Inter-hospital renal meeting

KM CHAN

YH CHAN

29/3/2017

Case history

• 61 year old

• HT

• ESRF of unknown cause

• Started CAPD since 2013

Renal Tx in overseas

• Renal Tx 22/4/2016

• Induction with ATG followed by FK/MMF/steroid

• Slow graft function, post op 2 weeks Cr 614

• Complicated with pneumonia, resolved after treatment with antibiotics

Slow graft function…..

• Given total 5 courses of ATG for suspected rejection in May for suspected rejection

• Serial USG showed increased hydronephrosis of renal graft

• Flexible cystoscopy failed to put in JJ

EOT….

• EOT: noticed ureteric gangrene, partial resection of renal graft ureter and reinsertion to bladder

• UO improved and Cr improved after OT • Tubal drain also increase output due to ?ureteric

leak • 24/5/2016: decrease GC, anuria, melaena

started CRRT / Withhold FK due to ?encephalopathy • 26/5/2016: GC improve a bit • Back to HK 29/5/2016

QEH

• Arrival to QEH on 29/5/2016

• Fever 38 degree

• Malaise

• GCS 14/15

• PE: unremarkable

• BP 154/99 P 110 , SaO2 100% 2L

• PICC, Left femoral HD cath, 2 abdominal tubal drains

Bld test on admission

• CBC: Hb 8.9 WCC normal, plt 22

• Na 130, K 4.0,Ur 39, Cr 400, CO2 18

• Normal clotting profile

• Medications from previous hospital: – Meronem 500mg q8H – Linzeolid 600mg q12H – Caspofungin 50mg Q24H – IVIG 100ml Q24H – IV prostaglandin 20mcg Q24H – IV Nexium 40mg Q12H – SC octerotide 200mcg Q8h – IV vitamin K1 20mg Q24H – Betaloc 12.5mg bd po – Elantan 20mg Q24h – IV TPN

What problems…

• Renal transplant with allograft dysfunction

• Suspected rejection, given ATG

• Complicated with pneumonia

• Ureteric gangrene with reinsertion, partial improvement

• ?ureteric leak ?encephalopathy

• Anemia and thrombocytopenia

• ?????????

• Further management 9

• Continue with Abx

• Meronem IV and hydrocortisone

• Repeat septic workup

• Check bld x CMvpp65

• Tubal drain x Cr

• Tubal drain: 3300 umol/L

• Initial septic workup –ve

• CMVpp65 262 +ve/2x 10^5 WC

• CT brain: NAD

• USG abdomen: graft with no hydronephrosis 12.3cm, renal parenchymal change, perinephric collection, RI high side

• Increase WCC up to 21

• IV ganciclovir 1.25mg/kg Q24H

• IV daptomycin 10mg/kg Q48H

• Book CT TAP

• Continue HD

c/o headache

• CT brain: NAD

CT TAP

CT TAP

• Impression: • Parenchymal disease of the transplant kidney with

hydronephrosis • The lower pole of the transplant kidney is especially

poorly enhanced with an irregular outline, ?due to infarction or focal pyelonephritis

• Perinephric fluid collection with two large bore catheters in it

• Progress:

• Fever down

• Plt improving 125

• CMVpp65 26012 1

Finally….

• Decided for graft nephrectomy 13/6/2016

• Intraop: • Gapped renal transplant wound and two large drains in situ • Infected and swollen graft kidney with necrotic lower pole, renal pelvis and

ureter with double J already exposed • Necrotic Rt anterior and lateral bladder wall extended to near native Rt UO • Necrosis of extraperitoneal fat, muscles and fascia near above lesions

• Procedure: • Total nephrectomy, unilateral ( graft ) • Partial cystectomy of urinary bladder

Problems…

• ESRF

• Failed KT

• CMV disease

• Necrotic kidney and ureter and bladder

Renal Infarction A large renal arterial branch

showing luminal thrombosis

Thrombus

The arterial wall is necrotic, and is invaded by fungi

The fungi are hyphae which show a variable calibre & infrequent septation, consistent with mucormycosis

Final report

• Gross examination • parenchymal necrosis in the inferior pole of the kidney. • Thrombosis of the renal blood vessels at the hilum • Multiple pieces of necrotic and irregular shaped soft tissue in bladder wall

• Microscopic Examination : • angioinvasive fungal infection involving the kidney and the bladder wall,

resulting in hemorrhagic infarct and acute suppurative inflammation • Fungal hyphae show a variable caliber, infrequent septate and right angle

branching, morphologically consistent with mucormycosis.

• Amp B 40mg daily then step down therapy to posaconazole

• Start posaconazole 200mg qid po

• Fever again and decrease GC

• Tubal drain yield acineobacter and klebsiella intraabdominal infection

• added Amikacin

CT brain

5/7/2016 CTB:

• A ring-like hypoattenuating lesion in the right temporal lobe, measuring 2.0cm x 1.9cm x 2.0cm

• Perifocal vasogenic oedema, with sulcal effacement and mild effacement of the temporal horn of right lateral ventricle

• In the current context, an infective lesion should be considered, especially an abscess.

• A small hypodense area is noted in the posterior pons (1.0cm x 0.8cm). Additional infective focus should be considred. DDX: infarct.

6/7/2016: CTB + C

• Three hypodense lesions showing faint rim enhancement in right temporal region and right posterior pons

• In view of rapid progression and underlying immunosuppression, these are highly suspicious of brain abscesses.

• Proceed to LP

• Send CSF x cell count, microscopy, c/st

• TB PCR, cryptococcal ag, culture for mucormycosis, nocardia, and rhodococcus

• LP clear CSF, OP 10

• TP 0.39 , glu 3.1 (hstix 6.2) WCC 2

• Cytology –ve

• Gram stain – ve

• Indian ink –ve , TB PCR –ve

• Fungal culture -ve

• -> add amp B

12/7/2016 Cystogram

• Post bladder repair

• Cystogram:

• Leakage over right side into right extra-peritoneal space of previous graft site

Finally….

• Condition further deteriorated

• Complicated with pneumonia

• Septic shock

• Intubated and double inotropes

• For DNAR

• Succumbed on 18/7/2016

Summary

• Failed graft kidney complicated with mucormycosis of graft kidney,ureter and bladder

• Further complicated with Brain abscesses

• CMV disease

MUCORMYCOSIS

Introduction

• Uncommon but fatal mycoses caused by fungi of the class Zygomycetes, the organisms of which are usually found in decaying organic matter

• Disease can be transmitted by the inhalation of spores or by direct inoculation on disrupted skin or mucosa

• For rare diseases such as zygomycosis, two or more cases occurring in a short time should be investigated as a probable epidemic

Introduction

• Mucormycosis, now a preferred term over Zygomycosis on the basis of taxonomy, commonly presents as rhino-sino-orbital infection

• Mucormyscosis is a rare opportunistic fungal infection with a fulminant course and high Mortality rate

• Rhizopus species are the most common causative organisms, others including Mucor, Absidia, and Cunninghamella species

Introduction

• Found in soil, bread molds, decayed fruits, and vegetables

• Can be cultured from the nasal cavity, the throat, the oral cavity, and the stools of healthy patients

• Everybody is exposed to this infection, inhales the spores

• Nasal ciliary system transports these spores down in the pharynx where it is finally cleared in the gastrointestinal tract

• The spores inhaled by the lungs are cleared by the phagocytes

Zygomycosis Hospital Outbreaks 1966–2008

• Orthopaedic patients who had undergone spinal surgery and in whom a superficial skin infection along the surgical wound

• The next three cases occurred in paediatric patients, including two children and a pre-term neonate

• The children had acute lymphocytic leukaemia as an underlying disease and presented with buttock abscesses several weeks after bone marrow biopsy

• The neonate was operated on for gastric perforation and gastrointestinal zygomycosis was diagnosed

• The common source for all cases was the Elastoplast adhesive dressings used to cover the surgical wounds in the orthopaedic patients, to control superficial bleeding from the bone marrow biopsy site, and to secure a nasogastric tube and an umbilical catheter in the neonate

Mucormycosis and KT

• Incidence in kidney transplant recipients is even lower compared with other solid-organ transplant recipients

• Disseminated mucormycosis is described mainly in hematopoietic stem cell transplant recipients

• Mucormycosis is at least 5- to 10-fold less common than other molds, such as aspergillosis

• The onset of mucormycosis after kidney transplant varied between 1 month and 4 years , most common between 1st month to 6th month

• J Infect Dis 2005;191(8):1350-1360.

• Haematologica 2006;91(7):986-989

• TRANSNET Clin Infect Dis. 2010;50(8):1101-1111.

Factors favoring mucormycosis over aspergillosis

42

Epidemiologic and host clues Comments

Institution with high background rates of mucormycosis Unique geographic exposures vs institution-specific differences in immunosuppression and anti-infective practices

Iron overload The most reliable method of diagnosis is unclear

Hyperglycemia with or without DM Degree and duration are undefined

Prior voriconazole or echinocandin use The magnitude and specificity of such association are debatable

Clinical, radiologic, and laboratory clues

Community-acquired sinusitis Pansinusitis or ethmoid involvement are important clinical clues of mucormycosis

Oral necrotic lesions in hard palate or nasal turbinates

Chest wall cellulitis adjacent to a lung infarct Mucormycosis can spread across tissue planes

Acute vascular event (eg, MI, GI bleeding) Resulting from the acute hemorrhagic infarct caused by Mucorales

Multiple (n > 10) nodules in CT and pleural effusion

Reverse halo sign in CXR or CT Halo sign is as common in IPM as in IPA

Presumed (by CT findings) fungal pneumonia with adequate (eg, > 2 μg/mL) voriconazole levels

Presumed (by CT findings) fungal pneumonia with repetitively negative GM and G-glucan serum levels

Risk factors for Mucormycosis

• Diabetes mellitus, particularly with ketoacidosis • Treatment with glucocorticoids • Hematologic malignancies • Hematopoietic cell transplantation • Solid organ transplantation • Treatment with deferoxamine • Iron overload • AIDS • Injection drug use • Trauma/burns • Malnutrition

Pathogenesis

• Rhizopus organisms have an enzyme, ketone reductase, which allows them to thrive in high glucose, acidic conditions

• Invade into the vascular network • Thrombosis and necrosis of surrounding tissue

45

Pathophysiology of invasive pulmonary mucormycosis.

Dimitrios P. Kontoyiannis, and Russell E. Lewis Blood 2011;118:1216-1224

© 2011 by American Society of Hematology

Clinical manifestation

● The predominant organ involvements of mucormycosis are pulmonary (24%), rhino cerebral (21%), cutaneous (19%), gastrointestinal (7%), renal (2%), and disseminated (3%)

● Infection among kidney transplant recipients around 0.2-1.2%

● Infection of the graft kidney is extremely rare

● Few case reports published

● Principles and practice of infectious disease. 7th ed. New York: Churchill Livingstone; 2011. p. 3257

● Urol J 2005;2:54.

● J Clin Microbiol 2009;47:2834.

● Principles and Practice of Infectious Diseases. 6th ed. Vol 2. Philadelphia, PA: Elsevier Churchill Livingstone; 2005. p. 2973.

The clinical signs and symptoms of mucormycosis are nonspecific No biomarkers to indentify this disease. β-D-glucan test and Aspergillus galactomannan tests do not detect antigen components of the Mucorales cell wall A high level of suspicion in susceptible patient subgroups

Principles and Practice of Infectious Diseases. 6th ed. Vol 2. Philadelphia, PA: Elsevier Churchill Livingstone; 2005. p. 2973.

48

Types of mucormycosis

• Rhinocerebral (sinus and brain) mucormycosis is an infection in the sinuses that can spread to the brain. This form of mucormycosis is most common in people with uncontrolled diabetes

• Pulmonary (lung) mucormycosis is the most common type of mucormycosis in people with cancer and in people who have had an organ transplant or a stem cell transplant

• Gastrointestinal mucormycosis can result from ingestion of the fungal spores. This type of mucormycosis is less common among adults and is more common among young children, especially infants <1 month of age

• Cutaneous (skin) mucormycosis: occurs after the fungi enter the body through a break in the skin (for example, after surgery, a burn, or other type of skin trauma). This is the most common form of mucormycosis among people who do not have weakened immune systems

• Disseminated mucormycosis occurs when the infection spreads through the bloodstream to affect another part of the body. The brain is the most commonly affected part of the body, but other organs such as the spleen, heart, and skin can also be affected

Rhino-orbital-cerebral mucormycosis

• Fever – 44 percent

• Nasal ulceration or necrosis – 38 percent

• Periorbital or facial swelling – 34 percent

• Decreased vision – 30 percent

• Ophthalmoplegia – 29 percent

• Sinusitis – 26 percent

• Headache – 25 percent

Pulmonary mucormycosis

Gastrointestinal mucormycosis

• Stomach was the most common site (58 percent), followed by the colon (32 percent)

• Necrotic ulcers that can lead to perforation and peritonitis

Diagnosis

• Large ribbon like aseptate fungal hyphae in histology

• PCR amplification and sequencing of the 18S (nuclear small subunit) and 28S (nuclear large subunit) rRNA genes and the internal transcribed spacer (ITS) region of rRNA

54

Diagnosis is difficult

• Clinical and radiologic presentation can be nonspecific—mucormycosis mimics other fungal infections (eg. aspergillosis)

• Mycological cultures of the clinical samples are regularly negative

• No antigen-based detection test is available

• No standardized polymerase chain reaction assay has been evaluated in large multicentric studies

Mortality

• up to 90-100% • Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of

zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005;41:634.

57

Mucormycosis in graft

Clin Kidney J (2012) 5: 502–507

Mucormycosis in graft

Mucormycosis in graft

• The presenting clinical features included renal dysfunction in 20 (83.3%), tenderness over the transplanted kidney in 19 (79.1%) and fever in 18 (75%)

• There was concomitant bacterial urinary tract infection in seven (29.4%)

• Seven patients had coexistent cytomegalovirus (CMV) infection

Transplant Tourism

• ‘transplant tourism’ in developing countries has become increasingly common and is a well-recognized risk factor for serious opportunistic infections

Shoham S, Hinestrosa F, Moore J Jr et al. Invasive filamentous fungal infections associated with renal transplant tourism. Transpl Infect Dis 2010; 12: 371–374

CMV infection

• CMV infection triggers fungal infections such as aspergillosis or candidiasis in renal transplant recipients

Treatment

• Tissue debridement: nephrectomy

• Antifungal agents: Amphotercin B and Posaconzaole

• Withdrawal of immunosuppression

Posaconazole

• Posaconazole, new triazole, with its pharmacokinetic advantages and low side-effect profile, has been increasingly used in mucormycosis both as a ‘step-down’ therapy following initial amphotericin administration

• ‘salvage’ therapy in patients with resistance to amphotericin B

LamB-POS

• The LAmB-POS combination therapy has been mainly investigated as salvage therapy

• Clinical data are sparse

• 2 studies report a 60% to 79% response rate

» Crit Rev Microbiol. 2013;39(3):310-324.

» Antimicrob Agents Chemother. 2006;50(1):126-133.

» Clin Infect Dis. 2006;42(7):e61- e65. Erratum in: Clin Infect Dis. 2006;43(10):1376.

Summary

• Mucormycosis remains a rare disease

• Diagnosis is difficult and requires high clinical suspicion

• Never treat rejection with ATG without a biopsy proven rejection

• Thank you

Predisposing risk factors for mucormycosis in patients with hematologic malignancies and/or stem cell transplantation

69

Prolonged (> 3 wk) and severe (ANC < 200) neutropenia

Monocytopenia (< 100 mm3)

Prolonged (> 3 wk) high-dose systemic corticosteroids (eg, prednisone or equivalent of > 1 mg/kg/d)

Iron overload (assessed by high iron indices, high iron storage by MRI, or high iron staining in bone marrow biopsy)

High-risk SCT (eg, matched-unrelated donor SCT, haploidentical donor SCT, cord blood SCT, T cell-depleted SCT)

Severe GVHD and its treatment (especially corticosteroids)

Prolonged hyperglycemia (fasting serum glucose > 200 mg/dL), corticosteroid-associated hyperglycemia, diabetes mellitus

Colonization by mucormycetes or heavy environmental exposure?

Previous exposure to Aspergillus-active antifungal agents, especially voriconazole?

Relapsed leukemia

Transplantation 2014

70

Case Rep Nephrol Urol 2013;3:58–63

71

Experimental and clinical transplantation 2016

72

Experimental and Clinical Transplantation (2013) 6: 554-557