Impact of tozinameran (BNT162b2) mRNA vaccine on kidney transplant and chronic dialysis patients: 3-5 months follow-up.

BACKGROUND: Determining the humoral immunogenicity of tozinameran (BNT162b2) in patients requiring chronic renal replacement therapy, and its impact on COVID-19 morbidity several months after vaccination, may guide risk assessment and changes in vaccination policy. METHODS: In a prospective post-vaccination cohort study with up to 5 months follow-up we studied outpatient dialysis and kidney transplant patients and respective healthcare teams. Outcomes were anti S1/S2 antibody responses to vaccine or infection, and infection rate during follow-up. RESULTS: One hundred seventy-five dialysis patients (40% women, 65 ± 15 years), 252 kidney transplant patients (33% women, 54 ± 14 years) and 71 controls (65% women, 44 ± 14 years) were followed. Three months or longer after vaccination we detected anti S1/S2 IgG antibodies in 79% of dialysis patients, 42% of transplant recipients and 100% of controls, whereas respective rates after infection were 94%, 69% and 100%. Predictors of non-response were older age, diabetes, history of cancer, lower lymphocyte count and lower vitamin-D levels. Factors associated with lower antibody levels in dialysis patients were modality (hemodialysis vs peritoneal) and high serum ferritin levels. In transplant patients, hypertension and higher calcineurin or mTOR inhibitor drug levels were linked with lower antibody response. Vaccination was associated with fewer subsequent infections (HR 0.23, p < 0.05). Moreover, higher antibody levels (particularly above 59 AU/ml) were associated with fewer events, with a HR 0.41 for each unit increased in log10titer (p < 0.05). CONCLUSIONS: Dialysis patients, and more strikingly kidney transplant recipients, mounted reduced antibody response to COVID-19 mRNA vaccination. Lesser humoral response was associated with more infections. Measures to identify and protect non-responsive patients are required.

The Effect of a 26-Hour Fast in Living Kidney Donors.

BACKGROUND: Living kidney donation is widely practiced, and short- and long-term outcomes are acceptable. Within the living kidney donor population there are unique ethnic groups who practice customs that affect kidney function. In Judaism, Yom Kippur (Day of Atonement) is a 25- to 26-hour fast practiced yearly. There are no studies describing the effect of this fast on LKDs. METHODS: Living kidney donors were approached via e-mail. Exclusion criteria were conditions considered prohibitive of fasting. Control participants were potential living kidney donors approved by the standard medical evaluation but that had not yet donated. Blood and urine samples were obtained at 3 time points: baseline: 3 months before fast; fasting: 1 hour after fast; and follow-up: 14 days after fast. RESULTS: In total, 85 living kidney donors and 27 control participants were included. Donors were older (42.8 vs 38.8 years) and had a higher baseline creatinine (103 vs 72 umol/L). All other parameters were the same. The percent change between fasting and nonfasting creatinine was smaller in living kidney donors than in control participants (0.12% vs 0.21% change, P = .04). Values of sodium, albumin, and osmolarity were not different between groups. Time from donation did not influence results. CONCLUSIONS: Living kidney donors practicing a day fast showed a different pattern regarding the change in creatinine levels. This pattern cannot be considered hazardous for living kidney donors. The emotional wellbeing of living kidney donors is of utmost importance, and this first report of the safety of a 24-hour fast is reassuring. These findings may be of interest to other religious groups, for example, the Muslim community which observes Ramadan.

Practical recommendations for kidney transplantation in the COVID-19 pandemic.

Kidney transplantation at the time of a global viral pandemic has become challenging in many aspects. Firstly, we must reassess deceased donor safety (for the recipient) especially in communities with a relatively high incidence of coronavirus disease 19 (COVID-19). With respect to elective live donors, if one decides to do them at all, similar considerations must be made that may impose undue hardship on the donor. Recipient selection is also problematic since there is clear evidence of a much higher morbidity and mortality from COVID-19 for patients older than 60 and those with comorbidities such as hypertension, diabetes, obesity and lung disease. Unfortunately, many, if not most of dialysis patients fit that mold. We may and indeed must reassess our allocation policies, but this must be done based on data rather than conjecture. Follow-up routines must be re-engineered to minimize patient travel and exposure. Reliance on technology and telemedicine is paramount. Making this technology available to patients is extremely important. Modifying or changing immunosuppression protocols is controversial and not based on clinical studies. Nevertheless, we should reassess the need for induction therapy across the board for ordinary patients and the more liberal use of mammalian target of rapamycin inhibitors in transplant patients with proven infection.

Ambulatory monitoring unmasks hypertension among kidney transplant patients: single center experience and review of the literature.

BACKGROUND: Disagreements between clinic and ambulatory blood pressure (BP) measurements are well-described in the general population. Though hypertension is frequent in renal transplant recipients, only a few studies address the clinic-ambulatory discordance in this population. We aimed to describe the difference between clinic and ambulatory BP in kidney transplant patients at our institution. METHODS: We compared the clinic and ambulatory BP of 76 adult recipients of a kidney allograft followed at our transplant center and investigated the difference between these methods, considering confounding by demographic and clinical variables. RESULTS: Clinic systolic BP (SBP) and diastolic BP (DBP) were 128 ± 13/79 ± 9 mmHg. Awake SBP and DBP were 147 ± 18/85 ± 10 mmHg. The clinic-minus-awake SBP and DBP differences were - 18 and - 6 mmHg, respectively. The negative clinic-awake ΔSBP was more pronounced at age > 60 years (p = 0.026) and with tacrolimus use compared to cyclosporine (p = 0.046). Sleep SBP and DBP were 139 ± 21/78 ± 11 mmHg. A non-dipping sleep BP pattern was noted in 73% of patients and was associated with tacrolimus use (p = 0.020). CONCLUSIONS: Our findings suggest pervasive underestimation of BP when measured in the kidney transplant clinic, emphasizes the high frequency of a non-dipping pattern in this population and calls for liberal use of ambulatory BP monitoring to detect and manage hypertension.

Let-7 and MicroRNA-148 Regulate Parathyroid Hormone Levels in Secondary Hyperparathyroidism.

Secondary hyperparathyroidism commonly complicates CKD and associates with morbidity and mortality. We profiled microRNA (miRNA) in parathyroid glands from experimental hyperparathyroidism models and patients receiving dialysis and studied the function of specific miRNAs. miRNA deep-sequencing showed that human and rodent parathyroids share similar profiles. Parathyroids from uremic and normal rats segregated on the basis of their miRNA expression profiles, and a similar finding was observed in humans. We identified parathyroid miRNAs that were dysregulated in experimental hyperparathyroidism, including miR-29, miR-21, miR-148, miR-30, and miR-141 (upregulated); and miR-10, miR-125, and miR-25 (downregulated). Inhibition of the abundant let-7 family increased parathyroid hormone (PTH) secretion in normal and uremic rats, as well as in mouse parathyroid organ cultures. Conversely, inhibition of the upregulated miR-148 family prevented the increase in serum PTH level in uremic rats and decreased levels of secreted PTH in parathyroid cultures. The evolutionary conservation of abundant miRNAs in normal parathyroid glands and the regulation of these miRNAs in secondary hyperparathyroidism indicates their importance for parathyroid function and the development of hyperparathyroidism. Specifically, let-7 and miR-148 antagonism modified PTH secretion in vivo and in vitro, implying roles for these specific miRNAs. These findings may be utilized for therapeutic interventions aimed at altering PTH expression in diseases such as osteoporosis and secondary hyperparathyroidism.

The gut-kidney axis in chronic renal failure: A new potential target for therapy.

Evidence is accumulating to consider the gut microbiome as a central player in the gut-kidney axis. Microbiome products, such as advanced glycation end products, phenols, and indoles, are absorbed into the circulation but are cleared by normal-functioning kidneys. These products then become toxic and contribute to the uremic load and to the progression of chronic kidney failure. In this review, we discuss the gut-kidney interaction under the state of chronic kidney failure as well as the potential mechanisms by which a change in the gut flora (termed gut dysbiosis) in chronic kidney disease (CKD) exacerbates uremia and leads to further progression of CKD and inflammation. Finally, the potential therapeutic interventions to target the gut microbiome in CKD are discussed.

Mycoplasma pneumoniae Pneumonia Associated With Methemoglobinemia and Anemia: An Overlooked Association?

We report a case of acute methemoglobinemia and anemia in a patient with Mycoplasma pneumoniae pneumonia. We suggest that M. pneumoniae secretes a putative protein that can induce methemoglobin in red blood cells. Thus, Mycoplasma pneumoniae may induce methemoglobinemia in patients who have low oxygen saturation and anemia.

Inhibition of nuclear factor-κB activation in pancreatic ß-cells has a protective effect on allogeneic pancreatic islet graft survival.

Pancreatic islet transplantation, a treatment for type 1 diabetes, has met significant challenges, as a substantial fraction of the islet mass fails to engraft, partly due to death by apoptosis in the peri- and post-transplantation periods. Previous evidence has suggested that NF-κB activation is involved in cytokine-mediated ß-cell apoptosis and regulates the expression of pro-inflammatory and chemokine genes. We therefore sought to explore the effects of ß-cell-specific inhibition of NF-κB activation as a means of cytoprotection in an allogeneic model of islet transplantation. To this end, we used islets isolated from the ToI-ß transgenic mouse, where NF-κB signalling can specifically and conditionally be inhibited in ß-cells by expressing an inducible and non-degradable form of IκBα regulated by the tet-on system. Our results show that ß-cell-specific blockade of NF-κB led to a prolonged islet graft survival, with a relative higher preservation of the engrafted endocrine tissue and reduced inflammation. Importantly, a longer delay in allograft rejection was achieved when mice were systemically treated with the proteasome inhibitor, Bortezomib. Our findings emphasize the contribution of NF-κB activation in the allograft rejection process, and suggest an involvement of the CXCL10/IP-10 chemokine. Furthermore, we suggest a potential, readily available therapeutic agent that may temper this process.

The ToI-beta transgenic mouse: a model to study the specific role of NF-kappaB in beta-cells.

Type 1 diabetes is characterized by the infiltration of inflammatory cells into pancreatic islets of Langerhans, followed by the selective and progressive destruction of insulin-secreting beta-cells. Islet infiltrating leukocytes secrete cytokines including IL-1beta and IFN-gamma, which contribute to beta-cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-kappaB is an important component of the signal triggering beta-cell apoptosis. To study the role of NF-kappaB in vivo we generated a transgenic mouse line expressing a degradation-resistant NF-kappaB protein inhibitor (DeltaNIkappaBalpha) and the luciferase gene, acting specifically in beta-cells, in an inducible and reversible manner, by using the tet-on regulation system. Using this new mouse model, termed the ToI-beta mouse (for Tet-Ondelta I kappaB in beta-cells) we have previously shown in vitro, that islets expressing the DeltaNIkappaBalpha protein were resistant to the deleterious effects of IL-1beta and IFN-gamma, as assessed by reduced NO production and beta-cell apoptosis. In vivo, a nearly complete protection against multiple low dose streptozocin-induced diabetes was observed, with reduced intra-islet lymphocytic infiltration. In the present study we demonstrate the tight regulated and reversible expression of the DeltaNIkappaBalpha transgene in the ToI-beta mouse model as well as the effect of its overexpression on glucose metabolism and insulin secretion. The results show a lack of effect of transgene induction on both in vivo glucose tolerance tests and in vitro islet insulin secretion and content. Furthermore, to prove the tight control of induction in the model, luciferase mediated light emission was only detected at constant levels in Dox-treated double transgenic mice or islets as well as in a model of islet transplantation. Upon removal of the inducing stimulus, complete reversal of both NF-kappaB inhibition and luciferase activity were observed. Together, our results show the ToI-beta mouse model to be a highly controlled and very accurate model for examining pancreatic beta-cell-specific temporal inhibition of NF-kappaB.