Urinary Dickkopf 3 Is Not an Independent Risk Factor in a Cohort of Kidney Transplant Recipients and Living Donors.

Urinary dickkopf 3 (uDKK3) is a marker released by kidney tubular epithelial cells that is associated with the progression of chronic kidney disease (CKD) and may cause interstitial fibrosis and tubular atrophy. Recent evidence suggests that uDKK3 can also predict the loss of kidney function in CKD patients and kidney transplant recipients, regardless of their current renal function. We conducted a prospective study on 181 kidney transplant (KTx) recipients who underwent allograft biopsy to determine the cause, analyzing the relationship between uDKK3 levels in urine, histological findings, and future allograft function progression. Additionally, we studied 82 living kidney donors before unilateral nephrectomy (Nx), 1-3 days after surgery, and 1 year post-surgery to observe the effects of rapid kidney function loss. In living donors, the uDKK3/creatinine ratio significantly increased 5.3-fold 1-3 days after Nx. However, it decreased significantly to a median level of 620 pg/mg after one year, despite the absence of underlying primary kidney pathology. The estimated glomerular filtration rate (eGFR) decreased by an average of 29.3% to approximately 66.5 (±13.5) mL/min/1.73 m2 after one year, with no further decline in the subsequent years. uDKK3 levels increased in line with eGFR loss after Nx, followed by a decrease as the eGFR partially recovered within the following year. However, uDKK3 did not correlate with the eGFR at the single time points in living donors. In KTx recipients, the uDKK3/creatinine ratio was significantly elevated with a median of 1550 pg/mg compared to healthy individuals or donors after Nx. The mean eGFR in the recipient group was 35.5 mL/min/1.73 m2. The uDKK3/creatinine ratio was statistically associated with the eGFR at biopsy but was not independently associated with the eGFR one year after biopsy or allograft loss. In conclusion, uDKK3 correlates with recent and future kidney function and kidney allograft survival in the renal transplant cohort. Nevertheless, our findings indicate that the uDKK3/creatinine ratio has no prognostic influence on future renal outcome in living donors and kidney recipients beyond the eGFR, independent of the presence of acute renal graft pathology, as correlations are GFR-dependent.

Corrigendum: Novel Therapeutic Strategies for Dyslipidemia: First Report of Inclisiran Therapy in a Kidney Transplanted Patient.

[This corrects the article DOI: 10.3389/ti.2023.11104.].

Fast Tacrolimus Metabolism Does Not Promote Post-Transplant Diabetes Mellitus after Kidney Transplantation.

Post-transplant diabetes mellitus (PTDM) after kidney transplantation induced by tacrolimus is an important issue. Fast tacrolimus metabolism, which can be estimated by concentration-to-dose (C/D) ratio, is associated with increased nephrotoxicity and unfavorable outcomes after kidney transplantation. Herein, we elucidate whether fast tacrolimus metabolism also increases the risk for PTDM. Data from 596 non-diabetic patients treated with tacrolimus-based immunosuppression at the time of kidney transplantation between 2007 and 2015 were retrospectively analyzed. The median follow-up time after kidney transplantation was 4.7 years (IQR 4.2 years). Our analysis was complemented by experimental modeling of fast and slow tacrolimus metabolism kinetics in cultured insulin-producing pancreatic cells (INS-1 cells). During the follow-up period, 117 (19.6%) patients developed PTDM. Of all patients, 210 (35.2%) were classified as fast metabolizers (C/D ratio < 1.05 ng/mL × 1/mg). Fast tacrolimus metabolizers did not have a higher incidence of PTDM than slow tacrolimus metabolizers (p = 0.496). Consistent with this, insulin secretion and the viability of tacrolimus-treated INS-1 cells exposed to 12 h of tacrolimus concentrations analogous to the serum profiles of fast or slow tacrolimus metabolizers or to continuous exposure did not differ (p = 0.286). In conclusion, fast tacrolimus metabolism is not associated with increased incidence of PTDM after kidney transplantation, either in vitro or in vivo. A short period of incubation of INS-1 cells with tacrolimus using different concentration profiles led to comparable effects on cell viability and insulin secretion in vitro. Consistent with this, in our patient, collective fast Tac metabolizers did not show a higher PTDM incidence compared to slow metabolizers.

Exercise capacity, cardiovascular and metabolic risk of the sample of German police officers in a descriptive international comparison.

Background: The police force has the mandate to protect citizens and enforce the law for public safety. Employment in the police force is recognized as a dangerous occupation and characterized by job-related physical hazards. Therefore, good health and adequate physical condition are necessary. This study aimed to determine cardiovascular, cardiorespiratory, and metabolic risk parameters of German police officers (POs) in comparison to POs from other nations. Methods: 55 male police officers from Germany participated in the survey. We examined anthropometric measurements, cardiovascular/metabolic risk factors and blood parameters. Additionally, we calculated 10-year cardiovascular risk using the Framingham Risk Score. The diagnosis of metabolic syndrome bases on the criteria of the International Diabetes Federation. We assessed cardiorespiratory status by exercise spirometry. Results: The analyzed group of POs demonstrated a high prevalence of pre obesity (BMI: 28.0±3.2 kg/m², waist circumference: 97.8±12.4 cm). 61.8 % of POs showed an increased waist circumference. POs showed high prevalence of abnormal values of triglyceride (n: 24, 43,6%), and systolic (n: 29, 52,7%) and diastolic (n: 27, 49%) blood pressure. The average 10-year cardiovascular risk (by Framingham) was classified as moderate (9.6 ± 7.4 %). 32 % (n: 18) of POs in our study group were diagnosed with metabolic syndrome. Maximal relative oxygen uptake of POs was 34.1 ± 8.0 ·ml/kg-1 ·min-1. Conclusions: To our knowledge, this study was one of the first to assess data on cardiovascular health, metabolic syndrome and cardiorespiratory status of police officers in Germany. The results of our study demonstrated an increased cardiovascular and metabolic risk and decreased cardiorespiratory fitness in German police officers. The present study results underline the need to implement health-promoting interventions and concepts like corporate sports activities or nutrition courses to counteract cardiovascular and metabolic risk factors. We have to reduce the subsequent development of cardiovascular and metabolic disease in this occupational group.

α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes.

Fabry disease (FD) is caused by mutations in the α-galactosidase A (GLA) gene encoding the lysosomal AGAL enzyme. Loss of enzymatic AGAL activity and cellular accumulation of sphingolipids (mainly globotriaosylcermide) may lead to podocyturia and renal loss of function with increased cardiovascular morbidity and mortality in affected patients. To identify dysregulated cellular pathways in FD, we established a stable AGAL-deficient podocyte cell line to perform a comprehensive proteome analysis. Imbalanced protein expression and function were analyzed in additional FD cell lines including endothelial, epithelial kidney, patient-derived urinary cells and kidney biopsies. AGAL-deficient podocytes showed dysregulated proteins involved in thermogenesis, lysosomal trafficking and function, metabolic activity, cell-cell interactions and cell cycle. Proteins associated with neurological diseases were upregulated in AGAL-deficient podocytes. Rescues with inducible AGAL expression only partially normalized protein expression. A disturbed protein expression was confirmed in endothelial, epithelial and patient-specific cells, pointing toward fundamental pathway disturbances rather than to cell type-specific alterations in FD. We conclude that a loss of AGAL function results in profound changes of cellular pathways, which are ubiquitously in different cell types. Due to these profound alterations, current approved FD-specific therapies may not be sufficient to completely reverse all dysregulated pathways.

Specific scoring systems to predict survival of patients with high-risk myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) after intensive antileukemic treatment based on results of the EORTC-GIMEMA AML-10 and intergroup CRIANT studies.

High-risk myelodysplastic syndrome (MDS) patients have usually a less favorable outcome after intensive treatment compared with de novo acute myeloid leukemia (AML) patients. This may reflect different disease-related and patient-related factors. The purpose of this analysis is to identify disease-specific prognostic factors and to develop prognostic scores for both patient groups. A total of 692 patients in the EORTC/GIMEMA AML-10 study and 289 patients in the CRIANT study received identical remission-induction and consolidation treatment. Estimated 5-year survival rate was 34 % in the AML-10 versus 27 % in the CRIANT study, and estimated disease-free survival was 40 % versus 28 %, respectively. In multivariate analysis, cytogenetic characteristics, white blood count, and age appeared prognostic for survival in both studies. French-American-British (FAB) subtype and performance status were prognostic in the AML-10 study only, whereas number of cytopenias and duration of antecedent hematologic disorder >6 months were prognostic in the CRIANT study only. The prognostic scores distinguish three groups with a 5-year survival rate of 54, 38, and 19 % in the AML-10 study versus 69, 37, and 5 % in the CRIANT study. The prognostic value of these scores has been validated on two external series. The new scoring systems form a practical tool to predict the outcome of individual MDS and AML patients treated with intensive antileukemic therapy.

Structural and functional cardiac parameters across occupations: a cross-sectional study in differing work environments.

Previous investigations have highlighted notable variations in cardiovascular risk indicators associated with various professional categories. However, only a few studies have examined structural and functional cardiac parameters using echocardiography within distinct occupational groups. Hence, this study endeavored to assess cardiac structural and functional parameters in three additional occupations: firefighters (FFs), police officers (POs), and office workers (OWs). This prospective study encompassed 197 male participants (97 FFs, 54 POs, and 46 OWs) from Germany. All participants underwent 2D and Doppler echocardiography in resting conditions; standard parasternal and apical axis views were employed to evaluate structural (diastolic and systolic) and functional (systolic and diastolic function, and strain) cardiac parameters. All three occupational groups exhibited a tendency towards septal hypertrophy. Notably, OWs exhibited the largest diastolic interventricular septum diameter (IVSd), at 1.33 ± 0.25 cm. IVSd significantly varied between POs and OWs (p = 0.000) and between POs and FFs (p = 0.025). Additionally, during diastole a substantially larger left ventricular posterior wall diameter (LVPWd) was observed in OWs compared to FFs (p = 0.001) and POs (p = 0.013). The left ventricular diastolic cavity diameter (LVIDd) and the left ventricular systolic cavity diameter (LVIDs) were significantly higher in POs than they were in FFs (LVIDd: p = 0.001; LVIDs: p = 0.009), and the LVIDd was notably higher in FFs (p = 0.015) and POs compared to OWs (p = 0.000). FFs exhibited significantly better diastolic function, indicated by higher diastolic peak velocity ratios (MV E/A ratio) and E/E' ratios, compared to POs (E/A ratio: p = 0.025; E/E' ratio: p = 0.014). No significant difference in diastolic performance was found between OWs and FFs. Significantly higher E'(lateral) values were noted in POs compared to FFs (p = 0.003) and OWs (p = 0.004). Ejection fraction did not significantly differ among FFs, POs, and OWs (p > 0.6). The left ventricular mass (LV Mass) was notably higher in POs than it was in FFs (p = 0.039) and OWs (p = 0.033). Strain parameter differences were notably improved in two- (p = 0.006) and four-chamber (p = 0.018) views for FFs compared to POs. Concentric remodeling was the predominant change observed in all three occupational groups. Significant differences in the presence of various forms of hypertrophy were observed in FFs, POs, and OWs (exact Fisher test p-values: FFs vs. OWs = 0.021, POs vs. OWs = 0.002). OWs demonstrated notably higher rates of concentric remodeling than FFs did (71.77% vs. 47.9%). This study underscores disparities in both functional and structural parameters in diverse occupational groups. Larger prospective studies are warranted to investigate and delineate differences in structural and functional cardiac parameters across occupational groups, and to discern their associated effects and risks on the cardiovascular health of these distinct professional cohorts.

Hydroxychloroquine-Induced Renal Phospholipidosis: Case Report and Review of Differential Diagnoses.

Introduction: Renal phospholipidosis describes the accumulation of phospholipids in the lysosomes of kidney cells, in particular podocytes. Originally, this was described primarily in the context of the lysosomal storage disorder Fabry disease. It is now known that a variety of drugs can lead to the accumulation of lysosomal phospholipids. Case Presentation: We present the case of a 69-year-old female patient suffering chronic kidney disease and systemic lupus erythematosus who underwent a kidney biopsy because of a further increase in serum creatinine levels. There was no evidence of lupus nephritis, but electron microscopy showed zebra bodies as a morphological sign of phospholipidosis. This was most likely drug-induced after 25 years of continuous medication with hydroxychloroquine. A renal biopsy 2 years and 6 months earlier, when the renal function of the patient was distinctively better, showed no signs of renal phospholipidosis. Afterward, medication with hydroxychloroquine was discontinued, and renal function parameters remained stable in the 1-year course. Conclusion: This case raises the question of how severely impaired renal function affects the risk of hydroxychloroquine-induced renal phospholipidosis and underlines that hydroxychloroquine should be administered with caution in patients with kidney insufficiency. Moreover, we provide a review of the causes of renal phospholipidosis, which have been described in the literature and give an overview of possible differential diagnoses in cases with histologically proven phospholipidosis in renal biopsies.

Unveiling systemic responses in kidney transplantation: interplay between the allograft transcriptome and serum proteins.

Immunity, as defined by systems biology, encompasses a holistic response throughout the body, characterized by intricate connections with various tissues and compartments. However, this concept has been rarely explored in kidney transplantation. In this proof-of-concept study, we investigated a direct association between the allograft phenotype and serum protein signatures. Time-matched samples of graft biopsies and blood serum were collected in a heterogeneous cohort of kidney-transplanted patients (n = 15) for bulk RNA sequencing and proteomics, respectively. RNA transcripts exhibit distinct and reproducible, coregulated gene networks with specific functional profiles. We measured 159 serum proteins and investigated correlations with gene expression networks. Two opposing axes-one related to metabolism and the other to inflammation-were identified. They may represent a biological continuum between the allograft and the serum and correlate with allograft function, but not with interstitial fibrosis or proteinuria. For signature validation, we used two independent proteomic data sets (n = 21). Our findings establish a biological link between the allograft transcriptome and the blood serum proteome, highlighting systemic immune effects in kidney transplantation and offering a promising framework for developing allograft-linked biomarkers.

Tacrolimus-why pharmacokinetics matter in the clinic.

The calcineurin inhibitor (CNI) Tacrolimus (Tac) is the most prescribed immunosuppressant drug after solid organ transplantation. After renal transplantation (RTx) approximately 95% of recipients are discharged with a Tac-based immunosuppressive regime. Despite the high immunosuppressive efficacy, its adverse effects, narrow therapeutic window and high intra- and interpatient variability (IPV) in pharmacokinetics require therapeutic drug monitoring (TDM), which makes treatment with Tac a major challenge for physicians. The C/D ratio (full blood trough level normalized by daily dose) is able to classify patients receiving Tac into two major metabolism groups, which were significantly associated with the clinical outcomes of patients after renal or liver transplantation. Therefore, the C/D ratio is a simple but effective tool to identify patients at risk of an unfavorable outcome. This review highlights the challenges of Tac-based immunosuppressive therapy faced by transplant physicians in their daily routine, the underlying causes and pharmacokinetics (including genetics, interactions, and differences between available Tac formulations), and the latest data on potential solutions to optimize treatment of high-risk patients.

Plasma protein signatures reflect systemic immunity and allograft function in kidney transplantation.

Kidney transplantation causes large perturbations of the immune system. While many studies focus on the allograft, insights into systemic effects are largely missing. Here, we analyzed the systemic immune response in 3 cohorts of kidney transplanted patients. Using serum proteomics, laboratory values, mass cytometry, histological and clinical parameters, inter-patient heterogeneity was leveraged for multi-omic co-variation analysis. We identified circulating immune modules (CIM) that describe extra-renal signatures of co-regulated plasma proteins. CIM are present in nontransplanted controls, in transplant conditions and during rejection. They are enriched in pathways linked to kidney function, extracellular matrix, signaling, and cellular activation. A complex leukocyte response in the blood during allograft quiescence and rejection is associated with CIM activity and CIM-specific cytokines. CIM activity correlates with kidney function including a 2-month prediction. Together, the data suggest a systemic and multi-layered response of transplant immunity that might be insightful for understanding allograft dysfunction and developing translational biomarkers.

Belatacept as a Treatment Option in Patients with Severe BK Polyomavirus Infection and High Immunological Risk-Walking a Tightrope between Viral Control and Prevention of Rejection.

Balancing the immune system with immunosuppressive treatment is essential in kidney transplant recipients to avoid allograft rejection on the one hand and infectious complications on the other. BK polyomavirus nephropathy (BKPyVAN) is a viral complication that seriously threatens kidney allograft survival. Therefore, the main treatment strategy is to reduce immunosuppression, but this is associated with an increased rejection risk. Belatacept is an immunosuppressant that acts by blocking the CD80/86-CD28 co-stimulatory pathway of effector T-cells with marked effects on the humoral response. However, when compared with calcineurin-inhibitors (CNI), the cellular rejection rate is higher. With this in mind, we hypothesized that belatacept could be used as rescue therapy in severely BKPyV-affected patients with high immunological risk. We present three cases of patients with BKPyVAN-associated complications and donor-specific antibodies (DSA) and one patient who developed T-cell-mediated rejection after a reduction in immunosuppression in response to BKPyVAN. Patients were switched to a belatacept-based immunosuppressive regimen and showed significantly improved viral control and stabilized graft function. The cases presented here suggest that belatacept is a potential treatment option in the complicated situation of refractory BKPyV infection in patients with high immunological risk.

A Novel Homozygous Mutation in the COL4A4 Gene (Gly1436del) Causing Alport Syndrome Exposed by Pregnancy: A Case Report and Review of the Literature.

BACKGROUND: Alport syndrome results from a hereditary defect of collagen IV synthesis. This causes progressive glomerular disease, ocular abnormalities, and inner ear impairment. Case Presentation. Herein, we present a case of Alport syndrome in a 28-year-old woman caused by a novel mutation (Gly1436del) in the COL4A4 gene that was not unveiled until her first pregnancy. Within the 29th pregnancy week, our patient presented with massive proteinuria and nephrotic syndrome. Light microscopic examination of a kidney biopsy showed typical histological features of segmental sclerosis, and electron microscopy revealed extensive podocyte alterations as well as thickness of glomerular basement membranes with splitting of the lamina densa. One and a half years after childbirth, renal function deteriorated to a preterminal stage, whereas nephrotic syndrome subsided quickly after delivery. CONCLUSION: This case report highlights the awareness of atypical AS courses and emphasizes the importance of genetic testing in such cases.

Improved Kidney Allograft Function after Early Conversion of Fast IR-Tac Metabolizers to LCP-Tac.

Fast tacrolimus (Tac) metabolism is associated with a more rapid decline of renal function after renal transplantation (RTx). Because the pharmacokinetics of LCP-Tac (LCPT) and immediate-release Tac (IR-Tac) differ, we hypothesized that switching from IR-Tac to LCPT in kidney transplant recipients would improve the estimated glomerular filtration rate (eGFR), particularly in fast metabolizers. For proof of concept, we performed a pilot study including RTx patients who received de novo immunosuppression with IR-Tac. A Tac concentration-to-dose ratio (C/D ratio) < 1.05 ng/mL·1/mg defined fast metabolizers and ≥1.05 ng/mL·1/mg slow metabolizers one month after RTx. Patients were switched to LCPT ≥ 1 month after transplantation and followed for 3 years. Fast metabolizers (n = 58) were switched to LCPT earlier than slow metabolizers (n = 22) after RTx (2.0 (1.0−253.1) vs. 13.2 (1.2−172.8) months, p = 0.005). Twelve months after the conversion to LCPT, Tac doses were reduced by about 65% in both groups. The C/D ratios at 12 months had increased from 0.66 (0.24−2.10) to 1.74 (0.42−5.43) in fast and from 1.15 (0.32−3.60) to 2.75 (1.08−5.90) in slow metabolizers. Fast metabolizers showed noticeable recovery of mean eGFR already one month after the conversion (48.5 ± 17.6 vs. 41.5 ± 17.0 mL/min/1.73 m², p = 0.032) and at all subsequent time points, whereas the eGFR in slow metabolizers remained stable. Switching to LCPT increased Tac bioavailability, C/D ratio, and was associated with a noticeable recovery of renal function in fast metabolizers. Conversion to LCPT is safe and beneficial early after RTx.

The Influence of Parathyroidectomy on Osteoporotic Fractures in Kidney Transplant Recipients: Results from a Retrospective Single-Center Trial.

Kidney transplant (KTx) recipients are a high-risk population for osteoporotic fractures. We herein aim to identify the role of pre-transplant parathyroidectomy (PTX) and other modifiable factors associated with osteoporotic fractures in KTx recipients. We conducted a retrospective study involving 711 adult patients (4608 patient-years) who were transplanted at our center between January 2007 and June 2015. Clinical data were extracted from patients' electronic medical records. Different laboratory and clinical parameters for mineral bone disease (MBD) and osteoporosis, including medication, were evaluated. We chose fracture events unrelated to malignancies or adequate trauma as the primary endpoint. Osteoporotic fractures occurred in 47 (6.6%) patients (median 36.7 months, IQR 45.9) after KTx (fracture incidence of 10 per 1000 person-years). Prior to KTx, subtotal PTX was performed in 116 patients (16.3%, median time 4.2 years before KTx, IQR 5.0). Of the patients with fracture (n = 47), only one (2.2%) patient had previously undergone PTX. After adjusting for the known fracture risk factors MBD and osteoporosis, PTX remained a protective factor against fractures (HR 0.134, CI 0.018-0.991, p = 0.049). We observed a reduced risk for pathological fractures in KTx patients who underwent PTX, independent from elevated parathyroid hormone at the time of KTx or afterwards.