Eculizumab in Acute Recurrence of Thrombotic Microangiopathy After Renal Transplantation

Renal thrombotic microangiopathy (TMA) is a severe complication of systemic lupus erythematosus (SLE), which is associated with the presence of antiphospholipid (aPL) antibodies. In its most fulminant form, TMA leads to a rapid and irreversible end‐stage renal failure. Eculizumab, an anti‐C5 monoclonal antibody, is a novel therapy of choice for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. Here, we report the case of a 27‐year‐old woman, known for SLE and end‐stage renal disease due to fulminant TMA. Both aPL antibodies and antinucleosome antibodies were positive. The patient underwent a living‐related kidney transplantation with immediate production of urine. Although serum creatinine was remaining high, a graft biopsy, performed on day 6, demonstrated a TMA recurrence. Despite a treatment with plasma exchange, the situation got worse and dialysis was started. Eculizumab treatment was subsequently administered and renal function improved rapidly. Three months after transplantation, serum creatinine was at 100 μmol/L, without proteinuria. This case illustrates the benefit of eculizumab therapy in a fulminant recurrence of TMA after kidney transplantation, resistant to classical therapy.     

Thrombotic Microangiopathy After Kidney Transplantation

Thrombotic microangiopathy (TMA) is a severe complication of kidney transplantation that often causes graft failure. TMA may occur de novo, often triggered by immunosuppressive drugs and acute antibody‐mediated rejection, or recur in patients with previous history of hemolytic uremic syndrome (HUS). Recurrent TMA is very rare in patients who had developed end‐stage renal failure following HUS caused by Shiga‐toxin producing E. scherichia coli, whereas disease recurrence is common in patients with atypical HUS (aHUS). The underlying genetic defect greatly impacts the risk of posttransplant recurrence in aHUS. Indeed recurrence is almost the rule in patients with mutations in genes encoding factor H or factor I, whereas patients with a mutation in membrane‐cofactor‐protein gene have a good transplant outcome. Prophylactic and therapeutic options for posttransplant TMA, including plasma therapy, combined kidney and liver transplantation and targeted complement inhibitors are discussed in this review.     

De novo Thrombotic Microangiopathy in Renal Allograft Biopsies—Role of Antibody‐Mediated Rejection

The most common cause of thrombotic microangiopathy (TMA) in renal allografts is thought to be calcineurin inhibitor toxicity. Antibody‐mediated rejection (AMR) can also cause TMA, but its true impact on de novo TMA is unknown. In a retrospective review of renal allograft biopsies from January 2003 to December 2008 at our institution, we determined the prevalence of TMA in patients with C4d positive (n = 243) and C4d negative (n = 715) biopsies. Over 90% of patients received cyclosporine in both groups. De novo TMA was seen in 59 (6.1%) patients; most of them (55%) with C4d positive biopsy. Among patients with C4d positive biopsies, 13.6% had TMA, as compared to only 3.6% patients with C4d negative biopsies (p < 0.0001). Incidence of graft loss between C4d positive and C4d negative TMA groups was not significantly different, but 70% of patients with C4d positive TMA who received plasmapheresis had slightly lower graft loss rate. In biopsies with AMR‐associated TMA, glomerulitis and peritubular capillaritis were significantly more prominent. AMR is the most common cause of TMA in renal allografts in our patient population. It is important to recognize AMR‐related TMA because plasmapheresis treatment may be beneficial.     

Calcineurin Inhibitor-Free Immunosuppression in Renal Allograft Recipients with Thrombotic Microangiopathy/Hemolytic Uremic Syndrome

Thrombotic microangiopathy (TMA) and hemolytic uremic syndrome (HUS) represent serious threats to kidney allograft recipients. During a 4-year period, among 850 kidney transplantations, seven recipients with primary HUS and seven recipients (eight transplants) with previous or de novo TMA/HUS were identified and given calcineurin inhibitor (CNI)-free immunosuppression by sirolimus (SRL), mycophenolate mofetil and steroids. Thirteen out of 15 transplantations were successful in the long term; resulting in a mean creatinine of 101 mumol/L (16.4 months follow-up). In patients maintained on CNI-free regimen, no TMA/HUS recurrences were observed. A high rate of acute rejections (53%) may indicate insufficient immunosuppressive power and/or a causative relationship between TMA/HUS and rejection. Wound-related complications were abundant (60%), and call for surgical/immunosuppressive countermeasures. Our experience supports the idea that CNI's are major offenders in TMA/HUS induction. Total CNI elimination seems essential, as the nephrotoxic combination CNI + SRL may promote TMA. Features of TMA/HUS should be carefully explored in recurrent 'high responders'.     

Belatacept as Maintenance Immunosuppression for Postrenal Transplant de novo Drug-Induced Thrombotic Microangiopathy

De novo posttransplant thrombotic microangiopathy (TMA) is a complication of solid organ transplantation, which remains difficult to treat. In many cases, immunosuppressants and particularly calcineurin inhibitors, trigger TMA. Although withdrawing the offending drug may lead to resolution of TMA, graft and patient outcomes are poor. Specific treatments, including plasma exchange, have not gained widespread acceptance in those with fulminant disease and new approaches to the condition are urgently needed.
We report a case of posttransplant de novo TMA presenting serially in association with ciclosporin, tacrolimus and sirolimus in a young recipient of a living donor kidney transplant. We describe a patient treated with belatacept, a novel CTLA4 Ig fusion protein, as ongoing maintenance immunosuppression to allow avoidance of conventional agents once associated with TMA. We report excellent early graft outcome, with no adverse events using this strategy. We suggest that belatacept may have a role in this traditionally difficult-to-treat group of patients.     

Complement Mutation-Associated De Novo Thrombotic Microangiopathy Following Kidney Transplantation

Mutations in one or more genes encoding complement-regulatory proteins predispose to atypical hemolytic uremic syndrome (aHUS) and its recurrence following kidney transplantation. We evaluated plasma complement level and performed a screening for mutations in genes encoding complement Factors H and I (CFH, CFI) and membrane cofactor protein (MCP) in 24 kidney transplant recipients experiencing de novo thrombotic microangiopathy (TMA). Six patients presented with low C3 and/or low Factor B levels suggestive complement alternative pathway. A mutation in the CFH or CFI gene was found in 7/24 patients (29%), two of whom had a mutation in both genes. On the contrary, no mutation was identified in a control kidney transplant patients group (n = 25) without TMA. Patients with or without mutations were similar with regard to clinical features. Eight out of 24 patients lost their graft within 1 year of posttransplantation including six patients with a CFH mutation or a decrease of C3 or CFB in plasma. To conclude, kidney transplant patients with de novo TMA exhibit an unexpectedly high frequency of CFH and CFI mutations. These results suggest that genetic abnormalities may represent risk factors for de novo TMA after kidney transplantation and raise the question of the best therapeutic strategy.     

Outcome of Plasma Exchange Therapy in Thrombotic Microangiopathy After Renal Transplantation

Thrombotic microangiopathy (TMA) in renal transplant recipients is commonly associated with calcineurin inhibitors (CNIs), though several factors such as vascular rejection, viral infections and other drugs may play a contributory role. We report a series of 29 patients with TMA, all of whom were on CNIs. Though plasma exchange (PEx) is widely used to treat TMA, therapeutic guidelines are not well defined. All our patients were treated with PEx and discontinuation of CNIs. Thrombotic microangiopathy was diagnosed at a median of 7 days post-transplant. The mean decrease in Hgb and platelets during TMA was 66% and 64%, respectively, and peak serum creatinine during TMA was 7.4 ± 2.9 mg%. Mean duration of PEx therapy was 8.5 (range 5–23) days. Recovery of platelet count to 150K/mcL and Hgb to 8–10 g/dL were used as endpoints for PEx. Twenty-three/29 (80%) patients recovered graft function after PEx. Twenty/23 (87%) patients who recovered were placed back on CNl. Nineteen/20 (95%) patients tolerated reinstitution of CNl without recurrence of TMA. In post-transplant TMA, PEx was associated with a graft salvage rate of 80%, reversal of hematological changes can be used as the endpoint for PEx therapy and CNl can be reintroduced without risk of recurrence in the majority of patients .     

Sirolimus-Induced Thrombotic Microangiopathy is Associated with Decreased Expression of Vascular Endothelial Growth Factor in Kidneys

The aim of this study was to examine the clinical characteristics, the histological features and the renal expression of vascular endothelial growth factor (VEGF) of five patients with sirolimus-associated thrombotic microangiopathy (TMA). Sirolimus-induced TMA occurs preferentially in kidneys with concomitant endothelial injury: it was observed in three patients with acute cellular rejection on calcineurin inhibitor-free regimen, in one patient with chronic graft rejection on a calcineurin inhibitor-free protocol and in one patient with chronic calcineurin inhibitor nephrotoxicity. We found that renal VEGF expression during sirolimus-induced TMA was significantly lower than VEGF expression in normal transplanted kidneys (p < 0.01). Decreased expression of VEGF seems to be a consequence of sirolimus treatment since (i) analysis of two biopsies performed after the switch of sirolimus to calcineurin inhibitor showed reappearance of VEGF expression, (ii) no decreased expression of VEGF was found in five kidneys with classical TMA and, (iii) an increased expression of VEGF was observed in seven kidneys with acute cellular rejection on a sirolimus-free immunosuppressive regimen (p < 0.01). The potential role of sirolimus-induced downregulation of VEGF as a predisposing factor to the development of TMA is discussed.     

Complement Factor H Deficiency in Acute Allograft Glomerulopathy and Post-Transplant Hemolytic Uremic Syndrome

Acute allograft glomerulopathy (AAG) is a distinct form of allograft rejection characterized by cytotoxic T-cell-mediated injury to the renal glomerular and arteriolar endothelium. Acute allograft glomerulopathy is characterized by mononuclear cell infiltration of glomerular capillary tufts in association with endothelial cell hypertrophy and injury. Intra-glomerular thrombi have been described in AAG, suggesting that overlapping features of AAG and post-transplant thrombotic microangiopathy (TMA) may coexist. We present a case suggesting that complement factor H deficiency, a known hereditary risk factor for TMA, may also favor development of AAG. We discuss the potential implications of factor H deficiency in the pathophysiology of renal allograft microvascular injury, leukocyte infiltration and formation of intraglomerular platelet thrombi. We propose that unopposed complement activation is a risk factor for both immune and nonimmune forms of microvascular injuries in renal allografts.     

Acute Kidney Injury Due to Acute Cortical Necrosis Following a Single Wasp Sting

Acute kidney injury (AKI) can develop after multiple wasp or bee stings. The etiology is the acute tubular necrosis secondary to shock, pigment toxicity, interstitial nephritis, or direct nephrotoxicity of venom. We report a 40-year-old female who presented with oliguric AKI after a single wasp sting on her hand. Her history, examination, and investigations did not support any of the established causes of AKI in such settings. She did not improve with supportive management and dialysis, and kidney biopsy showed acute cortical necrosis (ACN). This is the first report of ACN after a single wasp sting.     

Inflammation Lesions in Kidney Transplant Biopsies: Association with Survival Is Due to the Underlying Diseases

Assessment of kidney transplant biopsies relies on nonspecific inflammatory lesions: Interstitial infiltrates (i), tubulitis (t) and intimal arteritis (v). We studied the relationship between inflammation and prognosis in biopsies for clinical indications from 314 patients (median follow‐up 25 months). We used a modified Banff classification, separately assessing inflammation (i‐) in nonscarred (i‐Banff), scarred (i‐IFTA) and whole cortex (i‐total), plus tubulitis and intimal arteritis. In early biopsies (<1 year), i‐ and t‐lesions had no association with graft survival. In late (>1 year) biopsies, all i‐scores correlated with progression to failure, due to the association of these infiltrates with progressive diseases: antibody‐mediated rejection (ABMR) and glomerulonephritis. Tubulitis in nonscarred areas had no impact on survival. Severe tubulitis including scarred areas (tis3) was associated with worse survival, but reflected polyoma virus nephropathy or ABMR, not T‐cell‐mediated rejection. Intimal arteritis (v‐lesions) had no association with allograft loss in early or late biopsies. In multivariate analysis, outcome was better predicted by the presence of progressive disease than by inflammation. Thus inflammation in late kidney transplants has no inherent prognostic impact, but predicts reduced survival because inflammation indicates actively progressing diseases. The most important predictor of outcome is the diagnosis of a progressive disease.     

Complement Genes Strongly Predict Recurrence and Graft Outcome in Adult Renal Transplant Recipients with Atypical Hemolytic and Uremic Syndrome

Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor‐protein (MCP), C3 and factor B (CFB). At 5 years, death‐censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M‐TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence‐related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.     

Multicenter Clinicopathologic Correlation of Kidney Biopsies Performed in COVID-19 Patients Presenting With Acute Kidney Injury or Proteinuria

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