An ethical analysis of conditional and partially directed live kidney donation among strangers-The Israeli experience.

Living donor kidney transplantation (LDKT) is one of the most effective treatment options for people with end-stage renal disease. Traditionally, LDKT can be either "directed" or "nondirected," based on whether the recipient is specified by the donor. Recently, there has been an increase in conditional and semidirected live kidney donation among strangers, where the donor specifies the characteristics of the recipient whom they wish to donate to. This practice has both gained popularity and sparked controversy in the state of Israel through the nonprofit organization Matnat Chaim. We analyze the ethical implications of this practice by applying traditional principles of medical ethics to conditional LDKT. Although semidirected and conditional LDKT presents some ethical challenges, overall, its practice effectively aligns with core ethical principles. The donors' right to make stipulations respects the donor's autonomy, the practice avoids harm and benefits both donor and recipient, and justice and utility are upheld as the practice specifically benefits marginalized patients and optimizes resource utilization. Finally, we present data from our institution demonstrating how conditional LDKT increased transplantation for all ethnic groups; Jewish recipients of LDKT increased by 151.32% (P = .034) Arab recipients of LDKT increased by 111.11% (P = .036).

Acute diabetic foot in post kidney transplantation patients receiving chronic immunosuppression-clinical presentation and outcomes.

AIMS: Data regarding diabetic foot ulcers in patients after solid organ transplantation, particularly kidney transplantation, are limited. Chronic immunosuppression may be associated with impaired wound healing and a higher risk of amputations. In this study, we characterised the clinical presentation and outcomes of patients after kidney transplantation admitted to the diabetic foot unit, compared to non-kidney-transplant patients. MATERIALS AND METHODS: Data on the baseline characteristics, clinical presentation, and outcomes of all patients admitted to the diabetic foot unit of a large tertiary centre between the years 2014 and 2019 were collected. The most recent admission of each patient was considered. Primary outcomes were major amputations and 1 year mortality rate. RESULTS: During the study period, 537 patients were hospitalised, 18 of them were receiving immunosuppressive therapy due to kidney transplantation. Baseline characteristics of the patients were broadly similar, except that smoking was reported by 22.0% of the non-transplant patients and by none of the post-transplant patients (p = 0.01). Post-transplant patients tended to be younger (59.4 ± 11.1 vs. 65.3 ± 12.2; p = 0.07), were more likely to have type-1 diabetes (16.7% vs. 5.2%; p = 0.07) and had lower glucose levels upon admission (9.4 ± 4.3 vs. 12.0 ± 6.4 mmol/L; p = 0.07). Overall, 30% of the patients underwent major amputation, in-patient mortality rate was 9.3%, and 1 year mortality rate was 27.2%. Rates were similar in the post-transplant versus the non-post-transplant patients (p = 0.83, 1.00, 0.59, respectively). CONCLUSIONS: Post-transplant patients did not incur worse outcomes in spite of immunosuppressive therapy. Limb salvage efforts should be pursued in these patients similar to the overall population.

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.

Repeat Kidney Transplant in a Patient With a Double Inferior Vena Cava and Difficult Venous Access: A Case Report.

Many obstacles may complicate renal transplant, the preferred treatment for end-stage renal disease. Anatomic anomalies are of special importance during surgery. Double inferior vena cava is a rare anomaly reported in 0.2% to 3% of the population and may complicate renal transplant in certain cases. We present a case of a 29-year-old man with end-stage renal disease who was scheduled for repeat kidney renal transplant from a living related donor. His transplant posed many challenges to the transplant team. These included (1) difficult access for dialysis, which required transhepatic insertion of a dialysis catheter, (2) anomalous inferior vena cava anatomy with a double inferior vena cava, (3) a blocked right inferior vena cava, and (4) a small blocked bridging vein connecting the right inferior vena cava to an additional left inferior vena cava. A stent was inserted into the bridging vein to allow venous drainage from the graft. During the transplant procedure, the donated kidney was transplanted into the left iliac fossa and anastomosed to the left external iliac vein. The surgery was successful, without major operative or postoperative complications. The patient was discharged with normal renal function and enjoys normal renal function 6 months after surgery. This case emphasizes the importance of pretransplant evaluation and preparation and the need for high index of suspicion for anatomic variants in donors and recipients.

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.

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.

Implementation of guidelines for metabolic syndrome control in kidney transplant recipients: results at a single center.

BACKGROUND: Cardiovascular disease is a leading cause of death among kidney transplant recipients. Metabolic syndrome increases the risk for cardiovascular events and decreases graft survival. Lately, guidelines for management of the metabolic syndrome, primarily hypertension, diabetes mellitus (DM) and hypercholesterolemia have dramatically changed in an attempt to decrease cardiovascular risks among kidney transplant recipients. In the present study we examined whether these guideline changes had impact on our management of post-transplantation patients and the subsequent treatment outcomes for these diseases. METHODS: Data were obtained from kidney transplant clinic files from two follow-up (FU) periods-between 1994-1997 and between 2008-2011. Demographic data, monitoring and screening frequency for cardiovascular risk factors, immunosuppression regimen, treatment for hypertension, diabetes and hyperlipidemia, treatment outcomes and graft function changes were compared between the two follow-up periods. RESULTS: There was a significant increase in the percentage of patients undergoing transplantation due to renal failure secondary to diabetes and/or hypertension. Patient monitoring and screening during the second FU period were less frequent, but more targeted, reflecting changes in clinic routines. Blood pressure was better controlled in the second FU period (p < 0.01), as was hypercholesterolemia (p < 0.001). High fasting glucose levels were more prevalent among patients in the second group (p < 0.005), although more patients received treatment for DM (p < 0.001). Significantly, fewer patients experienced deterioration of kidney functions during the second FU period (p < 0.001). CONCLUSIONS: We found that guideline changes had impact on clinical practice, which translated to better control of the metabolic syndrome. DM control is challenging. Overall, stability of kidney function improved.

Carbapenem-resistant Klebsiella pneumoniae is associated with poor outcome in hemodialysis patients.

BACKGROUND: Hemodialysis (HD) units have become a source of resistant bacteria. One of the most alarming developments is the emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP). Risk factors and outcomes of CRKP isolation in HD patients have not been previously studied. METHODS: A nested case-control study was conducted in maintenance HD patients between January 1st 2006 and June 30th 2009. CRKP-positive patients were matched with randomly selected CRKP-negative HD patients. Demographics, clinical and laboratory data were collected for 24 months prior to the specimen collection. Multivariate analyses identified independent risk factors for CRKP. A prospective follow-up determined CRKP-associated outcome. RESULTS: Demographics associated with CRKP acquisition in HD patients were age between 65 and 75 and having no living offspring. Clinical conditions associated with CRKP were previous hospitalization, temporary HD catheter and previous isolation of vancomycin-resistant enterococcus. CRKP-related outcome was poor: median survival of one month and a hazard ratio [95% CI] of 5.9 [3.2-11.0] for mortality. CONCLUSIONS: Temporary HD catheters and previous treatment for VRE may predict subsequent CRKP isolation. A microbiological diagnosis of CRKP in HD patients is highly associated with imminent mortality. Meticulous measures to control the spread of CRKP bacteria among HD patients appear particularly warranted.

An in-vitro tumour microenvironment model using adhesion to type I collagen reveals Akt-dependent radiation resistance in renal cancer cells.

BACKGROUND: Renal cell carcinoma (RCC) is considered resistant to ionizing radiation. Recently, the extracellular matrix (ECM) has been shown to play a role in both drug resistance and radiation resistance (RR). While fibronectin has been extensively investigated in the context of RR, the role of type I collagen [col(I)], a principal constituent of the ECM in tumour metastases, in RR of RCC is unknown. METHODS: RCC cell adhesion to matrix was studied via pre-coating a variety of ECM glycoproteins onto plates. Cancer cell apoptosis and cell cycle were evaluated with flow cytometry using annexin V and propidium iodide stains, respectively. Activation of cellular survival signalling was analysed with western blots, and specific molecular inhibitors were correspondingly employed to block signalling. Hypoxia (<1%) was induced via N(2)/CO(2) gas flow in a specialized chamber. RESULTS: While adherence to col(I) enhanced RCC cell proliferation in general, col(I) and fibronectin, but not fibrinogen, could confer specific anti-apoptotic RR to RCC cells. The radioprotective effect of col(I) was maintained during both hypoxia/reoxygenation and normoxia conditions. In contrast to intact col(I), micronized col(I), lacking the natural fibrillar structure, was not radioprotective. The effect of col(I) in RCC cells is mediated via attenuation of apoptosis rather than cell cycle redistribution, involving the PI3 kinase/Akt pathway but not the MAP kinase pathway. CONCLUSIONS: Adherence to col(I) appears to be a relevant environmental cue enhancing RR in RCC cells, Akt dependently. Our results support inhibition of the PI3-kinase/Akt pathway as a radiosensitizing approach.

A novel dynamic matrix detachment model reveals a shift from apoptosis to necrosis in melanoma cells.

Anchorage-independence is a hallmark of invasive cancer. The setback of the classical poly-HEMA static matrix detachment (SMD) anoikis model is the absence of dynamic fluid circulation, resulting in cell aggregates. We addressed this problem by developing a novel 3D cell culture dynamic matrix detachment (DMD) model with a turbulent-free laminar flow, yielding a very low shear stress. In this study, we focused on melanoma cells where apoptosis was evaluated both via annexin V flow cytometry and caspase cleavage. The DMD model was superior to SMD in the induction of melanoma cell death and in revealing a shift from apoptosis to necrotic cell death, as evident by failure to activate caspase 9 and a decrease in annexin V stain. Combination of DMD with cisplatin could further accentuate necrotic cell death in cisplatin-resistant melanoma cells. Thus, the DMD model may be a useful matrix deprivation model to identify necrotic vs. apoptotic cell death pathways.

A 3D rotary renal and mesenchymal stem cell culture model unveils cell death mechanisms induced by matrix deficiency and low shear stress.

BACKGROUND: In epithelial and endothelial cells, detachment from the matrix results in anoikis, a form of apoptosis, whereas stromal and cancer cells are often anchorage independent. The classical anoikis model is based on static 3D epithelial cell culture conditions (STCK). METHODS: We characterized a new model of renal, stromal and mesenchymal stem cell (MSC) matrix deprivation, based on slow rotation cell culture conditions (ROCK). This model induces anoikis using a low shear stress, laminar flow. The mechanism of cell death was determined via FACS (fluorescence-activated cell sorting) analysis for annexin V and propidium iodide uptake and via DNA laddering. RESULTS: While only renal epithelial cells progressively died in STCK, the ROCK model could induce apoptosis in stromal and transformed cells; cell survival decreased in ROCK versus STCK to 40%, 52%, 62% and 7% in human fibroblast, rat MSC, renal cell carcinoma (RCC) and human melanoma cell lines, respectively. Furthermore, while ROCK induced primarily apoptosis in renal epithelial cells, necrosis was more prevalent in transformed and cancer cells [necrosis/apoptosis ratio of 72.7% in CaKi-1 RCC cells versus 4.3% in MDCK (Madin-Darby canine kidney) cells]. The ROCK-mediated shift to necrosis in RCC cells was further accentuated 3.4-fold by H(2)O(2)-mediated oxidative stress while in adherent HK-2 renal epithelial cells, oxidative stress enhanced apoptosis. ROCK conditions could also unveil a similar pattern in the LZ100 rat MSC line where in ROCK 44% less apoptosis was observed versus STCK and 45% less apoptosis versus monolayer conditions. Apoptosis in response to oxidative stress was also attenuated in the rat MSC line in ROCK, thereby highlighting rat MSC transformation. CONCLUSIONS: The ROCK matrix-deficiency cell culture model may provide a valuable insight into the mechanism of renal and MSC cell death in response to matrix deprivation.

Beta-arrestin-1 levels: reduced in leukocytes of patients with depression and elevated by antidepressants in rat brain.

OBJECTIVE: Beta-arrestins play a pivotal role in G protein-coupled receptor desensitization. beta-Arrestins interfere in G protein receptor interaction, thus leading to desensitization of G protein-mediated receptor signaling. G protein receptor signaling and its desensitization were previously implicated in the pathophysiology of mood disorders and in the mechanism of action of antidepressant and mood-stabilizing treatments. The present study aims at quantitatively evaluating beta-arrestin-1 levels in leukocytes of patients with major depression and the effect of antidepressants on beta-arrestin-1 levels in rat brain. METHOD: Beta-arrestin-1 measurements were carried out in cortical, hippocampal, and striatal brain regions of rats chronically intragastrically treated with either imipramine, desipramine, or fluvoxamine. Similar measurements were conducted in mononuclear leukocytes of 36 untreated patients with major depression and 32 healthy volunteer subjects. Beta-arrestin-1 levels were evaluated through immunoblot analyses using monoclonal antibodies to beta-arrestin-1. RESULTS: Beta-arrestin-1 levels were significantly elevated by all three antidepressants in rat cortex and hippocampus, while in the striatum no alterations could be detected. This process became significant within 10 days and took 2-3 weeks to reach maximal increase. Mononuclear leukocytes of patients with depression showed significantly reduced immunoreactive quantities of beta-arrestin-1. The reduction in beta-arrestin-1 levels was significantly correlated with the severity of depressive symptoms. CONCLUSIONS: The findings in the rat study suggest beta-arrestin-1 elevation as a biochemical mechanism for antidepressant-induced receptor down-regulation. The findings in human subjects support the implication of beta-arrestin-1 in the pathophysiology of mood disorders. Beta-arrestin-1 measurements in patients with depression may potentially serve as a biochemical marker for depression.