Although their efficacy has been well-established in Oncology, the use of platinum salts remains limited due to the occurrence of acute kidney injury (AKI). Caffeine has been suggested as a potential pathophysiological actor of platinum-salt-induced AKI, through its hemodynamic effects. This work aims to study the association between caffeine consumption and the risk of platinum-salt-induced AKI, based on both clinical and experimental data. The clinical study involved a single-center prospective cohort study including all consecutive thoracic cancer patients receiving a first-line platinum-salt (cisplatin or carboplatin) chemotherapy between January 2017 and December 2018. The association between daily caffeine consumption (assessed by a validated auto-questionnaire) and the risk of platinum-salt induced AKI or death was estimated by cause-specific Cox proportional hazards models adjusted for several known confounders. Cellular viability, relative renal NGAL expression and/or BUN levels were assessed in models of renal tubular cells and mice co-exposed to cisplatin and increasing doses of caffeine. Overall, 108 patients were included (mean age 61.7 years, 65% men, 80% tobacco users), among whom 34 (31.5%) experienced a platinum-salt-induced AKI (67% Grade 1) over a 6-month median follow-up. The group of high-caffeine consumption (≥386 mg/day) had a two-fold higher hazard of AKI (adjusted HR [95% CI], 2.19 [1.05; 4.57]), without any significant association with mortality. These results are consistent with experimental data confirming enhanced cisplatin-related nephrotoxicity in the presence of increasing doses of caffeine, in both in vitro and in vivo models. Overall, this study suggests a potentially deleterious effect of high doses of daily caffeine consumption on the risk of platinum-salt-related AKI, in both clinical and experimental settings.

Background Cancer-associated thrombotic microangiopathy (TMA) is a rare disease, with a poor prognosis. The classical treatment is urgent chemotherapy. Few data are available on the efficacy of plasma exchange (PE) and eculizumab in these patients. Methods Cases of cancer-related TMA treated between January 2008 and December 2019 in 12 French treatment centres were retrospectively analysed, excluding cases associated with chemotherapy and stem cell transplantation. Patients were divided into four groups depending on the treatment received: none, PE therapy alone, chemotherapy, with or without PE therapy, or eculizumab, with or without chemotherapy and PE therapy. Results The data of 59 patients with cancer-associated TMA were analysed. Twenty of these cases were related to a cancer recurrence. The cancer was metastatic in 90% of cases (53/59). Bone marrow invasion was observed in 20/41 biopsies. Some laboratory results, including disseminated intravascular coagulation high ferritin and C-reactive protein, were suggestive of cancer. None of the 16 patients whose alternative complement pathway was assessed had abnormal levels of protein expression or activity. The median survival time was 27 days. Chemotherapy was significantly associated with improved survival, with a 30-day survival rate of 85% (17/20) among patients who received PE and chemotherapy, versus 20% (3/15) among patients who received PE alone. Patients treated with eculizumab in addition to chemotherapy and PE therapy did not have longer overall survival or higher haematological remission rates than those treated with chemotherapy and PE therapy alone. Renal remission rates were non-significantly higher, and times to remission non-significantly shorter, in the eculizumab group. Conclusions Nephrologists and oncologists should make themselves aware of cancer diagnoses in patients with TMA and bone marrow biopsies should be performed systematically in these cases. All 59 patients had poor survival outcomes, but patients treated with urgent initiation of chemotherapy survived significantly longer than those who were not.

Hypercalcemia in pregnancy represents a challenge for the clinician. It is an uncommon condition with associated maternal and fetal complications. Diagnosing hypercalcemia is complex in pregnancy because symptoms are not specific and may mimic those in early pregnancy. Etiologic assessment and therapeutic management must also respect the fetal well-being.1 CYP24A1 loss of function leads to the overproduction of calcitriol, which can result in hypercalcemia. CYP24A1 screening should be considered in non-parathyroid hormone (PTH) hypercalcemia during pregnancy; particularly as pregnancy may exacerbate hypercalcemia in mutation carriers.

Abstract Background and Aims Thrombotic microangiopathy (TMA) are a heterogeneous group of diseases characterized by mechanical hemolytic anemia, peripheral thrombocytopenia, and organ failure of variable severity. In patients with cancer, TMAs are frequently induced by antineoplastic drugs but may be related to the malignant disease itself. Small series have reported poor prognosis. Only chemotherapy succeeded in lengthening life expectancy, even if few reports have described efficacy of therapeutic plasma exchange (TPE) or Eculizumab. Complement regulation was not studied in these publications, as the pathophysiology was rarely explored. In this study, we investigated retrospectively 59 cases of cancer-associated TMAs, to describe characteristics at diagnosis and efficacy of treatment. Method We conducted a retrospective multicentric observational study including all patients with a diagnosis of cancer-associated TMA, hospitalized in nephrological intensive care units (members of the French Intensive Care Network), between 2008 and 2019. We excluded patients receiving chemotherapy known to cause TMAs. We analyzed clinical and biological characteristics at diagnosis. We reported complement analysis when available. We defined four distinct treatment groups: No treatment (N), Plasmapheresis (P), Chemotherapy with or without chemotherapy (C+P), Eculizumab with or without Chemotherapy or Plasmapheresis (E+C+P). Renal remission and global survival were compared according to treatment group. Results We included 59 patients admitted to intensive care units for cancer-associated TMA. Twenty patients had a past history of cancer. Fifty percent was female, and mean age was 62.8 years. The primary cancer was breast (23.7%), lung (18.6%), stomach (10.2%), and prostate (10.2%). Adenocarcinoma was the most frequent histologic subtype (47.5%). The cancer was metastatic in almost cases (89.8%). At presentation, TMA manifestations were pulmonary (57.6%), neurologic (49.2%), bone pain (30.5%), and disseminated intravascular coagulopathy (DIVC) (55.9%). Forty-one patients had a bone marrow aspiration and/or biopsy. Among them, medullar metastases were found in 20 patients (48.7%). We observed low C3 in 14.7% of cases suggesting an activation of the alternative pathway. No genetic analysis was performed. Only one patient had an undetectable ADAMTS13 <5% without inhibitory ADAMTS13 antibodies. Renal failure was seen in 28 patients whom 63.7% had severe grade 3 acute kidney injury. Renal biopsy was performed in 6 patients with severe arteriolar TMA lesions. Seventeen patients had no treatment (N), fifteen patients were treated with TPE (P), twenty patients received chemotherapy with TPE (C+P), and seven patients received Eculizumab with TPE (E). Hematological and renal remission was not significantly different between treatment groups (p=0.74 and p=0.10 respectively). Mortality was high, 52.5% at one month, 90% after one year of follow-up. The median duration of survival was 27 days [8.5;95.5] in patients who received treatment. Survival was improved in (C+P) and (E+C+P) groups, significantly (p<0.0001). Conclusion We report the largest series of cancer-associated TMAS since the advent of Eculizumab for the treatment of HUS. Typical presentation included old age, bone pain, dyspnea, and DIVC. These symptoms, when associated with TMA, should therefore suggest a diagnosis of cancer. Bone marrow aspiration or biopsy led to diagnosis of cancer in half of cases, and should be systematically performed to rapidly confirm diagnosis. The overall prognosis remained dramatically poor, with a mortality rate of 90% in the first year. Chemotherapy is probably the most efficient therapy to delay the death. C3 serum level was decreased in only 7 patients, suggesting that the pathophysiology of cancer-associated TMA is not linked to complement activation. As a result, neither TPE nor Eculizumab improved survival rate.

Human herpesvirus (HHV)-6A can be inherited and chromosomally integrated (iciHHV-6A), and donor-to-recipient transmission has been reported in solid organ transplant. However, when HHV-6A reactivation happens after transplant, the source of HHV-6A is often not evident and its pathogenicity remains unclear. Here, we present an exhaustive case of donor-to-recipient transmission and reactivation of iciHHV-6A through kidney transplant. The absence of HHV-6A genome from the nails of the recipient excluded a recipient-related iciHHV-6A. Viral loads > 7 log10 copies/106 cells in donor blood samples and similarities of U38, U39, U69, and U100 viral genes between donor, recipient, and previously published iciHHV-6A strains are proof of donor-related transmission. Detection of noncoding HHV-6 snc-RNA14 using fluorescence in situ hybridization analysis and immunofluorescence staining of HHV-6A gp82/gp105 late proteins on kidney biopsies showed evidence of reactivation in the transplanted kidney. Because HHV-6A reactivation can be life threatening in immunocompromised patients, we provide several tools to help during the complete screening and diagnosis.