Presentation on theme: "FUNGAL INFECTIONS AND THE KIDNEY Prof K L GUPTA, Department of Internal Medicine, King Fahd Hospital of University, AL KOBAR."— Presentation transcript:
FUNGAL INFECTIONS AND THE KIDNEY Prof K L GUPTA, Department of Internal Medicine, King Fahd Hospital of University, AL KOBAR
OBJECTIVES & Parts of Talk PART 1. To discuss the kidney involvement in fungal infections Part 2. To discuss the fungal infections following renal transplantation Part 3. To discuss management of invasive fungal infections
Introduction Invasive fungal infections have recently. Renal involvement results in increased morbidity and mortality.Similarly fungal infections may complicate the course of renal transplant recipients. Clinical manifestations depend on pathogenic organism. And the organ involved Diagnosis is often delayed due to co-existing illnesses. Early identification is important in providing timely therapy.
Postgraduate Medical Journal (1987) 63, Disseminated mucormycosis presenting with acute renal failure K.L.Gupta, 1 Kusum Joshi, 2 Brian J.G.Pereira 1 and Kartar Singh 3 Departments of 1 Nephrology, 2 Pathology and 3 Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh , India. Summary : An unusual presentation of disseminated mucormycosis as acute renal failure in a patient without any predisposing condition, is reported. The diagnosis was established at autopsy.
Am Journal of Kidney Diseases,Vol 22, No 3(September),1993; pp Mucormycosis in patients with renal failure K.L. Gupta, B.D. Radotra, V. Sakhuja, A.K. Banerjee and K.S. Chugh Departments of Nephrology and Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh , India
Renal mycoses : Indian scene PGI,Chandigarh Study Data-sourceMedical & pathology records Diagnostic criteria Histological demonstration of tissue invasion in H&E, PAS & Silver Methenamine estained sections Identification by characteristic morphlology Isolation of in fungi culture Period of study No.of cases 85 ( 74 M, 11 F ) Age (yrs ) 24.2 ± 18.5
Rhizopus, Absidia and Mucor Large, aseptate,irregularly branching hyphae Clinical syndromes: PGI Study n=129* Rhinocerebral57 (44%) Pulmonary13(10%) Disseminated15 (12%) Gastrointestinal 6 ( 5%) Cutaneous20 ( 15%) Renal 18 (14%) Renal Mucormycosis *Chakrabarti et al J Infectious Dis 42; :2001
Case Discussion SJ 17 M Student admitted with Fever, flank pain (Lt.). Vomiting 。 Haematuria, and doligo-Anuria for 10 days Examination Pale, febrile, toxic, pt. B/L pedal oedema BP 150/90, Pulse-110/m Generalised tenderness in abdomen Fullness of C-V angles Investigations Hb-80g/L, WBC 23x109/L Urine Prot.++, pus cells , RBC 15-20/HPF Urea 240 mg/dl, Creat.10mg/dl, uric acid 12 mg/dl Sugar 100mg/dl ALB. 2.5g/dl, TP 5.1g/dl HIV Neg., T4/T8 Ratio normal, Fungal serology-Normal US and CT Abdomen:
Course & Management Hemodialysis, antibiotics, Laparotomy and aspiration of perinephric collection Pus direct smear-Mucor hyphae Culture-Apophysomyces elegans Kidney biopsy: Ischemic necrosis with vessel invasion by mucor Amphotericin B total dose -560mg( 2 weeks) B/L nephrectomy Patient died after two weeks of diagnosis Autopsy: No other organ involvement Comments: Isolated renal mucormycosis with ARF
Sex ratio M:F22:3 Age (yrs. )33.1±15.1 Presenting featuresNo.% Fever2185 Flank pain2080 Luekocytosis2080 Hematuria1872 Pyuria1872 Renal failure*1872 * In (95%) pts with bilateral involvement Renal Mucormycosis: PGI Study (n=25)
Nephrology Dialysis Transplantation Nephrol Dial Transplant (1999) 14: Clinical Observations Renal Zygomycosis: an under-diagnosed cause of acute renal failure Krishan Lal Gupta, Kusum Joshi 1, Kamal Sud, Harbir S. Kohli and Vivekanand Jha, Bishan D. Radotra 1 and Vinay Sakhuja Departments of Nephrology and 1 Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Ultrasonography ( n-24) Enlarged kidneys22 Perinephric collection 10 Computerised tomography ( n-12 ) Enlargement of kidneys 11 Absence of contrast 10 Low attenuated areas 10 Perinephric collection 9 Renal Mucormycosis: Radiological Features
Am Journal of Kidney Diseases,Vol 22, No 3(September),1993; pp Renal Mucormycosis: Computerized Tomographic Findings and Their Diagnostic Significance K.S.Chugh, MD, FACP, V.Sakhuja, MD, DM, FAMS, K.L.Gupta, MD, DM, V.Jha, MD, DM, A.Chakravarty, MD, N.Malik, MD, P.Kathuria, MD, N.Pahwa, MD, and O.P.Kalra, MD
(A fumigatus, A.flavus, A.niger ) Identified by slender,regular,dichtomously branching,septate hyphae Invariably associated with debilitated state Usually part of disseminated disease & rarely isolated Other organs lungs (94%),GIT (92%),brain (13%) † Clinically: Three patterns 1)Disseminated aspergillosis with renal involvement 2) Aspergillus cast of renal pelvis 3) Ascending panurothelial aspergillosis Renal Aspergillosis † Wise & Silver (1993)
Sex ratio M:F23:4 Age (yrs. )22.6 ± 19.5 Presenting features Renal failure15 (55%) Pathologic findings Microabscesses19 Vasculitis13 Papillary necrosis 6 Culture identification 6 Aspergillosis: PGI Study (n=27)
Renal Failure, 20(6), (1998) Isolated Bilateral Renal Aspergillosis: An unusual Presentation in an Immunocompetent Host Kamal Sud, 1 MD, DM, Sanjay D’Cruz, 1 MD, DM, Harbir S Kohli, 1 MD, DM, Vivekanand Jha, 1 MD, DM, Krishan L Gupta, 1 MD, DM, Arunaloke Chakrabarti, 2 MD, Kusum Joshi, 3 MD, and Vinay Sakhuja, 1 MD, DM 1 Department of Nephrology Postgraduate Institute of Medical Education and Research, Chandigarh, India. 2 Department of Microbiology Postgraduate Institute of Medical Education and Research, Chandigarh, India. 3 Department of Pathology Postgraduate Institute of Medical Education and Research, Chandigarh, India. CASE REPORT
Sex ratio M:F23:7 Age (yrs.)18.2±18.0 Presenting features Acute pyelonephritis21 Pyonephrosis14 Renal failure 12* (40%) Pathologic findings Microabscesses24 Papillary necrosis 15 Vasculitis 5 Mixed infections Renal3 Extrarenal5 Candidiasis: PGI Study (n=30)
Renal cryptococcosis C.neoformans identified by large clear capsules sorrounding yeast cells Usually a disseminated disease involving brain,lungs,GIT,kidneys,prostate etc. Renal lesions include Sparse lymphocytic infiltrate and rarely Microabscesses,granulomas & caseation Papillary necrosis &tubular atrophy. Clinically no significant abnormality
Renal mycoses: incidence of papillary necrosis Fungal TotalRPN% Infections Candidiasis Aspergillosis Mucormycosis Cryptococcosis 4 0- Histoplasmosis 1 0- Total
Conclusions Fungal infections have been being increasingly seen in the last decade Renal involvement occured as disseminated (57%) or isolated form ( 43%) Candidiasis was the commonest renal infection but had a low incidence of renal failure ( 40%)*. Mucormycosis causes most severe lesions. Irreversible ARF occurred in 92% of pts with bilateral renal invlvement. Aspergillus is less angioinvasive. ARF occurred in 55% pts.
Conclusions (contd.) Most fungal infection occurred in presence of predisposing conditions. However 68% of pts. with mucormycosis had no apparent underlying disease. Renal mycoses has a very high mortality ( 80% ). Diagnosis is usually made at autopsy. Disease was recognised in life only in 1/3rd of pts. A high index of suspicion is required to identify renal mycoses. Imaging techniques combined with interventions including kidney biopsy may clinch the diagnosis and help in initiating antifungal therapy.
PART II INVASIVE FUNGAL INFECTIONS FOLLOWING RENAL TRANSPLANTATION
Introduction Increased occurrence of opportunistic infections in solid organ transplant recipients Incidence related to organ transplanted, immunosuppressive regimen, induction therapy and anti- fungal prophylaxis Diagnosis often difficult and delayed because of Paucity of rapid diagnostic tests Concomitant infections (90% have Bacteria, CMV and P car) Presence of comorbid conditions High index of suspicion is thus necessary to provide timely therapy.
ISSUES IN MANAGEMENT OF INVASIVE FUNGAL INFECTIONS Discussion points: Epiedemiology of IFIS and its Risk factors Local experience of IFIS Clinical and Laboratory Diagnosis of IFIS Advances in management of IFIS Triazoles, Echinos. Ampho-B and its formulations Role of combination therapy Summarized managemet of IFIS Role of prophylaxis therapy
a)Epidemiological exposure b)Net state of immunosuppression Immunosuppressive therapy Integrity of muco-cutaneous barrier Devitalised tissues, fluid collection Metabolic factors ; uremia and diabetes Immuno-modulating viruses: CMV, EBV, HBV Hospital exposures/adjacent construction Selected agricultural, occupational, and recreational activities Risk factors in Tx recipients
Immunosuppressants and Fungi Calcineurin inhibitors Antifungal activity of the CNIs is mediated through inhibition of Calcineurin phosphatase. Mycophenolic acid MPA activity against P jiroveci (Inhibition of IMPDH) Sirolimus TOR kinases promote cell proliferation in fungi. SRL on fungi with TOR activity ALA Both for induction and anti-rejection therapy Corticosteroids Medications with myelosuppressive properties (miscellaneous)
Time-table of Post-Tx Fungal Infections
Fungal Infections following renal Transplantation Therapy and Outcome Fungal infection Pts diagnosed Pts surviving Overall * alive & treated with therapy Mortality N N (%) N (%) Candidiasis (n= 32)18 14 (78)13 (48) Cryptococcosis (n= 23 ) 238 (47) 9 ( 53) Aspergillosis( n=32) 137 (54)16 (70) Mucormycosis (n= 26) 92 (23)18 (80) *Including those diagnosed at autopsy
Case Discussion Renal Tx Donor Triple drug therapy Acute Graft Rejection Admitted on with c/o
Clinical features suggesting IFI Fever resistant to BSA ± severe neutropenia S/S of resistant or progressive LRI or URI Periorbital or Maxillary swelling / tenderness Palatal necrosis or perforation Focal neurological or meningeal irritation S/S Unexplained mental changes with fever Papular or nodular skin lesions
Laboratory Diagnosis OF IFIS Histopathologic diagnosis: Using special stains like Periodic acid-Schiff, Grocott-Gomori methenamine silver and Gridley fungal stains. Demonstration of the Yeast cells or hyphae in FNAC or Bx of infected tissue Culture on solid media Blood culture may not detect all IFIS (50% yield) Other fluids like urine,CSF, BAL etc may be cultured Growth of any mould from biopsies by sterile technique is always very significant
Immunological /DNA assays for IFIS Detection of fungal cell wall components and antigens Antigen detection e.g. Double sandwich ELISA for candidal antigen and Galactomannan ELISA for Asper and Cryptococcal antigen by RIA Detection of 1, 3-β-D-Glucan synthetase Molecular diagnosis, like PCR for DNA assay Nucleic acid probes
Radiological diagnosis of IFIS Plain chest X-ray Normal in upto 29% of Pulmonary IFIS Findings include segmental or subsegmental consolidation, patchy infiltrates, nodules (single or multiple), nodular infiltrates and cavitation CT Scans HRCT should be undertaken with 1 mm slices “Early” CT findings in IFI are single or multiple nodules or mass like infiltrates and the “Halo sign” “Late” signs are cavitation, with or without the air “crescent sign”, which correspond to the CXR findings
Pneumocystis jirovecii (P Carinii) Universal seropositive status by age two Usually air-borne transmission Diffuse alveolar damage, impaired gas exchange, and respiratory failure (More in Non-HIV) Usually occurs with 6-12 mon but sometimes late Presents with fever, nonproductive cough Tachypnoea, cyanosis, hypoxemia Diffuse crepitations BAL and lung biopsy help in confirming Dx Radiology : B/L ground glass opacities, homogenous and diffuse; HRCT- more sensitive
Imaging in P carinii infection
Pulmonary Infections in RTX Pts ( )* Pts. with infections34/81 (42%) Organism identified by BAL 20/28 (71%) Pyogenic bacteria33% M. tuberculosis31% P. carinii15% Candida10% Aspergillus 8% CMV8% Others 5% * Kidney International 56(5), , 1999.
Specimen: BALStain: GM Sx1000 BAL;Stain: Fungi-Fluor x400 Lung specimen x 1000 Parenthesis or comma like internal dots surrounded by cyst walls. ( Dx 2 cysts reqd)
P. jirovecii : USRDS 2009 No series available from India, limited cases included 4% of opportunistic infections in HIV patients USEDS - 32,757 renal TX recorded 142 (04% ) PCP Cases Median post-tx time was 0.80±0.95 yrs Risk factors in Transplant patients, o Expanded criteria donor o Donation after cardiac death o Concomitant viral, HCV o Prednisone ≥ 16 mg for > eight weeks o Combination immunosupression Tacrolimus and sirolimus Neoral and MMF Sirolimus and MMF (Analysis of USRDS: July )
Part III Advances in Management of Invasive Fungal Infections
Why we need new antigumgal ? Several new antifungal drugs licensed in last 5 yrs ; Intrinsic or acquired antifungal resistance, Organ dysfunction preventing use of some agents Poor penetrabilty into sanctuary sites (eye /urinine) Drug interactions and considerable adverse events Still some patients remain difficult to treat
Wish List for an Antifungal Drug Broad spectrum fungicidal Nontoxic even with prolonged use Can be administered parenterally and orally Favorable pharmacokinetic properties, Minimal drug interactions Minimal genetic variation in metabolism
Mechanisms of Action Cell Wall Synthesis: Echinocandins inhibit glucan synthesis via inhibition of 1,3--D- glucan synthase, blocking chitin synthesis fungal cell lysis. Inhibition of Cell Membrane Function: Polyenes bind to ergosterol, principal sterol in fungal cell membrane causing cell wall disruption, loss of integrity of the cell membrane, and cell death. Ergosterol Synthesis: Azoles inhibit 14-demethylation of lanosterol by binding to fungal cytochrome P450 enzymes, thus preventing the synthesis of ergosterol
What are the targets for antifungal therapy? Cell membrane Fungi use principally ergosterol instead of cholesterol Cell Wall Unlike mammalian cells, fungi have a cell wall DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis. Atlas of fungal Infections, Richard Diamond Ed Introduction to Medical Mycology. Merck and Co Polyenes Candins Azoles
Dose IV 6 mg/kg X 2 doses, then 3 to 4 mg/kg every 12 Hrs PO > 40 kg— mg PO every 12 hours < 40 kg— mg PO every 12 hours Cirrhosis: IV 6 mg/kg X 2 doses, then 2 mg/kg every 12 Hrs PO > 40 kg—100 mg PO every 12 hours < 40 kg— 50 mg PO every 12 hours Renal impairment: If CrCl<50 ml/min, use oral formulation to avoid accumulation of cyclodextrin solubilizer Voriconazole ; Dosing schedule
VORICONAZOLE : TOXICITY Visual hallucinations Hepatotoxicity Drug interactions – via CYP 3A4. Rifampin, LA-barbiturates,carbamazepine vori conc. Vori interferes in metabolism of SRL and better avoided dose of immsupps drugs TAC, CSA Metabolised by CYP 2C19 Polymorphism : 3% whites; 15 –20% Asians ? Therapeutic drug monitoring needed
Posaconazole: Dosing schedule Spectrum: Zygo, Asper, Fusarium and candida Dosing (only available PO admn with food supplement) –Prophylaxis of invasive Aspergillus and Candida species 200 mg 3 times/day –Treatment of oropharyngeal candidiasis 100 mg twice daily for 1 day, then 100 mg once daily for 13 days –Treatment or refractory oropharyngeal candidiasis 400 mg twice daily –Treatment of refractory invasive fungal infections 800 mg/day in divided doses Drug Interactions –Moderate inhibitor of CYP3A4 (AVOID coadmPPI & H2 Blocker) Adverse Reactions –Hepatotoxicity, GI: Diarrhea. QTc prolongation SAFE in Ren Insuff.
Prophylactic therapy ; Incidence of Proven/Probable IFIs PosaconazoleFluconazole Number of IFIs All IFIsInvasive Aspergillosis P =.004 P =.001 While on treatment All IFIsInvasive Aspergillosis P =.074 P =.006 Primary time period 112 days after randomization Ullmann AJ et al. NEJM 2007.
The Fungal Cell Wall Atlas of fungal Infections, Richard Diamond Ed Introduction to Medical Mycology. Merck and Co. 2001
Echinocandins: Capso,Mica,Anidula-fungin Mechanism of Action Cyclic lipopeptide antibiotics that interfere with fungal cell wall synthesis by inhibition of ß-(1,3) D-glucan synthase Loss of cell wall glucan results in osmotic fragility Spectrum: Candida species including non-albicans isolates resistant to fluconazole Aspergillus spp. but not activity against other moulds (Fusarium, Zygomycosis) No coverage of Cryptococcus neoformans Dose and modification Water soluble available only in IV form Dose - 70 mg day 1 and 50 mg afterwards Dosage adjustment in hepatic insufficiency Metabolites excreted by kidneys and GI tract Emerging ECHDN Aminococandin
Echinocandins act at the apical tips of Aspergillus hyphae DiBAC Bowman et al. Antimicrob Agent Chemother 2002;46:
Caspofungin - Adverse effects Most common AEs are infusion related: –Intravenous site irritation (15-20%) –Mild to moderate infusion-related AE including fever, headache, flushing, erythema, rash (5-20%) –Symptoms consistent with histamine release (2%) Most AEs were mild and did not require treatment discontinuation Most common laboratory AE –Asymptomatic of serum transaminases (10-15%) Clinical experience to date suggests that these drugs are extremely well-tolerated Antiviral Drug Products Advisory Committee, January 10,
Amphotericin B Polyene, Fermentation product of Streptomyces nodusus Long time gold standard in treatment of serious fungal infection with Broad spectrum activity Highly insoluble. Exists in micellar mixture with deoxycholate No oral bioavailability; intravenous formulation Relatively poor penetration of urinary tract, CNS
Amphotericin B is active in vitro against Candida spp. (including azole-resistant species) Aspergillus spp. Cryptococcus neoformans Mucor spp. Blastomyces dermatitidis Coccidioides immitis Histoplasma capsulatum Paracoccidioides brasiliensis
Toxicities of Amphotericin B “Don’t look cross-eyed at it” -- comes out of micellar mixture with contact with blood, potassium, saline, etc. anaphylactoid reaction “Cytokine storm” -- Fever and chills; TNF, IL-1, IL-6. Patient usually becomes tachyphylactic Renal toxicity -- RTA; K+ and Mg++ wasting, S cr. Dose Related. renal toxicity in hypovolemia in and those receiving other nephrotoxic drugs. Amphotericin B - Drug Interactions Uncommon except with high doses: Liver toxicity; bone marrow toxicity
Lipid Formulations of Amphotericin B All three approved for “rescue therapy” (failure of previous therapy or toxicity) Liposomal amphotericin successful for empiric therapy in febrile neutropenia Less nephrotoxicity and cytokine storms Lipid preparations are thus preferred for inhalation delivery Lipid firms distributes mostly in reticular endothelial tissue (liver, spleen, lung), but less in kidney. Hypothesis: By encapsulating ampho-B in liposomal vesicles or binding it to other lipid carriers, protect kidneys and achieve higher concentrations in liver and spleen and RE system.
Combination Anti-fungal Therapy Potential benefits Enhanced potency of antifungal efficacy, Reduced selection of resistant organisms and Reduced toxicities due to lower dosing. Evidence of benefit Rx cryptococcal meningitis, AmB-D and Flucytosine Amphotericin B plus Fluconazole However few large studies in IA
Combination treatment IA=invasive aspergillosis AuthorYearN=OrgCombinationResp Kotoyiannis Aliff Marr Maartens Nivoix IA Any Caspo+LAmB ” Caspo+ Voric Caspo+ either Caspo + any 42% 60% 65% 57% 71%
SUMMARY OF FUNGAL THERAPY PathogenPrimarySecondary Candida albicansFluconazole Amphotericin B Caspofungin Posaconazole Anidulafungin Voriconazole, Itraconazole Cryptococcus neoformans Amphotericin B ± Flucytosine followed by Fluconazole Itraconazole or Amphotericin B Aspergillus fumigatus Voriconazole Posaconazole Itraconazole, Caspofungin Amphotericin Cryptococcus neoformans Amphotericin B ± Flucytosine followed by Fluconazole Itraconazole or Amphotericin B Histoplasma capsulatum Itraconazole or Amphotericin B Fluconazole MucomycosisAmphotericin BPosaconazole
Antifungal Prophylaxis in SOT Recipients Prophylaxis reasonable given the high incidence/ mortality However In 14 RCT with 1497 participants AFP did not mortality ( [RR] 0.90, 95% CI ). Current data supports limited benefit (Aspergillus in liver/ lung and Candida in liver, bowel, and pancreas tx recipients. Fluc significantly early IFIs in liver tx with no mortality. Assuming 10%, 14 pts require prophylaxis to prevent 1 IFI. Less data are available for other agents/transplants. Drug interactions and toxicities must be considered Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).
Antifungal Prophylaxis : Indications High risk patents with: Renal and hepatic dysfunction Large blood transfusion requirements Prolonged ICU stays Additional surgery post transplant including laparotomy and re-transplantation Known fungal colonization pretransplantation Prior (broad-spectrum) antimicrobial use
Antifungal Prophylaxis: Drug Regimens None is ideal for all of the indications for post-tx prophylaxis Fluconazole — Safe,no hepatotox in liver tx used only for Candida Itraconazole — Poor bioavailability unreliable for AFP Use in lung tx ? Voriconazole — Offers filamentous mold activity > Flucon or Itracon but not against the zygo. However, no prophylactic studies. Posaconazole — Its use in SOT AFP have not yet been defined. Ampho- B — Failure of low-dose regimens as AFP. Few studies suggested aerosolized forms benefitted in lung tx against Asper Echinocandins — No trials of SOT AFP have been performed to date. Choice of drug — The 2009 Infectious Diseases Society of America 1. Fluconazole (200 to 400 mg [3 to 6 mg/kg] daily) OR 2. Liposomal Ampho- B (1 to 2 mg/kg IV/d) for 7 to 14 days as AFP for liver, pancreas, and small bowel transplant recipients at of IFIs
Conclusions Incidence of IFI in Transplant recipients is increasing partcularly that of angio-invasive filamentous fungi with morbidity and mortality Diagnosis depends on understanding of Risk factors and incidence rates, Significance of different clinical presentation and Timely use of mycological and radiological investigations. Antifungal Therapy Empirical use should be discouraged. Azoles hold Good Promise but all IFI do not respond (Except Posa) Lowest toxicity seen with caspo and L-Ampho B Prophylaxis of IFI should be confined to high risk patients and drugs of choice are itraconazole and posaconazole.
Conclusions Incidence of IFI in Transplant recipients is increasing partcularly that of angio- invasive filamentous fungi with morbidity and mortality Diagnosis depends on understanding of Risk factors and incidence rates, Significance of different clinical presentation and Timely use of mycological and radiological investigations. Antifungal Therapy Empirical use should be discouraged. Azoles Hold Good Promise but all IFI do not respond (Exception Posa) Lowest toxicity seen with caspo and L-Ampho B Prophylaxis of IFI should be confined to high risk patients and drugs of choice are itraconazole and posaconazole.