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Plasma Exchange for Disseminated Cryptococcosis
CASE REPORTS Plasma Exchange for Disseminated Cryptococcosis Guillaume Bollée, MD,1 Maxime Touzot, MD,1 Fredéric Mechai, MD,2 Virgine Royal, MD,3 Francois Lefrère, MD,4 Marie-Elisabeth Bougnoux, MD,5 Claudine Duvivier, MD,2 Jean-Paul Viard, MD,2 Olivier Lortholary, MD, PhD,2 and Fadi Fakhouri, MD1 Acute renal failure is frequent in HIV–infected patients and may be related to HIV–associated nephropathy, drugs, or opportunistic infections. We report a peculiar case of disseminated cryptococcosis complicated by acute renal failure associated with obstruction of intrarenal capillaries by Cryptococus neoformans dead bodies and successfully treated with plasma exchanges. Am J Kidney Dis 53:673-676. © 2009 by the National Kidney Foundation, Inc. INDEX WORDS: Cryptococcosis; acquired immunodeficiency syndrome (AIDS); acute renal failure; plasma exchange.
A
cute renal failure (ARF) is common in human immunodeficiency virus (HIV)-infected patients,1 with an estimated incidence of 5.9 cases/100 patient-years.2 ARF may be related to HIV-associated nephropathy, drugs (eg, tenofovir),3 or opportunistic infections.4 Cryptococcosis is a deadly opportunistic infection caused by the encapsulated yeast Cryptococcus neoformans (CN). It occurs mainly in patients with a marked cellular immunity defect, ie, HIV-infected patients. Despite major advances in the treatment of patients with HIV infection, including highly active antiretroviral therapy, cryptococcosis is regularly diagnosed in western countries and is a leading cause of mortality and morbidity in emerging countries.5,6 ARF has been reported rarely in the setting of disseminated cryptococcosis.7 We report a peculiar case of a patient with disseminated cryptococcosis complicated by ARF successfully treated with plasma exchanges (PEs).
CASE REPORT A 48-year-old white man presented with oligoanuric ARF. His medical history showed drug abuse and ill-controlled HIV infection (viral load, 4.5 log; CD4⫹ lymphocyte count, 20/L) acquired 18 years earlier. Highly active antiretroviral therapy, including raltegravir, ritonavir, darunavir, emtricitabin, and tenofovir, recently (15 days) had been reinstituted. Three weeks earlier, he was admitted for severe pneumopathy. Bronchoalveolar lavage and blood culture results were positive for CN. The patient was treated with intravenous amphotericin B (subsequently by liposomal formulation after 4 days because serum creatinine level increased to 14 mg/L [120 mol/L]) and 5-fluocytosine for 2 weeks, followed by fluconazole as maintenance therapy. Pneumopathy rapidly improved and repeated blood culture results were negative.
However, at day 20, altered consciousness occurred and rapidly worsened, although the patient was still treated with fluconazole. Brain magnetic resonance imaging findings were unremarkable, and cerebrospinal fluid culture was sterile. At day 21, serum creatinine level increased to 20 mg/L (179 mol/L), and nephrotic syndrome occurred (proteinuria, 3 g/d of protein; albuminemia of 27 g/L). Features of thrombotic microangiopathy were absent (lactate dehydrogenase, to 540 IU/L; haptoglobin to 0.6 g/L; and no schistocytes on blood smear), except for long-lasting anemia (hemoglobin, 8 g/dL) and thrombocytopenia (platelets, 20,000/ L). However, no megakaryocytes were present on bone marrow aspiration, suggesting that thrombocytopenia was mainly of central origin. Hypercalcemia was noted (calcium, 112 mg/L [2.8 mmol/L]). At that time, HIV viral load had decreased to 2.7 log, and CD4⫹ lymphocyte count was 20/L. Serum CN antigen titer remained very high (2,101; negative, ⬍2; Table 1). At day 27, hemodialysis therapy had to be started. Transjugular renal and liver biopsies were performed. The renal biopsy specimen contained 14 glomeruli, of which 1 was sclerotic. CN was frequently present in capillary lumens of all glomeruli, associated with focal glomerular basement membrane ruptures (Fig 1). CN also was observed in several peritubular capillaries. Focally, endothelial cell swelling and mesangiolysis were seen. No intravascular thrombosis was noted. In the interstitium, scattered CN dead bodies were
From the Departments of 1Nephrology, 2Infectious Diseases, 3Pathology, 4Hematology, and 5Microbiology, APHP, Hôpital Necker, Université Paris V, Paris, France. Received June 2, 2008. Accepted in revised form August 4, 2008. Originally published online as doi: 10.1053/j.ajkd.2008.08.019 on October 13, 2008. Address correspondence to Fadi Fakhouri, Department of Nephrology, AP-HP, Hôpital Necker, Université Paris V, Paris, France. E mail:[email protected] © 2009 by the National Kidney Foundation, Inc. 0272-6386/09/5304-0014$36.00/0 doi:10.1053/j.ajkd.2008.08.019
American Journal of Kidney Diseases, Vol 53, No 4 (April), 2009: pp 673-676
673
674
Bollée et al Table 1. Biological Features at Time of Hemodialysis Initiation
Serum creatinine 61 mg/L (540 mol/L) Hemoglobin 8.2 g/dL Platelets 28.000/L Schistocytes No Haptoglobin 0.6 g/L (normal, 0.5-1.5) Lactate dehydrogenase 540 IU/L CD4⫹ lymphocytes 20/L Human immunodeficiency virus viral load 2.7 log C3 368 mg/L (normal, 660-1,250) C4 110 mg/L (normal, 93-380) Total hemolytic complement 64% (normal, 70-130) Cryptococcus neoformans antigen 2,101 (normal, ⬍2)
surrounded by rare giant cells. In addition, some areas of acute tubular necrosis were observed. Immunofluorescence study showed strong staining with anti-C3 antibodies outlining CN capsules. Liver biopsy study showed numerous yeasts with granuloma surrounding CN dead bodies. Culture results of liver tissue were negative. Additional workup showed major activation of the complement alternative pathway with decreased C3 level (368 mg/L; normal, 660 to 1,250 mg/L) and total hemolytic complement (64%; normal, 70% to 130%), whereas C4 level was normal (110 mg/L; normal, 93 to 380 mg/L). At day 30, the patient was started on PE. PE was performed by using centrifugation, and removed plasma (5,000 mL/PE) was replaced by fresh frozen plasma (2,000 mL/PE) and 5% albumin (3,000 mL/PE). Considering the granulomatous reaction in the liver, corticosteroids were simultaneously administered (prednisone, 30 mg/d from days 30 to 43, then 15 mg/d from days 43 to 58, then 10 mg/d until cessation at day 72). PE initiation was followed by a dramatic recovery: neurological status normalized after 3 days, patient urine output increased, proteinuria decreased (protein, 0.6 g/d), and dialysis therapy was discontinued after 2 PEs. In all, 10 PEs were performed. CN was detected by means of enzyme-linked immunosorbent assay in removed plasma (CN antigen titer ⬎3,000 in 3 samples; negative, ⬍2). Serum cryptococcal antigen decreased from 3,705 to 625 after 2 PEs, but subsequently increased to 2,017 at day 39. At day 57, serum creatinine level was 12 mg/L (109 mol/L). Although neurological and renal status dramatically improved, severe thrombopenia persisted (platelets, 22,000/L) after PE. Three months later, the patient is doing well, with improving clinical status and stable kidney function (serum creatinine, 11 mg/L [100 mol/L]).
DISCUSSION Despite negativation of repeated blood, cerebrospinal fluid, and, subsequently, liver culture results, our patient’s neurological and renal status dramatically worsened. Renal biopsy showed
that ARF mainly was caused by the occlusion of capillary lumens by CN dead bodies. Conversely, a granulomatous reaction took place in the liver and may have been related to immune restoration because HIV viral load had decreased after the reinstitution of highly active antiretroviral therapy. An inflammatory reaction with granuloma secondary to immune restoration (called immune restoration inflammatory syndrome) previously has been reported in the setting of cryptococcosis, including lymphadenitis, meningitis, and cellulitis.8,9 However, to our knowledge, immune restoration inflammatory syndrome–related renal failure has not been reported in patients with CN infection. In addition, no increase in CD4⫹ cell count occurred in our patient and no significant inflammatory cell infiltration was noted in the kidney biopsy specimen. Severe renal involvement in the setting of cryptococcosis is particularly rare, despite the high rate in autopsy series of infraclinical renal involvement during disseminated cryptococcosis.10 We are aware of only 1 previously reported case of ARF related to renal intracapillary clotting of CN dead bodies.7 Renal pathological data were very similar to those noted in our patient. This intravascular clotting of CN may be related to a high CN load in the setting of severe immunodeficiency and/or peculiar CN or host endothelium characteristics. Moreover, the decreased serum C3 level and immunofluorescence study in the kidney biopsy specimen showing strong staining of anti-C3 antibodies outlining CN capsules suggest intrarenal complement activation by CN capsule, a potent activator of the complement alternative pathway.11 We postulated that the altered consciousness in our patient was caused by the occurrence of the same fungic “thrombi” in the cerebral microvasculature. The neurotropism of CN and its interaction with brain endothelial cells through CD44 are well established.12 Despite some suggestive features (anemia, thrombopenia, endothelial cell swelling, and mesangiolysis in the kidney biopsy specimen), hemolytic uremic syndrome or thrombotic thrombocytopenic purpura diagnosis is very unlikely. There were no signs of hemolysis (normal haptoglobin levels, no schistocytes detected) and thrombocytopenia was of central origin. Moreover, thrombocytopenia persisted despite renal
Plasma Exchange for Cryptococcosis
675
†
#
㫝
A
㫬
C
D PE
E
PRED 10
AMP
FLU
AMB
600
SCr (µmol/l)
Figure 1. (A-C) Transjugular kidney biopsy performed at day 29. (A) Light microscopy study. Frequent rounded encapsulated yeast (#) consistent with Cryptococcus neoformans (CN) were observed in capillaries of almost all glomeruli. (Periodic acid–Schiff staining; original magnification ⫻ 200.) (B) Light microscopy study. Capillary dilation (†), swelling of endothelial cells, focal mesangiolysis, and glomerular basement membrane rupture (§) were present. (Masson trichrome staining; original magnification ⫻400.) (C) On immunofluorescence study, staining with anti-C3 antibodies outlined CN capsules. (Original magnification ⫻200.) (D) Transjugular liver biopsy performed at day 29. Light microscopy study shows the presence of tissular infiltration by CN with a granulomatosis reaction (¶). (Periodic acid–Schiff staining; original magnification ⫻200.) (E) Evolution over time of serum creatinine (SCR) levels. Abbreviations: AMB, ambisome; AMP, amphotericin B; CSF, cerebrospinal fluid; FLU, fluconazole; HD, hemodialysis; PE, plasma exchange; Plts, platelets; PRED, prednisone (milligrams per day).
B
HD
300
500
250
400
200
300
150
200
100
100
50
0 1
Blood culture CSF culture
3
++ -
5
7
9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57
- -
and neurological improvement, which is not typical of hemolytic uremic syndrome or thrombotic thrombocytopenic purpura. Finally, no fibrin thrombi were detected in renal capillaries or small arteries. In addition, the absence of immunoglobin thrombi on the renal biopsy specimen ruled out the diagnosis of cryoglobulinemia. Although serum was not tested for cryoglobulinemia, this diagnosis also is unlikely. Moreover, in analogy to thrombotic microangiopathy or cryoglobulinemic nephropathy, we initiated PE to remove circulating CN dead bod-
-
-
- -
- -
0
Days
SCr
ies. The cryptococcal yeast measures 4 to 6 m in diameter, allowing, at least theoretically, its removal by PE performed by using centrifugation without a membrane, as in our patient. The very rapid and impressive clinical improvement after PE therapy was started supports our hypothesis of a beneficial effect of PE through the removal of CN. However, one cannot exclude that improvement may be linked to immune reactant removal. Although high CN antigen titers were detected in removed plasma, serum cryptococcal antigen evolution was disconcert-
676
Bollée et al
ing because it decreased after PE before increasing again. However, because of the lack of correlation between serum cryptococcal antigen evolution and clinical outcome, follow-up monitoring of serum cryptococcal antigen titer has proved to be of little value.13 The amount of CN in the plasma exchanged could not be determined. In addition, the patient simultaneously was administered corticosteroids because the liver biopsy specimen showed intense inflammatory infiltration and granulomatous reaction. We cannot rule out that corticosteroids may have exerted a beneficial effect on kidney and/or central nervous system involvement. However, the lack of significant inflammatory cell infiltration in the kidney biopsy specimen argues against this hypothesis. Furthermore, kidney function improvement could be related to concomitant healing of acute tubular necrosis. In conclusion, clinicians must be aware that despite apparent control of cryptococcosis with antifungal agents, multiple organ failure may occur in the setting of capillary involvement by CN dead bodies. PE should be discussed in this setting.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: None.
REFERENCES 1. Izzedine H, Baumelou A, Deray G: Acute renal failure in HIV patients. Nephrol Dial Transplant 22:2757-2762, 2007 2. Franceschini N, Napravnik S, Eron JJ Jr, Szczech LA, Finn WF: Incidence and etiology of acute renal failure
among ambulatory HIV-infected patients. Kidney Int 67:1526-1531, 2005 3. Karras A, Lafaurie M, Furco A, et al: Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: Three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis 36:10701073, 2003 4. Fine DM, Perazella MA, Lucas GM, Atta MG: Kidney biopsy in HIV: Beyond HIV-associated nephropathy. Am J Kidney Dis 51:504-514, 2008 5. Lortholary O: Management of cryptococcal meningitis in AIDS: The need for specific studies in developing countries. Clin Infect Dis 45:81-83, 2007 6. McCarthy KM, Morgan J, Wannemuehler KA, et al: Population-based surveillance for cryptococcosis in an antiretroviral-naive South African province with a high HIV seroprevalence. AIDS (London) 20:2199-2206, 2006 7. Iglesias JI, Nasr SH, Markowitz GS, D’Agati VD: AIDS, nephrotic-range proteinuria, and renal failure. Kidney Int 69:2107-2110, 2006 8. Lanternier F, Chandesris MO, Poiree S, et al: Cellulitis revealing a cryptococcosis-related immune reconstitution inflammatory syndrome in a renal allograft recipient. Am J Transplant 7:2826-2828, 2007 9. Skiest DJ, Hester LJ, Hardy RD: Cryptococcal immune reconstitution inflammatory syndrome: Report of four cases in three patients and review of the literature. J Infect 51:e289-e297, 2005 10. Lewis JL, Rabinovich S: The wide spectrum of cryptococcal infections. Am J Med 53:315-322, 1972 11. Kozel TR, Wilson MA, Pfrommer GS, Schlageter AM: Activation and binding of opsonic fragments of C3 on encapsulated Cryptococcus neoformans by using an alternative complement pathway reconstituted from six isolated proteins. Infect Immun 57:1922-1927, 1989 12. Jong A, Wu CH, Shackleford GM, et al: Involvement of human CD44 during Cryptococcus neoformans infection of brain microvascular endothelial cells. Cell Microbiol 10:1313-1326, 2008 13. Aberg JA, Watson J, Segal M, Chang LW: Clinical utility of monitoring serum cryptococcal antigen (sCRAG) titers in patients with AIDS-related cryptococcal disease. HIV Clin Trials 1:1-6, 2000
A
cute renal failure (ARF) is common in human immunodeficiency virus (HIV)-infected patients,1 with an estimated incidence of 5.9 cases/100 patient-years.2 ARF may be related to HIV-associated nephropathy, drugs (eg, tenofovir),3 or opportunistic infections.4 Cryptococcosis is a deadly opportunistic infection caused by the encapsulated yeast Cryptococcus neoformans (CN). It occurs mainly in patients with a marked cellular immunity defect, ie, HIV-infected patients. Despite major advances in the treatment of patients with HIV infection, including highly active antiretroviral therapy, cryptococcosis is regularly diagnosed in western countries and is a leading cause of mortality and morbidity in emerging countries.5,6 ARF has been reported rarely in the setting of disseminated cryptococcosis.7 We report a peculiar case of a patient with disseminated cryptococcosis complicated by ARF successfully treated with plasma exchanges (PEs).
CASE REPORT A 48-year-old white man presented with oligoanuric ARF. His medical history showed drug abuse and ill-controlled HIV infection (viral load, 4.5 log; CD4⫹ lymphocyte count, 20/L) acquired 18 years earlier. Highly active antiretroviral therapy, including raltegravir, ritonavir, darunavir, emtricitabin, and tenofovir, recently (15 days) had been reinstituted. Three weeks earlier, he was admitted for severe pneumopathy. Bronchoalveolar lavage and blood culture results were positive for CN. The patient was treated with intravenous amphotericin B (subsequently by liposomal formulation after 4 days because serum creatinine level increased to 14 mg/L [120 mol/L]) and 5-fluocytosine for 2 weeks, followed by fluconazole as maintenance therapy. Pneumopathy rapidly improved and repeated blood culture results were negative.
However, at day 20, altered consciousness occurred and rapidly worsened, although the patient was still treated with fluconazole. Brain magnetic resonance imaging findings were unremarkable, and cerebrospinal fluid culture was sterile. At day 21, serum creatinine level increased to 20 mg/L (179 mol/L), and nephrotic syndrome occurred (proteinuria, 3 g/d of protein; albuminemia of 27 g/L). Features of thrombotic microangiopathy were absent (lactate dehydrogenase, to 540 IU/L; haptoglobin to 0.6 g/L; and no schistocytes on blood smear), except for long-lasting anemia (hemoglobin, 8 g/dL) and thrombocytopenia (platelets, 20,000/ L). However, no megakaryocytes were present on bone marrow aspiration, suggesting that thrombocytopenia was mainly of central origin. Hypercalcemia was noted (calcium, 112 mg/L [2.8 mmol/L]). At that time, HIV viral load had decreased to 2.7 log, and CD4⫹ lymphocyte count was 20/L. Serum CN antigen titer remained very high (2,101; negative, ⬍2; Table 1). At day 27, hemodialysis therapy had to be started. Transjugular renal and liver biopsies were performed. The renal biopsy specimen contained 14 glomeruli, of which 1 was sclerotic. CN was frequently present in capillary lumens of all glomeruli, associated with focal glomerular basement membrane ruptures (Fig 1). CN also was observed in several peritubular capillaries. Focally, endothelial cell swelling and mesangiolysis were seen. No intravascular thrombosis was noted. In the interstitium, scattered CN dead bodies were
From the Departments of 1Nephrology, 2Infectious Diseases, 3Pathology, 4Hematology, and 5Microbiology, APHP, Hôpital Necker, Université Paris V, Paris, France. Received June 2, 2008. Accepted in revised form August 4, 2008. Originally published online as doi: 10.1053/j.ajkd.2008.08.019 on October 13, 2008. Address correspondence to Fadi Fakhouri, Department of Nephrology, AP-HP, Hôpital Necker, Université Paris V, Paris, France. E mail:[email protected] © 2009 by the National Kidney Foundation, Inc. 0272-6386/09/5304-0014$36.00/0 doi:10.1053/j.ajkd.2008.08.019
American Journal of Kidney Diseases, Vol 53, No 4 (April), 2009: pp 673-676
673
674
Bollée et al Table 1. Biological Features at Time of Hemodialysis Initiation
Serum creatinine 61 mg/L (540 mol/L) Hemoglobin 8.2 g/dL Platelets 28.000/L Schistocytes No Haptoglobin 0.6 g/L (normal, 0.5-1.5) Lactate dehydrogenase 540 IU/L CD4⫹ lymphocytes 20/L Human immunodeficiency virus viral load 2.7 log C3 368 mg/L (normal, 660-1,250) C4 110 mg/L (normal, 93-380) Total hemolytic complement 64% (normal, 70-130) Cryptococcus neoformans antigen 2,101 (normal, ⬍2)
surrounded by rare giant cells. In addition, some areas of acute tubular necrosis were observed. Immunofluorescence study showed strong staining with anti-C3 antibodies outlining CN capsules. Liver biopsy study showed numerous yeasts with granuloma surrounding CN dead bodies. Culture results of liver tissue were negative. Additional workup showed major activation of the complement alternative pathway with decreased C3 level (368 mg/L; normal, 660 to 1,250 mg/L) and total hemolytic complement (64%; normal, 70% to 130%), whereas C4 level was normal (110 mg/L; normal, 93 to 380 mg/L). At day 30, the patient was started on PE. PE was performed by using centrifugation, and removed plasma (5,000 mL/PE) was replaced by fresh frozen plasma (2,000 mL/PE) and 5% albumin (3,000 mL/PE). Considering the granulomatous reaction in the liver, corticosteroids were simultaneously administered (prednisone, 30 mg/d from days 30 to 43, then 15 mg/d from days 43 to 58, then 10 mg/d until cessation at day 72). PE initiation was followed by a dramatic recovery: neurological status normalized after 3 days, patient urine output increased, proteinuria decreased (protein, 0.6 g/d), and dialysis therapy was discontinued after 2 PEs. In all, 10 PEs were performed. CN was detected by means of enzyme-linked immunosorbent assay in removed plasma (CN antigen titer ⬎3,000 in 3 samples; negative, ⬍2). Serum cryptococcal antigen decreased from 3,705 to 625 after 2 PEs, but subsequently increased to 2,017 at day 39. At day 57, serum creatinine level was 12 mg/L (109 mol/L). Although neurological and renal status dramatically improved, severe thrombopenia persisted (platelets, 22,000/L) after PE. Three months later, the patient is doing well, with improving clinical status and stable kidney function (serum creatinine, 11 mg/L [100 mol/L]).
DISCUSSION Despite negativation of repeated blood, cerebrospinal fluid, and, subsequently, liver culture results, our patient’s neurological and renal status dramatically worsened. Renal biopsy showed
that ARF mainly was caused by the occlusion of capillary lumens by CN dead bodies. Conversely, a granulomatous reaction took place in the liver and may have been related to immune restoration because HIV viral load had decreased after the reinstitution of highly active antiretroviral therapy. An inflammatory reaction with granuloma secondary to immune restoration (called immune restoration inflammatory syndrome) previously has been reported in the setting of cryptococcosis, including lymphadenitis, meningitis, and cellulitis.8,9 However, to our knowledge, immune restoration inflammatory syndrome–related renal failure has not been reported in patients with CN infection. In addition, no increase in CD4⫹ cell count occurred in our patient and no significant inflammatory cell infiltration was noted in the kidney biopsy specimen. Severe renal involvement in the setting of cryptococcosis is particularly rare, despite the high rate in autopsy series of infraclinical renal involvement during disseminated cryptococcosis.10 We are aware of only 1 previously reported case of ARF related to renal intracapillary clotting of CN dead bodies.7 Renal pathological data were very similar to those noted in our patient. This intravascular clotting of CN may be related to a high CN load in the setting of severe immunodeficiency and/or peculiar CN or host endothelium characteristics. Moreover, the decreased serum C3 level and immunofluorescence study in the kidney biopsy specimen showing strong staining of anti-C3 antibodies outlining CN capsules suggest intrarenal complement activation by CN capsule, a potent activator of the complement alternative pathway.11 We postulated that the altered consciousness in our patient was caused by the occurrence of the same fungic “thrombi” in the cerebral microvasculature. The neurotropism of CN and its interaction with brain endothelial cells through CD44 are well established.12 Despite some suggestive features (anemia, thrombopenia, endothelial cell swelling, and mesangiolysis in the kidney biopsy specimen), hemolytic uremic syndrome or thrombotic thrombocytopenic purpura diagnosis is very unlikely. There were no signs of hemolysis (normal haptoglobin levels, no schistocytes detected) and thrombocytopenia was of central origin. Moreover, thrombocytopenia persisted despite renal
Plasma Exchange for Cryptococcosis
675
†
#
㫝
A
㫬
C
D PE
E
PRED 10
AMP
FLU
AMB
600
SCr (µmol/l)
Figure 1. (A-C) Transjugular kidney biopsy performed at day 29. (A) Light microscopy study. Frequent rounded encapsulated yeast (#) consistent with Cryptococcus neoformans (CN) were observed in capillaries of almost all glomeruli. (Periodic acid–Schiff staining; original magnification ⫻ 200.) (B) Light microscopy study. Capillary dilation (†), swelling of endothelial cells, focal mesangiolysis, and glomerular basement membrane rupture (§) were present. (Masson trichrome staining; original magnification ⫻400.) (C) On immunofluorescence study, staining with anti-C3 antibodies outlined CN capsules. (Original magnification ⫻200.) (D) Transjugular liver biopsy performed at day 29. Light microscopy study shows the presence of tissular infiltration by CN with a granulomatosis reaction (¶). (Periodic acid–Schiff staining; original magnification ⫻200.) (E) Evolution over time of serum creatinine (SCR) levels. Abbreviations: AMB, ambisome; AMP, amphotericin B; CSF, cerebrospinal fluid; FLU, fluconazole; HD, hemodialysis; PE, plasma exchange; Plts, platelets; PRED, prednisone (milligrams per day).
B
HD
300
500
250
400
200
300
150
200
100
100
50
0 1
Blood culture CSF culture
3
++ -
5
7
9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57
- -
and neurological improvement, which is not typical of hemolytic uremic syndrome or thrombotic thrombocytopenic purpura. Finally, no fibrin thrombi were detected in renal capillaries or small arteries. In addition, the absence of immunoglobin thrombi on the renal biopsy specimen ruled out the diagnosis of cryoglobulinemia. Although serum was not tested for cryoglobulinemia, this diagnosis also is unlikely. Moreover, in analogy to thrombotic microangiopathy or cryoglobulinemic nephropathy, we initiated PE to remove circulating CN dead bod-
-
-
- -
- -
0
Days
SCr
ies. The cryptococcal yeast measures 4 to 6 m in diameter, allowing, at least theoretically, its removal by PE performed by using centrifugation without a membrane, as in our patient. The very rapid and impressive clinical improvement after PE therapy was started supports our hypothesis of a beneficial effect of PE through the removal of CN. However, one cannot exclude that improvement may be linked to immune reactant removal. Although high CN antigen titers were detected in removed plasma, serum cryptococcal antigen evolution was disconcert-
676
Bollée et al
ing because it decreased after PE before increasing again. However, because of the lack of correlation between serum cryptococcal antigen evolution and clinical outcome, follow-up monitoring of serum cryptococcal antigen titer has proved to be of little value.13 The amount of CN in the plasma exchanged could not be determined. In addition, the patient simultaneously was administered corticosteroids because the liver biopsy specimen showed intense inflammatory infiltration and granulomatous reaction. We cannot rule out that corticosteroids may have exerted a beneficial effect on kidney and/or central nervous system involvement. However, the lack of significant inflammatory cell infiltration in the kidney biopsy specimen argues against this hypothesis. Furthermore, kidney function improvement could be related to concomitant healing of acute tubular necrosis. In conclusion, clinicians must be aware that despite apparent control of cryptococcosis with antifungal agents, multiple organ failure may occur in the setting of capillary involvement by CN dead bodies. PE should be discussed in this setting.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: None.
REFERENCES 1. Izzedine H, Baumelou A, Deray G: Acute renal failure in HIV patients. Nephrol Dial Transplant 22:2757-2762, 2007 2. Franceschini N, Napravnik S, Eron JJ Jr, Szczech LA, Finn WF: Incidence and etiology of acute renal failure
among ambulatory HIV-infected patients. Kidney Int 67:1526-1531, 2005 3. Karras A, Lafaurie M, Furco A, et al: Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: Three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis 36:10701073, 2003 4. Fine DM, Perazella MA, Lucas GM, Atta MG: Kidney biopsy in HIV: Beyond HIV-associated nephropathy. Am J Kidney Dis 51:504-514, 2008 5. Lortholary O: Management of cryptococcal meningitis in AIDS: The need for specific studies in developing countries. Clin Infect Dis 45:81-83, 2007 6. McCarthy KM, Morgan J, Wannemuehler KA, et al: Population-based surveillance for cryptococcosis in an antiretroviral-naive South African province with a high HIV seroprevalence. AIDS (London) 20:2199-2206, 2006 7. Iglesias JI, Nasr SH, Markowitz GS, D’Agati VD: AIDS, nephrotic-range proteinuria, and renal failure. Kidney Int 69:2107-2110, 2006 8. Lanternier F, Chandesris MO, Poiree S, et al: Cellulitis revealing a cryptococcosis-related immune reconstitution inflammatory syndrome in a renal allograft recipient. Am J Transplant 7:2826-2828, 2007 9. Skiest DJ, Hester LJ, Hardy RD: Cryptococcal immune reconstitution inflammatory syndrome: Report of four cases in three patients and review of the literature. J Infect 51:e289-e297, 2005 10. Lewis JL, Rabinovich S: The wide spectrum of cryptococcal infections. Am J Med 53:315-322, 1972 11. Kozel TR, Wilson MA, Pfrommer GS, Schlageter AM: Activation and binding of opsonic fragments of C3 on encapsulated Cryptococcus neoformans by using an alternative complement pathway reconstituted from six isolated proteins. Infect Immun 57:1922-1927, 1989 12. Jong A, Wu CH, Shackleford GM, et al: Involvement of human CD44 during Cryptococcus neoformans infection of brain microvascular endothelial cells. Cell Microbiol 10:1313-1326, 2008 13. Aberg JA, Watson J, Segal M, Chang LW: Clinical utility of monitoring serum cryptococcal antigen (sCRAG) titers in patients with AIDS-related cryptococcal disease. HIV Clin Trials 1:1-6, 2000