Immunosuppression reduction when administering a booster dose of the BNT162b2 mRNA SARS-CoV-2 vaccine in kidney transplant recipients without adequate humoral response following two vaccine doses: protocol for a randomised controlled trial (BECAME study).

INTRODUCTION: Inadequate antibody response to mRNA SARS-CoV-2 vaccination has been described among kidney transplant recipients. Immunosuppression level and specifically, use of antimetabolite in the maintenance immunosuppressive regimen, are associated with inadequate response. In light of the severe consequences of COVID-19 in solid organ transplant recipients, we believe it is justified to examine new vaccination strategies in these patients. METHODS AND ANALYSIS: BECAME is a single-centre, open-label, investigator-initiated randomised controlled, superiority trial, aiming to compare immunosuppression reduction combined with a third BNT162b2 vaccine dose versus third dose alone. The primary outcome will be seropositivity rate against SARS-CoV-2. A sample size of 154 patients was calculated for the seropositivity endpoint assuming 25% seropositivity in the control group and 50% in the intervention group. A sample of participants per arm will be also tested for T-cell response. We also plan to perform a prospective observational study, evaluating seropositivity among ~350 kidney transplant recipients consenting to receive a third vaccine dose, who are not eligible for the randomised controlled trial. ETHICS AND DISSEMINATION: The trial is approved by local ethics committee of Rabin Medical Center (RMC-0192-21). All participants will be required to provide written informed consent. Results of this trial will be published; trial data will be available. Protocol amendments will be submitted to the local ethics committee. TRAIL REGISTRATION NUMBER: NCT04961229.

New onset diabetes after kidney transplantation is associated with increased mortality-A retrospective cohort study.

OBJECTIVE: Clinical outcomes in individuals with new onset diabetes after transplantation (NODAT) and the optimal treatment for this complication are poorly characterized. This study was intended to better define these issues. METHODS: Patients who underwent kidney transplantation and did not have diabetes prior to transplantation were included in the study. Clinical outcomes were compared between those who developed NODAT and those who did not. In those who developed NODAT, oral therapy was compared with insulin based therapy. RESULTS: A total of 266 kidney transplant recipients were included, of which 71 (27%) developed NODAT during the time of the follow-up. Using Cox multivariate analysis adjusted for age and gender, hazard ratio for overall mortality among patients with NODAT versus those without NODAT was 2.69 (95% CI 1.04-7.01). Among patients who developed NODAT, 29 patients (40%) were treated with an insulin-based regimen. At the end of follow-up, no difference was found in mean HbA1c, and therapy regimen was not associated with greater mortality. CONCLUSIONS: New onset diabetes in kidney transplanted patients is associated with increased mortality compared with kidney transplanted patients without NODAT.

The impact of the israeli transplantation law on the socio-demographic profile of living kidney donors.

The Israeli transplantation law of 2008 stipulated that organ trading is a criminal offense, and banned the reimbursement of such transplants by insurance companies, thus decreasing dramatically transplant tourism from Israel. We evaluated the law's impact on the number and the socio-demographic features of 575 consecutive living donors, transplanted in the largest Israeli transplantation center, spanning 5 years prior to 5 years after the law's implementation. Living kidney donations increased from 3.5 ± 1.5 donations per month in the pre-law period to 6.1 ± 2.4 per month post-law (p < 0.001). This was mainly due to a rise in intra-familial donations from 2.1 ± 1.1 per month to 4.6 ± 2.1 per month (p < 0.001). In unrelated donors we found a significant change in their socio-demographic characteristics: mean age increased from 35.4 ± 7.4 to 39.9 ± 10.2 (p = 0.001), an increase in the proportion of donors with college level or higher education (31.0% to 63.1%; p < 0.001) and donors with white collar occupations (33.3% to 48.3%, p = 0.023). In conclusion, the Israeli legislation that prohibited transplant tourism and organ trading in accordance with Istanbul Declaration, was associated with an increase in local transplantation activity, mainly from related living kidney donors, and a change in the profile of unrelated donors into an older, higher educated, white collar population.

Effect of a legal initiative on deceased- and living-donor kidney transplantation in Israel.

The severe organ shortage in Israel has prompted many patients to undergo kidney transplantation abroad. In May 2008, the Israeli Knesset approved the Israel Transplant Law prohibiting organ trade and disallowing health insurers to reimburse the cost of illegal transplantation abroad. The aim of this study was to assess the initial effect of the law on kidney transplantations inside and outside the country. The number of kidney transplantations performed inside and outside Israel was compared between the 3-year periods before and after implementation of the transplant law (2006-2008 and 2009-2011). Further analysis compared the number of deceased-donor and live-donor transplantations performed in Israel during the same periods. The results showed that the number of transplants performed abroad dropped significantly, from a median of 143 per year during 2006-2008 to <45 per year during 2009-2011. There was a parallel increase in the number of kidney transplantations from living donors, from a median of 56 transplants per year in 2006-2008 to 78 per year in 2008-2011, with a peak of 117 transplants in 2011. In conclusion, the Israel Transplant Law has dramatically affected kidney transplantation practices in Israel by reducing transplantation tourism and increasing living-donor kidney transplantations.

Consequences of treated versus untreated asymptomatic bacteriuria in the first year following kidney transplantation: retrospective observational study.

Asymptomatic bacteriuria (AB) is frequent among kidney transplant patients during the first year post transplantation. Currently, there are no clear guidelines for the antibiotic treatment of AB among these patients. We examined the outcomes of treatment versus no treatment of AB in kidney transplant patients during the first year post transplantation. A retrospective cohort study including adults >16 years of age transplanted in one center between 1/2004 and 12/2010 was undertaken. The primary outcome was a composite of hospitalization for symptomatic urinary tract infection (UTI) or more than 25 % reduction in the estimated glomerular filtration rate (eGFR) 30 days after the documentation of AB. Secondary outcomes included symptomatic UTIs following the episode of AB, persistent recurrent AB, total days in hospital, mortality, adverse events, and resistance development. A total of 112 patients with AB fulfilled the inclusion criteria. Twenty-two patients received antibiotic treatment (19.6 %), while 90 patients did not. The primary outcome occurred in 4/22 (18.2 %) of the treated patients versus 5/90 (5.6 %) of the untreated patients [odds ratio (OR) = 3.78, 95 % confidence interval (CI) 0.9-15]. The risk of developing symptomatic UTI after AB was almost three times higher (p < 0.05) and the total number of hospitalization days at 6 months post AB was also significantly higher (p < 0.026) in the treated group. No patient died during the study period. UTI caused by bacteria resistant to the antibiotic used for the treatment of AB occurred in 36 % of the treated patients. We observed no benefit for the antibiotic treatment of AB in the short- and long-term follow-up. A prospective observational study is needed.

Antibiotic prophylaxis for urinary tract infections in renal transplant recipients: a systematic review and meta-analysis.

Urinary tract infection (UTI) is the most common bacterial infection in renal transplant recipients. To date there are no guidelines on antibiotic prophylaxis for UTI in this population. We conducted a systematic review and meta-analysis of randomized controlled trials comparing antibiotic prophylaxis vs. placebo, no intervention, or different antibiotics, all beginning postoperatively and continued for at least 1 month during the first 6 months post transplantation. The search included CENTRAL, PubMed, LILACS, and relevant conference abstracts up to August 2009. The primary outcome was graft loss. Six trials were included in this review, including 545 patients. No significant difference was seen in graft loss (risk ratio [RR] 0.99, 95% confidence interval [CI] 0.91-1.81). Prophylaxis lowered the risk for developing sepsis with bacteremia by 87% (RR 0.13, 95% CI 0.02-0.7) and the risk for developing bacteriuria (symptomatic or asymptomatic) by 60% (RR 0.41, 95% CI 0.31-0.56; 3 trials). Symptomatic UTI and pyelonephritis were not reported. No significant reduction was found in all-cause mortality and adverse events rates; conflicting results were reported for the development of resistant bacteria. Very few trials assessed the efficacy of prophylaxis for UTI following renal transplantation. Prophylaxis reduced bacteriuria and sepsis with bacteremia; effects on graft survival could not be demonstrated.

Cavoatrial shunt: a graft salvage procedure for suprahepatic caval anastomosis obstruction after liver transplantation.

A liver transplant recipient developed the Budd-Chiari syndrome because of an obstruction of the suprahepatic inferior vena cava anastomosis. Percutaneous balloon dilatation angioplasty was not feasible. On exploration, dense retrohepatic fibrotic reaction was observed. The patient underwent successful retrohepatic cavoatrial shunt placement by means of a 16-mm, ring-enforced polytetrafluoroethylene graft. We conclude that this shunt should be considered an additional graft salvage procedure for this complication.

Where is the "inverting factor" in hormone secretion from parathyroid cells?

Secretion of hormones and transmitters in the body fall into two general categories. In the majority of the secreting cells, including the presynaptic terminals in the nervous system, an increase in the extracellular calcium causes an increase in secretion. There are two notable exceptions to this general rule: the parathyroid cells and the renal juxtaglomerular cells, where an increase in extracellular calcium leads to a decrease in secretion. Because these two cell types have a cardinal role in a wide variety of physiological and pathophysiological functions, it is of great importance to understand the regulation of their hormone secretion process. A key element to such an understanding is the identification of the location of the "inverting step," which makes the parathyroid cells behave in a fashion contrary to most other secretory cells. Whole cell imaging studies strongly suggested that the inversion factor is between the changes in intracellular calcium concentration ([Ca2+]i) and the secretion of the hormone. Surprisingly, confocal calcium imaging of the parathyroid cells did not support this dogma. It revealed that the interior of the parathyroid cell is a nonhomogeneous medium and that an increase in the extra-cellular calcium concentration produces changes in [Ca2+]i, in both the same and opposite directions, in different parts of the parathyroid cell.

Hepatitis C-associated cryoglobulinemia after liver transplantation.

Mixed cryoglobulinemia is well known to be associated with hepatitis C virus (HCV) infection. We report two cases in which cryoglobulinemia appeared or became grossly exacerbated after orthotopic liver transplantation. In both cases, there was co-appearance of cryoglobulinemia with the reinfection of the grafted liver with HCV. It is postulated that the cryoglobulinemia might be related to secondary HCV infection in these patients.

Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D.

Secondary hyperparathyroidism is characterized by an increase in parathyroid (PT) cell number, and parathyroid hormone (PTH) synthesis and secretion. It is still unknown as to what stimuli regulate PT cell proliferation and how they do this. We have studied rats with dietary-induced secondary hyper- and hypoparathyroidism, rats given 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and rats after 5/6 nephrectomy for the presence of PT cell proliferation and apoptosis. PT cell proliferation has been measured by staining for proliferating cell nuclear antigen (PCNA) and apoptosis by in situ detection of nuclear DNA fragmentation and correlated with serum biochemistry and PTH mRNA levels. A low calcium diet led to increased levels of PTH mRNA and a 10-fold increase in PT cell proliferation. A low phosphate diet led to decreased levels of PTH mRNA and the complete absence of PT cell proliferation. 1,25 (OH)2D3 (25 pmol/d x 3) led to a decrease in PTH mRNA levels and unlike the hypophosphatemic rats there was no decrease in cell proliferation. There were no cells undergoing apoptosis in any of the experimental conditions. The secondary hyperparathyroidism of 5/6 nephrectomized rats was characterized by an increase in PTH mRNA levels and PT cell proliferation which were both markedly decreased by a low phosphate diet. The number of PCNA positive cells was increased by a high phosphate diet. Therefore hypocalcemia, hyperphosphatemia and uremia lead to PT cell proliferation, and hypophosphatemia completely abolishes this effect. Injected 1,25 (OH)2D3 had no effect. These findings emphasize the importance of a normal phosphate and calcium in the prevention of PT cell hyperplasia.

The molecular basis of secondary hyperparathyroidism in chronic renal failure.

Renal osteodystrophy is a debilitating complication of chronic renal failure and secondary hyperparathyroidism (2HPTH) is one of its central features. 2HPTH develops as a result of the low levels of serum calcium and 1,25-dihydroxyvitamin D [1,25(OH)2D3] and the high serum phosphate that occur in chronic renal failure. 1,25(OH)2D3 markedly decreases PTH gene transcription and its lack leads to 2HPTH. A low serum calcium increases PTH mRNA and iPTH levels while a high serum calcium has no effect on PTH gene expression. In experimental uremia there are increased levels of PTH mRNA. In chronic renal failure there is a shift in the calcium set-point to the right. This may be a function of a change in properties of the parathyroid cell calcium receptor, which is a G-protein coupled calcium sensor.

[Idiopathic hypereosinophilic syndrome].

The idiopathic hypereosinophilic syndrome is a heterogeneous group of disorders characterized by persistent eosinophilia of undetected cause, and multiple organ system involvement. The systems affected include the central and peripheral nervous, cardiovascular, respiratory and gastrointestinal systems and the kidneys, skin, muscles and joints. Treatment is mainly by immunosuppressive drugs to prevent organ system complications. Prognosis is variable, depending mainly on heart involvement.

Acute colchicine intoxication--possible role of erythromycin administration.

A 29-year-old patient with familial Mediterranean fever and amyloidosis involving the kidney, liver, and gastrointestinal tract received longterm colchicine, 1 mg daily. In the last year she developed diarrhea and abdominal pain, that coincided with toxic colchicine blood levels. After 2 weeks of oral erythromycin therapy she was hospitalized for acute, life threatening colchicine toxicity, with fever, diarrhea, abdominal pain, myalgia and lower extremity parasthesias and later convulsions and alopecia. Pancytopenia evolved into rebound leukocytosis, disturbed liver function and hypoglycemia. After a long stormy course she improved. Colchicine toxicity with combined liver and renal impairment and the role of erythromycin in her colchicine toxicity are discussed.