CASE-LETTER
Vancomycin-Induced Interstitial Nephritis Superimposed on Coexisting Renal Disease: The Importance of Renal Biopsy
N
ephrotoxicity because of vancomycin is increasingly recognized and reported, especially with utilization of larger doses and maintenance of higher trough levels.1 The histology of most cases of vancomycin-induced nephrotoxicity is unknown as prospective biopsy studies have not been attempted, but it is presumed to be tubular injury resembling acute tubular necrosis as demonstrated in animal models and a small number of case reports in humans and as supported by the absence of evidence for an inflammatory renal process (such as cellular elements on urinalysis [UA] and eosinophiluria).2 A small number of cases of acute interstitial nephritis (AIN) secondary to vancomycin have been reported.3 The proportion of vancomycin-induced renal injury because of AIN as opposed to tubular injury is unknown as renal biopsies are not routinely performed in patients with vancomycin-induced renal dysfunction in the absence of atypical features such as indicators of an allergic reaction (such as rash, fever or eosinophilia), eosinophiluria, heavy proteinuria or hematuria of glomerular origin. Only a prospective study of vancomycin-induced nephrotoxicity with routine renal biopsies would answer the questions of relative importance of various mechanisms of renal injury and the prevalence of preexisting chronic renal disease or a coexisting acute renal pathology unrelated to vancomycin. Two recently encountered patients with suspected vancomycin-induced renal injury underwent renal biopsies. Each biopsy showed AIN and an unrelated renal disease (chronic diabetic glomerulopathy and a postinfectious IgA nephropathy, respectively). A 45-year-old woman with type 2 diabetes, hypertension and previous gastric bypass was referred for evaluation of a chronic non-healing ulcer at the site of amputation of the right 4th toe. Her home medications of metformin and an angiotensin converting enzyme inhibitor had not been changed for several years. UA evaluation showed protein of 300 mg/dL and 30–40 red blood cells or high power field. Magnetic resonance imaging was consistent with osteomyelitis of the 4th metatarsal bone and a remnant of the proximal phalanx. Deep wound culture had a heavy growth of Staphylococcus epidermidis, and the patient was begun on vancomycin 1 gram intravenously (IV) every 12 hours. Baseline renal function tests showed serum blood urea nitrogen of 16 mg/dL and serum creatinine of 1.2 mg/dL. After 5 days of vancomycin therapy, serum creatinine increased to 1.5 mg/dL and a trough vancomycin level was 29.4 mg/L. Vancomycin dose was reduced to 750 mg IV every 12 hours. Twenty-one days after vancomycin was begun, the serum creatinine was noted to be 2.3 mg/dL and vancomycin trough level was 37.2 mg/L. Vancomycin dose was changed to 1.4 g IV every 24 hours. On the 24th day of vancomycin therapy, vancomycin trough level was 12.9 mg/L and serum creatinine was 2.3 mg/dL. On the 26th day of vancomycin treatment, vancomycin trough level was 24.3 mg/L and serum creatinine was 2.1 mg/dL.
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The next day, vancomycin was discontinued and a nephrology consultation was performed. Rash, fever and arthralgias were absent and examination was remarkable only for a healing foot wound. Numerous studies were obtained (Table 1). Due to suspected glomerulopathy, renal biopsy was performed showing both AIN with no granulomas and moderately advanced diabetic nephropathy with glomerulosclerosis. Serum creatinine improved to 1.9 mg/dL after 7 days of oral prednisone (40 mg daily). Over the next several years, the patient developed progressive renal failure thought secondary to diabetic glomerulopathy and is being considered for renal transplantation. A 61-year-old man with a history of depression, gout and hypertension underwent L2-S1 spinal fusion with instrumentation and right iliac bone graft due to spinal stenosis. Chronic home medications included diltiazem, allopurinol, metoprolol and trazodone. Preoperative testing revealed normal measures of renal function, normal complete blood count and an unremarkable UA. Postoperatively, he developed a surgical site infection with methicillin-resistant Staphylococcus aureus susceptible to vancomycin with a minimal inhibitory concentration of 1 mg/L. Blood cultures were negative and a transthoracic echocardiogram showed no vegetations. The wound was surgically irrigated and vancomycin 1.75 g IV every 12 hours was begun. Vancomycin peak and trough levels obtained around the 5th dose were 31.1 mg/L and 12.8 mg/L, respectively. Serum blood urea nitrogen and creatinine were 12 mg/dL and 1 mg/dL, respectively. The patient was discharged on the same dose of vancomycin but returned 7 days later when his wound exhibited a recurrence of erythema and purulent drainage. Serum creatinine was noted to be 1.9 mg/dL and vancomycin trough level was 36 mg/L. Repeat wound irrigation was performed and a culture of drainage again grew methicillin-resistant Staphylococcus aureus with the same vancomycin susceptibility. Vancomycin was replaced by daptomycin 6 mg/kg IV every 48 hours. Three days later serum creatinine increased to 3.1 mg/dL, and a nephrology consultation was obtained. The patient was afebrile and had no history of pharyngitis, diarrhea, rash or arthralgia. Examination was unremarkable except for a clean surgical incision with no erythema or drainage. Numerous studies were obtained (Table 1). Renal biopsy showed both AIN without granulomas and IgA nephropathy with 20% crescent formation. IgA glomerulonephritis was thought to be of a postinfectious etiology, likely related to staphylococcal infection. Serum creatinine worsened to 7.1 mg/dL, and 80 mg of oral prednisone was begun daily. After 14 days, serum creatinine decreased to 2.4 mg/dL. Vancomycin is a widely used antibiotic and is now recognized to be associated with a relatively common acute renal injury, especially in the setting of prolonged high-dose therapy and the presence of other risk factors such as conephrotoxins and preexisting renal disease.1 Recent reviews have reported rates of vancomycin renal injury up to 40%.1,2 Acute tubular injury is thought to be responsible for the majority of cases of vancomycin renal toxicity, but no prospective renal biopsy-based studies have been attempted. A few case reports have demonstrated acute tubular injury. Although most cases of vancomycin-induced renal toxicity are thought to be reversible after discontinuation of vancomycin (and occasionally even while the drug is being continued), no specific therapy is available.1,4
The American Journal of the Medical Sciences
Volume 347, Number 4, April 2014
Case-Letter
TABLE 1. Results of studies after development of renal insufficiency Study Patient 1 Creatinine (baseline) Creatinine (apogee) Creatinine (after prednisone) UA
Hansel’s stain of urine CBC ALT and AST HIV antibody Rapid plasma regain Antinuclear antibody Anti-dsDNA antibody Anti-GBM antibody ANCA Hepatitis B serologies Hepatitis C antibody C3 level C4 level CH50 level Serum cryoglobulin screen SPEP UPEP 24 hr urine collection Renal ultrasound
Patient 2
1.2 mg/dL 2.6 mg/dL 1.9 mg/dL 30–40 RBC/HPF 3–4 WBC/HPF Protein 300 mg/dL No eosinophils No eosinophils Normal Negative Nonreactive Negative Negative Negative Negative Negative Negative Normal Normal Not tested Negative No monoclonal spike No monoclonal spike 12 g of protein/24 hr Normal
1 mg/dL 7.1 mg/dL 2.4 mg/dL 20 RBC/HPF 180 WBC/HPF Protein 600 mg/dL 7% eosinophils No eosinophils Normal Negative Nonreactive Negative Negative Negative Negative Negative Negative Normal Normal Normal Negative No monoclonal spike Not tested Not tested Normal
UA, urinalysis; RBC, red blood cell; HPF, high power field; WBC, white blood cell; CBC, complete blood count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ANCA, anti-neutrophil cytoplasmic antibody; GBM, glomerular basement membrane; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.
AIN is an alternative pathological process associated with vancomycin therapy. A small number of biopsy-proven case reports have been published. The selection of patients for renal biopsy is likely related to the clinical and/or laboratory features suggestive of an allergic reaction. An immunologic reaction to vancomycin is thought to be the mechanism of renal injury, and a recurrence of interstitial nephritis after a rechallenge with vancomycin has been reported.5 Although no controlled study data of glucocorticoid therapy of vancomycin-induced AIN are available, glucocorticoids offer a potential therapeutic strategy. Both patients in this report received a trial of prednisone with improvement in renal function. Vancomycin-induced renal injury is more likely to occur in a setting of preexisting renal disease. Renal biopsy offers the benefits of distinguishing a potentially treatable interstitial nephritis from acute tubular injury and a recognition of underlying renal pathology not related to vancomycin therapy. Prompted by proteinuria and concerns for glomerulopathy, renal biopsy led to a diagnosis of chronic diabetic nephropathy with superimposed acute vancomycin-induced interstitial nephritis in the 1st patient reported here. Renal biopsy of the 2nd reported patient showed 2 processes: AIN (likely related to vancomycin) and either a crescentic IgA glomerulonephritis (felt to be postinfectious) or IgA nephropathy (either idiopathic or related to vancomycin). Vancomycin is a well-known cause of IgA-mediated bullous linear dermatosis, but has not been, to the best of our knowledge, reported to cause IgA glomerulonephritis. The absence of Ó 2014 Lippincott Williams & Wilkins
proteinuria and hematuria on the baseline UA and the presence of crescent formation do not support the possibility of a long-standing IgA nephropathy. The biopsy pattern was thought to be characteristic of an IgA-mediated postinfectious glomerulonephritis.6 The recognition of vancomycin-unrelated renal disease may have important prognostic and therapeutic implications. In addition, the recognition of AIN because of vancomycin will likely lead to a choice of alternative therapy (if needed in the future) as a number of non-glycopeptide antimicrobial agents with anti-Gram positive activity are now available. Patients who receive vancomycin therapy and suffer acute renal injury should be considered for renal biopsy, especially in the presence of atypical clinical or laboratory features suggestive of AIN or an unrelated renal disorder.
Michael S. Gelfand, MD *Kerry O. Cleveland, MD Shirin A. Mazumder, MD Division of Infectious Diseases Department of Medicine The University of Tennessee Health Science Center Memphis, Tennessee *E-mail: [email protected] The authors have no financial or other conflicts of interest to disclose.
339
Case-Letter
REFERENCES 1. van Hal SJ, Paterson DL, Lodise TP. Systematic review and metaanalysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother 2013;57:734–44. 2. Elyasi S, Khalili H, Dashti-Khavidaki S, et al. Vancomycininduced nephrotoxicity: mechanism, incidence, risk factors and special populations. A literature review. Eur J Clin Pharmacol 2012;68: 1243–55.
340
3. Hong S, Valderrama E, Mattana J, et al. Vancomycin-induced acute granulomatous interstitial nephritis: therapeutic options. Am J Med Sci 2007;334:296–300. 4. Teng CB, Rezai K, Itokazu GS, et al. Continuation of high-dose vancomycin despite nephrotoxicity. Antimicrob Agents Chemother 2012;56:3470–1. 5. Azar R, Bakhache E, Boldron A. Acute interstitial nephropathy induced by vancomycin [in French]. Nephrologie 1996;17:327–8. 6. Nasr SH, D’Agati VD. IgA-dominant postinfectious glomerulonephritis: a new twist on an old disease. Nephron Clin Pract 2011;119:c18–26.
Volume 347, Number 4, April 2014
Vancomycin-Induced Interstitial Nephritis Superimposed on Coexisting Renal Disease: The Importance of Renal Biopsy
N
ephrotoxicity because of vancomycin is increasingly recognized and reported, especially with utilization of larger doses and maintenance of higher trough levels.1 The histology of most cases of vancomycin-induced nephrotoxicity is unknown as prospective biopsy studies have not been attempted, but it is presumed to be tubular injury resembling acute tubular necrosis as demonstrated in animal models and a small number of case reports in humans and as supported by the absence of evidence for an inflammatory renal process (such as cellular elements on urinalysis [UA] and eosinophiluria).2 A small number of cases of acute interstitial nephritis (AIN) secondary to vancomycin have been reported.3 The proportion of vancomycin-induced renal injury because of AIN as opposed to tubular injury is unknown as renal biopsies are not routinely performed in patients with vancomycin-induced renal dysfunction in the absence of atypical features such as indicators of an allergic reaction (such as rash, fever or eosinophilia), eosinophiluria, heavy proteinuria or hematuria of glomerular origin. Only a prospective study of vancomycin-induced nephrotoxicity with routine renal biopsies would answer the questions of relative importance of various mechanisms of renal injury and the prevalence of preexisting chronic renal disease or a coexisting acute renal pathology unrelated to vancomycin. Two recently encountered patients with suspected vancomycin-induced renal injury underwent renal biopsies. Each biopsy showed AIN and an unrelated renal disease (chronic diabetic glomerulopathy and a postinfectious IgA nephropathy, respectively). A 45-year-old woman with type 2 diabetes, hypertension and previous gastric bypass was referred for evaluation of a chronic non-healing ulcer at the site of amputation of the right 4th toe. Her home medications of metformin and an angiotensin converting enzyme inhibitor had not been changed for several years. UA evaluation showed protein of 300 mg/dL and 30–40 red blood cells or high power field. Magnetic resonance imaging was consistent with osteomyelitis of the 4th metatarsal bone and a remnant of the proximal phalanx. Deep wound culture had a heavy growth of Staphylococcus epidermidis, and the patient was begun on vancomycin 1 gram intravenously (IV) every 12 hours. Baseline renal function tests showed serum blood urea nitrogen of 16 mg/dL and serum creatinine of 1.2 mg/dL. After 5 days of vancomycin therapy, serum creatinine increased to 1.5 mg/dL and a trough vancomycin level was 29.4 mg/L. Vancomycin dose was reduced to 750 mg IV every 12 hours. Twenty-one days after vancomycin was begun, the serum creatinine was noted to be 2.3 mg/dL and vancomycin trough level was 37.2 mg/L. Vancomycin dose was changed to 1.4 g IV every 24 hours. On the 24th day of vancomycin therapy, vancomycin trough level was 12.9 mg/L and serum creatinine was 2.3 mg/dL. On the 26th day of vancomycin treatment, vancomycin trough level was 24.3 mg/L and serum creatinine was 2.1 mg/dL.
338
The next day, vancomycin was discontinued and a nephrology consultation was performed. Rash, fever and arthralgias were absent and examination was remarkable only for a healing foot wound. Numerous studies were obtained (Table 1). Due to suspected glomerulopathy, renal biopsy was performed showing both AIN with no granulomas and moderately advanced diabetic nephropathy with glomerulosclerosis. Serum creatinine improved to 1.9 mg/dL after 7 days of oral prednisone (40 mg daily). Over the next several years, the patient developed progressive renal failure thought secondary to diabetic glomerulopathy and is being considered for renal transplantation. A 61-year-old man with a history of depression, gout and hypertension underwent L2-S1 spinal fusion with instrumentation and right iliac bone graft due to spinal stenosis. Chronic home medications included diltiazem, allopurinol, metoprolol and trazodone. Preoperative testing revealed normal measures of renal function, normal complete blood count and an unremarkable UA. Postoperatively, he developed a surgical site infection with methicillin-resistant Staphylococcus aureus susceptible to vancomycin with a minimal inhibitory concentration of 1 mg/L. Blood cultures were negative and a transthoracic echocardiogram showed no vegetations. The wound was surgically irrigated and vancomycin 1.75 g IV every 12 hours was begun. Vancomycin peak and trough levels obtained around the 5th dose were 31.1 mg/L and 12.8 mg/L, respectively. Serum blood urea nitrogen and creatinine were 12 mg/dL and 1 mg/dL, respectively. The patient was discharged on the same dose of vancomycin but returned 7 days later when his wound exhibited a recurrence of erythema and purulent drainage. Serum creatinine was noted to be 1.9 mg/dL and vancomycin trough level was 36 mg/L. Repeat wound irrigation was performed and a culture of drainage again grew methicillin-resistant Staphylococcus aureus with the same vancomycin susceptibility. Vancomycin was replaced by daptomycin 6 mg/kg IV every 48 hours. Three days later serum creatinine increased to 3.1 mg/dL, and a nephrology consultation was obtained. The patient was afebrile and had no history of pharyngitis, diarrhea, rash or arthralgia. Examination was unremarkable except for a clean surgical incision with no erythema or drainage. Numerous studies were obtained (Table 1). Renal biopsy showed both AIN without granulomas and IgA nephropathy with 20% crescent formation. IgA glomerulonephritis was thought to be of a postinfectious etiology, likely related to staphylococcal infection. Serum creatinine worsened to 7.1 mg/dL, and 80 mg of oral prednisone was begun daily. After 14 days, serum creatinine decreased to 2.4 mg/dL. Vancomycin is a widely used antibiotic and is now recognized to be associated with a relatively common acute renal injury, especially in the setting of prolonged high-dose therapy and the presence of other risk factors such as conephrotoxins and preexisting renal disease.1 Recent reviews have reported rates of vancomycin renal injury up to 40%.1,2 Acute tubular injury is thought to be responsible for the majority of cases of vancomycin renal toxicity, but no prospective renal biopsy-based studies have been attempted. A few case reports have demonstrated acute tubular injury. Although most cases of vancomycin-induced renal toxicity are thought to be reversible after discontinuation of vancomycin (and occasionally even while the drug is being continued), no specific therapy is available.1,4
The American Journal of the Medical Sciences
Volume 347, Number 4, April 2014
Case-Letter
TABLE 1. Results of studies after development of renal insufficiency Study Patient 1 Creatinine (baseline) Creatinine (apogee) Creatinine (after prednisone) UA
Hansel’s stain of urine CBC ALT and AST HIV antibody Rapid plasma regain Antinuclear antibody Anti-dsDNA antibody Anti-GBM antibody ANCA Hepatitis B serologies Hepatitis C antibody C3 level C4 level CH50 level Serum cryoglobulin screen SPEP UPEP 24 hr urine collection Renal ultrasound
Patient 2
1.2 mg/dL 2.6 mg/dL 1.9 mg/dL 30–40 RBC/HPF 3–4 WBC/HPF Protein 300 mg/dL No eosinophils No eosinophils Normal Negative Nonreactive Negative Negative Negative Negative Negative Negative Normal Normal Not tested Negative No monoclonal spike No monoclonal spike 12 g of protein/24 hr Normal
1 mg/dL 7.1 mg/dL 2.4 mg/dL 20 RBC/HPF 180 WBC/HPF Protein 600 mg/dL 7% eosinophils No eosinophils Normal Negative Nonreactive Negative Negative Negative Negative Negative Negative Normal Normal Normal Negative No monoclonal spike Not tested Not tested Normal
UA, urinalysis; RBC, red blood cell; HPF, high power field; WBC, white blood cell; CBC, complete blood count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ANCA, anti-neutrophil cytoplasmic antibody; GBM, glomerular basement membrane; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.
AIN is an alternative pathological process associated with vancomycin therapy. A small number of biopsy-proven case reports have been published. The selection of patients for renal biopsy is likely related to the clinical and/or laboratory features suggestive of an allergic reaction. An immunologic reaction to vancomycin is thought to be the mechanism of renal injury, and a recurrence of interstitial nephritis after a rechallenge with vancomycin has been reported.5 Although no controlled study data of glucocorticoid therapy of vancomycin-induced AIN are available, glucocorticoids offer a potential therapeutic strategy. Both patients in this report received a trial of prednisone with improvement in renal function. Vancomycin-induced renal injury is more likely to occur in a setting of preexisting renal disease. Renal biopsy offers the benefits of distinguishing a potentially treatable interstitial nephritis from acute tubular injury and a recognition of underlying renal pathology not related to vancomycin therapy. Prompted by proteinuria and concerns for glomerulopathy, renal biopsy led to a diagnosis of chronic diabetic nephropathy with superimposed acute vancomycin-induced interstitial nephritis in the 1st patient reported here. Renal biopsy of the 2nd reported patient showed 2 processes: AIN (likely related to vancomycin) and either a crescentic IgA glomerulonephritis (felt to be postinfectious) or IgA nephropathy (either idiopathic or related to vancomycin). Vancomycin is a well-known cause of IgA-mediated bullous linear dermatosis, but has not been, to the best of our knowledge, reported to cause IgA glomerulonephritis. The absence of Ó 2014 Lippincott Williams & Wilkins
proteinuria and hematuria on the baseline UA and the presence of crescent formation do not support the possibility of a long-standing IgA nephropathy. The biopsy pattern was thought to be characteristic of an IgA-mediated postinfectious glomerulonephritis.6 The recognition of vancomycin-unrelated renal disease may have important prognostic and therapeutic implications. In addition, the recognition of AIN because of vancomycin will likely lead to a choice of alternative therapy (if needed in the future) as a number of non-glycopeptide antimicrobial agents with anti-Gram positive activity are now available. Patients who receive vancomycin therapy and suffer acute renal injury should be considered for renal biopsy, especially in the presence of atypical clinical or laboratory features suggestive of AIN or an unrelated renal disorder.
Michael S. Gelfand, MD *Kerry O. Cleveland, MD Shirin A. Mazumder, MD Division of Infectious Diseases Department of Medicine The University of Tennessee Health Science Center Memphis, Tennessee *E-mail: [email protected] The authors have no financial or other conflicts of interest to disclose.
339
Case-Letter
REFERENCES 1. van Hal SJ, Paterson DL, Lodise TP. Systematic review and metaanalysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother 2013;57:734–44. 2. Elyasi S, Khalili H, Dashti-Khavidaki S, et al. Vancomycininduced nephrotoxicity: mechanism, incidence, risk factors and special populations. A literature review. Eur J Clin Pharmacol 2012;68: 1243–55.
340
3. Hong S, Valderrama E, Mattana J, et al. Vancomycin-induced acute granulomatous interstitial nephritis: therapeutic options. Am J Med Sci 2007;334:296–300. 4. Teng CB, Rezai K, Itokazu GS, et al. Continuation of high-dose vancomycin despite nephrotoxicity. Antimicrob Agents Chemother 2012;56:3470–1. 5. Azar R, Bakhache E, Boldron A. Acute interstitial nephropathy induced by vancomycin [in French]. Nephrologie 1996;17:327–8. 6. Nasr SH, D’Agati VD. IgA-dominant postinfectious glomerulonephritis: a new twist on an old disease. Nephron Clin Pract 2011;119:c18–26.
Volume 347, Number 4, April 2014
