Effects of Cinacalcet on Post-transplantation Hypercalcemia and Hyperparathyroidism in Adult Kidney Transplant Patients: A Single-Center Experience.

OBJECTIVE: Secondary hyperparathyroidism may manifest as hypercalcemia in the post-transplant period. The classical treatment method is parathyroidectomy and the alternative is oral cinacalcet, a calcimimetic agent therapy. We retrospectively investigated the effect of cinacalcet therapy on kidney and patient survival in these patients. MATERIALS AND METHODS: In our single-center, retrospective, observational study, files of 934 patients who underwent renal transplantation in our unit between 2008 and 2022 were reviewed. A total of 23 patients were started on cinacalcet for the treatment of hypercalcemia (calcium > 10.3 mg/dl) and parathyroid hormone (PTH) elevation (>65 pg/ml). Patients with calcium < 10.3 mg/dl and PTH > 700 pg/ml at any time in the follow-up after renal transplantation were included in the study. In addition, the demographic data of the patients, baseline creatine, calcium, phosphorus, and PTH levels at the time of hypercalcemia, parathyroid ultrasonography, parathyroid scintigraphy, creatinine, calcium, phosphorus, and PTH levels in the last controls, and survival status were evaluated. RESULTS:  The mean age of 23 patients included in the study was 52.7 ± 11 years (minimum: 32; maximum: 66). Of the patients, 16 (69.6%) were male, and 15 (65.2%) were transplanted from a living donor. Parathyroid scintigraphic revealed adenoma in three (13%) patients, hyperplasia in five patients (21.7%), and no involvement in 15 patients (65.2%). Cinacalcet treatment was initiated at a median of 33 months (interquartile range (IQR) = 13-96) after the kidney transplant operation. There was no graft loss in the patients during the follow-up period. Twenty-two patients (95.7%) were alive, and one patient died. The calcium level of the patients decreased from 11.3 ± 0.64 mg/dl to 9.98 ± 0.78 mg/dl (p = 0.001) after cinacalcet treatment. Phosphorus values increased from 2.7 ± 0.65 mg/dl to 3.10 ± 0.65 mg/dl (p = 0.004). On the other hand, there was no significant difference in PTH levels between the initial and final controls (285 (IQR = 150-573) vs. 260 pg/ml (IQR = 175-411), p = 0.650). Also, creatinine levels were similar (1.2 ± 0.38 vs. 1.24 ± 0.48 mg/dl, p = 0.43). Despite cinacalcet treatment, calcium levels did not decrease in eight patients. Complications such as renal dysfunction and pathological fracture did not develop in these patients. CONCLUSIONS: It seems that cinacalcet treatment is a suitable option for patients with hypercalcemia and/or hyperparathyroidism with low drug interactions and good biochemical control after renal transplantation.

Peripheral innate and adaptive immune cells during COVID-19: Functional neutrophils, pro-inflammatory monocytes, and half-dead lymphocytes.

BACKGROUND: A better understanding of innate and adaptive cells in COVID-19 is necessary for the development of effective treatment methods and vaccines. METHODS: We studied phenotypic features of innate and adaptive immune cells, oxidative burst, phagocytosis, and apoptosis. One hundred and three patients with COVID-19 were grouped according to their clinical features into the categories of mild (35%), moderate (40.8%), and severe (24.3%). RESULTS: Monocytes were CD16+ pro-inflammatory monocytes and tended to shed their HLA-DR, especially in severe cases (p < 0.01). Neutrophils were mature and functional, although a decline of their CD10 and CD16 was observed (p < 0.01). No defect was found in the reactive oxygen species production and their apoptosis. The percentage of natural killer cells was in the normal range, whereas the percentages of CD8+ NK and CD56+ T lymphocytes were found to be high (p < 0.01). Although the absolute numbers of all lymphocyte subsets were low and showed a tendency for a gradual decrease in accordance with the disease progression, the most decreased absolute number was that of B lymphocytes, followed by CD4+ T cells in the severe cases. The percentages of double-negative T cells; HLA-DR+ CD3+ and CD28- CD8+ subsets were found to be significantly increased. Importantly, we demonstrated the increased baseline activation of caspase-3 and increased lymphocyte apoptosis. CONCLUSION: We suggest that SARS-CoV-2 primarily affects the lymphocytes and not the innate cells. The increased baseline activation of Caspase-3 could make the COVID-19 lymphocytes more vulnerable to cell death. Therefore, this may interrupt the crosstalk between the adaptive and innate immune systems.

Immunological parameters associated with the severity of COVID-19 pneumonia in kidney transplant recipients.

PURPOSE: An outbreak of a novel respiratory disease due to coronavirus species was emerged in 2019 and named as Coronavirus Disease-2019 (COVID-19). Clinical and immunological factors affecting the course of COVID-19 in kidney transplant recipients (KTR) are not well-known. METHODS: In this prospective observational study, we presented 20 KTR with COVID-19 pnemonia and examined the factors predicting the severity of COVID-19. A total of 10 KTR without COVID-19 was used as control group. Lymphocyte subsets were determined by flow cytometry. In 13/20 patients, immunophenotyping was repeated 1 week later. RESULTS: Mean age of the patients was 50 ± 9 years. Patients were classified as mild-moderate (oxygen saturation: SO2 > 90%) and severe disease groups (SO2 ≤ 90%). Serum albumin and hemoglobin were lower and CRP, fibrinogen and peak D-dimer were higher in severe group. Peak CRP was inversely associated with nadir SO2 (r = - 0.68, p = 0.001). Neutrophil/lymphocyte ratio was higher in severe group (p = 0.01). CD3 + and CD4 + cells were lower and NK cell percentage (CD16 + 56 +) was higher in severe group. Percentage of spontaneously activated CD8 cells (CD8 + CD69 +) was higher in severe group. In comparison of KTR with and without COVID-19, CD8 + cells were lower but NK cell percentage was higher in KTR with COVID-19. CONCLUSION: In this pilot study, increased NK cells, activated CD8 + cells and decreased CD3 + and CD4 + cells were associated with severity of COVID-19 in KTR. Peripheral immunophenotyping of lymphocyte subtypes may provide prognostic information about the clinical course of COVID-19 in KTR.

Predicting the outcome of COVID-19 infection in kidney transplant recipients.

BACKGROUND: We aimed to present the demographic characteristics, clinical presentation, and outcomes of our multicenter cohort of adult KTx recipients with COVID-19. METHODS: We conducted a multicenter, retrospective study using data of patients hospitalized for COVID-19 collected from 34 centers in Turkey. Demographic characteristics, clinical findings, laboratory parameters (hemogram, CRP, AST, ALT, LDH, and ferritin) at admission and follow-up, and treatment strategies were reviewed. Predictors of poor clinical outcomes were analyzed. The primary outcomes were in-hospital mortality and the need for ICU admission. The secondary outcome was composite in-hospital mortality and/or ICU admission. RESULTS: One hundred nine patients (male/female: 63/46, mean age: 48.4 ± 12.4 years) were included in the study. Acute kidney injury (AKI) developed in 46 (42.2%) patients, and 4 (3.7%) of the patients required renal replacement therapy (RRT). A total of 22 (20.2%) patients were admitted in the ICU, and 19 (17.4%) patients required invasive mechanical ventilation. 14 (12.8%) of the patients died. Patients who were admitted in the ICU were significantly older (age over 60 years) (38.1% vs 14.9%, p = 0.016). 23 (21.1%) patients reached to composite outcome and these patients were significantly older (age over 60 years) (39.1% vs. 13.9%; p = 0.004), and had lower serum albumin (3.4 g/dl [2.9-3.8] vs. 3.8 g/dl [3.5-4.1], p = 0.002), higher serum ferritin (679 µg/L [184-2260] vs. 331 µg/L [128-839], p = 0.048), and lower lymphocyte counts (700/µl [460-950] vs. 860 /µl [545-1385], p = 0.018). Multivariable analysis identified presence of ischemic heart disease and initial serum creatinine levels as independent risk factors for mortality, whereas age over 60 years and initial serum creatinine levels were independently associated with ICU admission. On analysis for predicting secondary outcome, age above 60 and initial lymphocyte count were found to be independent variables in multivariable analysis. CONCLUSION: Over the age of 60, ischemic heart disease, lymphopenia, poor graft function were independent risk factors for severe COVID-19 in this patient group. Whereas presence of ischemic heart disease and poor graft function were independently associated with mortality.

Mortality analysis of COVID-19 infection in chronic kidney disease, haemodialysis and renal transplant patients compared with patients without kidney disease: a nationwide analysis from Turkey.

BACKGROUND: Chronic kidney disease (CKD) and immunosuppression, such as in renal transplantation (RT), stand as one of the established potential risk factors for severe coronavirus disease 2019 (COVID-19). Case morbidity and mortality rates for any type of infection have always been much higher in CKD, haemodialysis (HD) and RT patients than in the general population. A large study comparing COVID-19 outcome in moderate to advanced CKD (Stages 3-5), HD and RT patients with a control group of patients is still lacking. METHODS: We conducted a multicentre, retrospective, observational study, involving hospitalized adult patients with COVID-19 from 47 centres in Turkey. Patients with CKD Stages 3-5, chronic HD and RT were compared with patients who had COVID-19 but no kidney disease. Demographics, comorbidities, medications, laboratory tests, COVID-19 treatments and outcome [in-hospital mortality and combined in-hospital outcome mortality or admission to the intensive care unit (ICU)] were compared. RESULTS: A total of 1210 patients were included [median age, 61 (quartile 1-quartile 3 48-71) years, female 551 (45.5%)] composed of four groups: control (n = 450), HD (n = 390), RT (n = 81) and CKD (n = 289). The ICU admission rate was 266/1210 (22.0%). A total of 172/1210 (14.2%) patients died. The ICU admission and in-hospital mortality rates in the CKD group [114/289 (39.4%); 95% confidence interval (CI) 33.9-45.2; and 82/289 (28.4%); 95% CI 23.9-34.5)] were significantly higher than the other groups: HD = 99/390 (25.4%; 95% CI 21.3-29.9; P < 0.001) and 63/390 (16.2%; 95% CI 13.0-20.4; P < 0.001); RT = 17/81 (21.0%; 95% CI 13.2-30.8; P = 0.002) and 9/81 (11.1%; 95% CI 5.7-19.5; P = 0.001); and control = 36/450 (8.0%; 95% CI 5.8-10.8; P < 0.001) and 18/450 (4%; 95% CI 2.5-6.2; P < 0.001). Adjusted mortality and adjusted combined outcomes in CKD group and HD groups were significantly higher than the control group [hazard ratio (HR) (95% CI) CKD: 2.88 (1.52-5.44); P = 0.001; 2.44 (1.35-4.40); P = 0.003; HD: 2.32 (1.21-4.46); P = 0.011; 2.25 (1.23-4.12); P = 0.008), respectively], but these were not significantly different in the RT from in the control group [HR (95% CI) 1.89 (0.76-4.72); P = 0.169; 1.87 (0.81-4.28); P = 0.138, respectively]. CONCLUSIONS: Hospitalized COVID-19 patients with CKDs, including Stages 3-5 CKD, HD and RT, have significantly higher mortality than patients without kidney disease. Stages 3-5 CKD patients have an in-hospital mortality rate as much as HD patients, which may be in part because of similar age and comorbidity burden. We were unable to assess if RT patients were or were not at increased risk for in-hospital mortality because of the relatively small sample size of the RT patients in this study.

Renal Transplantation in High Immunological Risk Patients: A Single-Center Experience.

BACKGROUND: Renal transplantation (RT) in high-risk patients is increasingly performed due to an inadequate organ pool and increased rate of RT after a failed transplantation. Safety and prognosis of RT in such patients with high risk is an ongoing debate. Herein we aimed to present our single-center experience on RT of high-risk patients. METHODS: A total of 89 consecutive RT patients were included into this study in a 10-month period. Patients were divided into 3 groups: the low-risk group (n = 47) with negative panel reactive antibody (PRA), medium-risk group (n = 18) with positive PRA but mean fluorescence intensity (MFI) < 2000, and high-risk group (n = 24) with positive PRA and MFI >2000 or donor specific antibody (DSA) positivity. Groups were compared in terms of demographic features, serum creatinine levels, acute rejection rates, delayed graft function (DGF), and patient or graft loss. RESULTS: Age of the recipients were similar between the groups. Desensitization (7% vs 11% vs 42%, respectively, in low-, medium-, and high-risk groups; P = .001), plasmapheresis (6% vs 11% vs 46%, respectively, P < .001), and rituximab treatments (0% vs 0% vs 25%, respectively, P < .001) were significantly more frequently performed in high-risk patients. Serum creatinine levels at 1 month and 6 months after RT were similar between the groups (P = .43 and P = .71, respectively). Rates of acute rejection (6% vs 6% vs 16%, respectively, P = .52) and DGF (9% vs 11% vs 29%, respectively, P = .15) were similar between the groups. Frequencies of loss of patient or graft were also similar (0% vs 6% vs 4%, P = .15). CONCLUSION: RT may be successfully performed in high-risk patients without an increase in the risk of acute rejection, DGF, or patient/graft loss.

Renal Transplantation in Patients With Atypical Hemolytic Uremic Syndrome: A Single Center Experience.

PURPOSE: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic anemia, thrombocytopenia, and acute kidney injury. HUS is mostly associated with diarrhea (90%). However, 10% of cases are not associated with diarrhea and are thus called as atypical HUS (aHUS); these cases are usually caused by dysregulation of the complement system. Eculizumab, a monoclonal antibody against C5, is the drug of choice for treating aHUS. Herein we aimed to present 8 cases of renal transplantation performed on patients with aHUS. MATERIALS AND METHODS: A total of 8 patients who had been diagnosed with aHUS between the years 2012 to 2018 were enrolled and underwent transplantations. All patients received induction treatment, standard immunosuppresive treatment (tacrolimus, mycophenolic acid, prednisolone), and eculizumab. Eculizumab was administered at a dosage of 900 mg/wk for the first month and 1200 mg every 2 weeks thereafter. Patients were followed up and recorded in terms of demographic features, serum creatinine, lactate dehydrogenase, acute rejection episodes, and allograft outcomes. RESULTS: Mean age was 34 ± 8 years (Male/Female: 6/2). One of the patients had a second transplantation. Median hemodialysis vintage (25%-75% interquartile range) was 37 (9-63) months. Four patients had pretransplant plasmapheresis and 2 patients had posttransplant plasmapheresis. Induction treatment was ATG in 7 patients, and basiliximab was used only in 1 patient. The median follow-up period was 25 (13-59) months. Mean serum creatinine levels were 1.9 ± .6, 1.2 ± .7, and 1 ± .1 mg/dL for the first day, first month, and last values, respectively. Mean lactate dehydrogenase levels were 286 ± 203, 239 ± 27, and 218 ± 86 U/L for first day, first month, and last values, respectively. None of the patients had an acute rejection episode. Currently, all patients have functioning allografts. CONCLUSION: Patients with aHUS may be transplanted successfully with eculizumab with good allograft outcomes.

Volume status and arterial blood pressures are associated with arterial stiffness in hemodialysis patients.

BACKGROUND: Arterial stiffness is a strong predictor of mortality in hemodialysis patients. In this study, we aimed to investigate possible relations of arterial stiffness with volume status determined by bioimpedance analysis and aortic blood pressure parameters. Also, effects of a single hemodialysis session on these parameters were studied. METHODS: A total of 75 hemodialysis patients (M/F: 43/32; mean age: 53 ± 17) were enrolled. Carotid-femoral pulse wave velocity, augmentation index, and aortic pulse pressure were measured by applanation tonometry before and after hemodialysis. Extracellular fluid and total body fluid volumes were determined by bioimpedance analysis. RESULTS: Carotid-femoral pulse wave velocity (9.30 ± 3.30 vs 7.59 ± 2.66 m/s, p < 0.001), augmentation index (24.52 ± 9.42 vs 20.28 ± 10.19, p < 0.001), and aortic pulse pressure (38 ± 14 vs 29 ± 8 mmHg, p < 0.001) significantly decreased after hemodialysis. Pre-dialysis carotid-femoral pulse wave velocity was associated with age (r2 = 0.15, p = 0.01), total cholesterol (r2 = 0.06, p = 0.02), peripheral mean blood pressure (r2 = 0.10, p = 0.005), aortic-mean blood pressure (r2 = 0.06, p = 0.02), aortic pulse pressure (r2 = 0.14, p = 0.001), and extracellular fluid/total body fluid (r2 = 0.30, p < 0.0001). Pre-dialysis augmentation index was associated with total cholesterol (r2 = 0.06, p = 0,02), aortic-mean blood pressure (r2 = 0.16, p < 0.001), and aortic pulse pressure (r2 = 0.22, p < 0.001). Δcarotid-femoral pulse wave velocity was associated with Δaortic-mean blood pressure (r2 = 0.06, p = 0.02) and inversely correlated with baseline carotid-femoral pulse wave velocity (r2 = 0.29, p < 0.001). Pre-dialysis Δaugmentation index was significantly associated with Δaortic-mean blood pressure (r2 = 0.09, p = 0.009) and Δaortic pulse pressure (r2 = 0.06, p = 0.03) and inversely associated with baseline augmentation index (r2 = 0.14, p = 0.001). In multiple linear regression analysis (adjusted R2 = 0.46, p < 0.001) to determine the factors predicting Log carotid-femoral pulse wave velocity, extracellular fluid/total body fluid and peripheral mean blood pressure significantly predicted Log carotid-femoral pulse wave velocity (p = 0.001 and p = 0.006, respectively). CONCLUSION: Carotid-femoral pulse wave velocity, augmentation index, and aortic pulse pressure significantly decreased after hemodialysis. Arterial stiffness was associated with both peripheral and aortic blood pressure. Furthermore, reduction in arterial stiffness parameters was related to reduction in aortic blood pressure. Pre-dialysis carotid-femoral pulse wave velocity was associated with volume status determined by bioimpedance analysis. Volume control may improve not only the aortic blood pressure measurements but also arterial stiffness in hemodialysis patients.

Interferon Induced Focal Segmental Glomerulosclerosis.

Behçet's disease is an inflammatory disease of unknown etiology which involves recurring oral and genital aphthous ulcers and ocular lesions as well as articular, vascular, and nervous system involvement. Focal segmental glomerulosclerosis (FSGS) is usually seen in viral infections, immune deficiency syndrome, sickle cell anemia, and hyperfiltration and secondary to interferon therapy. Here, we present a case of FSGS identified with kidney biopsy in a patient who had been diagnosed with Behçet's disease and received interferon-alpha treatment for uveitis and presented with acute renal failure and nephrotic syndrome associated with interferon.

Influence of conversion from calcineurin inhibitors to everolimus on fibrosis, inflammation, tubular damage and vascular function in renal transplant patients.

BACKGROUND: Conversion from calcineurin inhibitor (CNI) to mTOR inhibitors may reduce and even halt the progression of chronic allograft dysfunction (CAD) which is the most important cause of renal allograft loss. We aimed to investigate the effects of conversion from CNI to everolimus on parameters of fibrosis, inflammation, glomerulotubular damage and vascular functions in renal transplant recipients. METHODS: Fifteen stable renal transplant recipients who were under CNI treatment (male/female 13/2, mean age 41 ± 10 years) were enrolled and switched to everolimus. Serum and urinary transforming growth factor-ß (TGF-ß), urinary neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein-1 (MCP-1) were measured as markers of fibrosis, tubular damage and inflammation. As parameters of vascular functions, pulse wave velocity (PWV), augmentation index (AIx), serum asymmetric dimethyl-arginine and fibroblast growth factor-23 (FGF-23) were measured. All these measurements were repeated at the 3rd month of conversion. RESULTS: Estimated GFR (52 ± 7-57 ± 11 ml/min/l.73 m(2), p = 0.02) (was increased after conversion to everolimus. However, serum uric acid levels were significantly decreased (6.21 ± 1.21-5.50 ± 1.39 mg/dL, p = 0.01). Serum TGF-ß levels (8727 ± 2897-1943 ± 365 pg/mL, p = 0.03) and urinary NGAL levels (26 ± 10-12 ± 2 ng/mg creatinine, p = 0.05) were significantly decreased. However, urinary MCP-1, FGF-23, PWV and AIx did not change. Urinary TGF-ß was associated with urinary NGAL (r = 0.62, p = 0.01), urinary MCP-1 (r = 0.68, p = 0.005) and proteinuria (r = 0.50, p = 0.05). CONCLUSION: Conversion from CNI to everolimus resulted in significant decreases of serum TGF-ß and urinary NGAL which may represent less fibrosis and tubular damage. Association of urinary TGF-ß with NGAL and MCP-1 suggests that tubular damage, fibrosis and inflammation may act together for progression of CAD.

Cardiac biomarkers and noninvasive predictors of atherosclerosis in chronic peritoneal dialysis patients.

BACKGROUND: We investigated the relationship among serum cardiac biomarkers including N-terminal pro-brain natriuretic peptide (NT-pro-BNP), cardiac troponin T (cTnT), uric acid and high-sensitive C-reactive protein (hs-CRP) and noninvasive predictors of atherosclerosis including carotid intima-media thickness (IMT), aortic stiffness (pulse wave velocity (PWV)) and transthoracic coronary flow reserve (CFR) in peritoneal dialysis (PD) patients. METHODS: 37 PD patients were included in the study. We measured (1) carotid IMT, (2) PWV and augmentation index (AIx), and (3) CFR. Simultaneous measurements of serum NT-pro-BNP, cTnT, uric acid and hs-CRP were also performed. Associations among these variables were analyzed. RESULTS: cTnT was significantly associated with carotid IMT (r = 0.747, p < 0.001), PWV (r = 0.431, p = 0.035) and CFR (r = -0.439, p = 0.007). In multivariate analysis, cTnT was a significant independent predictor of carotid IMT (ß = 4.446, p < 0.001) and CFR (ß = -2.272, p = 0.013). Patients with high cTnT levels (≥0.01 ng/ml) significantly hadhigher carotid IMT and PWV values. Only the aortic PWV significantly correlated with residual renal function (r = -0.574, p = 0.004). CONCLUSIONS: Serum cTnT appeared to be a useful clinical biomarker for evaluating noninvasive predictors of atherosclerosis in chronic PD patients. Arterial stiffness as determined by PWV is also correlated with residual renal function.