Association between Kidney Donor Risk Index, kidney graft function and histological changes in early post-transplant graft biopsy.

Background: Proper assessment of donor organ quality is crucial for optimal kidney allocation and best long-term outcomes. The aim of this study was to analyze the association between the Kidney Donor Risk Index (KDRI) and histological parameters in early post-transplant graft biopsy in a Polish cohort of kidney transplant recipients. Methods: In 418 consecutive kidney transplant recipients, a histological evaluation of very early [at median 11 (9-13) post-transplant day] protocol core needle biopsy was performed and analyzed according to the Banff classification. Subjects were divided into quartiles of the KDRI value. Kidney graft function, patient and graft survival were also analyzed over a median follow-up period of 44 (26-56) months. Results: There was a significant trend toward greater intensity of chronic histology changes along the KDRI quartiles (χ2 = 20.8; P < .001), including interstitial fibrosis, tubular atrophy, mesangial matrix increase and arteriolar hyalinosis. Stepwise multivariate regression analysis revealed that only higher KDRI value independently increased the severity of chronic graft injury (rpartial = 0.340, P < .001). KDRI values were valuable in the determination of both early and long-term graft function. Conclusion: The KDRI values correlate with chronic histological changes found in early post-implantation kidney biopsies and can also be helpful in the prediction of graft outcome.

Intestinal Permeability in Patients Early after Kidney Transplantation Treated with Two Different Formulations of Once-Daily Tacrolimus.

Adequate tacrolimus blood exposure is crucial in the early post-renal transplant period and a gut epithelial barrier integrity may play a role. We prospectively investigated several markers of intestinal permeability in recent kidney transplant recipients (KTRs) treated with different tacrolimus extended-release formulations. Within each of the 49 KTR pairs that received grafts from the same donor, an early randomized conversion was performed from twice-daily (Prograf) to once-daily tacrolimus formulation: Advagraf or Envarsus. Plasma zonulin, calprotectin, circulating lipopolysaccharide (LPS), LPS-binding protein (LBP), intestinal fatty acid binding protein (FABP-2), and CD-14 levels were measured. There was no difference in the recipient age, dialysis vintage, BMI, and residual diuresis between Advagraf and Envarsus groups. FABP-2 and LPS levels were significantly associated with tacrolimus trough level, 3-h level, and area under the curve (AUC) in the Envarsus but not in the Advagraf group. AUC was independently increased by LPS and decreased by age, FABP-2 concentration, and the use of Envarsus formulation as compared with Advagraf. Functional changes of gastrointestinal tract in patients treated with Envarsus may influence intestinal tacrolimus absorption to a greater extent than in Advagraf-treated KTRs and may lead to inadequate variability of tacrolimus exposure early after kidney transplantation.

Clinical Outcomes of Transplanted Kidneys from Deceased Donors Using Different Generic Preservation Solutions.

Background and Objectives: StoreProtect Plus® is a preserving solution for cold organ storage, with a composition identical to Institute Georges Lopez (IGL-1) solution. The aim of this single center study was to compare the clinical performance of StoreProtect Plus with the generic counterpart of University of Wisconsin preservation fluid, named SPS-1®. Materials and Methods: The clinical outcomes of 168 consecutive organs preserved with StoreProtect Plus solution and 167 organs preserved with SPS-1 solution were compared. During an 18-month post-transplant follow-up period, kidney graft function, the frequency of acute rejection, post-transplant diabetes, and infectious complications, as well as patient and graft survival were analyzed. Results: There was significantly more immediate graft function (IGF) (39.3 vs. 24.0%; p < 0.01) and less slow graft function (SGF) (38.7 vs. 51.5%; p < 0.05) in the StoreProtect Plus group in comparison with the SPS-1 group, whereas the occurrence of DGF was similar in both groups. Long-term kidney graft function was comparable. Multivariate regression analysis showed that the use of StoreProtect Plus vs. SPS-1 solution (rpartial = 0.217; p < 0.001) and the amount of residual diuresis (rpartial = 0.147; p < 0.001) independently increased the occurrence of IGF, whereas Scr > 1.5 mg/dL prior to organ procurement (rpartial = −0.198; p < 0.001), longer CIT (rpartial = −0.170; p < 0.01), and CVD donor death (rpartial = −0.214; p < 0.001) were associated with SGF. Conclusions: The higher occurrence of IGF was found in kidney transplant recipients whose organs were preserved using StoreProtect Plus solution as compared with SPS-1 solution. The two groups did not differ in kidney graft function, the frequency of post-transplant complications, as well as patient and graft survival.

Clinical insights into the role of immunosuppression in solid organ transplant recipients with COVID-19.

INTRODUCTION: The COVID-19 pandemic has disproportionately affected patients who have undergone solid organ transplantation (SOT). OBJECTIVES: We aimed to assess a cohort of transplant recipients who developed COVID­19, with a focus on immunosuppressive regimen, blood tacrolimus levels, clinical course, and patient and graft outcomes. PATIENTS AND METHODS: During the first 12 months of the pandemic, we identified ambulatory SOT recipients, including kidney, liver, and heart transplant recipients, diagnosed with SARS­CoV­2 infection. Baseline and follow­up data on graft function, immunosuppression, and patient and graft outcomes were assessed. RESULTS: Of the 2091 ambulatory patients, we identified 201 transplant recipients (9.6%) with SARS­CoV­2 infection (kidney transplant, n = 112; heart transplant, n = 56; liver transplant, n = 33). Patients after recent kidney (during 2015-2020) or heart (during 2020) transplant were significantly more often diagnosed with COVID ­19 than patients with a longer time since transplant. Additionally, blood trough tacrolimus levels measured during or shortly after COVID­19 in 23 kidney graft recipients were significantly increased by a median of 76.1% (interquartile range, 47.4%-109.4%) relative to predose trough levels. However, liver function parameters were not elevated, necessitating a tacrolimus dose reduction in 73.9% of the patients. CONCLUSIONS: In our study, kidney transplant recipients showed significant disturbances of tacrolimus metabolism, which may account for kidney function worsening during COVID­19. Moreover, infection was more common in patients with recent kidney or heart transplant, which suggests that the level of immunosuppression may affect morbidity related to SARS­CoV­2 infection.

The Relationship between Initial Tacrolimus Metabolism Rate and Recipients Body Composition in Kidney Transplantation.

There are several premises that the body composition of kidney transplant recipients may play a role in tacrolimus metabolism early after transplantation. The present study aimed at analyzing the relationship between the body composition parameters assessed by bioimpedance analysis (BIA) and initial tacrolimus metabolism. Immediately prior to transplantation, BIA using InBody 770 device was performed in 122 subjects. Tacrolimus concentration-to-dose (C/D) ratio was calculated based on the first blood trough level measurement. There was no difference in phase angle, visceral fat area, lean body mass index (LBMI) and the proportion of lean mass as a percentage of total body mass between the subgroups of slow and fast metabolizers. However, subjects with LBMI ≥ median value of 18.7 kg/m2, despite similar initial tacrolimus dose per kg of body weight, were characterized by a significantly lower tacrolimus C/D ratio (median 1.39 vs. 1.67, respectively; p < 0.05) in comparison with the subgroup of lower LBMI. Multivariate regression analysis confirmed that age (rpartial = 0.322; p < 0.001) and LBMI (rpartial = -0.254; p < 0.01) independently influenced the tacrolimus C/D ratio. A LBMI assessed by BIA may influence the tacrolimus metabolism in the early post-transplant period and can be a useful in the optimization of initial tacrolimus dosing.

Endogenous Mammalian Cardiotonic Steroids-A New Cardiovascular Risk Factor?-A Mini-Review.

The role of endogenous mammalian cardiotonic steroids (CTS) in the physiology and pathophysiology of the cardiovascular system and the kidneys has interested researchers for more than 20 years. Cardiotonic steroids extracted from toads or plants, such as digitalis, have been used to treat heart disease since ancient times. CTS, also called endogenous digitalis-like factors, take part in the regulation of blood pressure and sodium homeostasis through their effects on the transport enzyme called sodium-potassium adenosine triphosphatase (Na/K-ATPase) in renal and cardiovascular tissue. In recent years, there has been increasing evidence showing deleterious effects of CTS on the structure and function of the heart, vasculature and kidneys. Understanding the role of CTS may be useful in the development of potential new therapeutic strategies.

Changes in Office Blood Pressure Control, Augmentation Index, and Liver Steatosis in Kidney Transplant Patients after Successful Hepatitis C Infection Treatment with Direct Antiviral Agents.

Hepatitis C virus (HCV) infection in kidney transplant recipients (KTRs) can be successfully treated with direct antiviral agents (DAA). The aim of our study was to analyze different measures of vascular function during and after the DAA treatment. As we have observed the improvement of blood pressure (BP) control in some individuals, we have conducted an analysis of potential explanatory mechanisms behind this finding. Twenty-eight adult KTRs were prospectively evaluated before and 15 months after start of DAA therapy. Attended office BP (OBP), augmentation index (AIx), pulse wave velocity (PWV), flow-mediated dilation (FMD), liver stiffness measurement (LSM), and liver steatosis assessment (controlled attenuation parameter (CAP)) were measured. In half of the patients, improvement of OBP control (decline of systolic BP by at least 20 mmHg or reduction of the number of antihypertensive drugs used) and parallel central aortic pressure parameters, including AIx, was observed. There was a significant decrease in CAP mean values (241 ± 54 vs. 209 ± 30 dB/m, p < 0.05) only in patients with OBP control improvement. Half of our KTRs cohort after successful HCV eradication noted clinically important improvement of both OBP control and central aortic pressure parameters, including AIx. The concomitant decrease of liver steatosis was observed only in the subgroup of patients with improvement of blood pressure control.

The Preliminary Results of Bortezomib Used as A Primary Treatment for An Early Acute Antibody-Mediated Rejection after Kidney Transplantation-A Single-Center Case Series.

Proteasome inhibitor bortezomib has been used in the treatment of refractory cases of acute and chronic antibody-mediated rejection (AMR) in kidney transplant recipients. However, its efficacy and safety as a primary treatment for early AMR has been scarcely investigated. We herein present our preliminary experience with bortezomib- and plasmapheresis-based primary treatment for early AMR. Thirteen patients transplanted between October 2015 and September 2019 were treated (starting at median 19th post-transplant day) with bortezomib/plasmapheresis protocol for early biopsy-proven AMR. Twelve out of thirteen patients received 4 doses and one patient recieved 3 doses of bortezomib (1.3 mg/m2 per dose). In 11/13 patients, 4-7 concomitant plasmapheresis sessions were performed, with or without intravenous immunoglobulin (IVIG). Of note, rituximab was not used in all study patients. The kidney graft and patient survival were 100%. The mean 3-month estimated glomerular filtration rate (eGFR) was 55.3 (95%CI: 44.9-65.8) mL/min/1.73m2, 8/13 patients completed 12-month follow-up with mean eGFR 60.4 (45.4-75.4) mL/min/1.73m2, and 6/13 patients completed a 24-month follow-up period with mean eGFR 73.9 (56.7-91.1) mL/min/1.73m2. Neutropenia < 1 G/L was observed in one patient, third or fourth grade thrombocytopenia in two patients, and eleven patients needed a blood transfusion (median: 2 units/patient). The mid-term results of a primary bortezomib-based treatment for kidney AMR showed its non-inferiority as compared to preceding regimens and acceptable safety. However, our data should be validated in a multicenter randomized trial.

Arterial stiffness but not endothelial dysfunction is associated with multidrug antihypertensive therapy and nondipper blood pressure pattern in kidney transplant recipients.

Vascular injury related to chronic kidney disease results in increased arterial stiffness and endothelial dysfunction which may affect arterial blood pressure (BP) and influence patient and graft survival in kidney transplant recipients (KTRs).This cross-sectional study aims to elucidate the relationship between the above-mentioned measures of vascular damage and effectiveness of antihypertensive treatment in KTR.One hundred forty-five KTRs 7.6 ±â€Š2.7 years after transplantation were enrolled in our study. Pulse wave velocity (PWV), flow-mediated dilation (FMD), and nitroglycerin-mediated dilation (NMD) were measured, and 24-hour ambulatory BP monitoring was performed.Overall, there were 62 patients with well-controlled or borderline BP and 83 subjects who did not achieve target BP despite antihypertensive treatment. Patients with suboptimal BP control were characterized by greater PWV (median 9.6/interquartile range: 3.9 vs 8.0/3.3 m/s, P = .002), but borderline lower FMD (8.4% ±â€Š5.0% vs 9.9% ±â€Š5.7%; P = .09) as compared with the group with better BP control. When patients were allocated to subgroups based on the number of current antihypertensive medications, no differences in FMD and NMD were found. However, a significant trend was observed for higher PWV values and decreased proportion of dippers along with the increasing number of drugs. PWV, diabetes, and total cholesterol level, but not FMD or NMD, were explanatory variables for systolic BP in multivariate analysis.Arterial stiffness but not endothelial dysfunction is associated with suboptimal BP control in stable KTRs. Less efficient antihypertensive treatment appears to be caused by inadequate control of nocturnal BP.

Administration of Cyclosporine A in Pregnant Rats - the Effect on Blood Pressure and on the Glomerular Number in Their Offspring.

BACKGROUND/AIMS: Cyclosporine A (CsA) is a commonly used immunosuppressive agent. In some patients treatment with CsA has to be continued during pregnancy. The aim of the study was to assess in an experimental model whether the exposure to CsA during fetal life influences the number and volume of glomeruli, kidney function and blood pressure in the offspring. METHODS: Eight pregnant female Sprague-Dawley rats were allocated to 2 treatment regimens: with CsA or solvent. Blood pressure was measured in the offspring at 7 and 11 weeks of age and albuminuria was determined at 11 weeks of age. In the kidney the number and mean volume of glomeruli was assessed using stereological methods. RESULTS: In the offspring of pregnant rats treated with CsA the number of glomeruli was significantly lower and the mean volume of glomeruli was higher when compared to the offspring of pregnant rats receiving solvent. Systolic and diastolic blood pressures as well as albuminuria were significantly higher in the offspring of mothers treated with CsA during gestation compared to the offspring from the control group. CONCLUSIONS: Exposure of rats to CsA during fetal life impairs kidney development, thus potentially predisposing to chronic kidney disease and hypertension in the adult life.

The odontogenic-related microinflammation in patients with chronic kidney disease.

OBJECTIVES: This study estimated plasma levels of interleukin IL-1ß, IL-6, tumour necrosis factor-α (TNF-α), interferon-γ (INF-γ) in chronic kidney disease (CKD) patients with a single odontogenic pathology. MATERIAL AND METHODS: Forty-nine selected adult CKD patients with single odontogenic pathology based on clinical and X-ray examination: patients after proper root canal treatment, without periapical lesions (n = 12), with pulp necrosis (n = 7), with asymptomatic periapical lesions (n = 22), with periodontal disease (n = 8), and 14 with healthy teeth were enrolled. Patients with coexisting different dental pathologies and the evidence of other infection were excluded. In all patients plasma concentrations of CRP, IL-1ß, IL-6, TNF-α, and INF-γ were measured. RESULTS: Patients with periodontitis were characterized by increased concentrations of IL-6 and TNF-α. Those with pulp necrosis had significantly more frequently serum CRP level over 2 mg/L and presented significantly elevated IL-6, but decreased TNF-α concentration than in the subjects with healthy teeth. In patients with periapical lesions and patients after root canal therapy, the concentrations of cytokines did not indicate for the systemic inflammation. CONCLUSIONS: Periodontitis and pulp necrosis are important sources of systemic microinflammation in CKD patients. Plasma concentrations of IL-6 and TNF-α appear to be more sensitive markers of odontogenic inflammation in CKD patients than CRP.