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Combined Herpes Viral and Candidal Esophagitis in a CAPD Patient: Case Report and Review of Literature
Combined Herpes Viral and Candidal Esophagitis in a CAPD Patient: Case Report and Review of Literature LING-I CHEN, MD; JER-MING CHANG, MD; MEI-CHUAN KUO, MD; SHANG-JYH HWANG, MD; HUNG-CHUN CHEN, MD, PHD
ABSTRACT: Concomitant herpetic and candidal esophagitis is a very rare disease that had not been reported in uremic patients. A 57-year-old woman receiving continuous ambulatory peritoneal dialysis (CAPD) therapy for 3 years was admitted due to CAPD-related peritonitis. Endoscopic examination was performed due to severe epigastralgia and upper gastrointestinal bleeding, and combined herpetic and candidal esophagitis was diagnosed.
Intravenous acyclovir and fluconazole were prescribed and symptoms improved. The patient subsequently died due to progressive sepsis and respiratory failure. This is the first report of a dual infectious esophagitis in a uremic patient. Since infectious esophagitis may cause severe complications, early diagnosis and aggressive treatment are important. KEY INDEXING TERMS: CAPD; Esophagitis; Herpes simplex; Candida. [Am J Med Sci 2007;333(3):191–193.]
E
On admission, physical examination showed body temperature 37.8° C, blood pressure 142/80 mm Hg, pulse rate 128 beats/min, and respiratory rate 22 breaths/min. The bowel sound was hypoactive with minimally distended abdomen. Diffuse abdominal tenderness with rebounding pain and muscle guarding over the periumbilical area was found. Major laboratory data were hemoglobin 8.5 g/dL, white blood cell count 23,940/L, platelet count 289,000/L, blood urea nitrogen 50.2 mg/dL, creatinine 7.77 mg/dL, sodium 132 mEq/L, potassium 3.4 mEq/L, chloride 104 mEq/L, albumin 2.91 g/dL, C-reactive protein 5.2 g/mL. Dialysate was cloudy with cell count of 828/mL, among them 98% were neutrophils and 2% were lymphocytes. Intraperitoneal antibiotic therapy with ceftazidime and gentamicin was given for 4 days initially to cover the possible pseudomonal infection and was then shifted to parenteral piperacillin/tazobactam after a positive culture of Escherichia coli and bacteroid vulgatus was obtained from dialysate. Because of refractory peritonitis after 1 week of aggressive antibiotic treatment, the Tenckhoff catheter was removed. Hemodialysis therapy was instituted as the alternative renal replacement therapy. The patient reported epigastralgia on the sixth day, and drainage of a coffee-ground-like substance from the nasogastric tube was found on the eighth day after admission, without tarry stool or melena. The endoscopic examination showed gastric ulcer (H2), esophageal ulcer, and esophagitis suspected to be of infectious origin. Esophageal biopsy was performed and it showed the content of typical intranuclear eosinophilic inclusions and multinucleated giant cells in the squamous epithelium adjacent to the ulcer and the presence of fungal spores (Figure 1); both were diagnostic for herpetic esophagitis with fungal infection. The patient was initially treated with nystatin 400,000 U every 6 hours for 4 days, followed by oral fluconazole 100 mg per day for 2 days, and was finally shifted to an intravenous form for 10 days until death. Intravenous acyclovir 250 mg per day was given in the last 7 days of hospitalization. The epigastralgia improved during fluconazole and acyclovir treatment. Immunologic testing showed IgG, 1330 mg/dL; IgA, 518 mg/dL; IgM, 54.8 mg/dL; CD4 lymphocyte cell count, 4745/L; and CD8 lymphocyte cell count, 3932/L. No antibodies to type 1 or 2 HIV were detected by Western blotting. Endoscopic examination was performed again due to recurrent gastrointestinal bleeding and revealed esopha-
sophageal infections are rare, although they can be seen occasionally in immunocompromised individuals. Common infectious pathogens are Candida species, followed by herpes simplex virus and cytomegalovirus.1 Esophagitis caused by herpes simplex virus has been reported as an opportunistic infection in immunocompromised patients, especially in those receiving immunosuppressive agents such as solid organ and bone marrow transplant recipients, and in 5% of patients infected with human immunodeficiency virus (HIV).2,3 Concomitant herpetic and candidal infection, however, is very rare and has not been reported in uremic patients. Case Report A 57-year-old woman with hypertension and end-stage renal disease was admitted due to abdominal pain, which was refractory to antibiotic treatment for 3 days. The patient had received continuous ambulatory peritoneal dialysis (CAPD) as the renal replacement therapy for 3 years, and she had 1 episode of CAPDrelated peritonitis in 1999 and another episode of tunnel infection in 2000. Abdominal pain and turbid dialysate were noted 3 days prior to admission and were refractory to intraperitoneal cefazolin (250 mg/bag) and gentamicin (8 mg/bag) prescribed as the empirical treatment on an outpatient basis.
From the Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Submitted August 9, 2006; accepted in revised form September 6, 2006. Correspondence: Shang-Jyh Hwang, MD, Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University, 100 Tzyou 1st Road, Kaohsiung 807, Taiwan (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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Combined Herpetic and Candidal Esophagitis in CAPD
Figure 1. Concomitant herpetic and candidal esophagitis. Highpower view of an esophageal biopsy sample showing multinucleated giant cells, chromatin margination, intranuclear eosinophilic inclusions and nuclear molding (arrow), and the presence of fungal spore (arrowhead). (H&E stain; original magnification ⫻400.)
geal ulceration with whitish coating typical of candidal esophagitis. Severe ileus and malnutrition developed later and total parenteral nutrition was given. During hospitalization, blood cultures were negative for aerobic and anaerobic bacteria, and fungal cultures were all negative. Unfortunately, sepsis and respiratory failure occurred despite intensive antibiotic treatment, and the patient died 30 days after admission.
Discussion This is the first report of concomitant herpetic and candidal esophagitis in a uremic patient receiving CAPD therapy, although patients receiving CAPD therapy are thought to be relatively immunocompromised, with impairment of innate cellular response to in vitro stimulation.4 Simultaneous esophageal infection with herpes simplex and Candida is very rare. People with defects of cellular immunity such as acquired immunodeficiency syndrome (AIDS) and those receiving chemotherapy, radiotherapy, or corticosteroid treatment are at particular risk. There have been only 15 cases of dual infections reported in the English literature. Among them, 5 cases were associated with HIV infection, 3 cases were associated with malignancy treated by chemotherapy or radiotherapy, and other individual cases included a prolonged steroid user, a diabetic patient, a recipient of bone marrow transplantation, and 3 other immunocompromised patients.1,2,5–9 Recently, 1 episode of the dual infection in an immunocompetent teenager was also reported.10 Patients with infectious esophagitis usually present with acute onset of odynophagia, dysphagia, and sometimes severe complications such as bleeding, perforation, or systemic dissemination. It is difficult to 192
distinguish herpetic from candidal esophagitis by symptoms alone, and the definite diagnosis can be made only by histologic examination and culture. Herpetic esophagitis is usually established by gastroendoscopic examination. Lesions of the herpetic esophagitis begin with vesicle formation, which is very rare under light microscopy, followed by lesions coalescing to form ulcers with a volcano-like appearance. In cases of candidal esophagitis, endoscopy often shows white mucosal plaque-like lesions. Histologic findings in cases of herpetic esophagitis include the characteristic finding of multinucleated giant cells, with ground-glass nuclei and eosinophilic inclusions. Candidal esophagitis, however, is confirmed by the presence of yeasts and pseudohyphae invading mucosal cells. Herpetic esophagitis is usually self-limited in immunocompetent hosts and the symptoms usually resolve within 1 to 2 weeks, although patients may respond more quickly if treated with intravenous acyclovir.11 In immunocompromised patients or in those who are unable to swallow, with poor absorption like our patient, intravenous acyclovir 250 mg/m2 every 8 hours for 2 weeks is recommended. Foscarnet is effective in treating most strains of acyclovir-resistant herpes simplex virus.12 For treatment of esophageal candidiasis, a 14- to 21-day course of oral or intravenous fluconazole 100 to 200 mg/day or itraconazole 200 mg/day is effective. Fluconazole-refractory esophageal candidiasis should be treated with voriconazole, caspofungin, or intravenous amphotericin B.13 In combined herpetic and candidal esophagitis, as in the case of this patient, intravenous acyclovir and fluconazole may be required March 2007 Volume 333 Number 3
Chen et al
and the dose should be adjusted according to the patient’s renal function. Uremia is supposed to be an immunocompromised status in that the disease is associated with the suppression of immunity with a decreased T-cell response. Defects in the costimulatory function of antigen-presenting cells and a persistent inflammatory state of monocytes are related to uremia and dialysis treatment.4 Other contributing factors include malnutrition, vitamin D deficiency, and hyperparathyroidism.14 Furthermore, the reaction of monocytes upon lipopolysaccharide stimulation and the differentiation of helper T-cells into type 1 (Th1) and type 2 (Th2) subsets are also significantly reduced in CAPD patients. T-cell insufficiency and delayed cytokine response may blunt the immune reaction and increase the risk of infection in CAPD patients.4 Injury to the esophageal epithelium by herpes simplex virus may disrupt the mucosal barrier and create a supportive environment for the subsequent candidal infection.9 In this case of a patient with uremia under CAPD therapy, severe malnutrition with sepsis may have been the precipitating factor for the rare dual infection. In conclusion, concomitant herpetic and candidal esophagitis is a very rare disease that affects mainly immunocompromised individuals and may also occur in uremic patients receiving CAPD therapy. Since early diagnosis and aggressive treatment are important for preventing severe complications, we suggest empirical parenteral acyclovir plus fluconazole for severe infections or for CAPD patients with poor drug absorption when dual esophagitis is suspected. References 1. Agha FP, Lee HH, Nostrant TT. Herpetic esophagitis: a diagnostic challenge in immunocompromised patients. Am J Gastroenterol 1986;81:246–53.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
2. McDonald GB, Sharma P, Hackman RC, et al. Esophageal infections in immunosuppressed patients after marrow transplantation. Gastroenterology 1985;88:1111–7. 3. Wilcox CM, Schwartz DA, Clark WS. Esophageal ulceration in human immunodeficiency virus infection: causes, response to therapy, and long-term outcome. Ann Intern Med 1995;123:143–9. 4. Ando M, Shibuya A, Yasuda M, et al. Impairment of innate cellular response to in vitro stimuli in patients on continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 2005;20:2497–503. 5. Brayko CM, Kozarek RA, Sanowski RA, et al. Type I herpes simplex esophagitis with concomitant esophageal moniliasis. J Clin Gastroenterol 1982;4:351–5. 6. Bonacini M, Young T, Laine L. The causes of esophageal symptoms in human immunodeficiency virus infection: a prospective study of 110 patients. Arch Intern Med 1991;151: 1567–72. 7. Bonacini M, Young T, Laine L. Histopathology of human immunodeficiency virus-associated esophageal disease. Am J Gastroenterol 1993;88:549–51. 8. Fried RL, Brandt LJ, Kauvar D, et al. Esophageal motility in AIDS patients with symptomatic opportunistic infections of the esophagus. Am J Gastroenterol 1994;89: 2003–5. 9. Mirra SS, Bryan JA, Butz WC, et al. Concomitant herpesmonilial esophagitis: case report with ultrastructural study. Hum Pathol 1982;13:760–3. 10. Rahhal RM, Ramkumar DP, Pashankar DS. Simultaneous herpetic and candidal esophagitis in an immunocompetent teenager. J Pediatr Gastroenterol Nutr 2005;40: 371–3. 11. Kurahara K, Aoyagi K, Nakamura S, et al. Treatment of herpes simplex esophagitis in an immunocompetent patient with intravenous acyclovir: a case report and review of the literature. Am J Gastroenterol 1998;93:2239–40. 12. Baehr PH, McDonald GB. Esophageal infections: risk factors, presentation, diagnosis, and treatment. Gastroenterology 1994;106:509–32. 13. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for the treatment of candidiasis. Clin Infect Dis 2004;38:161–89. 14. Hussein MM, Mooij JM, Roujouleh H. Tuberculosis and chronic renal disease. Semin Dial 2003;16:38–44.
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ABSTRACT: Concomitant herpetic and candidal esophagitis is a very rare disease that had not been reported in uremic patients. A 57-year-old woman receiving continuous ambulatory peritoneal dialysis (CAPD) therapy for 3 years was admitted due to CAPD-related peritonitis. Endoscopic examination was performed due to severe epigastralgia and upper gastrointestinal bleeding, and combined herpetic and candidal esophagitis was diagnosed.
Intravenous acyclovir and fluconazole were prescribed and symptoms improved. The patient subsequently died due to progressive sepsis and respiratory failure. This is the first report of a dual infectious esophagitis in a uremic patient. Since infectious esophagitis may cause severe complications, early diagnosis and aggressive treatment are important. KEY INDEXING TERMS: CAPD; Esophagitis; Herpes simplex; Candida. [Am J Med Sci 2007;333(3):191–193.]
E
On admission, physical examination showed body temperature 37.8° C, blood pressure 142/80 mm Hg, pulse rate 128 beats/min, and respiratory rate 22 breaths/min. The bowel sound was hypoactive with minimally distended abdomen. Diffuse abdominal tenderness with rebounding pain and muscle guarding over the periumbilical area was found. Major laboratory data were hemoglobin 8.5 g/dL, white blood cell count 23,940/L, platelet count 289,000/L, blood urea nitrogen 50.2 mg/dL, creatinine 7.77 mg/dL, sodium 132 mEq/L, potassium 3.4 mEq/L, chloride 104 mEq/L, albumin 2.91 g/dL, C-reactive protein 5.2 g/mL. Dialysate was cloudy with cell count of 828/mL, among them 98% were neutrophils and 2% were lymphocytes. Intraperitoneal antibiotic therapy with ceftazidime and gentamicin was given for 4 days initially to cover the possible pseudomonal infection and was then shifted to parenteral piperacillin/tazobactam after a positive culture of Escherichia coli and bacteroid vulgatus was obtained from dialysate. Because of refractory peritonitis after 1 week of aggressive antibiotic treatment, the Tenckhoff catheter was removed. Hemodialysis therapy was instituted as the alternative renal replacement therapy. The patient reported epigastralgia on the sixth day, and drainage of a coffee-ground-like substance from the nasogastric tube was found on the eighth day after admission, without tarry stool or melena. The endoscopic examination showed gastric ulcer (H2), esophageal ulcer, and esophagitis suspected to be of infectious origin. Esophageal biopsy was performed and it showed the content of typical intranuclear eosinophilic inclusions and multinucleated giant cells in the squamous epithelium adjacent to the ulcer and the presence of fungal spores (Figure 1); both were diagnostic for herpetic esophagitis with fungal infection. The patient was initially treated with nystatin 400,000 U every 6 hours for 4 days, followed by oral fluconazole 100 mg per day for 2 days, and was finally shifted to an intravenous form for 10 days until death. Intravenous acyclovir 250 mg per day was given in the last 7 days of hospitalization. The epigastralgia improved during fluconazole and acyclovir treatment. Immunologic testing showed IgG, 1330 mg/dL; IgA, 518 mg/dL; IgM, 54.8 mg/dL; CD4 lymphocyte cell count, 4745/L; and CD8 lymphocyte cell count, 3932/L. No antibodies to type 1 or 2 HIV were detected by Western blotting. Endoscopic examination was performed again due to recurrent gastrointestinal bleeding and revealed esopha-
sophageal infections are rare, although they can be seen occasionally in immunocompromised individuals. Common infectious pathogens are Candida species, followed by herpes simplex virus and cytomegalovirus.1 Esophagitis caused by herpes simplex virus has been reported as an opportunistic infection in immunocompromised patients, especially in those receiving immunosuppressive agents such as solid organ and bone marrow transplant recipients, and in 5% of patients infected with human immunodeficiency virus (HIV).2,3 Concomitant herpetic and candidal infection, however, is very rare and has not been reported in uremic patients. Case Report A 57-year-old woman with hypertension and end-stage renal disease was admitted due to abdominal pain, which was refractory to antibiotic treatment for 3 days. The patient had received continuous ambulatory peritoneal dialysis (CAPD) as the renal replacement therapy for 3 years, and she had 1 episode of CAPDrelated peritonitis in 1999 and another episode of tunnel infection in 2000. Abdominal pain and turbid dialysate were noted 3 days prior to admission and were refractory to intraperitoneal cefazolin (250 mg/bag) and gentamicin (8 mg/bag) prescribed as the empirical treatment on an outpatient basis.
From the Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Submitted August 9, 2006; accepted in revised form September 6, 2006. Correspondence: Shang-Jyh Hwang, MD, Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University, 100 Tzyou 1st Road, Kaohsiung 807, Taiwan (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
191
Combined Herpetic and Candidal Esophagitis in CAPD
Figure 1. Concomitant herpetic and candidal esophagitis. Highpower view of an esophageal biopsy sample showing multinucleated giant cells, chromatin margination, intranuclear eosinophilic inclusions and nuclear molding (arrow), and the presence of fungal spore (arrowhead). (H&E stain; original magnification ⫻400.)
geal ulceration with whitish coating typical of candidal esophagitis. Severe ileus and malnutrition developed later and total parenteral nutrition was given. During hospitalization, blood cultures were negative for aerobic and anaerobic bacteria, and fungal cultures were all negative. Unfortunately, sepsis and respiratory failure occurred despite intensive antibiotic treatment, and the patient died 30 days after admission.
Discussion This is the first report of concomitant herpetic and candidal esophagitis in a uremic patient receiving CAPD therapy, although patients receiving CAPD therapy are thought to be relatively immunocompromised, with impairment of innate cellular response to in vitro stimulation.4 Simultaneous esophageal infection with herpes simplex and Candida is very rare. People with defects of cellular immunity such as acquired immunodeficiency syndrome (AIDS) and those receiving chemotherapy, radiotherapy, or corticosteroid treatment are at particular risk. There have been only 15 cases of dual infections reported in the English literature. Among them, 5 cases were associated with HIV infection, 3 cases were associated with malignancy treated by chemotherapy or radiotherapy, and other individual cases included a prolonged steroid user, a diabetic patient, a recipient of bone marrow transplantation, and 3 other immunocompromised patients.1,2,5–9 Recently, 1 episode of the dual infection in an immunocompetent teenager was also reported.10 Patients with infectious esophagitis usually present with acute onset of odynophagia, dysphagia, and sometimes severe complications such as bleeding, perforation, or systemic dissemination. It is difficult to 192
distinguish herpetic from candidal esophagitis by symptoms alone, and the definite diagnosis can be made only by histologic examination and culture. Herpetic esophagitis is usually established by gastroendoscopic examination. Lesions of the herpetic esophagitis begin with vesicle formation, which is very rare under light microscopy, followed by lesions coalescing to form ulcers with a volcano-like appearance. In cases of candidal esophagitis, endoscopy often shows white mucosal plaque-like lesions. Histologic findings in cases of herpetic esophagitis include the characteristic finding of multinucleated giant cells, with ground-glass nuclei and eosinophilic inclusions. Candidal esophagitis, however, is confirmed by the presence of yeasts and pseudohyphae invading mucosal cells. Herpetic esophagitis is usually self-limited in immunocompetent hosts and the symptoms usually resolve within 1 to 2 weeks, although patients may respond more quickly if treated with intravenous acyclovir.11 In immunocompromised patients or in those who are unable to swallow, with poor absorption like our patient, intravenous acyclovir 250 mg/m2 every 8 hours for 2 weeks is recommended. Foscarnet is effective in treating most strains of acyclovir-resistant herpes simplex virus.12 For treatment of esophageal candidiasis, a 14- to 21-day course of oral or intravenous fluconazole 100 to 200 mg/day or itraconazole 200 mg/day is effective. Fluconazole-refractory esophageal candidiasis should be treated with voriconazole, caspofungin, or intravenous amphotericin B.13 In combined herpetic and candidal esophagitis, as in the case of this patient, intravenous acyclovir and fluconazole may be required March 2007 Volume 333 Number 3
Chen et al
and the dose should be adjusted according to the patient’s renal function. Uremia is supposed to be an immunocompromised status in that the disease is associated with the suppression of immunity with a decreased T-cell response. Defects in the costimulatory function of antigen-presenting cells and a persistent inflammatory state of monocytes are related to uremia and dialysis treatment.4 Other contributing factors include malnutrition, vitamin D deficiency, and hyperparathyroidism.14 Furthermore, the reaction of monocytes upon lipopolysaccharide stimulation and the differentiation of helper T-cells into type 1 (Th1) and type 2 (Th2) subsets are also significantly reduced in CAPD patients. T-cell insufficiency and delayed cytokine response may blunt the immune reaction and increase the risk of infection in CAPD patients.4 Injury to the esophageal epithelium by herpes simplex virus may disrupt the mucosal barrier and create a supportive environment for the subsequent candidal infection.9 In this case of a patient with uremia under CAPD therapy, severe malnutrition with sepsis may have been the precipitating factor for the rare dual infection. In conclusion, concomitant herpetic and candidal esophagitis is a very rare disease that affects mainly immunocompromised individuals and may also occur in uremic patients receiving CAPD therapy. Since early diagnosis and aggressive treatment are important for preventing severe complications, we suggest empirical parenteral acyclovir plus fluconazole for severe infections or for CAPD patients with poor drug absorption when dual esophagitis is suspected. References 1. Agha FP, Lee HH, Nostrant TT. Herpetic esophagitis: a diagnostic challenge in immunocompromised patients. Am J Gastroenterol 1986;81:246–53.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
2. McDonald GB, Sharma P, Hackman RC, et al. Esophageal infections in immunosuppressed patients after marrow transplantation. Gastroenterology 1985;88:1111–7. 3. Wilcox CM, Schwartz DA, Clark WS. Esophageal ulceration in human immunodeficiency virus infection: causes, response to therapy, and long-term outcome. Ann Intern Med 1995;123:143–9. 4. Ando M, Shibuya A, Yasuda M, et al. Impairment of innate cellular response to in vitro stimuli in patients on continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 2005;20:2497–503. 5. Brayko CM, Kozarek RA, Sanowski RA, et al. Type I herpes simplex esophagitis with concomitant esophageal moniliasis. J Clin Gastroenterol 1982;4:351–5. 6. Bonacini M, Young T, Laine L. The causes of esophageal symptoms in human immunodeficiency virus infection: a prospective study of 110 patients. Arch Intern Med 1991;151: 1567–72. 7. Bonacini M, Young T, Laine L. Histopathology of human immunodeficiency virus-associated esophageal disease. Am J Gastroenterol 1993;88:549–51. 8. Fried RL, Brandt LJ, Kauvar D, et al. Esophageal motility in AIDS patients with symptomatic opportunistic infections of the esophagus. Am J Gastroenterol 1994;89: 2003–5. 9. Mirra SS, Bryan JA, Butz WC, et al. Concomitant herpesmonilial esophagitis: case report with ultrastructural study. Hum Pathol 1982;13:760–3. 10. Rahhal RM, Ramkumar DP, Pashankar DS. Simultaneous herpetic and candidal esophagitis in an immunocompetent teenager. J Pediatr Gastroenterol Nutr 2005;40: 371–3. 11. Kurahara K, Aoyagi K, Nakamura S, et al. Treatment of herpes simplex esophagitis in an immunocompetent patient with intravenous acyclovir: a case report and review of the literature. Am J Gastroenterol 1998;93:2239–40. 12. Baehr PH, McDonald GB. Esophageal infections: risk factors, presentation, diagnosis, and treatment. Gastroenterology 1994;106:509–32. 13. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for the treatment of candidiasis. Clin Infect Dis 2004;38:161–89. 14. Hussein MM, Mooij JM, Roujouleh H. Tuberculosis and chronic renal disease. Semin Dial 2003;16:38–44.
193