• 1.

    Kaufman J, et al.. Community-acquired acute renal failure. Am J Kidney Dis 1991; 17:191198. doi: 10.1016/s0272-6386(12)81128-0

  • 2.

    Nash K, et al.. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002; 39:930936. doi: 10.1053/ajkd.2002.32766

  • 3.

    Bellomo R. The epidemiology of acute renal failure: 1975 versus 2005. Curr Opin Crit Care 2006; 12:557560. doi: 10.1097/01.ccx.0000247443.86628.68

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Kohli HS, et al.. Treatment-related acute renal failure in the elderly: a hospital-based prospective study. Nephrol Dial Transplant 2000; 15:212217. doi: 10.1093/ndt/15.2.212

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Mehta RL, et al.. Spectrum of acute renal failure in the intensive care unit: The PICARD experience. Kidney Int 2004; 66:16131621. doi: 10.1111/j.1523-1755.2004.00927.x

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Uchino S, et al.. Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA 2005; 294:813818. doi: 10.1001/jama.294.7.813

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Hoste EAJ, et al.. Epidemiology of acute kidney injury in critically ill patients: The multinational AKI-EPI study. Intensive Care Med 2015; 41:14111423. doi: 10.1007/s00134-015-3934-7

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Radhakrishnan J, Perazella MA. Drug-induced glomerular disease: Attention required! Clin J Am Soc Nephrol 2015; 10:12871290. doi: 10.2215/CJN.01010115

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Markowitz GS, et al.. Drug-induced glomerular disease: Direct cellular injury. Clin J Am Soc Nephrol 2015; 7:12921300. doi: 10.2215/CJN.00860115

    • Search Google Scholar
    • Export Citation
  • 10.

    Izzedine H, Perazella MA. Thrombotic microangiopathy, cancer, and cancer drugs. Am J Kidney Dis 2015; 66:857868. doi: 10.1053/j.ajkd.2015.02.340

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Palma LMP, et al.. Complement in secondary thrombotic microangiopathy. Kidney Int Rep 2021; 6:1123. doi: 10.1016/j.ekir.2020.10.009

  • 12.

    Nasr SH, D’Agati VD. Nodular glomerulosclerosis in the nondiabetic smoker. J Am Soc Nephrol 2007; 18:20322036. doi: 10.1681/ASN.2006121328

  • 13.

    Markowitz GS, et al.. Idiopathic nodular glomerulosclerosis is a distinct clinicopathologic entity linked to hypertension and smoking. Hum Pathol 2002; 33:826835. doi: 10.1053/hupa.2002.126189

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Kim JS, et al.. Concurrent drug-induced linear immunoglobulin A dermatosis and immunoglobulin A nephropathy. Ann Dermatol 2015; 27:315318. doi: 10.5021/ad.2015.27.3.315

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Hogan JJ, et al.. Drug-induced glomerular disease: Immune-mediated injury. Clin J Am Soc Nephrol 2015; 10:13001310. doi: 10.2215/CJN.01910215

  • 16.

    Xiao X, Chang C. Diagnosis and classification of drug-induced autoimmunity (DIA). J Autoimmun 2014; 48–49:6672. doi: 10.1016/j.jaut.2014.01.005

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Izzedine H, et al.. Drug-induced glomerulopathies. Expert Opin Drug Saf 2006; 5:95106. doi: 10.1517/14740338.5.1.95

  • 18.

    Kaneko T, et al.. A case of gefitinib-associated membranous nephropathy in treatment for pulmonary adenocarcinoma. CEN Case Rep 2015; 4:3137. doi: 10.1007/s13730-014-0135-0

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Lin JS, et al.. Immune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab. J Immunother Cancer 2020; 8:e001287. doi: 10.1136/jitc-2020-001287

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Radford MG Jr., et al.. Reversible membranous nephropathy associated with the use of nonsteroidal anti-inflammatory drugs. JAMA 1996; 276:466469. doi: 10.1001/jama.1996.03540060042033

    • Crossref
    • Search Google Scholar
    • Export Citation

Keep in Mind the Spectrum of Drug-Induced Glomerular Diseases

  • 1 Hassan Izzedine, MD, PhD, is with the Department of Nephrology, Peupliers Private Hospital, Ramsay Générale de Santé, Paris, France. Jia Hwei Ng, MD, MSCE, is an Assistant Professor of Medicine, Division of Nephrology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell and Northwell Health Physician, Hempstead, NY.
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Drugs cause approximately 20% of community- and hospital-acquired episodes of acute kidney failure (13). Among older adults, the incidence of drug-induced nephrotoxicity may be as high as 66% (4). Drug-induced nephrotoxicity may account for 20% of acute kidney injury (AKI), including both acute and chronic kidney disease. Prospective cohort studies of AKI have documented the frequency of drug-induced nephrotoxicity to be approximately 14%−26% in intensive care unit cohorts (57).

A growing body of literature highlights the potential for drugs to induce not only AKI but also glomerular diseases, termed drug-induced glomerular diseases. Patients with glomerular involvement generally present with one of five clinical syndromes: recurrent macroscopic hematuria, microscopic hematuria associated with proteinuria, heavy proteinuria or nephritic/nephrotic syndrome, rapidly progressive glomerulonephritis (RPGN), or chronic glomerulonephritis (GN). Strict monitoring of kidney function, urine and blood abnormalities, and blood pressure must be performed in patients undergoing therapy with potentially toxic drugs. It is critical to recognize these conditions early, because in many patients, there is improvement after removing the offending medication (8). In certain scenarios, removal of the offending agent plus an immunosuppressive strategy has been employed. However, the effectiveness of immunosuppressive therapy in this context has not been determined. From a diagnostic and therapeutic standpoint, it is sometimes difficult to ascribe a drug as being directly causative versus unmasking a preexisiting syndrome.

Drug-induced glomerular diseases can also be classified into two categories: direct cellular toxicity and immune-mediated injury (Table 1).

t1

Direct glomerular cell injury involving the visceral epithelial (or podocytes), endothelial, and mesangial cells

Podocyte injury: Drug-induced podocytopathies can manifest as nephrotic syndrome, nephrotic range proteinuria, with or without AKI. The spectrum of pathologic findings has consisted of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). This includes both FSGS, not otherwise specified, and collapsing glomerulopathy. Multiple therapeutic agents have been associated with these lesions (Table 1), including interferon, bisphosphonates, lithium, nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., indomethacin, celecoxib), and androgenic anabolic steroids (8).

Endothelial cell injury: Thrombotic microangiopathy (TMA) is characterized by mechanical microangiopathic hemolytic anemia, thrombocytopenia, and end organ injury. Pathologic findings include endothelial swelling and necrosis, glomerular and vascular thrombosis, mesangiolysis, glomerular basement membrane duplication with cellular interposition, mucoid intimal edema, and fibrin deposition (8). Drugs are an important acquired cause of TMA (Table 1) and include anti-angiogenesis drugs, chemotherapy, interferon, quinine, calcineurin inhibitors, and thienopyridines (9). It is of interest that drug-induced TMA may be immune mediated (ADAMTS-13 or antiplatelet antibodies induction), a consequence of direct toxicity of the offending drug to endothelial cells and more recently, inhibition of the vascular endothelial growth factor pathway to involve injury to kidney podocytes (10). Although the majority of patients lack complement genetic variants, the response of drug-induced TMA to eculizumab may provide indirect evidence of complement activation in some cases (11).

Mesangial cell/area injury: Smoking-associated nodular glomerulosclerosis is a lesion related to heavy cigarette smoking (12), and smoking cessation seems to reduce the likelihood of progression to end stage kidney disease (13). Although usually idiopathic, the immunoglobulin A (IgA) antibody is occasionally induced by drugs (e.g., vancomycin, carbamazepine, ceftriaxone, and cyclosporine), malignancies, infections, and other causes (14).

Immune-mediated injury from drug-induced autoimmunity

Drug-induced autoimmunity is an idiosyncratic (type B) reaction, which is generally unpredictable and unrelated to the mechanism of action of the drug, unlike the type A reaction, which is drug dependent and dose related (15). Drug-induced autoimmunity is a rare phenomenon, occurring in <1% of patients exposed to a drug, leading to manifestations of lupus or vasculitis; and kidney involvement—even rarer—occurs in about 5% of patients with drug-induced autoimmunity (15). Most of the disorders improve upon stopping the medication. In patients where major organ injury is present, immunosuppression may be needed to quell the inflammation and prevent permanent damage (16). The mechanism of glomerular injury is thought to be from the activation of the adaptive immune system by the offending drug or its metabolite. There is not a classic syndrome ascribed to any one particular drug class (15).

Membranous nephropathy is the other form of drug-induced autoimmunity. Drugs used to treat rheumatoid arthritis, rarely used now including penicillamine and gold salts, were associated with membranous nephropathy. Currently, drug-induced membranous nephropathy is rare and has been reported with organic mercurials in skin-lightening creams, the newer rheumatoid arthritis drug adalimumab, and NSAIDs including celecoxib (17), gefitinib (18), and nivolumab (19). Interestingly, NSAID-associated membranous nephropathy accounted for 10% of patients with early membranous nephropathy (20).

Drug-induced glomerular diseases should be part of the differential diagnosis in patients presenting with glomerular syndrome. Recognition of a drug-induced etiology and rapid withdrawal of the offending agent are essential to optimize the chances of recovery of kidney function. Steroids, eculizumab, and/or pheresis may not work in most of these cases. Clinicians must be aware of this clinical presentation in order to individualize patient management.

The authors report no conflicts of interest.

References

  • 1.

    Kaufman J, et al.. Community-acquired acute renal failure. Am J Kidney Dis 1991; 17:191198. doi: 10.1016/s0272-6386(12)81128-0

  • 2.

    Nash K, et al.. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002; 39:930936. doi: 10.1053/ajkd.2002.32766

  • 3.

    Bellomo R. The epidemiology of acute renal failure: 1975 versus 2005. Curr Opin Crit Care 2006; 12:557560. doi: 10.1097/01.ccx.0000247443.86628.68

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Kohli HS, et al.. Treatment-related acute renal failure in the elderly: a hospital-based prospective study. Nephrol Dial Transplant 2000; 15:212217. doi: 10.1093/ndt/15.2.212

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Mehta RL, et al.. Spectrum of acute renal failure in the intensive care unit: The PICARD experience. Kidney Int 2004; 66:16131621. doi: 10.1111/j.1523-1755.2004.00927.x

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Uchino S, et al.. Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA 2005; 294:813818. doi: 10.1001/jama.294.7.813

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Hoste EAJ, et al.. Epidemiology of acute kidney injury in critically ill patients: The multinational AKI-EPI study. Intensive Care Med 2015; 41:14111423. doi: 10.1007/s00134-015-3934-7

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Radhakrishnan J, Perazella MA. Drug-induced glomerular disease: Attention required! Clin J Am Soc Nephrol 2015; 10:12871290. doi: 10.2215/CJN.01010115

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Markowitz GS, et al.. Drug-induced glomerular disease: Direct cellular injury. Clin J Am Soc Nephrol 2015; 7:12921300. doi: 10.2215/CJN.00860115

    • Search Google Scholar
    • Export Citation
  • 10.

    Izzedine H, Perazella MA. Thrombotic microangiopathy, cancer, and cancer drugs. Am J Kidney Dis 2015; 66:857868. doi: 10.1053/j.ajkd.2015.02.340

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Palma LMP, et al.. Complement in secondary thrombotic microangiopathy. Kidney Int Rep 2021; 6:1123. doi: 10.1016/j.ekir.2020.10.009

  • 12.

    Nasr SH, D’Agati VD. Nodular glomerulosclerosis in the nondiabetic smoker. J Am Soc Nephrol 2007; 18:20322036. doi: 10.1681/ASN.2006121328

  • 13.

    Markowitz GS, et al.. Idiopathic nodular glomerulosclerosis is a distinct clinicopathologic entity linked to hypertension and smoking. Hum Pathol 2002; 33:826835. doi: 10.1053/hupa.2002.126189

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Kim JS, et al.. Concurrent drug-induced linear immunoglobulin A dermatosis and immunoglobulin A nephropathy. Ann Dermatol 2015; 27:315318. doi: 10.5021/ad.2015.27.3.315

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Hogan JJ, et al.. Drug-induced glomerular disease: Immune-mediated injury. Clin J Am Soc Nephrol 2015; 10:13001310. doi: 10.2215/CJN.01910215

  • 16.

    Xiao X, Chang C. Diagnosis and classification of drug-induced autoimmunity (DIA). J Autoimmun 2014; 48–49:6672. doi: 10.1016/j.jaut.2014.01.005

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Izzedine H, et al.. Drug-induced glomerulopathies. Expert Opin Drug Saf 2006; 5:95106. doi: 10.1517/14740338.5.1.95

  • 18.

    Kaneko T, et al.. A case of gefitinib-associated membranous nephropathy in treatment for pulmonary adenocarcinoma. CEN Case Rep 2015; 4:3137. doi: 10.1007/s13730-014-0135-0

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Lin JS, et al.. Immune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab. J Immunother Cancer 2020; 8:e001287. doi: 10.1136/jitc-2020-001287

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Radford MG Jr., et al.. Reversible membranous nephropathy associated with the use of nonsteroidal anti-inflammatory drugs. JAMA 1996; 276:466469. doi: 10.1001/jama.1996.03540060042033

    • Crossref
    • Search Google Scholar
    • Export Citation
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