Tacrolimus Associated Localized Thrombotic Microangiopathy Developing in Early Stage after Renal Transplantation

Abstract

Calcineurin inhibitor induced thrombotic microangiopathy is a rare but well recognized complication of a renal transplantation that occurs in 1% of the patients who are on tacrolimus immunosuppression. Among the other aetiological factors of the "de-novo" Thrombotic Microangiopathy (TMA), the condition especially has to be differentiated from an antibody mediated rejection, as both have different pathogenesis, therapeutic connotations and outcomes.We report a case of a middle aged female renal transplant recipient treated with tacrolimus, who developed localised thrombotic microangiopathy in the early post transplantation period. Despite the normal trough levels of tacrolimus, a diagnosis of "Tacrolimus induced TMA" was rendered after excluding other causes of the "de-novo" TMA, which included an antibody mediated rejection, a meticulous clinico-pathological correlation and serological studies. The treatment included the substitution of tacrolimus by rapamycin, with the subsequent normalization of the renal function. INTRODUCTIONPost renal transplant thrombotic microangiopathy (PT-TMA) is a "recurrent" or "denovo" ,"localized" or a "systemic" devastating disorder that, as per the USRDS data analysis, occurs with an incidence of 5-6 episodes per 1000 people years [1,2].Among the proposed aetiological factors, Calcineurin inhibitor induced TMA (CNI-TMA) is a rare but well documented cause of acute renal failure [3]. An early allograft biopsy with a prompt diagnosis of the condition, its distinction from an antibody mediated rejection and its management by drug substitution, plays a vital role in the allograft outcome.We report a case of localized tacrolimus associated TMA occurring in the early stage after renal transplantation. CASE REPORTA 52 year-old Caucasian female underwent a living, non-related, donor transplantation for ESRD. After an initial induction with basiliximab, the post transplant immunosuppression consisted of methylprednisolone (10 mg/day), mycophenolate mofetil (1g/ day) and tacrolimus (5 mg/day). A clinical improvement with good diuresis was achieved for 48 hours, following which the renal functions deteriorated, with a reduction in the urine output and peak serum creatinine levels of 3.8 mg/dl. The laboratory investigations (before dialysis) showed the following: haemoglobin -11.1 g/dl, platelets -1.64 lakhs/mm 3 , blood urea nitrogen -62 mg/dl, sodium -136 mEq/l, potassium -5.9 mEq/l, chloride -117 mEq/l, phosphate -4.9 mEq/l, uric acid -8.9 mg/dl, complement C3c-95mgm/dl, C4-25mgm/dl and lactate dehydrogenase -210 u/l. With a clinical suspicion of acute tubular necrosis/acute rejection, a renal biopsy was done, which revealed fibrin thrombi in the glomerular capillaries [Table/ Fig-1 A and B] and arterioles at the glomerular vascular pole with associated fibrinoid necrosis, in a focal and segmental fashion [Table/ Fig-2 A and B]. Some of the glomeruli exhibited tuft collapse and widening of the Bowman space. The proximal tubular epithelial cells showed isometric cytoplasmic vacuoliz...

Ehrlichiosis infection mimicking thrombotic microangiopathy syndrome early after kidney transplantation

“…Table 2 as calcineurin inhibitors that could also provoke TMA. 17 In addition, antibody-mediated rejection is within the differential diagnosis and could mimic TMA. 18 Ehrlichiosis is a rare infectious disease that could present with FUO or with 1-13 a wide spectrum of clinical presentations both in transplant recipients and in the general population.…”

“…The combination of TMA with fever and graft dysfunction suggests infection, with or without sepsis, or rejection. Clinical picture of TMA induced by human ehrlichiosis can pose significant diagnostic challenge in renal transplant recipients with the background of immunosuppressive medication use such as calcineurin inhibitors that could also provoke TMA 17 . In addition, antibody‐mediated rejection is within the differential diagnosis and could mimic TMA 18 .…”

Metastatic lung adenocarcinoma- associated thrombotic microangiopathy in a renal transplant recipient

“…A component of medication-related TMA cannot be excluded. TMA caused by calcineurin inhibitors occurs in 1% of patients after transplant and is typically restricted to the kidneys 16. This disease can mimic AMR and a biopsy is required to exclude this.…”

“…The mechanism of tacrolimus-related TMA is not fully understood, however, may be related to a dose-dependent inhibition of prostacyclin, leading to vasoconstriction 17 18. With elevated drug levels, some centres advocate for drug conversion and others alter dosing to aim for normal levels 16. Management is controversial in the presence of normal drug levels.…”

Cytopenias in Transplant Patients

“…Calcineurin inhibitor induced TMA often occurs within weeks following SOT, and the CIs are thought to cause direct endothelial injury and platelet aggregation, although the specific mechanism has not been identified. When this is identified, numerous case studies in multiple different organ systems (lung, liver, kidney solid organ transplant) have reported that changing from one CI to another (tacrolimus to cyclosporine or vice versa) or to another class of medication such as sirolimus or mycophenolate mofetil can prevent further episodes of TMA from occurring [61][62][63][64]. However, the addition of the mTOR inhibitor sirolimus to a calcineurin inhibitor also increases the chance of developing TMA [57,65].…”