Acute Interstitial Nephritis
Acute interstitial nephritis may occur as an adverse reaction to many different drugs. Patients present with acute renal insufficiency following exposure to a medication. The renal insufficiency typically is unaccompanied by oliguria or the need for dialysis. AIN usually begins 2 weeks after exposure to a drug but may occur sooner if the patient has been previously sensitized to the same or a chemically-similar agent.^1-2  AIN is characterized by systemic signs of a hypersensitivity reaction including fever (87% of patients), eosinophilia (79%), and skin rash (24%).¹  Renal manifestations include acute renal insufficiency, sterile pyuria including eosinophiluria, and low grade proteinuria. The renal insufficiency usually resolves within several weeks after withdrawal of the offending agent. Commonly implicated drugs include b -lactam antibiotics (including cephalosporins), other antibiotics (sulfonamides, rifampin, vancomycin), non-steroidal anti-inflammatory drugs, phenytoin, and diuretics (furosemide, thiazides). Numerous drugs have been less commonly implicated in the development of AIN.

Pathologic findings in AIN include interstitial inflammation, edema, and tubulitis. In addition to lymphocytes (mainly T cells) and monocytes, the interstitial infiltrate typically includes eosinophils. Importantly, interstitial granulomas are commonly seen in AIN and may represent the predominant pattern of injury ("granulomatous interstitial nephritis").

The pathogenesis of the majority of cases of AIN is thought to involve a cell mediated hypersensitivity reaction to a drug. This is supported by the observation that T cells are the predominant cell type comprising the interstitial infiltrate. Factors that are likely to play a role include drugs acting as haptens, molecular mimicry, and an individual's immune response genes. A humoral response underlies rare cases of AIN in which a portion of a drug (i.e. methicillin) may act as a hapten, bind to the tubular basement membrane (TBM), and elicit anti-TBM antibodies.³ 

Acute Tubular Necrosis (ATN)
The role of the proximal tubule in concentrating and reabsorbing the glomerular filtrate renders it vulnerable to toxic injury. Toxic ATN has a predilection for the proximal tubule and is caused by a wide variety of substances including heavy metals, organic solvents, pigments, and multiple classes of drugs. Therapeutic agents commonly implicated in toxic ATN include aminoglycoside antibiotics, amphotericin B, cisplatin, anesthetic agents (methoxyflurane), calcineurin inhibitors, mannitol, and radiocontrast media. An increasing number of therapeutic agents are currently being identified as possible causes of tubular damage. Most of these agents, which are normally eliminated through the kidneys, are more likely to induce severe renal failure if kidney function is already impaired prior to their administration.

Patients with toxic ATN present with acute renal failure which may be oliguric and/or require dialysis. Tubular injury is often accompanied by an increased fractional excretion of sodium. The majority of cases have minimal proteinuria (typically < 1 g/day) and a bland urinary sediment. The development of ARF is often dose-dependent and may develop rapidly following exposure to certain therapeutic agents such as aminoglycoside antibiotics. Other agents require prolonged exposure before the development of toxic ATN. In time, the majority of cases will recover following discontinuation of the offending agent and institution of supportive measures, including hydration and hemodialysis when necessary.

The kidneys from patients with toxic ATN grossly appear pale and swollen. Histologic findings include interstitial edema and tubular degenerative changes including luminal ectasia, loss of brush border, cytoplasmic simplification and vacuolization, nuclear enlargement and pleomorphism, cellular necrosis, and apoptotic figures. Interstitial inflammation and tubulitis are not prominently seen. Some forms of toxic ATN exhibit findings which strongly implicate a particular etiologic agent. For instance, severe swelling and vacuolization of tubular epithelia producing a pattern of "osmotic nephrosis" can be seen following use of mannitol, intravenous immunoglobulin, and radiocontrast agents. In patients with ATN secondary to gentamicin, electron microscopy may reveal cytoplasmic myeloid bodies.

Therapeutic agents may be injurious to tubules via a variety of subcellular mechanisms. The drugs or their derivatives may impair the normal function of mitochrondia, disrupt lysosomal and cell membranes, shift ion gradients (i.e. intracellular calcium), and lead to free radical formation. For instance, cisplatin toxicity is thought to involve oxygen free radical formation,⁴  reduction in renal perfusion (4), and disruption of DNA and RNA synthesis.^5-6  Aminoglycoside nephrotoxicity involves disruption of membrane structure and function and alterations in membrane permeability, which lead to inhibition of lysosomal phospholipases, lysosomal rupture, and cytoplasmic release of lysosomal acid hydrolases.⁷  Free radical formation also has been shown to play a role in aminoglycoside nephrotoxicity.⁸  Vasoconstriction ⁹ and modifications in cell membrane integrity and permeability ¹⁰ have been implicated in amphotericin nephrotoxity.

The following sections will focus on newer patterns of drug-induced tubulointerstitial nephropathies which are of particular interest.

Non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used agents in the treatment of pain and inflammation. NSAIDs act by inhibiting cyclooxygenase (COX), the enzyme that converts arachadonic acid into prostaglandins, prostacyclin, and thromboxane. NSAID use has been associated with multiple patterns of renal toxicity.¹¹  Prostaglandin-mediated vasodilation plays an important autoregulatory role in the maintenance of renal perfusion. In the setting of volume depletion (i.e. heart failure) or chronic renal insufficiency, NSAID use can attenuate prostaglandin-mediated vasodilation and precipitate hemodynamically-mediated acute renal failure (ARF) that histologically resembles ischemic ATN. While ATN is the most common renal injury seen following NSAID use, this pattern of disease is often clinically recognizable and as such, is a relatively infrequent finding on renal biopsy. Other patterns of renal disease seen following treatment with NSAIDs include AIN, minimal change disease, membranous glomerulopathy, and papillary necrosis.

Acute interstitial nephritis following treatment with NSAIDs bears important differences from that seen with b -lactam antibiotics, the most frequent therapeutic agents implicated in AIN. NSAID-associated AIN typically follows treatment for greater than one year (in contrast to mean 12 days with b -lactam antibiotics) and has a much lower incidence of fever, rash, and eosinophilia.²  Histologically NSAID-associated AIN exhibits a lesser degree of interstitial inflammation, tubulitis, and eosinophilic infiltration. It is has been suggested that the unique clinical and pathologic characteristics of AIN following treatment with NSAIDs may be explained by the anti-inflammatory properties of this class of drugs.²  The similar patterns of renal toxicity seen with a wide range of NSAIDs suggests that the renal injury may relate not only to the chemical structure and immunogenicity but also to the physiologic effects of COX inhibition and possibly to the shunting of arachadonic acid metabolites into alternative pathways that modify immune function.

The major limitation of NSAID use is gastrointestinal and renal toxicity. The COX enzyme exists in two isoforms. COX-1 is constitutively expressed in many tissues and plays a critical role in gastric prostaglandin production and cytoprotection. COX-2 is expressed at lower levels but is upregulated in the setting of inflammation. In an effort to decrease gastrointestinal toxicity, a new class of drugs that selectively inhibit COX-2 have been developed. The COX-2 inhibitors celecoxib (Celebrex) and rofecoxib (Vioxx) have a lower incidence of gastrointestinal side effects but appear to offer no advantage with respect to hemodynamically-mediated ARF.¹²  More recently, cases of membranous glomerulopathy, minimal change disease, and AIN following treatment with COX-2 inhibitors have been reported.^13-16 

Bisphosphonates
The bisphosphonates, a class of drugs that inhibit bone resorption, are in widespread use for the treatment of hypercalcemia of malignancy. The mechanism of action of bisphosphonates involves both extracellular calcium chelation and internal effects within the osteoclast including altered protein trafficking, impaired energetics, and disruption of the cytoskeleton.¹⁷  Bisphosphonates are widely prescribed to patients with multiple myeloma or metastatic carcinoma of the breast. We previously reported a series of patients who developed collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate.¹⁸ 

More recently zoledronate, a newer and more potent bisphosphonate, has been widely utilized in the treatment of hypercalcemia of malignancy. Zoledronate differs chemically from pamidronate by the substitution of an imidazole ring for an amino group in the R² side chain. Compared to pamidronate, zoledronate requires a shorter infusion time and appears to be superior with respect to control of hypercalcemia of malignancy.¹⁹ 

The nephrotoxicity of zoledronate is not well established. In phase III double-blind trials comparing zoledronate and pamidronate, dosing of zoledronate underwent two protocol adjustments due to concerns regarding renal toxicity.¹⁹  This included an increase in infusion time from 5 to 15 minutes and a decrease in dosage from 8 mg to 4 mg IV once per month. Following the protocol adjustments, the two agents were found to have similar degrees of nephrotoxicity, confirming that renal impairment following treatment with zoledronate is both dose-dependent and infusion time-dependent. In this study, there is no mention of renal biopsies or histologic findings.

We recently reported a series of six patients who developed acute renal failure following treatment with zoledronate.²⁰  The cohort consisted of 4 males and 2 females with mean age of 69.2 years. All patients were treated with zoledronate at the recommended dose (4 mg IV once per month) and infusion time (15 minutes). Following a mean duration of therapy of 4.7 months (range 3-9), all six patients developed acute renal failure with a rise in serum creatinine from a mean baseline of 1.4 mg/dl to a mean peak of 3.4 mg/dl. Renal biopsy revealed toxic ATN with severe tubular degenerative changes notable for cytoplasmic eosinophilia, prominent apoptosis, an increase in cell cycle-engaged cells (Ki-67 positive), and derangements in tubular Na⁺,K⁺-ATPase expression. Following renal biopsy, all patients discontinued treatment with zoledronate and all had subsequent improvements in renal function, with a mean serum creatinine of 2.3 gm/dl at 1-4 months of follow-up. The close temporal relationship between zoledronate administration and the onset of ARF and the partial recovery following discontinuation of treatment strongly implicate zoledronate in the development of toxic ATN. The markedly different clinical and pathologic findings that may occur following treatment with two chemically similar bisphosphonates, pamidronate and zoledronate, is of interest.

Adefovir Nephroxicity: Toxic ATN and mitochondrial DNA depletion
Adefovir dipivoxil is a nucleoside analogue reverse transcriptase inhibitor that is effective in the treatment of HIV infection.²¹  ATN and Fanconi syndrome are known complications of treatment with adefovir.²²  The mechanism of adefovir-associated nephrotoxicity is poorly understood. In addition to inhibiting reverse transcriptase, adefovir also is able to inhibit DNA polymerase g ²³ which is the sole DNA polymerase involved in mitochrondrial DNA (mtDNA) replication.²⁴  Depletion of muscle mtDNA has previously been shown to mediate the myopathy associated with zidovudine, a related nucleoside analogue.²⁵ 

We recently saw a renal biopsy from a 38 year old HIV positive male with ARF and partial Fanconi syndrome that revealed toxic ATN.²⁶  Ultrastructural evaluation revealed marked mitochondrial abnormalities including enlargement, convoluted contours, and clumping of cristae. In an effort to better understand the mechanism of adefovir-associated nephrotoxicity, additional studies were performed.

Cytochrome C oxidase is a mitochrondrial respiratory chain enzyme that is encoded by both mtDNA and nuclear DNA (nDNA) while succinate dehydrogenase (SDH) is encoded entirely by nDNA. Functional histochemistry revealed loss of COX activity in approximately 50% of tubules but complete preservation of SDH activity. Immunohistochemical staining revealed loss of tubular COX subunit I (encoded by mtDNA), preserved expression of COX subunit IV (encoded by nDNA), and depletion of cytoplasmic but not nuclear DNA. Single-renal tubule polymerase chain reaction disclosed a 35-64% reduction in mtDNA in COX negative tubules compared to COX positive tubules within the same biopsy sample. These findings suggest a novel mechanism of nephrotoxicity mediated by inhibition of proximal tubular oxidative phosphorylation due to mtDNA depletion.²⁶  Due to toxicity, clinical trials using adefovir in HIV infection have been discontinued.

Chronic lithium nephrotoxicity
Lithium is commonly used in the treatment of bipolar disorder. Treatment with lithium may be complicated by one of three main types of nephrotoxicity: nephrogenic diabetes insipidus (NDI), acute lithium intoxication, and chronic lithium nephrotoxicity. Among the three, NDI is the most common and likely results from lithium-induced down-regulation of the vasopressin-regulated water channel aquaporin-2 which is expressed on the apical plasma membrane of principal cells of the collecting duct.²⁷  Acute intoxication due to lithium overdose can lead to ARF and volume depletion; primary treatment consists of hemodialysis.

The main pattern of lithium-associated renal injury that is encountered on renal biopsy is chronic lithium nephrotoxicity which typically manifests as a chronic tubulointerstitial nephropathy (CTIN) notable for the presence of distal tubular cysts.^28-29  We recently reported the clinicopathologic findings and outcomes in 24 patients with biopsy-proven chronic lithium nephrotoxicity.³⁰  The cohort consisted of an equal number of males and females with a mean age of 42.5 years and a mean duration of lithium therapy of 13.6 years. There was clinical evidence of NDI in 87% of patients. The mean serum creatinine at the time of biopsy was 2.8 gm/dl and 41.7% of patients had greater than 1 gm of proteinuria/24 hour urine collection. Renal biopsies from all 24 patients exhibited a CTIN with disproportionately severe tubular atrophy and interstitial fibrosis and lesser degrees of glomerulosclerosis and vascular disease. Interstitial inflammation ranged from scant to absent and when present was confined to zones of tubulointerstitial scarring. Cortical or medullary tubular cysts were identified in 62.5% of biopsies and were found to predominantly originate from the distal tubule (EMA positive, Arachnis hypogaea (AH) negative) and collecting duct (EMA and AH positive). In addition to CTIN, lesions of FSGS were identified in 50% of biopsies and their occurrence correlated with the presence of proteinuria > 1 g/day. Following renal biopsy, all but one patient discontinued treatment with lithium. Nonetheless, seven patients progressed to ESRD. By Kaplan-Meier survival analysis, the only significant predictor of progression to ESRD was a serum creatinine > 2.5 mg/dl at the time of biopsy.

In addition to FSGS, minimal change disease also has been described in the setting of treatment with lithium.^31-32 

References

1. Ditlove J, Weidmann P, Bernstein M, Massry SG: Methicillin nephritis. Medicine 56:483-491, 1977
2. Pirani CL, Valeri A, D'Agati V, Appel GB: Renal toxicity of nonsteroidal anti- inflammatory drugs. Contr Nephrol 55:159-175, 1987
3. Border WA, Lehman DH, Egan JD, Sass HJ, Glode JE, Wilson CB: Antitubular basement-membrane antibodies in methicillin-associated interstitial nephritis. N Engl J Med 291:381-4, 1974
4. Matushima H, Yonemura K, Ohishi K, Hishida A: The role of oxygen free radicals in cisplatin-induced acute renal failure in rats. J Lab Clin Med 131:518-526, 1998
5. Tay LK, Bregman CL, Masters BA, Williams PD: Effects of cis- diamminedichloroplatinum (II) on rabbit kidney in vivo or rabbit renal proximal tubule cells in culture. Cancer Res 48:2538-2543, 1988
6. Leibbrandt MEI, Wolfgang GHI, Metz AL, Ozobia AA, Haskins JR: Critical subcellular targets of cisplatin and related platinum analogs in rat renal proximal tubule cells. Kidney Int 48:761-770, 1995
7. Kaloyanides GJ: Drug-phospholipid interactions: Role in aminoglycoside nephrotoxicity. Ren Fail 14:351-7, 1992
8. Walker PD, Shah SV: Evidence suggesting a role for hydroxyl radical in gentamicin- induced acute renal failure in rats. J Clin Invest 81:334-341, 1988
9. Sawaya BP, Weihprecht H, Campbell WR, Lorenz JN, Webb RC, Briggs JP, Schnermann J: Direct vasoconstriction as a possible cause for amphotericin B- induced nephrotoxicity n rats. J Clin Invest 87:2097-2107, 1991
10. Sawaya BP, Briggs JP, Schnermann J: Amphotericin B nephrotoxicity: The adverse consequences of altered membrane properties. J Am Soc Nephrol 6:154-164, 1995
11. Clive DM, Stoff JS: Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Engl J Med. 310:563-572, 1984
12. Woywodt A, Schwarz A, Mengel M, Haller H, Zeidler H, Kohler L: Nephrotoxicity of selective COX-2 inhibitors. J Rheumatol 28:2133-5, 2001
13. Rocha JL, Fernandez-Alonso J: Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, rofecoxib. Lancet 357:1946-7, 2001
14. Alper AB, Meleg-Smith S, Krane NK: Nephrotic syndrome and interstitial nephritis associated with celecoxib. Am J Kidn Dis 40:1086-1090, 2002.
15. Henao J, Hisamuddin I, Nzerue CM, Vasandani G, Hewan-Lowe K: Celecoxib- induced acute interstitial nephritis. Am J Kidn Dis 39:1313-7, 2002
16. Markowitz GS, Falkowitz DC, Isom R, Zaki M, Imaizumi S, Appel GB, D'Agati VD: Membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib. Clin Nephrol. IN PRESS, 2003
17. Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC: Cellular and molecular mechanisms of action of bisphosphonates. Cancer 88:2961-2978, 2000
18. Markowitz GS, Appel GB, Fine PL, Fenves AZ, Loon NR, Jagannath S, Kuhn JA, Dratch AD, D'Agati VD: Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol 12:1164- 1172, 2001
19. Rosen LS, Gordon D, Kaminski M, et al: Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: A phase III, double-blind comparative trial. Cancer J 7:377- 387, 2001
20. Markowitz GS, Fine PL, Stack JI, Kunis CL, Radhakrishnan J, Palecki W, Park J, Nasr SH, Hoh S, Siegel DS, D'Agati VD: Toxic acute tubular necrosis following treatment with zoledronate (Zometa). IN PRESS 2003
21. Barditch-Crovo P, Toole J, Hendrix CW, Cundy KC, Ebeling D, Jaffe HS, Lietman PS: Anti-human immunodeficiency virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxil (9-2-(bis-pivaloyloxymethyl)- phosphonylmethoxyethyl adenine) in HIV-infected patients. J Inf Dis 176: 406-13, 1997
22. Kahn J, Lagakos S, Wulfsohn M, Cherng D, Miller M, Cherrington J, Hardy D, Beall G, Cooper R, Murphy R, Basgoz N, Ng E, Deeks S, Winslow D, Toole JJ, Coakley D: Efficacy and safety of adefovir dipivoxil with antiretroviral therapy; a randomized controlled trial. JAMA 282:2305-2312, 1999
23. Cherrington JM, Allen SJW, Bischofberger N, Chen MS: Kinetic interaction of the diphosphates of 9-(2-phosphonylmethoxyethyl)adenine and other anti-HIV active purine congeners with HIV reverse transcriptase and human DNA polymerases a , b , and g . Antiviral Chem Chemother 6: 217-221, 1995
24. Brinkman K, ter Hofstede HJM, Burger DM, Smeitink JAM, Koopmans PB; Adverse effects of reverse transcriptase inhibitors; mitochondrial toxicity as common pathway. AIDS 12:1735-1744, 1998
25. Arnaudo E, Dalakas M, Shanske S, et al.: Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 337:508-510, 1991
26. Tanji N, Tanji K, Kambham N, Markowitz GS, Bell A, D'Agati VD: Adefovir nephrotoxicity: Possible role of mitochondrial DNA depletion. Hum Pathol 32:734-740, 2001
27. Marples D, Christensen S, Christensen EI, Ottosen PD, Nielsen S: Lithium-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla. J Clin Invest 95:1838-1845, 1995
28. Hestbech J, Hansen HE, Amdisen A, Olsen S: Chronic renal lesions following long- term treatment with lithium. Kidney Int 12:205-213, 1977
29. Aurell M, Svalander C, Wallin L, Alling C: Renal function and biopsy findings in patients on long-term lithium treatment. Kidney Int 20:663-670, 1981
30. Markowitz GS, Radhakrishnan J, Kambham N, Valeri AM, Hines WH, D'Agati VD: Lithium nephrotoxicity: A progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 11:1439-1448, 2000
31. Alexander F, Martin J: Nephrotic syndrome associated with lithium therapy. Clin Nephrol 15:267-271, 1981
32. Tamm VKK, Green J, Schwieger J, Cohen AH: Nephrotic syndrome and renal insufficiency associated with lithium therapy. Am J Kidn Dis 27:715-720, 1996