Calcineurin is an important signaling molecule in the kidney and may be involved in a variety of processes. The phosphatase subunit of calcineurin (CnA) has three isoforms, alpha, beta, and gamma. In this study, we investigated the effect of loss of calcineurin A-alpha (CnA-alpha) or calcineurin A-beta (CnA-beta) on the development and function of the kidney. Total calcineurin expression and activity was significantly reduced in whole kidney homogenates from both CnA-alpha -/- and CnA-beta -/- mice. Kidneys of CnA-beta -/- mice appear normal and the mice develop with no phenotypic abnormalities. In contrast, kidneys of CnA-alpha -/- animals fail to fully develop. In particular, postnatal maturation of the nephrogenic zone (NZ) is defective. Within the NZ, glomeruli also fail to mature and lack mesangial cells. In addition to alterations in development, there is an absence of proliferation and an increase of cell death in the NZ with loss of CnA-alpha. Finally, increased collagen deposition is observed and serum creatinine levels are significantly increased in CnA-alpha -/- animals compared to wild-type littermates, indicating that kidney function is impaired. In summary, absence of CnA-alpha but not CnA-beta leads to a defect in normal maturation of the NZ and glomeruli, alterations in the cell cycle, and impaired kidney function.

Toxicity associated with a second autologous peripheral blood stem cell transplant (APBSCT) in patients who relapse following initial APBSCT for multiple myeloma (MM) has not been well described. We conducted a retrospective, case-series of 25 consecutive patients who received a second APBSCT for relapsed or progressive disease following prior APBSCT to describe associated toxicity. Grade 3 or 4 toxicities were observed in 92% of patients after each APBSCT. More patients developed an elevated serum creatinine (4%vs. 36%; p = 0.011) following the second APBSCT. Median time to neutrophil engraftment was 10 days following both transplants (p = 0.428). Platelet engraftment was delayed by 2 days after the second APBSCT (median 12 vs.14 days; p < 0.025). There were two deaths before day 100. In conclusion, patients who undergo a second APBSCT for relapsed MM experience more nephrotoxicity. Delayed platelet engraftment and an 8% treatment-related mortality were observed following the second APBSCT.

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The serine/threonine phosphatase calcineurin is an important signaling molecule involved in kidney development and function. One potential target of calcineurin action is the water channel aquaporin 2 (AQP2). In this study, we examined the effect of loss of calcineurin Aα (CnAα) on AQP2 function in vivo. CnAα null mice were found to have defective post-natal urine-concentrating ability and an impaired urine-concentrating response to vasopressin. Expression of AQP2 is normal but, paradoxically, vasopressin-mediated phosphorylation of the channel is decreased compared with wild-type littermates and there is no accumulation of AQP2 in the apical membrane. Calcineurin protein and activity was found in innermedullary collecting duct vesicles, and loss of calcineurin expression and activity was associated with a loss of AQP2 in the vesicle fraction. As such, the lack of vasopressin-mediated phosphorylation of AQP2 might be the result of a defect in normal trafficking of AQP2 to apical-targeted vesicles. Likewise, treatment of wild-type mice with cyclosporin A to inhibit calcineurin produces a similarly impaired urine-concentrating response to vasopressin and alterations in AQP2 phosphorylation and trafficking. These experiments demonstrate that, CnAα is required for normal intracellular trafficking of AQP2 and loss of calcineurin protein or activity disrupts AQP2 function.

Multiple myeloma is the most frequent indication for high-dose melphalan (HDM) chemotherapy with autologous stem cell transplantation (ASCT). Gastrointestinal symptoms represent the most significant non-hematological toxicity of HDM. However, specific, especially genetic, predictors of their incidence or clinical severity are lacking. The amino acid transporters LAT1 and LAT2 encoded by the SLC7A5 and SLC7A8 genes, respectively, are the principal mediators of melphalan uptake into cells. To determine whether genetic variability at these loci contributed to inter-individual differences in the development of gastrointestinal complications of HDM, we analyzed single-nucleotide polymorphisms (SNPs) in these genes in 135 patients with multiple myeloma treated with HDM and ASCT and need for total parenteral nutrition (TPN). Seven SNPs in SLC7A5 and twenty in SLC7A8 were genotyped. Multiple analyses indicated that one SNP in the first intron of SLC7A5, rs4240803, significantly associated with TPN use (OR= 0.45, 95% CI 0.25 – 0.79, p = 0.007). Further, every haplotype that correlated with TPN requirement incorporated this SNP. These results suggest that variability in melphalan transport impacts mucosal injury after HDM. This finding could help in individualizing the dose of this effective and widely used chemotherapeutic agent for multiple myeloma.

Yeasts other than Candida albicans have emerged as important causes of fungal infection in hemopoietic stem cell transplant (HSCT) patients, particularly those receiving fluconazole prophylaxis. We report on an autologous hemopoietic stem cell transplant recipient who developed Candida krusei sepsis from pre-existing oral colonization.

Objetivo: Identificar los factores de riesgo asociados con la mortalidad a las seis semanas. Diseño: Estudio prospectivo multicéntrico. Ámbito: 26 UCI de Andalucía. Pacientes o participantes: Pacientes ingresados en UCI por neumonía grave por SARS COV 2 en el periodo de tiempo comprendido entre el 8 de marzo y el 30 de mayo. Intervenciones: Ninguna. Variables de interés principales: características demográficas, clínicas y escalas de gravedad. Se analizaron tratamientos de soporte, fármacos y la mortalidad. Resultados: 495 pacientes fueron incluidos, 73 fueron excluidos por incompletos. 422 pacientes fueron incluidos en el análisis final. La mediana de edad fue de 63 años, 305 (72,3%) eran hombres. La mortalidad en la UCI fue: 144/422 34%; mortalidad a los 14 días: 81/422 (19,2%); mortalidad a los 28 días: 121/422 (28,7%); mortalidad a las 6 semanas 152/422 36,5%. Los factores asociados con la mortalidad a los 42 días fueron la edad, APACHE II, SOFA >6 y LDH al ingreso > 470 U/L, uso de vasopresores, necesidad de técnicas de reemplazo de la función renal, porcentaje de linfocitos a las 72 horas del ingreso en UCI < 6,5%, y trombocitopenia, mientras que el uso de lopinavir/ritonavir fue identificado como un factor protector. Conclusiones: La edad, gravedad y fracaso orgánico junto con la necesidad de terapias de soporte fueron identificadas como factores predictores de mortalidad a las seis semanas.

Objective We monitored the epidemiology and microbiology of oral yeast colonization in patients undergoing hemopoietic progenitor cell transplantation (HPCT) to examine associations between yeast colonization and oral mucositis. Study Design One hundred twenty-one consecutive HPCT patients were sampled for oral yeasts prior to fluconazole (FLC) prophylaxis, at transplant, and weekly until discharge. Clinical oral mucositis screenings were performed tri-weekly. Results Yeast colonization was evident at 216 of 510 total visits. Candida albicans and C. glabrata were the predominate organisms. Eight patients showed elevated MICs to FLC. One patient developed fungal septicemia. Patients with OMAS mucositis scores <20 had higher colonization rates than those with higher scores. Conclusions FLC is very effective in controlling a variety of oral yeasts in HPCT recipients. FLC resistant yeasts do emerge and can be the source of fungal sepsis. A positive association was not shown between yeast colonization and presence or severity of oral mucositis.