http://informahealthcare.com/rnf ISSN: 0886-022X (print), 1525-6049 (electronic) Ren Fail, 2014; 36(5): 804–807 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2014.890054
CASE REPORT
Phenazopyridine associated acute interstitial nephritis and review of literature Manisha Singh1, Fnu Shailesh2, Upasana Tiwari3, Shree G. Sharma4, and Bilal Malik1 1
Department of Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR, USA, 2Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA, 3Department of Clinical & Translational Research, University of Arkansas for Medical Sciences, Little Rock, AR, USA, and 4Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA Abstract
Keywords
Phenazopyridine is a urinary analgesic; commonly seen side-effects of this drug include, orange discoloration of urine, methemoglobinemia, yellowish skin discoloration, hepatitis and acute renal failure. Various case reports with phenazopyridine associated acute renal failure secondary to acute tubular necrosis have been reported in the literature. Acute kidney injury in these patients is caused by either direct injury to renal tubular epithelial cells or secondary to pigment induced nephropathy from hemolytic anemia. Hypoxic injury from phenazopyridineinduced methemoglobinemia has been well documented. We report a case of biopsy proven acute interstitial nephritis, associated with therapeutic doses of phenazopyridine without any evidence of methemoglobinemia or other mechanism of renal injury. Clinicians should be aware of the toxicity of this commonly used drug and should look closely for signs of renal insufficiency. Identifying and stopping the offending medication stays as the first step, but recent studies indicate that early steroid administration improves renal recovery, as well as decreasing the risk of progression to chronic kidney disease with fibrosis and consequent permanent renal damage.
Acute kidney injury, acute interstitial nephritis, creatinine, phenazopyridine, renal biopsy
Introduction Phenazopyridine is used to relieve pain, burning and discomfort caused by irritation or infection of the urinary tract.1 Various case reports with phenazopyridine associated acute renal failure secondary to acute tubular necrosis (ATN) have been reported in the literature. We hereby, report a biopsy proven case of acute interstitial nephritis (AIN) solely related to therapeutic use of phenazopyridine. Patient had normal renal function until starting the medication and showed improvement after stopping it. Upon reintroducing phenazopyridine, he had accelerated worsening of his renal function; which again stabilized upon withdrawal of this agent. There were no other potential offending agents that could be implicated. Our report also highlights a new pathology of injury in the form of AIN resulting from phenazopyridine use.
Case presentation A 78-year-old white man presented to emergency department with two week history of dull pain in lower abdomen and burning urination for one week duration in June 2012.
Address correspondence to Upasana Tiwari, Department of Clinical & Translational Research, University of Arkansas for Medical Sciences, 4301, W Markham St, # 634, Little Rock, AR 72205-7199, USA. Tel: +001 501 773 2811; E-mail: [email protected]
History Received 17 October 2013 Revised 8 January 2014 Accepted 26 January 2014 Published online 26 February 2014
He denied any nausea, vomiting, fever and diarrhea. He had a transient rash that dissipated by the time of the hospital visit. He was found to have acute kidney injury (AKI) and was admitted for further work up. He had past medical history of prostate cancer (adenocarcinoma, stage T1C); for which he underwent treatment with external beam radiation and hormone therapy, completed in January 2012. His medications included lisinopril and hydrochlorothiazide for hypertension, and tamsulosin 0.4 mg for prostatism. He was taking these medications for over one year prior to this episode. Patient presented to his primary care physician with complaints of dysuria in February 2012 and was started on phenazopyridine 100 mg three times a day, with improvement in symptoms. No other medication changes were made. On examination, his vitals were stable. He was slightly tremulous with no signs of uremia. There was no costovertebral angle tenderness, rash or edema; rest of the physical examination was unremarkable. His serum creatinine and blood urea nitrogen were elevated to 3.5 mg/dL and 54 mg/dL, respectively. Urinalysis showed specific gravity of 1.005, pH 7.0, 6 white blood cells/high power field without blood or protein. Urine eosinophils were absent and culture showed no growth after three days. Renal ultrasound showed normal kidneys without hydronephrosis. Post void residual volume was 60 mL. Serologic workup of glomerulonephritis was negative.
Phenazopyridine as a cause of interstitial nephritis
DOI: 10.3109/0886022X.2014.890054
(a)
(b)
(c)
(d)
805
Figure 1. The photomicrograph illustrates the presence of interstitial inflammation with scattered eosinophils (a) hematoxylin and eosin stain, 40X; arrow showing eosinophil and foci of tubulitis (b) Periodic acid Schiff stain, 40X; arrow showing tubulitis. The glomeruli are unremarkable (c) hematoxylin and eosin stain, 40X, (d) Periodic acid Schiff stain, 40X.
During his hospital stay, hydrochlorothiazide, lisinopril and phenazopyridine were stopped and he was treated with ceftriaxone for urinary tract infection. The patient was discharged when his symptoms improved with serum creatinine trending down to 2.8 mg/dL, at the time of discharge. Patient resumed phenazopyridine at home and presented within two weeks with worsened renal function (serum creatinine 5.8 mg/dL). Re-evaluation was otherwise unchanged. His phenazopyridine was stopped again, and serum creatinine was noted to trend down to 3.6 mg/dL. Renal biopsy was done the next day and two cores were obtained. The light microscopy specimen showed renal cortex containing 23 glomeruli, 5 of which were globally sclerotic. Glomeruli were histologically unremarkable. Tubulointerstitial compartment showed moderate to severe; diffuse interstitial inflammation was composed of predominantly lymphocytes and plasma cells with rare eosinophils. The interstitial inflammation extended across tubular basement membranes to produce multifocal tubulitis. On immunofluorescence and electron microscopy, no evidence of immune complex disease was identified. In summary, the kidney biopsy (Figure 1) showed significant underlying changes of acute interstitial process with nephrosclerosis. Patient was started on prednisone 1 mg/kg and his serum creatinine steadily decreased to 2.8 mg/dL in one week. He was discharged on prednisone taper and his serum creatinine was 0.8 mg/dL at 4 weeks follow up.
Discussion Phenazopyridine hydrochloride is used as an analgesic drug to reduce pain, burning and discomfort associated with urinary tract infections and irritation. The usual dose in adults is 100– 200 mg orally three times per day. Pharmacokinetics of phenazopyridine is not fully described; 65% of the drug is excreted unchanged in urine where it exerts local analgesic effect on urothelial mucosa.1 Commonly seen side-effects of phenazopyridine are orange discoloration of urine, hepatitis, yellowish discoloration of skin, nausea, vomiting, diarrhea, hemolytic anemia and methemoglobinemia.2–5 Phenazopyridine associated acute renal failure and AIN are rare but recognizable phenomena with phenazopyridine use in patients with renal dysfunction.6,7 Few case reports have highlighted renal failure due to phenazopyridine overdose in patients with normal renal function3–5,8–18 (Table 1). Various mechanisms have been postulated for phenazopyridine causing acute renal failure. Triaminopyridine, a metabolite of phenazopyridine, has a direct toxic effect on renal tubules causing vacuolization and necrosis of renal distal tubules leading to ATN.1–3 Secondly, phenazopyridine also causes acute hemolytic anemia, especially in patients with renal insufficiency leading to tubular damage.4,8 Thirdly, phenazopyridine overdose can cause methemoglobinemia, which leads to hypoxic injury to medullary and papillary segments. In rat models, phenazopyridine-induced methemoglobinemia has shown to cause interstitial edema, cast formation, tubular
806
M. Singh et al.
Ren Fail, 2014; 36(5): 804–807
Table 1. Previously reported cases of phenazopyridine-induced renal failure.
References
Patient characteristics
Alano and Webster6
Reported 2 patients475 years of age with preexisting renal disease
Eybel et al.10
85-year-old white woman 200 mg daily three times a day for bladder irritation 18-year-old female with overdose of 2.4 g of phenazopyridine over 24 h 13-year-old female with overdose of 2 g of phenazopyridine
Nathan et al.4 Feinfield et al.3
Quershi and Hedger5
20-year-old female with overdose of 4 g phenazopyridine
Engle and Schoolwerth18
64-year-old woman taking phenazopyridine 200 mg 4 times a day for 6 weeks
Tomlinson et al.2 Rule and Biggs11 Gavish et al.12
Fincher and Campbell7
Kornowski et al.14
Rivas et al.21 Scheurer15
Other medications
ARF Skin pigmentation Diarrhea ARF Skin pigmentation ARF methemoglobinemia ARF Yellow discoloration of skin Dark urine Vomiting Abdominal cramps ARF Nausea Vomiting ARF Yellow pigmentation of skin ARF ARF, gastrointestinal symptoms (nausea, vomiting) ARF Methemglobinemia Rhabdomyolysis Yellowish discoloration of skin Abdominal pain Nausea ARF Methemglobinemia Yellow pigmentation
18-year-old female 10–15, 200 mg tablets (2000–3000 mg) prior to admission 19-year-old female w/no history of renal or hematological impairment. 200 mg TID 2 days 6 g on day of admission(suicide attempt) 46-year-old male w/hx of schizophrenia and polypharmacy abuse 30–40, 100 mg tablets 1 week 24-year-old woman with 1 g of phenazopyridine ingestion
58-year-old with chronic use phenazopyridine
Phenazopyridine adverse effects
Onder et al.8
17-year-old with 1200 mg of phenazopyridine ingestion
Bupropion, alprazolam, levothyroxine, and omeprazole Over the counter medications (OTC) acetaminophen and ibuprofen Antiretroviraltherapy(noncompliant) Marijuana
Haigh and Dewar16
87-year-old male with phenazopyridine 4 times daily for 3 days
Digoxin, prednisone, furosemide, oxybutynin
Vega17
27-year-old with 2000 mg of phenazopyridine ingestion
ARF Methemoglobinemia hemolytic anemia ARF ARF Anemia Orange colored urine
ATN ARF Methemoglobinemia Yellowish discoloration of skin Orange colored urine ARF Myelosuppression Abdominal cramps jaundice Orange color urine ARF
ARF, acute renal failure; ATN, acute tubular necrosis.
degeneration and regeneration.1,3,9 Its overdose also causes dehydration, as a result of nausea and vomiting, leading to acute renal failure.19 We hereby report biopsy proven case of AIN, solely related to phenazopyridine, without any evidence of methemoglobinemia or hemolytic anemia. Patient had normal renal function up until starting the medication and showed improvement after stopping it. Upon reintroducing phenazopyridine, he had accelerated worsening of his renal function; which again stabilized with withdrawal of this agent, as well as supportive care and a brief tapering course of oral prednisolone therapy. There were no other potential offending agents that could be implicated. Other adverse effects of
phenazopyridine-like orange discoloration of urine, skin discoloration and hepatitis were not seen in our patient. Phenazopyridine is a commonly used drug, which is also available over the counter. Memory of phenazopyridine being associated with renal failure has dwindled in recent years. There are few reports of AKI resulting from phenazopyridine associated ATN from the 1970s (Table 1); thus, highlighting the importance of this report in revisiting the nephrotoxic potential of this agent that appears to have been forgotten. Our report also highlights a new pathology of injury in the form of AIN resulting from phenazopyridine use.20 Clinicians should be aware of the toxicity of this commonly used drug and should look closely for signs of
Phenazopyridine as a cause of interstitial nephritis
DOI: 10.3109/0886022X.2014.890054
renal insufficiency. Identifying and stopping the offending medication stays as the first step, but recent studies indicate that early steroid administration improves renal recovery, as well as decreasing the risk of progression to chronic kidney disease with fibrosis and consequent permanent renal damage.20
9. 10. 11.
Declaration of interest
12.
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
13.
References 1. Zelenitsky SA, Zhanel GG. Phenazopyridine in urinary tract infections. Ann pharmacother. 1996;30:866–868. 2. Tomlinson B, Cohen SL, Smith MR, Fisher C. Nephrotoxicity of phenazopyridine. Hum Toxicol. 1983;2:539–543. 3. Feinfield DA, Ranieri R, Lipner HI, Avram MM. Renal failure in phenazopyridine overdose. JAMA. 1978;240:2661. 4. Nathan DM, Siegel AJ, Bunn HF. Acute methemoglobinemia and hemolytic anemia with phenazopyridine: possible relation to acute renal failure. Arch Intern Med. 1977;137:1636–1638. 5. Quershi N, Hedger RW. Phenazopyridine (pyridium) and acute renal failure. Ann Intern Med. 1979;90:443. 6. Alano FA, Webster GD. Acute renal failure and pigmentation due to phenazopyridine (PyridiumR). Ann Intern Med. 1970;72:89–91. 7. Fincher ME, Campbell HT. Methemoglobinemia and hemolytic anemia after phenazopyridine hydrochloride (pyridium) administration in end-stage renal disease. South Med J. 1989;82:372–374. 8. Onder AM, Espinoza V, Berho ME, Chandar J, Zilleruelo G, Abitbol C. Acute renal failure due to phenazopyridine (PyridiumÕ )
14. 15. 16. 17. 18. 19. 20. 21.
807
overdose: case report and review of the literature. Pediatr Nephrol. 2006;21:1760–1764. Ruiz-Guinazu A, Coelho JD, Paz RA. Methemoglobin induced acute renal failure in the rat. Nephron. 1967;4:257–275. Eybel CE, Armbruster KF, Ing TS. Skin pigmentation and acute renal failure in a patient receiving phenazophyridine therapy. JAMA. 1974;228:1027–1028. Rule KA, Biggs AW. Transient renal failure following phenazopyridine overdose. Urology. 1984;24:178–179. Gavish D, Knobler H, Gotteher N, Israeli A, Kleinman Y. Methemoglobinemia, muscle damage and renal failure complicating phenazopyridine overdose. Isr J Med Sci. 1986;22:45–47. Sharon M, Puente G, Cohen LB. Phenazopyridine (pyridium) poisoning: possible toxicity of methylene blue administration in renal failure. Mt Sinai J Med. 1986;53:280–282. Kornowski R, Averbuch M, Jaffe A, Schwartz D, Levo Y. Sedural toxicity. Harefuah. 1991;120:324–325. Scheurer DB. An over-the-counter omission. South Med J. 2006;99: 1005–1006. Haigh C, Dewar JC. Multiple adverse effects of Pyridium: a case report. South Med J. 2006;99:90–92. Vega J. Acute renal failure caused by phenazopyridine. Rev Med Chil. 2003;131:541–544. Engle JE, Schoolwerth AC. Additive nephrotoxicity from roentgenographic contrast media. Its occurrence in phenazopyridineinduced acute renal failure. Arch Intern Med. 1981;141:784–786. Green ED, Zimmerman RC, Gurabi WH, Colohan DP. Phenazopyridine hydrochloride toxicity: a cause of drug-induced methemoglobinemia. JACEP. 1979;8:426–431. Praga M, Gonza´lez E. Acute interstitial nephritis. Kidney Int. 2010; 77:956–961. Rivas R, Martı´nez Torres A, Bohorques R, Martı´nez Albelo I. Acute kidney failure caused by phenazopyridine overdose. Nefrologia. 2001;21:97–98.
Copyright of Renal Failure is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
CASE REPORT
Phenazopyridine associated acute interstitial nephritis and review of literature Manisha Singh1, Fnu Shailesh2, Upasana Tiwari3, Shree G. Sharma4, and Bilal Malik1 1
Department of Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR, USA, 2Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA, 3Department of Clinical & Translational Research, University of Arkansas for Medical Sciences, Little Rock, AR, USA, and 4Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA Abstract
Keywords
Phenazopyridine is a urinary analgesic; commonly seen side-effects of this drug include, orange discoloration of urine, methemoglobinemia, yellowish skin discoloration, hepatitis and acute renal failure. Various case reports with phenazopyridine associated acute renal failure secondary to acute tubular necrosis have been reported in the literature. Acute kidney injury in these patients is caused by either direct injury to renal tubular epithelial cells or secondary to pigment induced nephropathy from hemolytic anemia. Hypoxic injury from phenazopyridineinduced methemoglobinemia has been well documented. We report a case of biopsy proven acute interstitial nephritis, associated with therapeutic doses of phenazopyridine without any evidence of methemoglobinemia or other mechanism of renal injury. Clinicians should be aware of the toxicity of this commonly used drug and should look closely for signs of renal insufficiency. Identifying and stopping the offending medication stays as the first step, but recent studies indicate that early steroid administration improves renal recovery, as well as decreasing the risk of progression to chronic kidney disease with fibrosis and consequent permanent renal damage.
Acute kidney injury, acute interstitial nephritis, creatinine, phenazopyridine, renal biopsy
Introduction Phenazopyridine is used to relieve pain, burning and discomfort caused by irritation or infection of the urinary tract.1 Various case reports with phenazopyridine associated acute renal failure secondary to acute tubular necrosis (ATN) have been reported in the literature. We hereby, report a biopsy proven case of acute interstitial nephritis (AIN) solely related to therapeutic use of phenazopyridine. Patient had normal renal function until starting the medication and showed improvement after stopping it. Upon reintroducing phenazopyridine, he had accelerated worsening of his renal function; which again stabilized upon withdrawal of this agent. There were no other potential offending agents that could be implicated. Our report also highlights a new pathology of injury in the form of AIN resulting from phenazopyridine use.
Case presentation A 78-year-old white man presented to emergency department with two week history of dull pain in lower abdomen and burning urination for one week duration in June 2012.
Address correspondence to Upasana Tiwari, Department of Clinical & Translational Research, University of Arkansas for Medical Sciences, 4301, W Markham St, # 634, Little Rock, AR 72205-7199, USA. Tel: +001 501 773 2811; E-mail: [email protected]
History Received 17 October 2013 Revised 8 January 2014 Accepted 26 January 2014 Published online 26 February 2014
He denied any nausea, vomiting, fever and diarrhea. He had a transient rash that dissipated by the time of the hospital visit. He was found to have acute kidney injury (AKI) and was admitted for further work up. He had past medical history of prostate cancer (adenocarcinoma, stage T1C); for which he underwent treatment with external beam radiation and hormone therapy, completed in January 2012. His medications included lisinopril and hydrochlorothiazide for hypertension, and tamsulosin 0.4 mg for prostatism. He was taking these medications for over one year prior to this episode. Patient presented to his primary care physician with complaints of dysuria in February 2012 and was started on phenazopyridine 100 mg three times a day, with improvement in symptoms. No other medication changes were made. On examination, his vitals were stable. He was slightly tremulous with no signs of uremia. There was no costovertebral angle tenderness, rash or edema; rest of the physical examination was unremarkable. His serum creatinine and blood urea nitrogen were elevated to 3.5 mg/dL and 54 mg/dL, respectively. Urinalysis showed specific gravity of 1.005, pH 7.0, 6 white blood cells/high power field without blood or protein. Urine eosinophils were absent and culture showed no growth after three days. Renal ultrasound showed normal kidneys without hydronephrosis. Post void residual volume was 60 mL. Serologic workup of glomerulonephritis was negative.
Phenazopyridine as a cause of interstitial nephritis
DOI: 10.3109/0886022X.2014.890054
(a)
(b)
(c)
(d)
805
Figure 1. The photomicrograph illustrates the presence of interstitial inflammation with scattered eosinophils (a) hematoxylin and eosin stain, 40X; arrow showing eosinophil and foci of tubulitis (b) Periodic acid Schiff stain, 40X; arrow showing tubulitis. The glomeruli are unremarkable (c) hematoxylin and eosin stain, 40X, (d) Periodic acid Schiff stain, 40X.
During his hospital stay, hydrochlorothiazide, lisinopril and phenazopyridine were stopped and he was treated with ceftriaxone for urinary tract infection. The patient was discharged when his symptoms improved with serum creatinine trending down to 2.8 mg/dL, at the time of discharge. Patient resumed phenazopyridine at home and presented within two weeks with worsened renal function (serum creatinine 5.8 mg/dL). Re-evaluation was otherwise unchanged. His phenazopyridine was stopped again, and serum creatinine was noted to trend down to 3.6 mg/dL. Renal biopsy was done the next day and two cores were obtained. The light microscopy specimen showed renal cortex containing 23 glomeruli, 5 of which were globally sclerotic. Glomeruli were histologically unremarkable. Tubulointerstitial compartment showed moderate to severe; diffuse interstitial inflammation was composed of predominantly lymphocytes and plasma cells with rare eosinophils. The interstitial inflammation extended across tubular basement membranes to produce multifocal tubulitis. On immunofluorescence and electron microscopy, no evidence of immune complex disease was identified. In summary, the kidney biopsy (Figure 1) showed significant underlying changes of acute interstitial process with nephrosclerosis. Patient was started on prednisone 1 mg/kg and his serum creatinine steadily decreased to 2.8 mg/dL in one week. He was discharged on prednisone taper and his serum creatinine was 0.8 mg/dL at 4 weeks follow up.
Discussion Phenazopyridine hydrochloride is used as an analgesic drug to reduce pain, burning and discomfort associated with urinary tract infections and irritation. The usual dose in adults is 100– 200 mg orally three times per day. Pharmacokinetics of phenazopyridine is not fully described; 65% of the drug is excreted unchanged in urine where it exerts local analgesic effect on urothelial mucosa.1 Commonly seen side-effects of phenazopyridine are orange discoloration of urine, hepatitis, yellowish discoloration of skin, nausea, vomiting, diarrhea, hemolytic anemia and methemoglobinemia.2–5 Phenazopyridine associated acute renal failure and AIN are rare but recognizable phenomena with phenazopyridine use in patients with renal dysfunction.6,7 Few case reports have highlighted renal failure due to phenazopyridine overdose in patients with normal renal function3–5,8–18 (Table 1). Various mechanisms have been postulated for phenazopyridine causing acute renal failure. Triaminopyridine, a metabolite of phenazopyridine, has a direct toxic effect on renal tubules causing vacuolization and necrosis of renal distal tubules leading to ATN.1–3 Secondly, phenazopyridine also causes acute hemolytic anemia, especially in patients with renal insufficiency leading to tubular damage.4,8 Thirdly, phenazopyridine overdose can cause methemoglobinemia, which leads to hypoxic injury to medullary and papillary segments. In rat models, phenazopyridine-induced methemoglobinemia has shown to cause interstitial edema, cast formation, tubular
806
M. Singh et al.
Ren Fail, 2014; 36(5): 804–807
Table 1. Previously reported cases of phenazopyridine-induced renal failure.
References
Patient characteristics
Alano and Webster6
Reported 2 patients475 years of age with preexisting renal disease
Eybel et al.10
85-year-old white woman 200 mg daily three times a day for bladder irritation 18-year-old female with overdose of 2.4 g of phenazopyridine over 24 h 13-year-old female with overdose of 2 g of phenazopyridine
Nathan et al.4 Feinfield et al.3
Quershi and Hedger5
20-year-old female with overdose of 4 g phenazopyridine
Engle and Schoolwerth18
64-year-old woman taking phenazopyridine 200 mg 4 times a day for 6 weeks
Tomlinson et al.2 Rule and Biggs11 Gavish et al.12
Fincher and Campbell7
Kornowski et al.14
Rivas et al.21 Scheurer15
Other medications
ARF Skin pigmentation Diarrhea ARF Skin pigmentation ARF methemoglobinemia ARF Yellow discoloration of skin Dark urine Vomiting Abdominal cramps ARF Nausea Vomiting ARF Yellow pigmentation of skin ARF ARF, gastrointestinal symptoms (nausea, vomiting) ARF Methemglobinemia Rhabdomyolysis Yellowish discoloration of skin Abdominal pain Nausea ARF Methemglobinemia Yellow pigmentation
18-year-old female 10–15, 200 mg tablets (2000–3000 mg) prior to admission 19-year-old female w/no history of renal or hematological impairment. 200 mg TID 2 days 6 g on day of admission(suicide attempt) 46-year-old male w/hx of schizophrenia and polypharmacy abuse 30–40, 100 mg tablets 1 week 24-year-old woman with 1 g of phenazopyridine ingestion
58-year-old with chronic use phenazopyridine
Phenazopyridine adverse effects
Onder et al.8
17-year-old with 1200 mg of phenazopyridine ingestion
Bupropion, alprazolam, levothyroxine, and omeprazole Over the counter medications (OTC) acetaminophen and ibuprofen Antiretroviraltherapy(noncompliant) Marijuana
Haigh and Dewar16
87-year-old male with phenazopyridine 4 times daily for 3 days
Digoxin, prednisone, furosemide, oxybutynin
Vega17
27-year-old with 2000 mg of phenazopyridine ingestion
ARF Methemoglobinemia hemolytic anemia ARF ARF Anemia Orange colored urine
ATN ARF Methemoglobinemia Yellowish discoloration of skin Orange colored urine ARF Myelosuppression Abdominal cramps jaundice Orange color urine ARF
ARF, acute renal failure; ATN, acute tubular necrosis.
degeneration and regeneration.1,3,9 Its overdose also causes dehydration, as a result of nausea and vomiting, leading to acute renal failure.19 We hereby report biopsy proven case of AIN, solely related to phenazopyridine, without any evidence of methemoglobinemia or hemolytic anemia. Patient had normal renal function up until starting the medication and showed improvement after stopping it. Upon reintroducing phenazopyridine, he had accelerated worsening of his renal function; which again stabilized with withdrawal of this agent, as well as supportive care and a brief tapering course of oral prednisolone therapy. There were no other potential offending agents that could be implicated. Other adverse effects of
phenazopyridine-like orange discoloration of urine, skin discoloration and hepatitis were not seen in our patient. Phenazopyridine is a commonly used drug, which is also available over the counter. Memory of phenazopyridine being associated with renal failure has dwindled in recent years. There are few reports of AKI resulting from phenazopyridine associated ATN from the 1970s (Table 1); thus, highlighting the importance of this report in revisiting the nephrotoxic potential of this agent that appears to have been forgotten. Our report also highlights a new pathology of injury in the form of AIN resulting from phenazopyridine use.20 Clinicians should be aware of the toxicity of this commonly used drug and should look closely for signs of
Phenazopyridine as a cause of interstitial nephritis
DOI: 10.3109/0886022X.2014.890054
renal insufficiency. Identifying and stopping the offending medication stays as the first step, but recent studies indicate that early steroid administration improves renal recovery, as well as decreasing the risk of progression to chronic kidney disease with fibrosis and consequent permanent renal damage.20
9. 10. 11.
Declaration of interest
12.
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
13.
References 1. Zelenitsky SA, Zhanel GG. Phenazopyridine in urinary tract infections. Ann pharmacother. 1996;30:866–868. 2. Tomlinson B, Cohen SL, Smith MR, Fisher C. Nephrotoxicity of phenazopyridine. Hum Toxicol. 1983;2:539–543. 3. Feinfield DA, Ranieri R, Lipner HI, Avram MM. Renal failure in phenazopyridine overdose. JAMA. 1978;240:2661. 4. Nathan DM, Siegel AJ, Bunn HF. Acute methemoglobinemia and hemolytic anemia with phenazopyridine: possible relation to acute renal failure. Arch Intern Med. 1977;137:1636–1638. 5. Quershi N, Hedger RW. Phenazopyridine (pyridium) and acute renal failure. Ann Intern Med. 1979;90:443. 6. Alano FA, Webster GD. Acute renal failure and pigmentation due to phenazopyridine (PyridiumR). Ann Intern Med. 1970;72:89–91. 7. Fincher ME, Campbell HT. Methemoglobinemia and hemolytic anemia after phenazopyridine hydrochloride (pyridium) administration in end-stage renal disease. South Med J. 1989;82:372–374. 8. Onder AM, Espinoza V, Berho ME, Chandar J, Zilleruelo G, Abitbol C. Acute renal failure due to phenazopyridine (PyridiumÕ )
14. 15. 16. 17. 18. 19. 20. 21.
807
overdose: case report and review of the literature. Pediatr Nephrol. 2006;21:1760–1764. Ruiz-Guinazu A, Coelho JD, Paz RA. Methemoglobin induced acute renal failure in the rat. Nephron. 1967;4:257–275. Eybel CE, Armbruster KF, Ing TS. Skin pigmentation and acute renal failure in a patient receiving phenazophyridine therapy. JAMA. 1974;228:1027–1028. Rule KA, Biggs AW. Transient renal failure following phenazopyridine overdose. Urology. 1984;24:178–179. Gavish D, Knobler H, Gotteher N, Israeli A, Kleinman Y. Methemoglobinemia, muscle damage and renal failure complicating phenazopyridine overdose. Isr J Med Sci. 1986;22:45–47. Sharon M, Puente G, Cohen LB. Phenazopyridine (pyridium) poisoning: possible toxicity of methylene blue administration in renal failure. Mt Sinai J Med. 1986;53:280–282. Kornowski R, Averbuch M, Jaffe A, Schwartz D, Levo Y. Sedural toxicity. Harefuah. 1991;120:324–325. Scheurer DB. An over-the-counter omission. South Med J. 2006;99: 1005–1006. Haigh C, Dewar JC. Multiple adverse effects of Pyridium: a case report. South Med J. 2006;99:90–92. Vega J. Acute renal failure caused by phenazopyridine. Rev Med Chil. 2003;131:541–544. Engle JE, Schoolwerth AC. Additive nephrotoxicity from roentgenographic contrast media. Its occurrence in phenazopyridineinduced acute renal failure. Arch Intern Med. 1981;141:784–786. Green ED, Zimmerman RC, Gurabi WH, Colohan DP. Phenazopyridine hydrochloride toxicity: a cause of drug-induced methemoglobinemia. JACEP. 1979;8:426–431. Praga M, Gonza´lez E. Acute interstitial nephritis. Kidney Int. 2010; 77:956–961. Rivas R, Martı´nez Torres A, Bohorques R, Martı´nez Albelo I. Acute kidney failure caused by phenazopyridine overdose. Nefrologia. 2001;21:97–98.
Copyright of Renal Failure is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
