The goal of this section is to serve as a guide for tackling the most common transplant complications as well as offer a few tips for managing immunosuppression while kidney transplant patients are admitted to the hospital
Alphabet soup
PRA: panel reactive antibodies
DSA: donor specific antibodies
SCD/ECD: standard or expanded criteria donors reflects quality of organ and risk of graft loss
DCD: donation after circulatory death
DGF: delayed graft function (required dialysis within 7 days post-transplant)
CMV (-/+): indicates the CMV status of both the recipient and the donor
FK506 or FK: another name for tacrolimus
KDPI: Kidney donor profile index used to “grade” the quality of the donated organ
X/6 MM: indicates the number of HLA subtypes that are mismatched between donor and recipient
CAN: chronic allograft nephropathy
Infections in Kidney Transplant Recipients
Infection Prophylaxis
Trimethoprim-Sulfamethoxazole (TMP-SMX) 80/400mg one tablet daily for at least six months for PJP ppx (12 months for toxo ppx)
Routine use reduces or eliminates the incidence of Pneumocystis jirovecii, Listeria monocytogenes, Nocardia asteroids, and Toxoplasma gondii and TMP-SMX is also effective as UTI prophylaxis
Monthly IV or aerosolized pentamidine, dapsone* or atovaquone
Replace TMP-SMX as PJP prophylaxis for patients with sulfa allergies or if treatment complications such as hyperkalemia or leukopenia arise
*pentamidine and dapsone are not sufficient for toxo ppx
Nystatin 100,000 units/mL, 4mL after meals and before bedtime OR Fluconazole 200mg one tablet daily generally 3 months after transplant
For fungal prophylaxis
**closely monitor cyclosporine and tacrolimus levels when starting and stopping antifungals (azoles)
Valganciclovir for 4-6 months after transplant
For CMV prophylaxis (also prevents HSV)
*Acyclovir for 3 months for HSV ppx in CMV recipient negative/donor negative individuals
Letermovir
An alternative for CMV prophylaxis in patients with significant myelosuppression
*would need HSV ppx with acyclovir
Background
Infections in a kidney transplant recipient can be divided into 3 phases
<1-month post-transplant
Surgical site infections, nosocomial infections (e.g. C. Diff, CAUTIs, and CLABSIs), and donor-derived infections/reactivation of latent recipient infections predominate
1-6 months post-transplant
Depleted immune-system regenerates increased risk for disseminated fungal (e.g. PJP, histo/blasto) and viral infections (HSV, adenovirus)
>6 months post-transplant
Risk for atypical infections persists, but common community acquired syndromes should still be on the differential
This section will focus on the most common infection in kidney transplant recipients- infections of the urinary tract
Evaluation
UA with culture
Examine the native kidneys (CVA tenderness) AND the allograft (almost always in RLQ, denervated so the graft itself will not be tender, but the surrounding soft-tissue may)
Renal U/S (of both allograft and native kidneys) or CT AP if
Early post-op (1 month)
Recurrent (2+ episodes in year)
History of nephrolithiasis or if sepsis/bacteremia
Blood cultures if systemic signs/symptoms
Consider testing for C. urealyticum, and sending fungal and AFB urine cultures if UA is recurrently positive but culture negative. Differential includes BK and adenovirus if hemorrhagic cystitis (test urine PCR)
Asymptomatic bacteriuria: treat with fluoroquinolone or beta lactam for 5-7 days if <3 mo post-transplant
Simple cystitis: Fluoroquinolones (ciprofloxacin 250 BID or Levaquin 500 mg daily), Augmentin (500 mg BID), 3rd gen cephalosporin (cefpodoxime 100 mg BID or cefixime 400 mg daily) or nitrofurantoin 100 mg BID (if GFR>30, only treats cystitis since drug only concentrates in the urine)
< 6 mos post-transplant: treat for 10-14 days
>6 mos post-transplant: treat for 5-7 days
Complicated UTI/Pyelonephritis (cover Pseudomonas, gram negatives and Enterococcus): Ceftriaxone 2g daily (preferred), Cefepime 2g q8hrs (add Vancomycin when using cephalosporin if suspicious for enterococcus) or Pip-tazo 3.75g q6hrs, can also use meropenem 1g q8h (need ID approval)
Treat for 14-21 days
For stable pts with mild complicated UTI, can consider giving more narrow empiric antibiotics: Augmentin 875 mg BID or ciprofloxacin 500 mg q12h
In pts with PCKD, include lipophilic antibiotic (such as ciprofloxacin) to penetrate cysts
Viral Infections
CMV
Most common opportunistic viral infection, typically in the first 6 months post-transplant
CMV infection can lead to acute rejection and graft failure
May manifest as a nonspecific febrile syndrome, gastrointestinal symptoms, or tissue-invasive infection, which may not cause CMV viremia but requires histologic diagnosis
In patients with active disease, weekly monitoring of CMV PCR, CBC and kidney function recommended
For severe disease treat with IV ganciclovir vs oral valganciclovir for mild or moderate disease
Ganciclovir and valganciclovir are renally dosed
Alternative treatments: IV Foscarnet (if resistant to ganciclovir) or maribavir in patients with severe leukopenia or ganciclovir-resistant
Check a resistance panel if CMV viral load not improving after first 2-3 weeks of treatment
BK Virus
Disease manifestations include BKV-associated nephropathy (BKVAN), ureteric stenosis, and hemorrhagic cystitis
Monitored by checking serum BK DNA PCR. BK nephropathy diagnosed by renal biopsy
Managed by reducing immunosuppression
EBV and post-transplant lymphoproliferative disease (PTLD)
Manifestations can include lymphadenopathy, fever, weight loss, and organ-specific symptoms such as gastrointestinal disturbances or respiratory issues
Key risk factors include EBV seronegativity at the time of transplantation, primary EBV infection post-transplant, and the overall level of immunosuppression
Monitoring EBV DNA levels may be used for early detection
Fungal Infections
Candida species infections account for up to 70% of fungal infections in kidney transplant recipients
Aspergillus
Cryptococcus
Pneumocystis jiroveci
Histoplasmosis, blastomycosis, and coccidioidomycosis
Acute Kidney Injury of Kidney Transplant
Background
Most patients admitted to medicine services with kidney transplants are >3 months post-op. Therefore, we are typically not managing perioperative complications such as delayed graft function, or hyper-acute rejection. Below are the most common causes of acute kidney injury in kidney transplant recipients
Evaluation
Signs and symptoms of UTI?
Assess volume status
Review meds for recent medication changes
Common offenders: NSAIDs, ACEi, diuretics, azole antifungals
Medication non-adherence
Tacrolimus (FK) or cyclosporine (CsA) level
FK levels increase with n/v, diarrhea due to alterations in p-glycoprotein expression within inflamed GI tract
FK toxicity also causes diarrhea and volume depletion
Proteinuria
Transplant patients with 1 g/day proteinuria usually get biopsies
BK PCR: consider only if unclear source of AKI and no recent titers
Serum PCR is test of choice
Renal transplant U/S (costly and not always warranted)
< 1 week post-transplant: If acute graft dysfunction, look for thrombosis, urine/ureter leak
> 1 week post-transplant
Cr does not respond to 48 hours of current management
Lack of clear, reversible causes
Hydronephrosis (can occur after stent removal 4-6 wks after transplant or due to perinephric fluid collection)
Arterial stenosis (↑ velocities in renal artery -- very concerning when velocity >300), tardus parvus waveforms)
Perinephric abscess with recurrent UTI/pyelonephritis
Urinoma (usually first 2-3 weeks), hematoma (after a biopsy)
Unique findings
Resistive indices: Reflect central renal vascular compliance. High indices in transplant patients signify parenchymal problem (rejection, infection, ATN)
Biopsy
To differentiate ATN vs. rejection vs. BK nephropathy vs. recurrent disease (FSGS, lupus, etc.)
Post biopsy care
Watch for bleeding and HTN
Blood can get into collecting system, then the capsule, and into the perinephric space causing Page Kidney (aka Pressure Tamponade)
Compressed renal vessels RAAS surge rapid, severe HTN (STAT page the renal fellow)
Kidney Transplant Rejection
Background
Rejection is divided into acute vs. chronic and T-cell mediated or antibody mediated
Pathologists can determine the type of rejection and the chronicity by observing the structures that are acutely involved (e.g. tubulitis, glomerulitis, arteritis, and capillaritis) as well as the time course of involvement (e.g. presence of fibrosis)
Structures exhibiting fibrosis represent chronic rejection that is unlikely to respond to treatment, whereas acute inflammation may be amenable to acute therapies
This section will focus on acute rejection since this is the clinical entity we will most likely manage while on the wards
Acute Rejection
Acute T cell mediated rejection
Infiltration of the graft by lymphocytes and inflammatory cells characterized by tubulitis, interstitial inflammation, and arteritis (on occasion)
Treatment
High dose glucocorticoids (methyl prednisolone) is first line (~ 5 days)
Thymoglobulin (polyclonal Ig anti-T cell)
Use depends on severity of rejection
Indicated if Cr fails to improve after steroids
T cell subsets are measured during treatment until depleted
Tacro target levels are reset to ~8-10 if treated for acute T cell mediated rejection
Acute antibody mediated rejection (ABMR)
Donor specific antibody mediated rejection characterized by glomerulitis, peri-tubular capillaritis (microcirculation inflammation), complement deposition (C4d staining), and presence of DSA
Treatment = B-cell depletion therapy
IV methyl prednisone 500 mg IV x 3-5 days
Plasmapheresis (If with high titers of DSA)
IVIG 2 g/kg (max 140 g)
Rituximab 375 mg/m2
Kidney Transplant Immunosuppression
Background
Induction therapy, which is administered at the time of transplantation, includes biologic agents such as rabbit anti-thymocyte globulin, anti-CD52 antibody alemtuzumab, or the anti-CD25 monoclonal antibody basiliximab, to provide an initial high level of immunosuppression
Maintenance therapy is continued long term and often involves triple therapy with an anti-metabolite (azathioprine or mycophenolate compound) or mTOR inhibitor + calcineurin inhibitor + corticosteroids
You may also come across patients who are on monthly infusions with belatacept, a selective T-cell co-stimulation blocker
Belatacept is only for use in patients who are EBV seropositive due to increased risk of post-transplant lymphoproliferative disorder (PTLD) in EBV seronegative patients
Calcineurin Inhibitors
Tacrolimus (FK), cyclosporine (CsA)
Envarsus XR is a once a day long acting formulation of tacrolimus
Common side effects:
Nephrotoxicity: mediated by vasoconstriction to the afferent arterioles and interstitial fibrosis
Hypertension- treat with CCBs
Diabetes
Neurotoxicity: Hand tremors, headache, seizures, PRES
Diarrhea, nausea
Thrombotic microangiopathy
T4 RTA- hyperkalemia
Gingival hyperplasia (more associated with cyclosporine)
MTOR Inhibitors
Sirolimus, Everolimus
Major side effects: poor wound healing, rarely pneumonitis, dyslipidemia, bone marrow suppression, proteinuria
Reduced incidence of nephrotoxicity, lower incidence of certain viral infections and malignancies, and decreased alloantibody production (useful in patients at risk for antibody mediated rejection) relative to CNI’s, though there are higher rates of delayed graft function, acute rejection and proteinuria
Increases nephrotoxicity when given with standard doses of CNIs so target trough levels are adjusted when patients are on both meds
Side effects: bone marrow suppression (hold if lymphopenia), GI upset (hold if diarrhea)
Mycophonolate generally preferred for superior efficacy in preventing acute rejection and improving graft survival, but azathioprine may be considered in specific patient scenarios (pregnancy, G intolerance/IBD, high cost of medications)
Additional Information for Overnight Admits
Do not change immunosuppression unless discussed with fellow
When to consider holding medications: known CMV infection or COVID infection w/ hypoxia (hold mycophenolate); if pt has multiple signs of CNI toxicity (AKI, severe diarrhea, and tremors/neurotoxicity)
If holding mycophenolate/anti-metabolite, prednisone is increased to 10 mg daily
Daily tacrolimus or cyclosporine level (order qam at 0500). Always order tacrolimus or cyclosporine dose at 6:00 am and 6:00 pm (regardless of what time patient takes at home, lab can only run am tacro levels at a certain time in batches) *check an everolimus or sirolimus AM level if patient takes an MTOR inhibitor
Transplant patients with normal kidney function can have regular diet
Renal transplant is consulted on every post-transplant patient admitted to the hospital
