Drug-Induced Glomerular Disease: Direct Cellular Injury

Glen S. Markowitz,* Andrew S. Bomback,† and Mark A. Perazella‡

Abstract The potential of medications to cause kidney injury is well known. Although nephrotoxicity is most commonly associated with injury in the tubulointerstitial compartment as either acute tubular necrosis or acute interstitial nephritis, a growing body of literature has also highlighted the potential for drug-induced glomerular lesions. This *Department of Pathology and Cell review surveys the three primary patterns of drug-induced glomerular diseases stratified by the cell type at which Biology and †Division the glomerular lesion is focused: visceral epithelial cell (or podoctye) injury, endothelial cell injury, and mesangial of Nephrology, cell injury. A number of commonly prescribed medications, including IFNs, bisphosphonates, nonsteroidal anti- Columbia University inflammatory drugs, antiplatelet agents, and antiangiogenesis drugs, that are both prescribed and available over Medical Center, New York, New York; the counter, have been implicated in these iatrogenic forms of glomerular disease. Recognition of these drug- and ‡Section of induced etiologies of glomerular disease and rapid discontinuation of the offending agent are critical to Nephrology, maximizing the likelihood of renal function recovery. Department of Clin J Am Soc Nephrol 10: 1291–1299, 2015. doi: 10.2215/CJN.00860115 Internal Medicine, Yale University School of Medicine, New Haven, Connecticut Introduction IFN Medications are a common cause of kidney injury, be- The IFNs are cytokines that were initially named for Correspondence: cause they have the capacity to damage cells within all the ability to interfere with viral replication (1). There Dr. Mark A. Perazella, compartments of the kidney. Nephrotoxicity is most are three main types of IFNs: a, b, and g.IFN-a is Section of commonly described as producing tubular or interstitial mainly synthesized by leukocytes (other than lympho- Nephrology, injury, resulting in acute tubular necrosis (ATN) or b fi g Department of cytes), IFN- is mainly broblast derived, and IFN- Internal Medicine, acute interstitial nephritis (AIN), respectively. Much less originates from T cells and natural killer cells. IFN-a Yale University School attention has been paid to drug-induced glomerular and -b are mainly produced by virally infected cells, of Medicine, injury. act through common receptors, and induce changes in Boardman Building The three main cell types within the glomerulus are 122, 330 Cedar Street, neighboring cells that block viral replication. In contrast, New Haven, CT the visceral epithelial cell (VEC; also referred to as the IFN-g acts to stimulate macrophage activation and 06520-8029. Email: podocyte), the endothelial cell, and the mesangial cell. MHC expression. Collectively, the IFNs are a critical mark.perazella@yale. This review will focus on patterns of nephrotoxicity component of the innate immune system that protects edu that primarily target each of the three cell types (Table 1). against viral infection. fi This is a simpli ed approach, because a medication may IFNs are indicated for the treatment of multiple medical directly affect a target cell, its metabolites may induce conditions. IFN-a is used in the treatment of hepatitis B the effect, or the agent may modify the immune system and C and various malignancies. IFN-b is extensively used fi or another cell type, resulting in a speci c pattern of to treat multiple sclerosis. IFN-g is indicated for chronic glomerular injury. Although the distinction may be granulomatous disease and malignant osteopetrosis. subtle, drug-induced glomerular injury may primarily All three forms are administered through the subcuta- affect the immune system and lead to the production of neous or intramuscular route and are associated with autoantibodies, resulting in various drug-induced glo- constitutional effects and laboratory abnormalities that merulopathies that are covered in an accompanying limit their use. review article. Treatment with IFN has been associated with ne- phrotic syndrome (NS) with histologic findings of MCD, Epithelial Cell Injury FSGS-NOS, or C-FSGS (2). Review of the literature on The drug-induced podocytopathies consist of IFN-a reveals six patients with MCD, nine patients with minimal-change disease (MCD) and FSGS, including FSGS-NOS, and nine patients with C-FSGS; 14 of the 24 both FSGS not otherwise specified (FSGS-NOS) and patients were treated for the hepatitis C virus. IFN-b collapsing FSGS (C-FSGS). It is notable that, although has been associated with two reports of MCD and three the relationship between MCD and FSGS has been an reports of C-FSGS, whereas there are two reports of area of longstanding debate and the majority of patients C-FSGS and one report of FSGS-NOS in patients treated with MCD do not progress to FSGS or vice versa, mul- with IFN-g (2). In virtually all instances, IFN was dis- tiple therapeutic agents are associated with both con- continued, and a significant percentage of patients was ditions (Table 2). treated with steroids. Outcomes were largely determined www.cjasn.org Vol 10 July, 2015 Copyright © 2015 by the American Society of Nephrology 1291 1292 Clinical Journal of the American Society of Nephrology

phenotype and that treatment with exogenous IFN may Table 1. Drug–induced glomerular lesions act as a second hit in patients with high-risk APOL1 alleles (5). Epithelial cells (podocytes) Minimal change disease IFN, pamidronate, lithium, nonsteroidal Bisphosphonates anti–inflammatory drugs Bisphosphonates are a class of drugs that are used to pre- FSGS vent bone resorption. Oral bisphosphonates are used to IFN, pamidronate, lithium, sirolimus, anabolic steroids treat osteoporosis and are not thought to be nephrotoxic. Endothelial cells The nitrogen-containing intravenous bisphosphonates Thrombotic microangipathy Antiangiogenesis drugs, mitomycin-C, gemcitabine are most commonly used to treat metastatic bone disease, IFN, thienopyridines (antiplatelet agents), quinine hypercalcemia of malignancy, and multiple myeloma. The Mesangial cells dosage for this indication is substantially higher and as- Idiopathic nodular glomerulosclerosis sociated with nephrotoxicity. Two bisphosphonates are ap- (mesangial sclerosis) proved for this indication in the United States: pamidronate Heavy tobacco smoking and zoledronic acid. NS has been reported after the use of pamidronate (6,7). In contrast, the main pattern of nephrotoxicity associated with zoledronic acid is ATN by the histology pattern of injury, with complete or partial (7,8). remission seen in all patients with MCD. Nearly all pa- The most common pattern of VEC injury associated with tients with FSGS-NOS or C-FSGS improved after discon- pamidronate is C-FSGS (Figure 1) (6,7). The initial report of tinuation of IFN, although less than one half reached C-FSGS after pamidronate therapy included seven patients partial or complete remission (2). with NS and renal insufficiency (6). Our experience has The reports of C-FSGS after treatment with IFN are dis- subsequently expanded to 19 patients (7), and at least 10 tinctive for a strong black racial predominance and the ultrastructural finding of endothelial tubuloreticular inclu- sions. Tubuloreticular inclusions are cytoplasmic micro- tubular structures found in endothelial cells that can be induced in animal models after administration of IFN (“IFN footprints”) (3). Recent studies have provided in- sight into the mechanism by which IFN may lead to the development of FSGS (4,5). APOL1 gene variants confer a significantly greater risk for the development of FSGS and more rapid progression to ESRD in black patients (4). DNA was analyzed from six black patients and one His- panic patient who developed C-FSGS while undergoing treatment with IFN, and all seven patients were found to be homozygous for high-risk APOL1 alleles (5). IFN increases APOL1 expression in vitro and quite possibly, in vivo. These studies raise the possibility that innate IFN production in response to viral infection may play a role in inducing renal disease in patients with the APOL1 high-risk

Table 2. Medications associated with minimal change disease and FSGS

Minimal change disease IFN-a and -b Pamidronate Lithium Nonsteroidal anti-inflammatory drugs Cyclooxygenase-2 inhibitors FSGS IFN-a and -g Pamidronate Lithium Figure 1. | Drug-induced epithelial cell injury. (A) A glomerulus from Sirolimus a patient treated with pamidronate exhibits collapsing FSGS with global Anabolic steroids wrinkling and retraction of the glomerular basement membrane asso- Collapsing FSGS ciated with swelling and proliferation of overlying epithelial cells. Jones 3 IFN-a,-b,and-g methenamine silver, 600. (B) In this patient treated for multiple scle- Pamidronate (rarely zoledronate or alendronate) rosis with IFN-b, glomeruli appear unremarkable by light microscopy. Anabolic steroids On ultrastructural evaluation, complete foot process effacement, di- agnostic of minimal change disease, is seen (36,000). Clin J Am Soc Nephrol 10: 1291–1299, July, 2015 Glomerular Injury from Drugs and Toxins, Markowitz et al. 1293

additional patients have been reported. Patients with The association between lithium and FSGS is more pamidronate-associated C-FSGS present with florid NS and nebulous (16,20,21). In 1988, three patients who developed renal insufficiency, often have received doses of pamidronate FSGS while treated with lithium were described (20). Al- that exceed recommended levels, and in most cases, have though all had nephrotic-range proteinuria, none had full poor outcomes, with approximately one half showing im- NS. Two patients had significant CKD and marked tubu- provement in renal function after drug discontinuation lointerstitial scarring on renal biopsy. In the largest report but none returning to baseline. In one patient, a partial on pathologic findings in chronic lithium nephrotoxicity, remission was seen after discontinuation of pamidronate, the CTIN characteristic of this condition was accompanied the drug was later reintroduced, and proteinuria immedi- by FSGS in 12 of 24 patients (16). Among 12 patients with ately worsened (9). There are rare reports of MCD and FSGS lesions, six patients had nephrotic-range proteinuria, FSGS-NOS with pamidronate; not surprisingly, the best including three patients with NS. These 12 patients also outcomes are seen in patients with MCD (10). There are had moderate to severe tubulointerstitial scarring, and also rare reports of C-FSGS after treatment with intrave- most had glomerulomegaly, favoring a secondary form fi nous zoledronate (11,12), and there was a single case after of FSGS resulting from hyper ltration in remnant neph- the use of oral alendronate in a recipient of a liver trans- rons. In most patients with lithium-associated CTIN, the fi plant (13). nding of FSGS is a secondary occurrence, but in rare The mechanism by which pamidronate produces C-FSGS instances, the presentation and extensive foot process ef- is unknown, although the pattern of injury favors direct facement favor a primary podocyte injury akin to lithium- or indirect podocyte effects. The nitrogen-containing in- associated MCD (16). Of note, a recent report described an travenous bisphosphonates mainly exert their therapeutic 11-year-old boy with 3 g/d proteinuria in the absence of effects on osteoclasts, a cell type with a complex, branching edema or hypoalbuminemia in the setting of lithium ther- cytoarchitecture that resembles the podocyte. Within the apy. Renal biopsy revealed FSGS, lithium was discontin- osteoclast, pamidronate inhibits the mevalonate pathway, ued, and the proteinuria resolved within 3 weeks (21). leading to altered cell signaling and apoptosis as well as impaired cellular energetics and disruption of the cyto- Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) are a skeleton assembly (7). Similar effects may be operant in broad class of medications with analgesic, antipyretic, and podocytes. anti-inflammatory properties. These widely used agents in- hibit cyclooxygenase-1 (COX-1) and COX-2, thereby blocking Lithium prostaglandin, prostacyclin, and thromboxane production. Lithium carbonate is widely used in the treatment of bi- NSAIDs are associated with multiple patterns of neph- polar disorder. Lithium therapy is associated with multiple rotoxicity, including hemodynamically-mediated ATN, adverse renal effects, most frequently nephrogenic diabetes AIN, MCD, papillary necrosis, and, rarely, membranous insipidus. Acute lithium intoxication is associated with AKI, nephropathy. with histologic findings of ATN (14). Chronic lithium tox- NSAID-associated MCD was first reported in three pa- icity, most commonly encountered after $10 years of therapy, tients with AKI and NS who had biopsy findings of both AIN is a distinctive chronic tubulointerstitial nephropathy (CTIN) and MCD that remitted after NSAID discontinuation (22). A characterized by distal tubular cysts (15,16). Treatment with subsequent literature review noted that NSAID-associated lithium is also associated with NS and histologic findings of MCD may occur in the absence of AIN (23). This report in- MCD (17–19). cluded 24 patients with MCD, among whom 15 patients re- Lithium-induced MCD was first reported in 1980 (17). ceived fenoprofen. Patients presented with full-blown NS A woman developed NS 10 months after commencing ther- and had excellent outcomes after NSAID discontinuation, apy. Lithium was withdrawn, NS resolved; lithium was re- often in the absence of corticosteroids (23). NSAIDs subse- instituted 2 years later, and NS recurred (17). During both quently have been recognized as a drug-induced etiology of NS episodes, renal biopsy revealed MCD. A patient with MCD. Unlike IFN, lithium, and bisphosphonates, which are lithium-associated MCD was reported in 1989, and eight associated with MCD and FSGS, available data do not additional reports were reviewed (18). Patients ranged in support a relationship between NSAIDs and FSGS. The ob- age from 14 to 60 years and included six women and three servation that MCD occurs with multiple classes of NSAIDs men. MCD was associated with abrupt onset of NS usually with distinct chemical structures suggests that the pathogen- during the initial 12 months of treatment, and after discon- esis of MCD and other NSAID-associated nephropathies may tinuation, NS resolved over 2–10 weeks. Three of nine pa- involve shunting of AA metabolites into alternative pathways tients had a recurrence of NS when rechallenged with that modify immune function (24). Of note, the COX-2 lithium (18). A later report described two patients with inhibitors, a newer class of NSAIDs that selectively inhibits MCD accompanied by AKI; complete remission followed COX-2, have also been associated rarely with MCD (25). Al- lithium discontinuation and treatment with steroids (19). though drug discontinuation is often associated with remis- The mechanism by which lithium leads to MCD is not sion of MCD, a course of steroids may be beneficial when known, although hypotheses have highlighted the interac- NS persists despite drug withdrawal. tions between the positively charged lithium and negatively charged glomerular basement membrane and the effects of Additional Therapeutics Agents Associated with FSGS lithium on lymphocyte function, possibly leading to release Treatment of recipients of renal transplants with of lymphocyte-derived factors that alter the glomerular fil- sirolimus, a mammalian target of rapamycin inhibitor, is tration barrier (19). commonly accompanied by an increase in proteinuria, which 1294 Clinical Journal of the American Society of Nephrology

is usually subnephrotic (26). In 2007, eight cases of biopsy- Adverse renal effects of AADs result from disturbance of proven FSGS were reported in recipients of renal transplants the normal housekeeping role and tissue repair of VEGF- treated with sirolimus, including three patients treated de associated angiogenesis in the kidneys. Constitutive ex- novo and five patients who previously received a calcineurin pression and secretion of VEGF by podocytes preserve inhibitor (CNI) (27). All three patients treated de novo had glomerular integrity through paracrine and, possibly auto- urine protein .6 g/d, whereas the mean urine protein in- crine binding of endothelial and epithelial receptors, re- creased from 0.28 to 2.54 g/d in five patients who previously spectively (34–36). This cross-talk between the VEC and received a CNI. When the patients treated de novo were endothelial cell plays a major role in maintaining the struc- switched to a CNI, proteinuria markedly diminished (27). ture and function of the filtering unit (34–36). Experimental Pathologic evaluation revealed FSGS-NOS with immunohis- evidence supports the importance of an intact VEGF path- tochemical evidence of podocyte dysregulation. In cell cul- way. Progressive inhibition of VEGF expression is associated ture, podocytes exposed to sirolimus exhibit reduced with glomerular endotheliosis, glomerular aneurysmal synaptopodin, nephrin, and podocin expression, increased change, mesangiolysis, and full-blown TMA (34–36). apoptosis, and actin cytoskeletal reorganization, forming a The most common renal manifestations of AAD-associated potential basis for this toxicity (28). Ironically, sirolimus has TMA are proteinuria and hypertension (HTN); in more been used with limited success as a treatment for FSGS in the native kidney (29). C-FSGS and FSGS-NOS have been reported in bodybuilders after long-term anabolic steroid use. In 2010, Herlitz et al. (30) Table 3. Medications associated with thrombotic described 10 patients with mean urine protein of 10.1 g/d and microangiopathy serum creatinine of 3.0 mg/dl, including three patients with classic NS. In seven patients with available follow- Antineoplastic agents up who discontinued anabolic steroid use, stabilization or Antiangiogenesis drugs improvement in proteinuria and kidney function was noted. Mitomycin-C Rechallenge in one patient led to rapid worsening of pro- Gemcitabine teinuria and renal dysfunction. The pathogenesis may in- Cisplatin/carboplatin volve hyperfiltration in response to increased (lean) body Estramustine/lomustine Cytarabine mass as well as direct nephrotoxic effects of anabolic Tamoxifen steroids (30). Bleomycin Daunorubicin Hydroxyurea Endothelial Cell Injury Antiplatelet agents Thrombotic microangiopathy (TMA) is a term that has Ticlopidine, clopidogrel, prasugrel been applied to multiple seemingly unrelated conditions Dipyradamole that share clinical and pathologic features. Clinically, TMA Defribrotide is characterized by microangiopathic hemolytic anemia IFNs (MAHA), thrombocytopenia, and end organ injury (31,32). IFN-a and -b Pathologic findings in TMA target the endothelial cell and Immunosuppressive agents include endothelial swelling and necrosis, glomerular and Calcineurin inhibitors Anti-CD33 (OKT3) vascular thrombosis, mesangiolysis, glomerular basement Antimicrobial agents membrane duplication with cellular interposition, mucoid Valacyclovir fi intimal edema, and brin deposition (31,32). Conditions Penicillins associated with TMA include hereditary and acquired dis- Rifampin orders and may present acutely with catastrophic effects or Metronidazole gradually with chronic end organ injury (31,32). Medications Tetracycline are an important acquired cause of TMA (Table 3). This sec- Sulfasoxazole tion will briefly review drug-induced forms of TMA, with Albendazole – fl the exception of CNIs, that are of interest to nephrologists. Nonsteroidal anti in ammatory drugs Diclofenac Piroxicam Antiangiogenesis Drugs Ketorolac Antiangiogenesis drugs (AADs) are used to treat a number Hormones ofcancersaswellasvariousneovasculareyedisorders(33). Conjugated estrogens alone or combined AADs include monoclonal antivascular endothelial growth with progestins factor (anti-VEGF) antibodies (bevacizumab), circulating Contraceptives, combination VEGF decoy-receptor molecule (aflibercept), and VEGF recep- Others tor tyrosine-kinase inhibitors (sunitinib, sorafenib, axitinib, Quinine and pazopanib) (33). Their anticancer efficacy is on the Intravenous oxymorphone (Opana) ER Simvastatin basis of observations that many malignancies proliferate and Iodine disseminate by promoting unregulated tumor angiogenesis Cocaine through dysregulation of the VEGF signaling pathway (33). Antiangiogenesis is also effective in nonmalignant neovascular ER, extended release. processes, where nephrotoxicity is a rare occurrence (33). Clin J Am Soc Nephrol 10: 1291–1299, July, 2015 Glomerular Injury from Drugs and Toxins, Markowitz et al. 1295

severe cases, AKI is seen (37–40). This pattern of renal injury, which is more common with anti-VEGF antibodies or decoy- receptor therapy than with tyrosine-kinase inhibitors, has been described in over 100 patients (41,42). These drugs produce a clinical-pathologic picture quite similar to pre- eclampsia, which is driven, in part, by a similar molecular mechanism. MAHA and thrombocytopenia are only observed in approximately 50% of patients, despite the findings of acute or chronic TMA in the kidney (36,41). HTN occurs in .80% of patients, whereas proteinuria is nearly universal and ranges from low grade to nephrotic range (36,41). Urine sediment can be active with cylinduria and cellular/granular casts or bland. Kidney function ranges from mild injury to severe AKI re- quiring dialysis. BP control and drug withdrawal can be associated with return of kidney function, which is rela- tively uncommon for TMA associated with others agents (43). Interestingly, adverse renal effects often correlate with effective antitumor activity (44). Thus, nephrologists and oncologists have to balance drug withdrawal for nephro- toxicity against effective cancer therapy. We suggest that HTN and proteinuria should prompt antihypertensive therapy, whereas AKI is an indication to interrupt drug therapy (42,45).

Chemotherapeutic Agents Mitomycin-C. Mitomycin-C is an alkylating agent used to treat various malignancies (46). After the recognition of the association between mitomycin-C therapy and TMA, a registry identified 85 patients, and subsequent clinical trials noted a TMA incidence ranging from 4% to 15% (46,47). Kidney injury is dose dependent, with a cumulative dose Figure 2. | Drug induced TMA. (A) A glomerulus from a patient treated .60 mg significantly increasing TMA risk. The mechanism with gemcitabine exhibits subacute findings of thrombotic micro- is unknown, but direct toxic endothelial injury is favored angiopathy, including global double contours of the glomerular base- over an immune-mediated process involving ADAMTS-13 ment membrane (tram tracking), cellular interposition, and dissolution or the alternative complement pathway (46,47). of the mesangial matrix consistent with mesangiolysis. Mild swelling of Although TMA can develop during drug exposure, it endothelial and visceral epithelial cells is also noted. Jones methena- mine silver, 3600. (B) A glomerulus from the same patient exhibits more often develops weeks to months after the last dose fi a fresh fibrin thrombus in a preglomerular arteriole. Hematoxylin and (mean of 75 days) (46,47). AKI is a de ning feature of eosin, 3600. TMA, thrombotic microangiopathy. mitomycin-C–associated TMA (46,47) and is often severe; one third of 85 registry patients required dialysis (46). Renal recovery can occur, but most patients are left with CKD. virtually all cases. In a case series of 29 patients with Systemic manifestations of MAHA and thrombocytopenia gemcitabine-associated TMA, all patients had MAHA, are common, whereas neurologic symptoms are rare (16%) thrombocytopenia, and AKI, whereas new or worsening (46,47). Treatment rests primarily on drug withdrawal, be- HTN, proteinuria, and hematuria were noted in 26 of cause steroids, plasma exchange/pheresis (PE/PH), and an- 29 patients (49). Drug discontinuation or future avoidance ticoagulation are generally ineffective. TMA-related resulted in full (n58) or partial (n511) recovery with CKD mortality is approximately 44% (46,47). in three patients and ESRD in seven patients (25%). PE/PH Gemcitabine. Gemcitabine is a cell cycle–specificpyrimidone had minimal or no effect. Reported mortality is wide-ranging antagonist that is used to treat a variety of malignancies (43). (0%–90%), with 15% a reasonable estimate for TMA-specific TMA (Figure 2) was described as a complication within a few death (43,46,48,49). years following approval, with an incidence ranging from 0.015% to 2.4% (43,46,48). Higher cumulative dose and prior exposure to other chemotherapeutic agents increase the risk IFN for TMA (43,46,48). Drug-induced endothelial injury is the In addition to their association with MCD and FSGS, the probable mechanism. Disruption of endothelial integrity IFNs are associated with the development of TMA (50,51). may cause release of vWf multimers and plasminogen acti- Over 30 patients with IFN-a–associated TMA have been re- vator inhibitor, reduce synthesis of prostacyclin and tissue ported, most often in the setting of chronic myelogenous leu- plasminogen activator, and expose a denuded endothelial kemia (50,52). High-dose and prolonged regimens are most surface that favors platelet adhesion, leading to fibrin and often associated with TMA (50,52). Patients present with platelet deposition in the renal microvasculature (43,46,48). HTN, severe AKI often requiring dialysis, proteinuria, and TMA most often develops weeks to months after ini- active urine sediment, whereas MAHA and thrombocytopenia tiating gemcitabine therapy (43,46,48). AKI is present in are variably present (50,52). In the patients reviewed, treatment 1296 Clinical Journal of the American Society of Nephrology

included drug discontinuation and BP control, whereas PE/PH 3–5 days required for ticlopidine-associated TMA. Recov- was performed in approximately two thirds of patients; anti- ery is common, but CKD is an established complication. platelet agents and steroids were occasionally used (50,52). Mortality from clopidogrel-associated TMA with and CKD and ESRD requiring dialysis are fairly common—nearly without PE/PH therapy is reported to be 28% and 33%, one half of patients reported developed long-standing kidney respectively (55,56). disease. Mortality occurs from TMA, but most deaths are Prasugrel was FDA approved in 2009 for coronary stent caused by underlying malignancy (50). thrombosis prevention, and as of 2011, 14 patients with TMA IFN-b causes TMA less commonly than IFN-a,withex- have been reported to the FDA (55,56). Notably, no TMA perience limited to a small number of cases and regulatory cases were described in clinical trials containing 1769 patients reports of patients with relapsing multiple sclerosis (51). Clin- treated with prasugrel (55). As with clopidogrel, TMA gener- ical features, treatment, and outcomes are similar to those de- ally develops within 2 weeks of exposure. Drug discontinua- scribed with IFN-a (51,53,54). The mechanism of IFN-associated tion and PE/PH are currently recommended. TMA remains unclear, although three reports describe ADAMTS-13 autoantibody/deficiency (50–54). Quinine Quinine has been used to treat muscle cramps and malaria, Thienopyridines and despite an FDA ban on over-the-counter marketing, it Ticlopidine, clopidogrel, and prasugrel are antiplatelet remains widely available by prescription, in beverages and agents that target the P2Y12ADP receptor, and they are used to nutrition/health store products, and on internet sites (58,59). prevent and/or treat cerebrovascular accidents and coronary Although well recognized as a cause of immune throm- artery events, including stent thrombosis (55,56). Paradoxically, bocytopenia, quinine is also an important cause of TMA this class of drugs is one of the most commonly implicated in (58,59). Quinine-induced TMA is often characterized by oli- drug-induced TMA (55,56). guric or anuric AKI, frequently requiring dialysis (up to Ticlopidine was Food and Drug Administration (FDA)- 85%), and laboratory manifestations of MAHA with severe approved in 1991, and a case series subsequently described thrombocytopenia (58,59). 60 patients with TMA (55,56). The incidence of TMA is The rapid development of TMA after a single quinine approximately 0.02%, with the syndrome developing 2–12 tablet bespeaks an immune-mediated process (37,38). weeks after drug exposure. Neurologic complications Quinine-dependent IgG antibodies drive this process (72%) of TMA dominate, with AKI noted to be less severe by binding to a broad range of cells, including platelets, and uncommon (29%) (55,56). MAHA and thrombocyto- white blood cells, and endothelial cells (59,60). Both penia are often present and can be severe. In contrast to antibody-induced endothelial injury and platelet activa- direct endothelial injury, ticlopidine appears to cause tion may underlie the development of TMA (59,60). Quinine TMA through reducing ADAMTS-13 activity (55,56). Pro- is not associated with ADAMTS-13 autoantibody or de- duction of an inhibiting autoantibody is described, al- ficiency (58–60). Drug discontinuation and plasmaphere- though how ticlopidine induces this effect is unknown. sis are indicated to remove the culprit antibody. Existing Molecular mimicry and hapten formation have been sug- literature suggests that ESRD and CKD develop com- gested. Interestingly, concomitant complement factor H mu- monly (approximately 50%) after TMA, with a mortality tations and ADAMTS-13 deficiency were described in four of 21% in one large series (58–60). Relapse may occur with patients with ticlopidine-induced TMA, suggesting that two re-exposure. hits may be required in some patients (57). Although dis- continuation of ticlopidine is required in patients with Mesangial Cell Injury TMA, PE/PH provided added benefit, presumably by re- Nodular glomerulosclerosis (NGS) has emerged as a moving autoantibodies that promote thrombosis. Patients specific glomerular lesion associated with cigarette smoking. treated with PE/PH more commonly recover and have The finding of nodular mesangial sclerosis with glomerular lower mortality rates (0%–40%) compared with drug dis- and tubular basement thickening, in the absence of immune continuation alone (50%–67%) (55,56). CKD is an uncom- deposits, is the classic description of nodular diabetic glo- mon complication. merulosclerosis. However, this same pattern of NGS (Figure Clopidogrel entered clinical practice as an antiplatelet 3) has been reported in patients without clinical evidence of agent in 1998 driven by clinical trials showing better safety diabetes. The lesion was first reported as “diabetic glomer- (no TMA in .20,000 patients) than ticlopidine (55,56). Cur- ulosclerosis without diabetes” (61,62) and subsequently re- rently, in part because of its sheer volume of use, clopidogrel branded “idiopathic nodular mesangial sclerosis” or has become the leading cause of drug-induced TMA (55,56). “idiopathic nodular glomerulosclerosis” (63,64). However, As of 2011, the FDA received 197 reports of clopidogrel- the publication of the first substantial case series on this associated TMA, with an incidence that approximates entity in 2002, which included 23 patients compared 0.012%. In contrast to ticlopidine, TMA develops more rap- with a total of 20 patients previously reported over 31 years idly, often within 2 weeks of exposure. AKI is more common and 13 publications (65), presented strong evidence that (55%) and typically more severe, whereas thrombocytopenia heavy cigarette smoking was linked to this lesion (66); 21 is mild (55,56). Interestingly, most cases are not explained by of 23 patients (91%) reported a history of tobacco use, with a ADAMTS-13 deficiency/inhibitor, favoring direct drug-induced mean cumulative smoking history of 52.9 pack-years, and endothelial injury, enhanced release of ultralarge vWF, or an more than one half of patients were still smoking at the time unknown mechanism (55,56). In addition to drug discontin- of biopsy. Longstanding HTN (mean duration of 15.1 years) uation, PE/PH has been used but seems to require prolonged was a similar common feature present in 22 of 23 patients. A treatment periods (3 weeks) for response in contrast to the more recent series detailed 15 patients with idiopathic NGS Clin J Am Soc Nephrol 10: 1291–1299, July, 2015 Glomerular Injury from Drugs and Toxins, Markowitz et al. 1297

insufficiency. Recognition of a drug-induced etiology and withdrawal of the offending agent provide the best hope for renal recovery. For most drugs, it impossible to predict thetimecourseforrecoveryofkidneyfunction.Asaresult, the clinician needs to observe closely and individualize patient management.

Disclosures None.

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