Emerging therapy-related kidney disease.
Abstract: * Context.--Many new therapies have emerged within the last 5 to 10 years to treat a variety of conditions. Several of these have direct or indirect renal toxicities that may go undiagnosed without careful attention of the pathologist to a patient's clinical history, particularly the addition of new medications or treatments.

Objective.--To discuss patterns of renal injury resulting from medications or therapeutic regimens that have been introduced within the last 10 years. Recognition of these patterns may allow the pathologist to alert the attending clinician to a possible drug-induced renal injury and prevent further deterioration of renal function and possible chronic kidney disease.

Data Sources.--A review of recent literature and unpublished observations of case-derived material.

Conclusions.--A number of newer therapies have emerged as agents of renal toxicity, producing a variety of pathologic changes in the kidney. The outcome can be acute or chronic glomerular, tubular, interstitial, and/or vascular injury. Some drugs will result in irreversible changes and end-stage renal disease, whereas many of the alterations can be reversed with removal of the offending agent, avoiding potential long-term kidney injury.

(Arch Pathol Lab Med. 2009;133:268-278)
Article Type: Report
Subject: Kidney diseases (Risk factors)
Kidney diseases (Diagnosis)
Drug therapy (Patient outcomes)
Pathology (Practice)
Histology (Analysis)
Pathologists (Practice)
Authors: Arend, Lois J.
Nadasdy, Tibor
Pub Date: 02/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: Feb, 2009 Source Volume: 133 Source Issue: 2
Topic: Event Code: 200 Management dynamics
Accession Number: 230151961
Full Text: The kidney may be affected adversely by a wide range of therapeutic agents, particularly by those that are secreted by the kidney. Although the range of nephrotoxic therapeutic compounds is quite diverse, the pattern of renal injury caused by them is limited. Roughly, these therapyinduced renal changes can be divided into glomerular and/or vascular injury and tubulointerstitial injury. There are several book chapters and review articles that address the issue of drug-induced renal injury, including the pathology of this condition. (1-4) Although renal toxicity in association with many agents (eg, antibiotics, nonsteroidal anti-inflammatories, and radiocontrast media) has been known for decades, new therapies are being introduced continuously, and many of these are now known to have adverse renal effects. In this review we will focus on pathologic patterns of renal parenchymal injury caused by more recently introduced therapeutic agents.

Because the pattern of renal injury caused by drugs can also be caused by myriad other injurious agents, it is extremely important that the pathologist have detailed knowledge about the clinical history, including the list of medications given prior to the biopsy procedure. In the absence of this knowledge, drug-induced renal diseases, in particular, renal lesions associated with novel therapeutic interventions, will not be recognized.

GLOMERULAR OR VASCULAR INJURY

Glomerular Changes Secondary to Anti-Tumor Necrosis Factor [alpha] Treatment

Treatment of many chronic inflammatory conditions, such as rheumatoid arthritis, ankylosing spondylitis, and Crohn disease, has recently targeted tumor necrosis factor [alpha] (TNF-[alpha]). Examples of anti-TNF-[alpha] agents include infliximab, adalimumab, and etanercept (Table 1). Increasingly, systemic and renal autoimmune-type disorders have been reported in association with these agents, including lupuslike syndromes with renal manifestations. (5-8) Stokes et al (9) reported 5 patients who developed glomerulonephritis (GN) with varying features, including membranous, proliferative GN and pauci-immune crescentic and necrotizing GN. All patients improved upon withdrawal of the anti-TNF-[alpha] treatment and initiation of immunosuppressive therapy. Separate reports detail cases of etanerceptand infliximab-related necrotizing and crescentic GN associated with anti-neutrophil cytoplasmic antibodies. (10,11) In 2006, Saint Marcoux and De Bandt (7) reported on 3 patients receiving TNF-[alpha] antagonists in whom renal biopsy showed extracapillary GN, with immunoglobulin (Ig) A deposits in 2 and necrotizing GN in 1. The mechanism of the disorders occurring in association with antiTNF therapy is unknown but may relate to formation of immune complexes of the drugs and their targets that are capable of activating the complement cascade, or to alterations in cytokines.

Thrombotic Microangiopathy-like Changes Secondary to Anti-Vascular Endothelial Growth Factor Treatment

Anti-vascular endothelial growth factor (anti-VEGF) antibodies, such as bevacuzimab, have been introduced recently for the treatment of a variety of metastatic cancers, including colorectal, renal, and pulmonary carcino mas. In the kidney VEGF is expressed in podocytes, and VEGF receptors are present on endothelial and mesangial cells. Although anti-VEGF treatment appears to be effective in metastatic carcinoma, side effects are not negligible. Recently, several reports appeared indicating prominent renal side effects, including hypertension, acute renal insufficiency, and proteinuria. (12-16) Some degree of proteinuria may develop in 21% to 63% of patients on bevacizumab; however, nephrotic-range proteinuria (more than 3.5 g/24 hours) develops in "only" 1.0% to 1.8% of patients, depending on the bevacizumab dose. (12)

Reports with documented renal biopsy findings are scarce, but it appears that the characteristic morphologic pattern is that of a glomerular thrombotic microangiopathy, occasionally combined with focal segmental glomerular sclerosis. (14,16-18) We have encountered 5 cases with glomerular thrombotic microangiopathy (TMA) associated with bevacizumab treatment. All patients had severe proteinuria and renal insufficiency. Light microscopy revealed variable degrees of glomerular capillary thickening and endothelial swelling resembling changes in preeclampsia (Figure 1, A). Double contours along the glomerular capillaries are seen commonly on methenamine silver stain (Figure 1, B). In our experience, segmental glomerular sclerosis, and in particular hyalinosis, may develop in patients who have been treated for a prolonged time (more than 1 year) with bevacizumab (Figure 1, C). Vascular changes of TMA are subtle, and fibrin thrombi are unusual. Immunofluorescence is mostly nonspecific; smudgy glomerular capillary fibrinogen staining may occur (Figure 1, D). In one of our cases, prominent glomerular IgA deposits were noted (Figure 1, E). (12) Interestingly, at the 2007 American Society of Nephrology annual meeting, an almost identical biopsy with large IgA deposits and thrombotic microangiopathy-like changes was presented by Sharan Singh, MD, during the Renal Biopsy Clinical Correlations session. Ultrastructural examination reveals endothelial swelling, loss of fenestration, subendothelial widening, and variable degrees of foot process effacement (Figure 1, F). Interestingly, the biopsies with IgA deposits contain homogenous electron-dense subendothelial and mesangial deposits. The exact nature and relevance of these IgA deposits is unclear; in our case, we proved that the IgA deposits appeared after the initiation of bevacizumab treatment because they were absent in the nephrectomy specimen containing the renal cell carcinoma. (12)

The differential diagnosis of this condition involves any form of TMA involving the glomeruli. Interestingly, in bevacizumab-induced TMA, the renal vasculature is relatively spared. If bevacizumab is stopped, proteinuria and renal function may improve. If glomerular TMA develops following the use of bevacizumab, the medication, unfortunately, should be stopped, and alternative treatment regimens will have to be used.

The pathogenesis of the condition is most likely related to blocking VEGF. The absence of VEGF probably prevents adequate repair of endothelial damage, which is most likely a common occurrence. Also, anti-VEGF antibodies may commonly cause hypertension, which could contribute to the endothelial damage. Such endothelial injury may be associated with low-level intraglomerular clotting, loss of endothelial fenestrations, and subendothelial glomerular capillary widening. Also, suppression of VEGF in the podocytes may play a role in the development of proteinuria. If patients are treated for long periods with anti-VEGF monoclonal antibodies, the chronic glomerular endothelial and podocyte injury may result in segmental glomerular sclerosis and hyalinosis. Using gene-targeted methodology, Eremina et al (18) deleted VEGF from podocytes in adult mice. The animals rapidly developed features of TMA, proving the key role of VEGF in the glomerular TMA in this animal model.

Glomerular and Vascular Injury in the Transplant Setting

Although TMA with calcineurin inhibitor (CNI)-based immunosuppression has been known to exist since the late 1980s, newer therapeutic regimens in transplantation also have been reported to cause this vascular and glomerular lesion, such as the anti-CD3 monoclonal antibody muronomab-CD3 (OKT3) (19) and the addition of the antiaggregating agents clopidogrel (20-22) and ticlopidine (22,23) to a CNI-based regimen. The mammalian target of the rapamycin inhibitor sirolimus has been used as rescue immunosuppression in patients who develop TMA or other injuries secondary to CNIs; however, sirolimus has itself been implicated in causing TMA in several cases, (24-27) which may be related to inhibition of VEGF (see the previous section). (28)

A variety of glomerular alterations associated with proteinuria have been attributed to sirolimus, including minimalchange disease, (29) focal segmental glomerulosclerosis, (30,31) membranous GN, membranoproliferative GN, and IgA nephropathy. (32) The proteinuria seen with either de novo sirolimus use or after conversion from CNI immunosuppression has been attributed variously to removal of CNI-mediated vasoconstriction, an increase in glomerular permeability, or proximal tubule cell injury occurring directly or indirectly. Letavernier et al (31) have shown apparent podocyte dysregulation resulting in de novo focal segmental glomerulosclerosis (31) secondary to sirolimus treatment.

These studies demonstrated a decrease in typical podocyte protein expression, such as synaptopodin, and expression of other, atypical proteins. Proposed underlying mechanisms include decreased cell survival or loss of differentiation due to a decrease in VEGF or inhibition of mammalian target of rapamycin.

[FIGURE 1 OMITTED]

Glomerular Injury Secondary to Antiviral Agents

Rare case reports of valacyclovir resulting in TMA have been published. (33-35) Although TMA-like syndromes have been reported in many human immunodeficiency virus (HIV)-infected individuals and may be related directly to virus-mediated endothelial cell injury, the study by Bell et al (33) showed a 4.7-fold greater risk of development of a TMA when patients were treated with acyclovir (Figure 2).

Glomerular Changes Related to Treatment With Bisphosphonates--Collapsing Glomerulopathy

First described by Weiss et al (36) in 1986, collapsing glomerulopathy (CGP), a subset of focal segmental glomerulosclerosis, is found idiopathically and in secondary form related to HIV and other viral infections, ischemic injury, and an increasing list of therapeutic agents. One of the first drugs to be associated with CGP was pamidronate. First described in 2001 (37) and followed soon thereafter by other bisphosphonates, such as alendronate, (38) these drugs are used typically in treatment of osteoporosis, frequently in patients with malignancies such as multiple myeloma. Patients who develop CGP associated with bisphosphonate use present with renal failure and the nephrotic syndrome. Unlike idiopathic CGP and CGP associated with HIV infection, CGP secondary to bisphosphonate treatment does not appear to show a predilection to black race. Collapsing glomerulopathy from any cause consists of segmental or global loss of glomerular capillaries and increased matrix with overlying cellular prominence (Figure 3), sometimes associated with marked tubular microcyst formation. Immunofluorescence microscopy is typically negative or may show minimal nonspecific mesangial deposition of IgM or C3. Ultrastructurally, the podocytes will show focal effacement, and the mesangial matrix often is increased. As in other forms of focal segmental glomerulosclerosis, podocyte injury is thought to be causative. (39) Although the first reported cases of CGP in association with bisphosphonates occurred with dosing that was higher than standard, a more recent report describes CGP following long-term treatment with a standard dose. (40) Unlike many other forms of therapy-induced renal injury, cessation of bisphosphonates after the development of CGP is not generally followed by a reduction in proteinuria or improvement of renal function.

TUBULOINTERSTITIAL INJURY

Tubulointerstitial nephritis is a common complication of therapeutic interventions (Table 2), found in up to 25% of all renal biopsies performed for acute renal failure. (1-4,41-43) Drugs often produce an allergic interstitial nephritis due to a hypersensitivity immune reaction. (44) Histologic findings vary only slightly in appearance, regardless of the inciting agent. Common characteristics include an interstitial infiltrate typically composed of lymphocytes and plasma cells with occasional histiocytes and a variable number of, and sometimes predominant, eosinophils (Figure 4). Antibiotics are common culprits in allergic interstitial nephritis, although scores of drugs have been reported to produce this effect. Other types of tubulointerstitial injury that can occur secondary to therapeutic agents include acute tubular necrosis, crystal nephropathy, tubular atrophy, and interstitial fibrosis (Table 2).

Acute Tubular Necrosis in Statin-Induced Rhabdomyolysis

Any 3-hydroxy-3-methyl-glutaryl CoA-reductase-based lipid-lowering agent can cause proteinuria, hematuria, and an increase in creatinine. (45,46) A risk of myopathy and rhabdomyolysis with subsequent acute renal failure has been shown (45,46); however, most cases of rhabdomyolysis occur at higher doses than are typically prescribed, such as the 80-mg dose of rosuvastatin, which has been discontinued. More recent reports actually show evidence for a beneficial renal effect of rosuvastatin and other statins, with overall increases in glomerular filtration rate (47-49) and no significant adverse renal events. Rhabdomyolysis, when it occurs from any cause, can result in myoglobinuriainduced acute tubular necrosis (ATN). In myoglobinassociated ATN, in addition to the typical tubular changes seen with any ischemic or toxic injury, intratubular deeply eosinophilic or pigmented coarse granular or globular material can be identified by light microscopy and should lead the pathologist to consider an immunostain for myoglobin (Figure 5). Although the risk of statin-induced adverse events is low with standard dosing regimens, at least one report has demonstrated the development of rhabdomyolysis and acute renal failure when standard-dose statin is used in combination with medications that affect liver metabolism, particularly cytochrome P450 3A4 inhibitors, (50) a relatively common situation in the population of patients prescribed statins.

Tubulointerstitial Injury Secondary to Immunosuppressive Regimens

Acute renal insufficiency associated with tubular injury has been reported in transplant patients taking sirolimus or sirolimus in combination with a CNI. (51-53) Acute tubular injury with varying histology has been shown in several case reports. Pelletier et al (53) reported myoglobinuric ATN in 2.6% of transplant patients from 2002 to 2004 following institution of a sirolimus-containing immunosuppressive regimen. Additional investigation was performed by the authors following this finding to clarify the role of sirolimus in the myoglobinuric ATN. Biopsies from patients not taking sirolimus in which a diagnosis of ATN was rendered and granular material was present in tubular casts were examined for intratubular myoglobin. In all of these cases, the biopsies were negative for myoglobin. In a combined sirolimus-tacrolimus protocol, 2 patients were reported to develop acute renal failure in the early posttransplantation period. (51) Biopsy of one of these patients demonstrated acute tubular necrosis. Both patients' renal function improved with removal of sirolimus; reinstitution of tacrolimus alone did not impede the recovery.

Tubular casts morphologically similar to those seen in myeloma light chain cast nephropathy have been reported in association with sirolimus-induced acute renal failure. (52) In this report transplant patients receiving sirolimus with a CNI developed delayed graft function at a higher rate than those not receiving the drug. More than 50% of the patients receiving sirolimus with tacrolimus had acute tubular necrosis on renal biopsy. The ATN in these cases had the unusual morphology characteristic of cast nephropathy, with amorphous, dense, eosinophilic, irregular, and sometimes fractured cast material. Rare casts were surrounded by multinucleated giant cells. None of these patients had evidence of myeloma or other plasma cell dyscrasia, and the tubular cast material was shown to consist of degenerating cells and cellular material rather than a paraprotein. These patients or the biopsies were not tested for the presence of myoglobin. (52) Resolution of cast nephropathy occurred following withdrawal of the sirolimus/ tacrolimus regimen.

[FIGURES 2-4 OMITTED]

The mechanism of this injury is unclear, but several reports suggest a combination of ischemic or hypoxic injury induced by the vasoconstrictive effect of CNIs and/or reperfusion injury combined with the antiproliferative and proapoptotic tendency of sirolimus. (54,55)

Tubulointerstitial Injury From 5-Aminosalicylic Acid

5-Aminosalicylic acids (such as sulfasalazine, mesalazine, and olsalazine) are used in the treatment of inflammatory bowel disease. Since the early 1990s, several case reports of acute and chronic interstitial nephritis have been published (56-59) (Figure 6). One case of papillary necrosis has been reported in association with mesalazine treatment. (60) As with most other drug-induced acute interstitial nephritis (AIN), cessation of the drug leads to improvement in renal function, with steroid treatment necessary in occasional cases. (56)

Tubulointerstitial Injury Associated With Bisphosphonates

Although the bisphosphonates are best known for their association with collapsing glomerulopathy (see above), a few case reports of toxic acute tubular necrosis due to pamidronate and zoledronate have been published recently, without the characteristic glomerular finding. (61,62) The mechanism of this effect is unclear.

Tubulointerstitial Injury Due to Nonprescription Drugs Medicinal herbs, particularly those containing aristolochic acid, have known renal toxicity, resulting in a severe tubulointerstitial nephritis and urinary tract carcinomas. (63,64) The tubulointerstitial injury appears to be extremely aggressive and leads rapidly to chronic kidney disease and end-stage kidney failure. A very characteristic pathologic picture is typically seen of extensive tubular loss and interstitial fibrosis with a sparse to moderately intense mononuclear inflammation. The glomeruli are characteristically uninvolved, even in the setting of seemingly advanced tubular injury (Figure 7). Other medicinal preparations that have been reported to induce tubulointerstitial injury include "cat's claw," used as an anti-inflammatory agent, (65) and CKLS (colon, kidney, liver, spleen), a mixture of 10 different herbs used as a purifying remedy. (66) Although the recognition of renal toxicity due to herbal remedies has increased, and with it a reduction in incidence, the possibility of renal injury related to alternative therapies continues to exist and warrants due diligence in the interpretation of renal biopsies.

Tubulointerstitial Injury Associated With Volume Expanders, Stabilizing/Carrier Agents, or Vehicles

Epidemic acute renal failure has been reported due to contamination of medicinal syrups by diethylene glycol. Epidemics of acute renal failure have been reported in Haiti, (67) Bangladesh, (68) and Nigeria. (69) The mechanism of injury appears to be different than the oxalate toxicity seen with ethylene glycol, because an experimental study, (70) as well as examination of human tissue from victims of diethylene glycol ingestion, (71) shows a lack of oxalate deposition despite hyperoxaluria. Hepatitis, pancreatitis, and neurologic manifestations are also seen with diethylene glycol ingestion. Intravenous diazepam or lorazepam, anxiolytics used in treatment of alcohol withdrawal symptoms or in ventilated patients, contain the solvent propylene glycol. Propylene glycol can be metabolized to lactic acid and produce a metabolic acidosis. It also appears to be capable of producing acute tubular injury, leading to osmotic nephrosis and acute tubular necrosis. (72-74)

[FIGURES 6-8 OMITTED]

The stabilizing agent used in preparations of intravenous immunoglobulin is sucrose, which can cause the classic hydropic tubular epithelial cell changes seen with mannitol administration (osmotic nephrosis). (75) Similarly, hydroxyethyl starch (HES), used as a volume expander, can result in hydropic degeneration (76-79) (Figure 8). Legendre et al (76) reported an increase in the incidence of osmotic nephrosis-like lesions in kidney biopsies of patients following the introduction of HES as a volume expander in kidney transplant recipients in 1993. Although no shortterm difference in renal function was correlated with the use of HES, a much higher number of grafts with this histologic feature were ultimately lost. A multicenter study examining the effects of HES on renal function in patients with sepsis or septic shock showed that use of HES was an independent predictor of acute renal failure, (77) whereas some reports suggest there are no short- or longterm deleterious effects of HES. (80) Renal outcome may depend on the type of HES used and/or the presence or type of underlying renal disease.

Tubulointerstitial Injury Associated With Antiviral or Antibacterial Therapy

Among recently reported therapies found to induce tubulointerstitial injury are drugs used in the treatment of AIDS. One Canadian study reported that 4.5% of patients treated with highly active antiretroviral therapy develop renal toxicity. (81) Acyclovir, ganciclovir, (82) indinavir, (83) foscarnet, (84) and sulfadiazine have all been associated with crystal nephropathy. (3,85) In particular, indinavir crystal precipitation can block tubule flow due to the formation of renal stones (nephrolithiasis), and was the leading cause of renal insufficiency related to protease inhibition in one study. (81) Asymptomatic crystal formations in urine are well-known complications of indinavir and acyclovir. Jaradat et al (83) reported 2 cases of acute renal failure related to a tubulointerstitial nephritis with giant cell formation associated with indinavir (Figure 9), demonstrating that asymptomatic crystalluria could be an indicator of more serious renal injury and warrants close monitoring of renal function. Both patients recovered renal function after discontinuing indinavir. Acyclovir and valacyclovir are known to produce crystal nephropathy, although thismost frequently occurs with intravenous administration. Nevi rapine, a reverse transcriptase inhibitor, used in combination antiretroviral therapy has resulted in typical systemic symptoms of hypersensitivity reaction with acute renal failure in a pregnant woman after 6 weeks of therapy. (86) The eosinophilia and renal insufficiency resolved after discontinuation of the drug and prednisone treatment. Tubulointerstitial nephritis was presumed to be present in this case, but renal biopsy was not performed. Rare cases of renal biopsy-proven interstitial nephritis have been reported in patients experiencing renal failure following treatment with atazanavir, a protease inhibitor, (87) and abacavir, a nucleoside reverse trancriptase inhibitor. (88) Several nucleotide reverse transcriptase inhibitors (tenofovir, adefovir, and cidofovir) have been associated with acute tubular injury (ATN). (17,89) The mechanism of tenofovir renal tubular toxicity may involve inhibition of the organic anion transporter normally mediating efflux of tenofovir from proximal tubule cells, leading to toxic intracellular levels of the drug. (17)

[FIGURES 9-10 OMITTED]

Quinolone-based antibiotics used to treat a variety of infections are agents well known to induce a tubulointerstitial hypersensitivity reaction, sometimes producing granulomatous interstitial nephritis or vasculitis. (90-93) Ciprofloxacin has been reported recently to cause crystal nephropathy as well. Reporting on 2 patients taking ciprofloxacin, Stratta et al (94) show that a crystal-induced nephropathy can occur despite a urine pH lower than 6. Most experimental evidence, as well as previously reported cases, suggested ciprofloxacin crystal formation could not occur in urine pH lower than than 6.8.

Tubulointerstitial Injury Associated With Proton Pump Inhibitors

Proton pump inhibitors (PPIs) used in the treatment and prevention of gastroesophageal reflux conditions have been reported since the early 1990s to be associated with acute tubulointerstitial nephritis (Figure 10). Numerous case reports describe AIN secondary to omeprazole use, (95-97) including the redevelopment of AIN upon rechallenge with the drug. (98) Newer PPIs, such as esomeprazole and pantoprazole, have most recently been implicated in causing AIN. (99-102) Because PPIs are metabolized in the liver by cytochrome P450 enzymes, interactions between PPIs and other drugs, or variations in metabolism of PPIs due to genetic polymorphisms, may lead to higher levels of these medications in some patients and increase their susceptibility to adverse reactions, such as AIN. (103)

Nephrocalcinosis Secondary to Acute Phosphate Nephropathy Following Oral Sodium Phosphate Bowel Purgatives

Oral sodium phosphate solutions are used for colorectal cleansing for colonoscopy. Recently, it became evident that some patients develop acute kidney injury (AKI) following the procedure. (104-107) Patients usually present with nonspecific symptoms and are discovered to have renal insufficiency weeks, sometimes months, following the colonoscopy. Rarely, the AKI may follow the oral sodium phosphate exposure within hours; however, nephrocalcinosis is usually not evident so early. (106) These patients usually do not have a history of abnormal phosphate or calcium metabolism, and most of them did not have previous chronic renal insufficiency. It appears that many of them are hypertensive and treated either with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. (105) A recent large cohort of almost 10 000 patients who underwent oral sodium phosphate bowel cleansing for colonoscopy found an association of subsequent AKI with age. (107) In this study renal biopsies were not performed; the diagnosis was based on the clinical history and subsequent otherwise unexplainable AKI.

Kidney biopsies are usually performed in patients who present weeks or months following the colonoscopy because of unexplained and progressive renal insufficiency. Light microscopy reveals extensive tubular calcium phosphate deposition. Depending on the stage of the disease, interstitial fibrosis and interstitial calcium phosphate deposits are also common (Figure 11, A and B). Variable degrees of acute tubular necrosis are seen almost invariably, usually associated with only relatively mild interstitial mononuclear cell infiltrate. von Kossa stain helps to highlight the calcium phosphate deposits in the tubuloin terstitium (Figure 11, C). It appears that the calcium deposition involves primarily the distal convoluted tubules. (103) Immunofluorescence is negative or shows a nonspecific pattern. Ultrastructurally, electron-dense calcium phosphate precipitates can be seen in the affected tubules along with evidence of tubular injury.

[FIGURE 11 OMITTED]

As described above, the findings are basically that of nephrocalcinosis and are therefore nonspecific. The correct diagnosis can only be made with careful correlation of histologic findings with the clinical history. If one encounters extensive nephrocalcinosis with primarily tubular calcium phosphate deposits in a patient with apparently unexplained progressive renal insufficiency, the possibility of bowel cleansing with oral sodium phosphate preparation in the recent past should be explored. Unfortunately, the outcome of acute phosphate nephropathy following oral sodium phosphate bowel purgatives is poor. Patients who present insidiously weeks, sometimes months, following exposure rarely recover normal renal function. (105) Some patients develop end-stage renal disease, and most of them will have persistent chronic renal insufficiency. One study indicates that if patients develop AKI quickly, usually within the same day following the oral sodium phosphate exposure, recovery of renal function is more likely, probably because of immediate correction of the electrolyte abnormalities. (106) The pathogenesis of the disease is most likely related to the intestinal absorption of sodium phosphate with subsequent excretion through the kidney and tubular deposition of calcium phosphate. This is facilitated by volume depletion from the diarrhea caused by the bowel cleansing preparation. It is difficult to determine precisely who is at risk, but it appears that preexisting renal disease is a prominent risk factor. (108) The prevalence of the disease is so high (1.16% in a recent large study (107)) that a task force from the American Society of Colon and Rectal Surgeons, the American Society for Gastrointestinal Endoscopy, and the American Society for Gastrointestinal Endoscopic Surgeons issued an alert regarding the use of oral sodium phosphate products for bowel preparations.109

CONGENITAL/INTRAUTERINE RENAL INJURY

Renal Injury From Drugs Targeting the Renin-Angiotensin System

Angiotensin-converting enzyme inhibitors, such as captopril, lisinopril, and enalapril, used at or near the 26th week of gestation affect the fetal renin-angiotensin system (RAS). (110-113) Angiotensin-converting enzyme inhibitor fetopathy results from direct effects on the renin-angiotensin system as well as a reduction in blood flow and oxygenation to the fetus. Renal and systemic abnormalities include oligohydramnios from anuria with pulmonary hypoplasia, renal tubular dysgenesis, intrauterine growth retardation, and patent ductus arteriosus. Intrauterine or neonatal death can occur. Angiotensin II receptor blockers can have similar effects. (114-116) New renin inhibitors, such as aliskiren, are classified as category C (first trimester) and category D (second and third trimesters) drugs because of the risk of fetopathy related to interference with the fetal renin-angiotensin system, (117) although no direct evidence for this effect has surfaced in human cases.

SUMMARY

New therapeutic regimens are being introduced almost daily. Many of these will have the capacity to injure the kidneys. A high index of suspicion for drug- or medication-induced renal failure is necessary on the part of the pathologist. The examples presented in this article highlight the importance of a comprehensive clinical history and careful correlation of histologic findings with the clinical scenario.

Accepted for publication September 22, 2008.

References

(1.) Nadasdy T, Racusen LC. Renal injury caused by therapeutic and diagnostic agents and abuse of analgesics and narcotics. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, eds. Heptinstall's Pathology of the Kidney. 5th ed. Philadelphia, PA: Lippincott-Raven; 1998:811-861.

(2.) Nolin TD, Himmelfarb J. Drug-induced kidney disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; 2008:795-810.

(3.) Markowitz GS, Perazella MA. Drug-induced renal failure: a focus on tubulointerstitial disease. Clin Chim Acta. 2005;351:31-47.

(4.) Silva FG. Chemical-induced nephropathy: a review of the renal tubulointerstitial lesions in humans. Toxicol Pathol. 2004;32(suppl 2):71-84.

(5.) Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology. 1999;117:761-769.

(6.) Sarzi-Puttini P, Atzeni F, Capsoni F, Lubrano E, Doria A. Drug-induced lupus erythematosus. Autoimmunity. 2005;38:507-518.

(7.) Saint Marcoux B, De Bandt M. Vasculitides induced by TNFalpha antagonists: a study in 39 patients in France. Joint Bone Spine. 2006;73:710-713.

(8.) Ramos-Casals M, Brito-Zeron P, Munoz S, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore). 2007;86:242-251.

(9.) Stokes MB, Foster K, Markowitz GS, et al. Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis. Nephrol DialTransplant. 2005;20:1400-1406.

(10.) Doulton TW, Tucker B, Reardon J, Velasco N. Antineutrophil cytoplasmic antibody-associated necrotizing crescentic glomerulonephritis in a patient receiving treatment with etanercept for severe rheumatoid arthritis. Clin Nephrol. 2004; 62:234-238.

(11.) Ashok D, Dubey S, Tomlinson I. C-ANCA positive systemic vasculitis in a patient with rheumatoid arthritis treated with infliximab. Clin Rheumatol. 2008; 27:261-264.

(12.) Roncone D, Satoskar A, Nadasdy T, Monk JP, Rovin BH. Proteinuria in a patient receiving anti-VEGF therapy for metastatic renal cell carcinoma. Nat Clin Pract Nephrol. 2007;3:287-293.

(13.) Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49:186-193.

(14.) George BA, Zhou XJ, Toto R. Nephrotic syndrome after bevacizumab: case report and literature review. Am J Kidney Dis. 2007;49:e23-e29.

(15.) Izzedine H, Rixe O, Billemont B, Baumelou A, Deray G. Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. Am J Kidney Dis. 2007;50:203-218.

(16.) Jefferson J, Kowalewska J, Richardson C, Quaggin S, Alpers C. Proteinuria and thrombotic microangiopathy secondary to anti-VEGF antibody (bevacizumab) therapy. J Am Soc Nephrol. 2007;18:186A.

(17.) Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced nephrotoxicity. Am J Kidney Dis. 2005;45:804-817.

(18.) Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358:1129-1136.

(19.) Abramowicz D, Pradier O, Marchant A, et al. Induction of thromboses within renal grafts by high-dose prophylactic OKT3. Lancet. 1992;339:777-778.

(20.) Evens AM, Kwaan HC, Kaufman DB, Bennett CL. TTP/HUS occurring in a simultaneous pancreas/kidney transplant recipient after clopidogrel treatment: evidence of a nonimmunological etiology. Transplantation. 2002;74:885-887.

(21.) Chinnakotla S, Leone JP, Fidler ME, Hammeke MD, Tarantolo S. Clopidogrelassociated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in a kidney/pancreas transplant recipient. Transplantation. 2000;70:550552.

(22.) Pisoni R, Ruggenenti P, Remuzzi G. Drug-induced thrombotic microangiopathy: incidence, prevention and management. Drug Saf. 2001;24:491-501.

(23.) de Mattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis. 2000;35:333-346.

(24.) Franco A, Hernandez D, Capdevilla L, et al. De novo hemolytic-uremic syndrome/thrombotic microangiopathy in renal transplant patients receiving calcineurin inhibitors: role of sirolimus. Transplant Proc. 2003;35:1764-1766.

(25.) Barone GW, Gurley BJ, Abul-Ezz SR, Gokden N. Sirolimus-induced thrombotic microangiopathy in a renal transplant recipient. Am J Kidney Dis. 2003;42: 202-206.

(26.) Robson M, Cote I, Abbs I, Koffman G, Goldsmith D. Thrombotic microangiopathy with sirolimus-based immunosuppression: potentiation of calcineurininhibitorinduced endothelial damage? Am J Transplant. 2003;3:324-327.

(27.) Saikali JA, Truong LD, Suki WN. Sirolimus may promote thrombotic microangiopathy. Am J Transplant. 2003;3:229-230.

(28.) Sartelet H, Toupance O, Lorenzato M, et al. Sirolimus-induced thrombotic microangiopathy is associated with decreased expression of vascular endothelial growth factor in kidneys. Am J Transplant. 2005;5:2441-2447.

(29.) Mainra R, Mulay A, Bell R, et al. Sirolimus use and de novo minimal change nephropathy following renal transplantation. Transplantation. 2005;80: 1816.

(30.) Franco AF, Martini D, Abensur H, Noronha IL. Proteinuria in transplant patients associated with sirolimus. Transplant Proc. 2007;39:449-452.

(31.) Letavernier E, Bruneval P, Mandet C, et al. High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clin J Am Soc Nephrol. 2007; 2:326-333.

(32.) Dittrich E, Schmaldienst S, Soleiman A, Horl WH, Pohanka E. Rapamycinassociated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy. Transpl Int. 2004;17:215-220.

(33.) Bell WR, Chulay JD, Feinberg JE. Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204). Medicine (Baltimore). 1997;76:369-380.

(34.) Griffiths PD, Feinberg JE, Fry J, et al. The effect of valaciclovir on cytomegalovirus viremia and viruria detected by polymerase chain reaction in patients with advanced human immunodeficiency virus disease: AIDS ClinicalTrials Group Protocol 204/Glaxo Wellcome 123-014 International CMV Prophylaxis Study Group. J Infect Dis. 1998;177:57-64.

(35.) Rivaud E, Massiani MA, Vincent F, Azoulay E, Coudrec LJ. Valacyclovir hydrochloride therapy and thrombotic thrombocytopenic purpura in an HIV-infected patient. Arch Intern Med. 2000;160:1705-1706.

(36.) Weiss MA, Daquioag E, Margolin EG, Pollak VE. Nephrotic syndrome, progressive irreversible renal failure, and glomerular "collapse": a new clinicopathologic entity? Am J Kidney Dis. 1986;7:20-28.

(37.) Markowitz GS, Appel GB, Fine PL, et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol. 2001;12:1164-1172.

(38.) Pascual J, Torrealba J, Myers J, et al. Collapsing focal segmental glomerulosclerosis in a liver transplant recipient on alendronate. Osteoporos Int. 2007; 18:1435-1438.

(39.) Barisoni L, Kriz W, Mundel P, D'Agati V. The dysregulated podocyte phenotype: a novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 1999;10:51-61.

(40.) Kunin M, Kopolovic J, Avigdor A, Holtzman EJ. Collapsing glomerulopathy induced by long-term treatment with standard-dose pamidronate in a myeloma patient. Nephrol Dial Transplant. 2004;19:723-726.

(41.) Cameron JS. Allergic interstitial nephritis: clinical features and pathogenesis. Q J Med. 1988;66:97-115.

(42.) Farrington K, Levison DA, Greenwood RN, Cattell WR, Baker LR. Renal biopsy in patients with unexplained renal impairment and normal kidney size. Q J Med. 1989;70:221-233.

(43.) Buysen JG, Houthoff HJ, Krediet RT, Arisz L. Acute interstitial nephritis: a clinical and morphological study in 27 patients. Nephrol Dial Transplant. 1990; 5:94-99.

(44.) Rossert J. Drug-induced acute interstitial nephritis. Kidney Int. 2001;60: 804-817.

(45.) Wolfe SM. Dangers of rosuvastatin identified before and after FDA approval. Lancet. 2004;363:2189-2190.

(46.) Alsheikh-Ali AA, Ambrose MS, Kuvin JT, Karas RH. The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis. Circulation. 2005;111:3051-3057.

(47.) Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Saf. 2004;13:417-426.

(48.) Shepherd J, Vidt DG, Miller E, Harris S, Blasetto J. Safety of rosuvastatin: update on 16,876 rosuvastatin-treated patients in a multinational clinical trial program. Cardiology. 2007;107:433-443.

(49.) Vidt DG, Harris S, McTaggart F, Ditmarsch M, Sager PT, Sorof JM. Effect of short-term rosuvastatin treatment on estimated glomerular filtration rate. Am J Cardiol. 2006;97:1602-1606.

(50.) Schmidt GA, Hoehns JD, Purcell JL, Friedman RL, Elhawi Y. Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin, amiodarone, and atazanavir. J Am Board Fam Med. 2007;20:411-416.

(51.) Lawsin L, Light JA. Severe acute renal failure after exposure to sirolimustacrolimus in two living donor kidney recipients. Transplantation. 2003;75:157160.

(52.) Smith KD, Wrenshall LE, Nicosia RF, et al. Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use. J Am Soc Nephrol. 2003;14:1037-1045.

(53.) Pelletier R, Nadasdy T, Nadasdy G, et al. Acute renal failure following kidney transplantation associated with myoglobinuria in patients treated with rapamycin. Transplantation. 2006;82:645-650.

(54.) Lieberthal W, Fuhro R, Andry CC, et al. Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells. Am J Physiol Renal Physiol. 2001;281:F693-F706.

(55.) Goncalves GM, Cenedeze MA, Feitoza CQ, et al. The role of immunosuppressive drugs in aggravating renal ischemia and reperfusion injury. Transplant Proc. 2007;39:417-420.

(56.) Arend LJ, Springate JE. Interstitial nephritis from mesalazine: case report and literature review. Pediatr Nephrol. 2004;19:550-553.

(57.) Fockens P, Mulder CJ, Tytgat GN, et al, Dutch Pentasa Study Group. Comparison of the efficacy and safety of 1.5 compared with 3.0 g oral slow-release mesalazine (Pentasa) in the maintenance treatment of ulcerative colitis. Eur J Gastroenterol Hepatol. 1995;7:1025-1030.

(58.) World MJ, Stevens PE, Ashton MA, Rainford DJ. Mesalazine-associated interstitial nephritis. Nephrol Dial Transplant. 1996;11:614-621.

(59.) Van Staa TP, Travis S, Leufkens HG, Logan RF. 5-Aminosalicylic acids and the risk of renal disease: a large British epidemiologic study. Gastroenterology. 2004;126:1733-1739.

(60.) Manenti L, De Rosa A, Buzio C. Mesalazine-associated interstitial nephritis: twice in the same patient. Nephrol Dial Transplant. 1997;12:2031.

(61.) Markowitz GS, Fine PL, Stack JI, et al. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int. 2003;64:281-289.

(62.) Smetana S, Michlin A, Rosenman E, Biro A, Boaz M, Katzir Z. Pamidronateinduced nephrotoxic tubular necrosis--a case report. Clin Nephrol. 2004;61: 63-67.

(63.) Wojcikowski K, Johnson DW, Gobe G. Medicinal herbal extracts--renal friend or foe? Part one: the toxicities of medicinal herbs. Nephrology (Carlton). 2004;9:313-318.

(64.) Gabardi S, Munz K, Ulbricht C. A review of dietary supplement-induced renal dysfunction. Clin J Am Soc Nephrol. 2007;2:757-765.

(65.) Hilepo JN, Bellucci AG, Mossey RT. Acute renal failure caused by 'cat's claw' herbal remedy in a patient with systemic lupus erythematosus. Nephron. 1997;77:361.

(66.) Adesunloye BA. Acute renal failure due to the herbal remedy CKLS. Am J Med. 2003;115:506-507.

(67.) O'Brien KL, Selanikio JD, Hecdivert C, et al, for the Acute Renal Failure Investigation Team. Epidemic of pediatric deaths from acute renal failure caused by diethylene glycol poisoning. JAMA. 1998;279:1175-1180.

(68.) Hanif M, Mobarak MR, Ronan A, Rahman D, Donovan JJ Jr, Bennish ML. Fatal renal failure caused by diethylene glycol in paracetamol elixir: the Bangladesh epidemic. BMJ. 1995;311:88-91.

(69.) Okuonghae HO, Ighogboja IS, Lawson JO, Nwana EJ. Diethylene glycol poisoning in Nigerian children. Ann Trop Paediatr. 1992;12:235-238.

(70.) Winek CL, Shingleton DP, Shanor SP. Ethylene and diethylene glycol toxicity. Clin Toxicol. 1978;13:297-324.

(71.) Drut R, Quijano G, Jones MC, Scanferla P. [Pathologic findings in diethylene glycol poisoning]. Medicina (B Aires). 1994;54:1-5.

(72.) Hayman M, Seidl EC, Ali M, Malik K. Acute tubular necrosis associated with propylene glycol from concomitant administration of intravenous lorazepam and trimethoprim-sulfamethoxazole. Pharmacotherapy. 2003;23:1190-1194.

(73.) Zar T, Yusufzai I, Sullivan A, Graeber C. Acute kidney injury, hyperosmolality and metabolic acidosis associated with lorazepam. Nat Clin Pract Nephrol. 2007;3:515-520.

(74.) Wilson KC, Reardon C, Farber HW. Propylene glycol toxicity in a patient receiving intravenous diazepam. N Engl J Med. 2000;343:815.

(75.) Tsinalis D, Dickenmann M, Brunner F, Gurke L, Mihatsch M, Nickeleit V. Acute renal failure in a renal allograft recipient treated with intravenous immunoglobulin. Am J Kidney Dis. 2002;40:667-670.

(76.) Legendre C, Thervet E, Page B, Percheron A, Noel LH, Kreis H. Hydroxyethylstarch and osmotic-nephrosis-like lesions in kidney transplantation. Lancet. 1993;342:248-249.

(77.) Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. 2001;357:911-916.

(78.) De Labarthe A, Jacobs F, Blot F, Glotz D. Acute renal failure secondary to hydroxyethylstarch administration in a surgical patient. Am J Med. 2001;111: 417-418.

(79.) Ebcioglu Z, Cohen DJ, Crew RJ, et al. Osmotic nephrosis in a renal transplant recipient. Kidney Int. 2006;70:1873-1876.

(80.) Boldt J, Brosch C, Ducke M, Papsdorf M, Lehmann A. Influence of volume therapy with a modern hydroxyethylstarch preparation on kidney function in cardiac surgery patients with compromised renal function: a comparison with human albumin. Crit Care Med. 2007;35:2740-2746.

(81.) Foisy MM, Gough K, Quan CM, Harris K, Ibanez D, Phillips A. Hospitalization due to adverse drug reactions and drug interactions before and after HAART. Can J Infect Dis. 2000;11:193-201.

(82.) Balfour HH Jr. Antiviral drugs. N Engl J Med. 1999;340:1255-1268.

(83.) Jaradat M, Phillips C, Yum MN, Cushing H, Moe S. Acute tubulointerstitial nephritis attributable to indinavir therapy. Am J Kidney Dis. 2000;35:16E.

(84.) Maurice-Estepa L, Daudon M, Katlama C, et al. Identification of crystals in kidneys of AIDS patients treated with foscarnet. Am J Kidney Dis. 1998;32: 392-400.

(85.) Kopp JB, Miller KD, Mican JA, et al. Crystalluria and urinary tract abnormalities associated with indinavir. Ann Intern Med. 1997;127:119-125.

(86.) Knudtson E, Para M, Boswell H, Fan-Havard P. Drug rash with eosinophilia and systemic symptoms syndrome and renal toxicity with a nevirapine-containing regimen in a pregnant patient with human immunodeficiency virus. Obstet Gynecol. 2003;101:1094-1097.

(87.) Brewster UC, Perazella MA. Acute interstitial nephritis associated with atazanavir, a new protease inhibitor. Am J Kidney Dis. 2004;44:e81-e84.

(88.) Krishnan M, Nair R, Haas M, Atta MG. Acute renal failure in an HIVpositive 50-year-old man. Am J Kidney Dis. 2000;36:1075-1078.

(89.) Verhelst D, Monge M, Meynard JL, et al. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis. 2002;40:13311333.

(90.) Bailey JR, Trott SA, Philbrick JT. Ciprofloxacin-induced acute interstitial nephritis. Am J Nephrol. 1992;12:271-273.

(91.) Reece RJ, Nicholls AJ. Ciprofloxacin-induced acute interstitial nephritis. Nephrol Dial Transplant. 1996;11:393.

(92.) Lomaestro BM. Fluoroquinolone-induced renal failure. Drug Saf. 2000;22: 479-485.

(93.) Fogo AB. Quiz page. Diabetic nephropathy with superimposed acute interstitial nephritis. Am J Kidney Dis. 2003;41:47A, 1E-3E.

(94.) Stratta P, Lazzarich E, Canavese C, Bozzola C, Monga G. Ciprofloxacin crystal nephropathy. Am J Kidney Dis. 2007;50:330-335.

(95.) Ruffenach SJ, Siskind MS, Lien YH. Acute interstitial nephritis due to omeprazole. Am J Med. 1992;93:472-473.

(96.) Kuiper JJ. Omeprazole-induced acute interstitial nephritis. Am J Med. 1993;95:248.

(97.) Torpey N, Barker T, Ross C. Drug-induced tubulo-interstitial nephritis secondary to proton pump inhibitors: experience from a single UK renal unit. Nephrol Dial Transplant. 2004;19:1441-1446.

(98.) Assouad M, Vicks SL, Pokroy MV, Willcourt RJ. Recurrent acute interstitial nephritis on rechallenge with omeprazole. Lancet. 1994;344:549.

(99.) Ra A, Tobe SW. Acute interstitial nephritis due to pantoprazole. Ann Pharmacother. 2004;38:41-45.

(100.) Geevasinga N, Coleman PL, Webster AC, Roger SD. Proton pump inhibitors and acute interstitial nephritis. Clin Gastroenterol Hepatol. 2006;4:597-604.

(101.) Simpson IJ, Marshall MR, Pilmore H, et al. Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases. Nephrology (Carlton). 2006;11:381-385.

(102.) Brewster UC, Perazella MA. Acute kidney injury following proton pump inhibitor therapy. Kidney Int. 2007;71:589-593.

(103.) Robinson M, Horn J. Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. Drugs. 2003;63:2739-2754.

(104.) Markowitz GS, Nasr SH, Klein P, et al. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol. 2004;35:675-684.

(105.) Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol. 2005;16:33893396.

(106.) Gonlusen G, Akgun H, Ertan A, Olivero J, Truong LD. Renal failure and nephrocalcinosis associated with oral sodium phosphate bowel cleansing: clinical patterns and renal biopsy findings. Arch Pathol Lab Med. 2006;130:101-106.

(107.) Hurst FP, Bohen EM, Osgard EM, et al. Association of oral sodium phosphate purgative use with acute kidney injury. J Am Soc Nephrol. 2007;18:31923198.

(108.) Russmann S, Lamerato L, Marfatia A, et al. Risk of impaired renal function after colonoscopy: a cohort study in patients receiving either oral sodium phosphate or polyethylene glycol. Am J Gastroenterol. 2007;102:2655-2663.

(109.) Wexner SD, Beck DE, Baron TH, et al. A consensus document on bowel preparation before colonoscopy: prepared by a Task Force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Surg Endosc. 2006;20:1161.

(110.) Barr M Jr. Teratogen update: angiotensin-converting enzyme inhibitors. Teratology. 1994;50:399-409.

(111.) Buttar HS. An overview of the influence of ACE inhibitors on fetal-placental circulation and perinatal development. Mol Cell Biochem. 1997;176:6171.

(112.) Tabacova SA, Kimmel CA. Enalapril: pharmacokinetic/dynamic inferences for comparative developmental toxicity: a review. Reprod Toxicol. 2001;15: 467-478.

(113.) Solhaug MJ, Bolger PM, Jose PA. The developing kidney and environmental toxins. Pediatrics. 2004;113:1084-1091.

(114.) Sorensen AM, Christensen S, Jonassen TE, Andersen D, Petersen JS. [Teratogenic effects of ACE-inhibitors and angiotensin II receptor antagonists]. Ugeskr Laeger. 1998;160:1460-1464.

(115.) Saji H, Yamanaka M, Hagiwara A, Ijiri R. Losartan and fetal toxic effects.] Lancet. 2001;357:363.

(116.) Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol Teratol. 2005;73:123-130.

(117.) Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet. 2006;368:14491456.

Lois J. Arend, PhD, MD; Tibor Nadasdy, MD, PhD

From the Department of Pathology and Laboratory Medicine, University of Cincinnati Academic Health Center, Cincinnati, Ohio (Dr Arend); and the Department of Pathology, The Ohio State University, Columbus (Dr Nadasdy).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Tibor Nadasdy, MD, PhD, Department of Pathology, The Ohio State University, M018 Starling Loving Hall, 320 W 10th Ave, Columbus, OH 43210 (e-mail: tibor.nadasdy@osumc.edu).
Table 1. Drug-Induced Glomerular/Vascular Injury

Glomerulonephritis

Anti-tumor necrosis factor [alpha] agents
 Infliximab
 Adalimumab
 Etanercept

Thrombotic microangiopathy
 Anti-vascular endothelial growth factor agents
  Bevacizumab

Immunosuppressive agents *
 OKT3
 Sirolimus
 Clopidogrel
 Ticlopidine
 Antiviral agents
 Acyclovir
 Valacyclovir

Focal segmental glomerulosclerosis
 Classic variant
  Sirolimus
 Collapsing variant
  Bisphosphonates
  Pamidronate
  Alendronate

* Especially when used in a calcineurin inhibitor-based regimen.

Table 2. Medication-Induced Tubulointerstitial Injury

Acute tubular necrosis
 Statins
 Immunosuppressive agents
  Sirolimus
 Bisphosphonates
  Pamidronate
  Zoledronate
 Antiviral agents
 Tenofovir
 Adefovir
 Cidofovir
 Oral sodium phosphate bowel cleanser

Cast nephropathy
 Sirolimus with calcineurin inhibitor

Acute or chronic tubulointerstitial nephritis
 5-Aminosalicylic acids
  Sulfasalazine
  Mesalazine
  Olsalazine
 Medicinal herbs
  Aristolochic acid
  Cat's claw
  CKLS mixture *
  Antiviral agents
  Indinavir
  Atazanavir
  Abacavir
 Antibacterial agents
  Ciprofloxacin
 Proton pump inhibitors
  Omeprazole
  Pantoprazole
  Esomeprazole
Osmotic nephrosis
 Solvents
  Proplyene glycol
  Stabilizing agents
  Sucrose
  Volume expanders
  Hydroxyethyl starch

Crystal nephropathy

 Antiviral agents
  Acyclovir/valacyclovir
  Ganciclovir
  Indinavir
  Foscarnet

Antibacterial agents
  Sulfadiazine
  Ciprofloxacin

Nephrolithiasis
  Antiviral agents
  Indinavir
Nephrocalcinosis
  Oral sodium phosphate bowel cleanser

* CKLS indicates colon, kidney, liver, spleen.
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