRF = chronic renal failure

      ECV = extra-cellular volume
      DAIN = drug-induced acute interstitial nephritis

      DM = diabetes mellitus

      ESRD = end-stage renal disease

      FENa = fraction of filtered Na excreted

      GFR = glomerular filtration rate

      HAART = highly active antiretroviral therapy

      HITP = heparin-induced thrombocytopenic purpura

      IC = immune complex

      LC = liver cirrhosis

      NDI = nephrogenic diabetes insipidus

      NMR = nuclear magnetic resonance

      NSAID = non-steroidal anti-inflammatory drugs
      NSF = nephrogenic systemic sclerosis

      PCr = plasma creatinine concentration (mg/dL)

      PG = prostaglandins

      PK = plasma potassium concentration (mEq/L)

      PNa = plasma sodium concentration (mEq/L)

      PT = proximal tubule

      PTCA = percutaneous

      coronary angiography

      RTA = renal tubular acidosis

      TGF = transforming growth factor

      TTP = thrombotic thrombo-cytopenic purpura

      2. Diagnosis and treatment

      When a physician recognizes a worsening of renal function, he should take a careful drug history and assess whether any of the drugs taken could be responsible for the renal impairment. PCr and electrolyte concentrations must be measured, and their time change examined. Uranalysis should be performed invariably, as well as other exams when necessary, like acid–base status, enzymuria, renal echography, urine cultures, eosinophiluria and eosinophil blood count. Analyzing and connecting the changes observed and the history taken, it is possible, on the grounds of the clinical-laboratory descriptions, to ascertain the likelihood of an adverse renal drug effect. In dubious circumstances, discontinuing the putative offending agent and instituting an appropriate steroid treatment can be a better option than performing a renal biopsy. This is indicated when it will help to diagnose an entity, or differentiate it from a drug reaction that requires a complex treatment and could avoid permanent damage to the kidney. It should be remembered that, although the more likely offending drugs have been discussed in this review, the possibility of a drug reaction cannot be excluded even when a thorough inspection of the literature does not disclose any previous offense by that substance. Table 2 summarizes the diagnostic findings important in identifying a possible drug offense.
      Table 2The horizontal lines contain the main characteristics of each entity of drug-induced renal disease, reported as Syndrome. For each of these the vertical columns report, from left to right, the main clinical and urinary (UE) findings, the causative drugs and their pathophysiologic mechanisms.
      Clinical symptomsExaminationSyndromeOffending drugsPathophysiology
      Oliguria progressing to anuria. PCr ↑in days; dull back pain↓ Specific gravity

      Leukocyte casts

      Epithelial casts

      Muddy-brown casts

      Low proteinuria

      FE Na > 0.25
      ATN-ARFContrast media miscellaneous drugsDirect toxicity to epithelium ischemia
      Asymptomatic. Oliguria–anuria only at ESRD. Slow PCr ↑Unrevealing for a long timeChronic interstitial nephritisHerbal medications. Exotic unlicensed, or over-the-counter drugsInterstitial fibrosis
      Short polyuric phase. Then, ↓ urine output. PCr ↑ in days to weeks. Dull back pain. Enlarged kidneys, normal outline↓ Specific gravity

      Leuko-epithelial casts, sterile pyuria

      Eosinophiluria

      Low “tubular” proteinuria, enzymuria. Single transport deficits

      Variable FENa
      AINNSAIDs

      Methicillin Penicillins Cephalosporins

      H-pump inhibitors

      Sporadic reports of several drugs
      Hapten-mediated immune mechanisms

      Other immune mechanisms (IC disease, anti-tubular basement membrane antibodies)

      T-lymphocyte activation in chronic phase
      Fever; oliguria; purpura; PCr ↑ in hoursUnrevealingThrombotic micro-angiopathyHeparin causing HITPThrombosis of pre-glomerular vessels
      Persistent polyuria

      Late oliguria

      PCr ↑ in > one week

      Dull back pain
      pH ≥ 7, low specific gravity, glycosuria

      Selective transport deficits (Ca, Mg, P, AA), epithelial casts

      RTA, variable FENa
      Selective epithelial injuryAminoglycosides

      Cisplatinum

      Iphosphamide

      Amphotericin B

      Occasional miscellaneous drugs
      Partial selective toxicity to epithelia; secondary interstitial damage and edema
      ↓Urine output. Sudden, variable PCr ↑

      Liver cirrhosis

      Heart failure

      Dehydration
      pH < 6; ↑ specific gravity

      Urine unrevealing

      No proteinuria-casts

      FENa < 0.01
      Prerenal azotemia

      Functional renal failure
      PG inhibitors

      ACE-Sartans

      Cyclosporin A

      Estroprogestins

      Diuretics
      Afferent arteriole constriction-Efferent arteriole dilatation

      Platelet aggregation-thrombotic microangiopathy (CyA)
      Oliguria–anuria

      PCr ↑ in hours to few days
      Crystalluria

      Other aspects variable
      Obstructive intratubular ARFHAART drugs

      Triamterene

      Sulfa drugs Uricosuric drugs
      Intratubular precipitation of drugs and urine components (uric acid and others)
      ↓ Urine output

      Variable ↑ PCr
      pH < 6

      ↑ Specific gravity

      Proteinuria, hematuria-red cell casts
      AGN

      AGN + AIN
      Penicillins

      Cephalosporins
      Glomerular injury

      Glomerular + interstitial injury
      Renal colic

      PCr ↑ in years

      Chronic pain
      Unrevealing initially

      Late pyelonephritis

      Sterile pyuria
      Analgesic nephropathyPhenacetinInterstitial damage

      Chronic interstitial disease and fibrosis
      After polyuria, anuria ensues

      PCr ↑ in hours
      UnrevealingARFMassive infusions of mannitol, glycerol, dextransOsmotic swelling of proximal tubular cells

      3. Learning points

      • When GFR is reduced, the drugs taken should be reviewed to verify their potential renal offending properties, checking the pertinent case reports on Medline
      • History-taking must be exhaustive and essential lab exams should be examined critically, targeting the different clinical syndromes known that are linked to specific drug exposure.
      • The potential offending agent must be withdrawn and substituted with medication of a different chemical class.
      • In the presence of the clinical lab picture of AIN, if a hapten or immune-mediated mechanism is likely, early steroid treatment must be considered.

      Conflict of Interest

      I declare that I do not have any conflict of interests in the submitted manuscript.

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