Carfilzomib-associated thrombotic microangiopathy: clinical features and outcomes.

BACKGROUND AND HYPOTHESIS: Carfilzomib, a new proteasome inhibitor indicated for patients with relapsed/refractory myeloma, has been associated with cases of thrombotic microangiopathy (CFZ-TMA). The role of variants in the complement alternative pathway and therapeutic potential of complement blockade with eculizumab remain to be determined. METHODS: We report 37 cases of CFZ-TMA recorded in the French reference center for TMA with their clinical characteristics, genetic analysis and outcome according to treatments. RESULTS: A trigger was identified in more than half of cases, including 8 influenza and 5 SARS-CoV-2 cases. All patients presented with acute kidney injury (AKI) (KDIGO stage 3 in 31 (84%) patients) while neurological (n=13, 36%) and cardiac damage (n=7, 19%) were less frequent. ADAMTS13 and complement activity were normal (n= 28 and 18 patients tested) and no pathogenic variant in the alternative complement pathway was found in 7 patients tested.TMA resolved in most (n=34, 94%) patients but 12 (44%) still displayed stage 3 AKI at discharge. Nineteen (51%) patients were treated with therapeutic plasma exchange, 14 (38%) patients received corticosteroids and 18 (50%) were treated with eculizumab. However none of these treatments demonstrated a significant impact on outcomes. CONCLUSION: This study is the largest case series of CFZ-TMA since its approval in 2012. Patients present with severe AKI and experience frequent sequelae. Complement variants and blockade therapy do not seem to play a role in the pathophysiology and prognosis of the disease.

Additional Benefits of Rituximab and Plasma Exchange on Top of Standard Induction Therapy in Kidney Transplant Recipients With a Negative CDC Crossmatch but High Preformed Donor Specific Antibody Titer.

Optimal induction strategy in highly sensitized kidney transplant recipients (KTRs) is still a matter of debate. The place of therapies, such as plasma exchange and rituximab, with potential side effects and high cost, is not clearly established. We compared two induction strategies with (intensive) or without (standard) rituximab and plasma exchange in KTRs with high levels of preformed DSA transplanted between 2012 and 2019. Sixty KTRs with a mean age of 52.2 ± 12.2 years were included, 36 receiving standard and 24 intensive induction. Mean fluorescence intensity of immunodominant DSA in the cohort was 8,903 ± 5,469 pre-transplantation and similar in both groups. DSA level decrease was similar at 3 and 12 months after transplantation in the two groups. An intensive induction strategy was not associated with better graft or patient survival, nor more infectious complications. The proportion of patients with rejection during the first year was similar (33% in each group), but rejection occurred later in the intensive group (211 ± 188 days, vs. 79 ± 158 days in the standard group, p < 0.01). Our study suggests that an intensive induction therapy including rituximab and plasma exchanges in highly sensitized kidney recipients is not associated with better graft survival but may delay biopsy-proven rejection.

Management of severe renal disease in anti-neutrophil-cytoplasmic-antibody-associated vasculitis: the place of rituximab and plasma exchange?

OBJECTIVE: The optimal induction therapy for severe glomerulonephritis of ANCA-associated vasculitis (AAV) is debated. We compared the efficacy of glucocorticoid and rituximab (RTX) or CYC induction therapy for severe AAV-related glomerulonephritis and evaluated the potential benefit of plasma exchange (PE) as adjunct therapy to CYC. METHODS: This retrospective, multicentre study included AAV patients with severe renal active disease (serum creatinine level ≥350 µmol/l and/or estimated glomerular filtration ratio ≤15 ml/min/1.73 m2). Propensity-score analysis was used to adjust for potential confounders. RESULTS: Between 2005 and 2017, 153 patients with AAV-related glomerulonephritis were studied (96 [60%] men; mean [s.d.] age 63 [13.1] years): 19 (12%) were treated with RTX and 134 (88%) with CYC. Remission rates did not differ between RTX- and CYC-treated groups. Although more patients with RTX than CYC were dialysis-free at month (M) 12 (79% vs 68%), the difference was not significant after adjustment. Among 134 patients with CYC-treated glomerulonephritis, 76 (57%) also had PE. M3 and M6 remission rates were comparable for weighted CYC groups with or without PE. For weighted groups, the dialysis-free survival rate with CYC was higher with than without PE at M6 (72% vs 64%; odds ratio 2.58) and M12 (74% vs 60%; odds ratio 2.78) reaching statistical significance at M12. CONCLUSION: We could not find any difference between RTX and CYC as induction therapy for patients with severe AAV-related glomerulonephritis. In patients receiving CYC induction regimen, the addition of PE conferred short-term benefits with higher dialysis-free rate at M12.

Kidney Histopathology Can Predict Kidney Function in ANCA-Associated Vasculitides with Acute Kidney Injury Treated with Plasma Exchanges.

BACKGROUND: Data from the PEXIVAS trial challenged the role of plasma exchange (PLEX) in ANCA-associated vasculitides (AAV). We aimed to describe kidney biopsy from patients with AAV treated with PLEX, evaluate whether histopathologic findings could predict kidney function, and identify which patients would most benefit from PLEX. METHODS: We performed a multicenter, retrospective study on 188 patients with AAV and AKI treated with PLEX and 237 not treated with PLEX. The primary outcome was mortality or KRT at 12 months (M12). RESULTS: No significant benefit of PLEX for the primary outcome was found. To identify patients benefitting from PLEX, we developed a model predicting the average treatment effect of PLEX for an individual depending on covariables. Using the prediction model, 223 patients had a better predicted outcome with PLEX than without PLEX, and 177 of them had >5% increased predicted probability with PLEX compared with without PLEX of being alive and free from KRT at M12, which defined the PLEX-recommended group. Risk difference for death or KRT at M12 was significantly lower with PLEX in the PLEX-recommended group (-15.9%; 95% CI, -29.4 to -2.5) compared with the PLEX not recommended group (-4.8%; 95% CI, 14.9 to 5.3). Microscopic polyangiitis, MPO-ANCA, higher serum creatinine, crescentic and sclerotic classes, and higher Brix score were more frequent in the PLEX-recommended group. An easy to use score identified patients who would benefit from PLEX. The average treatment effect of PLEX for those with recommended treatment corresponded to an absolute risk reduction for death or KRT at M12 of 24.6%. CONCLUSIONS: PLEX was not associated with a better primary outcome in the whole study population, but we identified a subset of patients who could benefit from PLEX. However, these findings must be validated before utilized in clinical decision making.

IgA vasculitis in patients with inflammatory bowel disease: new insights into the role of TNF-α blockers.

OBJECTIVE: The association of IgA vasculitis (IgAV) and IBD is rarely described, mainly during anti-TNF-α therapy. We aimed to describe the association of IgAV and IBD. METHODS: We retrospectively analysed the association of IgAV and IBD through the implication of the GETAID and FVSG networks. Characteristics of IBD and IgAV were collected using a standardized case report form. RESULTS: Forty-three cases were included. IBD [mainly Crohn's disease (CD) in 58%] preceded IgAV in 38 (88%), with median interval of 9.2 (IQR 5.4-15.4) years. In these 38 patients, at IgAV diagnosis, five (13%) had active IBD and 28 (74%) were treated with anti-TNF-α for a median duration of 31.5 (IQR 19-56) months. Main IgAV manifestations were purpura all patients (100%), joints in 20/35 (57%), renal in 15/35 (43%) and gastrointestinal in 11/35 (31%) involvement. IgAV was treated with glucocorticoids in 25 (66%), colchicine in six (16%), CYC in six (16%) and anti-TNF-α were discontinued in 15/28 (54%). No IgAV relapse occurred when TNF-α blockers were stopped, vs 23% in patients pursuing it. Conversely, five (33%) had IBD flare or complication after anti-TNF-α cessation vs one (8%) in those continuing biologics. Anti-TNF-α were resumed in six (40%), with subsequent IgAV relapse in four (67%). CONCLUSIONS: This large cohort suggests that TNF-α blockers may promote the onset of IgAV in IBD. Discontinuation of anti-TNF-α was associated with vasculitis remission but increased risk of IBD relapses, whereas continuation of anti-TNF-α was associated with IBD remission but vasculitis relapse.

Renal diseases secondary to interferon-ß treatment: a multicentre clinico-pathological study and systematic literature review.

Background: The spectrum of interferon-ß (IFN-ß)-associated nephropathy remains poorly described and the potential features of this uncommon association remain to be determined. Methods: In this study we retrospectively analysed the clinical, laboratory, histological and therapeutic data of patients with biopsy-proven renal disease in a context of IFN-ß treatment administered for at least 6 months. Results: Eighteen patients (13 women, median age 48 years) with biopsy-proven renal disease occurring during IFN-ß therapy were included. The median exposure to IFN-ß (14 patients were treated with IFN-ß1a and 4 patients with IFN-ß1b) was 67 months (range 23-165 months). The clinical presentation consists in hypertension (HT; 83%), malignant HT (44%), proteinuria (protU) >1 g/g (94%), reduced renal function (78%), biological hallmark suggesting thrombotic microangiopathy (TMA; 61%), oedematous syndrome (17%) or nephritic syndrome (11%). The pathological findings included typical features of isolated TMAs in 11 cases, isolated focal segmental glomerulosclerosis (FSGS) lesions in 2 cases and 5 cases with concomitant TMA and FSGS lesions. An exploration of the alternative complement pathway performed in 10 cases (63%) did not identify mutations in genes that regulate the complement system. The statistical analysis highlighted that the occurrence of IFN-ß-associated TMA was significantly associated with Rebif, with a weekly dose >50 µg and with multiple weekly injections. In all cases, IFN-ß therapy was discontinued. Patients with TMA lesions received other therapies, including corticosteroids (44%), eculizumab (13%) and plasma exchanges (25%). At the end of a 36-month median follow-up, persistent HT and persistent protU were observed in 61% and 22% of patients, respectively. Estimated glomerular filtration rate <60 mL/min/1.73 m2 was present in 61% of patients. Conclusions: IFN-ß-associated nephropathy must be sought in the case of HT and/or protU onset during treatment. When TMA and/or FSGS are observed on renal biopsy, early discontinuation of IFN-ß is essential.

[Acute renal failure and cancer treatment]. / Insuffisance rénale aiguë et traitement du cancer.

"Acute renal failure and cancer treatment The interplay between cancer and acute kidney injury is intricate. Cancer, as much as therapies developed against it, may be responsible for acute kidney injury. Tumor lysis syndrome stems from the synergetic effects of anti-tumoral therapies in combination with the specific characteristics of the underlying tumor. Intra-tubular methotrexate precipitation is characterized by extra-renal clinical manifestations due to delayed renal drug clearance: prophylactic therapy based on optimized hydration and avoidance of nephrotoxic drugs represent the cornerstone of its management whereas rescue therapy relies on folinic acid substitution and enzyme-based therapy. Thrombotic microangiopathy is likely to result either from the cancer per se or treatments targeting the cancer. Gemcitabine stands as one the drug well acknowledged for eliciting thrombotic microngioapathy with potentially devastating consequences so that eculizumab has been contemplated as a possible therapy, on a case to case basis. Finally, it should be kept in mind that acute kidney injury in the setting of cancer represents a severe complication in the course of the disease."

"insuffisance rénale aiguë et traitement du cancer La relation entre cancer et insuffisance rénale aiguë est complexe et intriquée. Les cancers autant que leur traitement sont susceptibles d'induire une insuffisance aiguë. Le syndrome de lyse tumorale procède d'un effet synergique des effets antitumoraux des thérapeutiques antinéoplasiques et des propriétés propres aux tumeurs. La précipitation intratubulaire de méthotrexate se complique d'atteintes extrarénales sévères par retard d'élimination de la molécule  : l'optimisation de l'hydratation et l'éviction des médications à risque constituent la base de la prévention de cette toxicité dont le traitement repose sur la supplémentation en acide folinique et souvent un traitement enzymatique. Le syndrome de microangiopathie thrombotique peut résulter aussi bien du cancer que des traitements dirigés contre celui-ci, notamment la gemcitabine. Compte tenu du pronostic rénal défavorable de cette dernière, il a été récemment proposé d'initier, au cas par cas, un traitement par éculizumab dans ces formes de microangiopathie thrombotique, par extrapolation des données acquises dans le syndrome hémolytique urémique complément dépendant. Enfin, il est important de rappeler que la survenue d'une insuffisance rénale aiguë constitue toujours un événement grave dans l'histoire du patient atteint de cancer."

Retinal Arteriolar Occlusions and Exudative Retinal Detachments in Malignant Hypertension: More Than Meets the Eye.

BACKGROUND: Malignant hypertension is macrovascular and microvascular endothelial injury responsible for multiple organ damage. Considering the anatomical and functional homologies between the posterior pole of the eye and the kidney, ophthalmological explorations may inform clinicians on the mechanisms underpinning concurrent kidney injury in this condition. More specifically, we investigated whether the wall-to-lumen ratio (WLR) of retinal arterioles measured by adaptive optics ophthalmoscopy could be correlated to WLR of kidney arterioles as determined by pathology. We sought to estimate the incidence of retinal arteriole occlusion a supposedly uncommon complication of malignant hypertension. METHODS: All patients hospitalized in our renal Intensive Care Unit for malignant hypertension between 2016 and 2019 were referred to ophthalmological examinations. RESULTS: Twenty-seven patients were included. Median retinal WLR was 0.39 [0.31-0.47] and was correlated with initial systolic (r = 0.56, P = 0.003) and mean blood pressure (r = 0.46, P = 0.02) upon admission. The retinal WLR was not correlated to renal pathological findings, as assessed by juxtaglomerular WLR (r = 0.38, P = 0.2), ratio of glomerulosclerosis (r = -0.39, P = 0.2), or tubulointerstitial fibrosis (r = -0.45, P = 0.08). Retinal WLR was not associated with neurological or cardiovascular end-organ damage. Branch retinal artery occlusion was detected in 18.5% of patients and exudative retinal detachment (ERD) in 29.6% of patients, without any significant correlation with canonical signs of retinal hypertension including optic disc swelling. CONCLUSIONS: In the setting of malignant hypertension, we failed to demonstrate a significant relationship between WLR and other meaningful end-organ injuries. However, branch retinal artery occlusion and ERD may have been hitherto underestimated.

Renal involvement in eosinophilic granulomatosis with polyangiitis (EGPA): a multicentric retrospective study of 63 biopsy-proven cases.

OBJECTIVE: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic small-vessel vasculitis characterized by asthma, hypereosinophilia and ANCA positivity in 40% of patients. Renal involvement is rare and poorly described, leading to this renal biopsy-proven based study in a large EGPA cohort. METHODS: We conducted a retrospective multicentre study including patients fulfilling the 1990 ACR criteria and/or the 2012 revised Chapel Hill Consensus Conference criteria for EGPA and/or the modified criteria of the MIRRA trial, with biopsy-proven nephropathy. RESULTS: Sixty-three patients [27 women, median age 60 years (18-83)] were included. Renal disease was present at vasculitis diagnosis in 54 patients (86%). ANCA were positive in 53 cases (84%) with anti-MPO specificity in 44 (83%). All patients had late-onset asthma. Peripheral neuropathy was present in 29 cases (46%), alveolar haemorrhage in 10 (16%). The most common renal presentation was acute renal failure (75%). Renal biopsy revealed pauci-immune necrotizing GN in 49 cases (78%). Membranous nephropathy (10%) and membranoproliferative GN (3%) were mostly observed in ANCA-negative patients. Pure acute interstitial nephritis was found in six cases (10%); important interstitial inflammation was observed in 28 (44%). All patients received steroids with adjunctive immunosuppression in 54 cases (86%). After a median follow-up of 51 months (1-296), 58 patients (92%) were alive, nine (14%) were on chronic dialysis and two (3%) had undergone kidney transplantation. CONCLUSION: Necrotizing pauci-immune GN is the most common renal presentation in ANCA-positive EGPA. ANCA-negative patients had frequent atypical renal presentation with other glomerulopathies such as membranous nephropathy. An important eosinophilic interstitial infiltration was observed in almost 50% of cases.

Malaria, Collapsing Glomerulopathy, and Focal and Segmental Glomerulosclerosis.

BACKGROUND AND OBJECTIVES: Malaria, a potentially life-threatening disease, is the most prevalent endemic infectious disease worldwide. In the modern era, the spectrum of glomerular involvement observed in patients after malarial infections remains poorly described. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We therefore performed a retrospective multicenter study to assess the clinical, biologic, pathologic, and therapeutic characteristics of patients with glomerular disease demonstrated by kidney biopsy in France within 3 months of an acute malaria episode. RESULTS: We identified 23 patients (12 men), all but 1 of African ancestry and including 10 patients with concomitant HIV infection. All of the imported cases were in French citizens living in France who had recently traveled back to France from an endemic area and developed malaria after their return to France. Eleven patients had to be admitted to an intensive care unit at presentation. Plasmodium falciparum was detected in 22 patients, and Plasmodium malariae was detected in 1 patient. Kidney biopsy was performed after the successful treatment of malaria, a mean of 24 days after initial presentation. At this time, all patients displayed AKI, requiring KRT in 12 patients. Nephrotic syndrome was diagnosed in 17 patients. Pathologic findings included FSGS in 21 patients and minimal change nephrotic syndrome in 2 patients. Among patients with FSGS, 18 had collapsing glomerulopathy (including 9 patients with HIV-associated nephropathy). In four patients, immunohistochemistry with an antibody targeting P. falciparum histidine-rich protein-2 demonstrated the presence of the malaria antigen in tubular cells but not in podocytes or parietal epithelial cells. An analysis of the apoL1 risk genotype showed that high-risk variants were present in all seven patients tested. After a mean follow-up of 23 months, eight patients required KRT (kidney transplantation in two patients), and mean eGFR for the other patients was 51 ml/min per 1.73 m2. CONCLUSIONS: In patients of African ancestry, imported Plasmodium infection may be a new causal factor for secondary FSGS, particularly for collapsing glomerulopathy variants in an APOL1 high-risk variant background.

Epidemiology, clinical features, and management of severe hypercalcemia in critically ill patients.

BACKGROUND: Severe hypercalcemia (HCM) is a common reason for admission in intensive-care unit (ICU). This case series aims to describe the clinical and biological features, etiologies, treatments, and outcome associated with severe HCM. This study included all patients with a total calcemia above 12 mg/dL (3 mmol/L) admitted in two ICUs from January 2007 to February 2017. RESULTS: 131 patients with HCM were included. HCM was related to hematologic malignancy in 58 (44.3%), solid tumors in 29 (22.1%), endocrinopathies in 16 (12.2%), and other causes in 28 (21.3%) patients. 108 (82.4%) patients fulfilled acute kidney injury (AKI) criteria. Among them, 25 (19%) patients required renal replacement therapy (RRT). 51 (38.9%) patients presented with neurological symptoms, 73 (55.7%) patients had cardiovascular manifestations, and 50 (38.1%) patients had digestive manifestations. The use of bisphosphonates (HR, 0.42; 95% CI, 0.27-0.67; P < 0.001) was the only treatment significantly associated with a decrease of total calcemia below 12 mg/dL (3 mmol/L) at day 5. ICU and Hospital mortality rates were, respectively, 9.9% and 21.3%. Simplified Acute Physiologic Score (SAPS II) (OR, 1.05; 95% CI 1.01-1.1; P = 0.03) and an underlying solid tumor (OR, 13.83; 95% CI 2.24-141.25; P = 0.01) were two independent factors associated with hospital mortality in multivariate analysis. CONCLUSIONS: HCM is associated with high mortality rates, mainly due to underlying malignancies. The course of HCM may be complicated by organ failures which are most of the time reversible with early ICU management. Early ICU admission and prompt HCM management are crucial, especially in patients with an underlying solid tumor presenting with neurological symptoms.

LDL-apheresis to decrease sFlt-1 during early severe preeclampsia: Report of two cases from a discontinued phase II trial.

OBJECTIVE: Severe preeclampsia may require the delivery of the placenta to avoid life-threatening complications for the mother. Before 26 weeks of gestation, this often results in perinatal death. A decrease in soluble fms-like tyrosine kinase 1 (sFlt1), an anti-angiogenic factor central to the pathophysiology of the maternal syndrome, has been reported after LDL- apheresis. The present study tested whether LDL-apheresis could be used to allow women with early and severe preeclampsia to reach a gestational age where the baby had a viable chance of survival. STUDY DESIGN: A phase II prospective study. Adult women were included if they had very early (<26 weeks of gestation) preeclampsia without severe (<5th percentile) intra-uterine growth retardation. Treatment consisted of two weekly sessions (90 min each) of LDL-apheresis of whole blood. The primary endpoint was the status of the baby (dead or living) at 6 months post-delivery. Sample size and stopping rules were calculated assuming a desired success rate of at least 90%. RESULTS: The study was interrupted for safety reasons after the inclusion of two patients: both developed secondary uncontrolled hypertension and blurred vision during the first week of treatment. The first neonate, born at 25 + 3 weeks of gestation, died of sepsis at day 5; the second, born at 26 + 2 weeks of gestation, is still alive and well. In these two patients, the impact of apheresis sessions on sFlt1 concentrations was inconsistent. CONCLUSION: LDL-apheresis did not result in the prolongation of pregnancy in this phase II trial. Further studies will be needed to delineate the appropriate contours of this therapeutic strategy.

Peritoneal implantation of pheochromocytoma following tumor capsule rupture during surgery.

CONTEXT: Patients with pheochromocytoma (PH) or paraganglioma (PGL) may suffer from tumor persistence or recurrence after resection of the primary tumor. Malignancy and genetic determinants account for the vast majority of these cases, but tumor recurrence or persistence may also arise from tumor spillage during primary resection, followed by peritoneal implantation. We report here five such cases. MATERIALS AND METHODS: Thirty-nine of the 181 patients referred to our unit for a PH experienced tumor persistence or recurrence as a result of malignant disease (n = 12), new PGL in a context of genetic determinants (n = 18) or incomplete primary surgical resection (n = 4). Another five patients presenting with adrenal PH could not be categorized into these three groups. RESULTS AND DISCUSSION: All five patients (age range 45-63 years) presented evidence of tumor capsule rupture documented upon macroscopic examination or in the surgical report. Initial diagnostic examinations provided no evidence of malignancy. All had a period of apparent remission, lasting from 24 to 106 months. The principal site of recurrence was invariably the peritoneum or the retroperitoneum. Two patients suffered solid organ metastasis, involving the liver (n = 2), bones (n = 1), and lung (n = 1). Therapeutic management involved a combination of (131)I-metaiodobenzylguanidine therapy and surgery. Two patients died due to tumor progression. One patient experienced tumor progression despite surgery. Two patients are currently in a satisfactory condition. CONCLUSION: Tumor rupture during surgical resection, with subsequent peritoneal and retroperitoneal dissemination, is a potentially lethal complication of primary pheochromocytoma resection. Even in cases of apparently benign disease, it may lead to peritoneal carcinomatosis and metastatic disease. Complete primary surgery is, therefore, crucial for a good prognosis in PH patients. Furthermore, in cases of tumor rupture, careful follow-up is mandatory, because recurrences may occur after long periods of apparent remission.

Sarcoidosis presenting as severe renin-dependent hypertension due to kidney vascular injury.

Renal sarcoidosis embraces a wide variety of clinical patterns. Renal vascular involvement has seldom been reported and usually in the setting of systemic vasculitis. We report the case of a 22-year-old patient in whom inaugural manifestation of renal sarcoidosis consisted of severe hypertension associated with bilateral perfusion defects and tumour-like nodules. In the setting of renal sarcoidosis, our case suggests that renin-dependant hypertension may arise from renal ischaemia as a result of extrinsic compression of kidney blood vessels due to severe granulomatous inflammation.

Bilirubin-associated acute tubular necrosis in a kidney transplant recipient.

Unlike hemoglobin or myoglobin, bilirubin, a breakdown product of the catabolism of heme molecules, usually is not seen as a nephrotoxic protein. We report the case of an adult kidney recipient who developed jaundice 4 years after transplantation because of a malignant cholangiocarcinoma. He progressively lost transplant function, accompanied by a continuous increase in bilirubinemia. Kidney biopsy showed bile granules in the cytoplasm of tubular epithelial cells and bile thrombi in dilated tubules, but no interstitial inflammation. The tumor was unresectable and the patient died 2 months later. Because the patient had no jaundice-associated confounding factor that could explain his kidney failure, such as sepsis, heart failure, or liver failure with hepatorenal syndrome, this exceptional case suggests that bilirubin per se should be seen as a potential cause of acute tubular necrosis.