Allogeneic Kidney Transplantation Research Articles

Murine kidney transplant outcome is best measured by transdermal glomerular filtration rate

Mouse kidney transplantation provides a powerful preclinical model for the study of kidney transplant alloimmunity. However, accurate measurement of graft function is difficult because of the inaccuracy of traditional surrogate markers serum creatinine and urea. We report the use of transdermal glomerular filtration rate measurement under the experimental conditions of unilateral nephrectomy and allogeneic kidney transplantation. Our findings demonstrate that transdermal glomerular filtration rate measurement is easy to perform, reproducible, and has more interexperimental consistency than serum creatinine or urea measurements. Most importantly, it significantly reduces the numbers of experimental animals required to detect subtle and yet clinically relevant differences in kidney function as often is the case in experimental murine kidney transplantation models.

Identification of Pathogenic Pathways for Recurrence of Focal Segmental Glomerulosclerosis after Kidney Transplantation.

Primary focal segmental glomerulosclerosis (FSGS) is a disease of the podocytes and glomerulus, leading to nephrotic syndrome and progressive loss of renal function. One of the most serious aspects is its recurrence of disease in over 30% of patients following allogeneic kidney transplantation, leading to early graft loss. This research investigates the individual genetic predispositions and differences in the immune responses leading to recurrence of FSGS after transplantation. We performed exome sequencing on six patients with recurrent FSGS to identify variants in fifty-one genes and found significant variations in the alpha-2-macroglobulin (A2M). Immunoblotting was used to investigate effects of specific gene variants at the protein level. Further expression analysis identified A2M, exophilin 5 (EXPH5) and plectin (PLEC) as specific proteins linked to podocytes, endothelial cells, and the glomerulus. Subsequent protein array screening revealed the presence of non-HLA-specific antibodies, including TRIM21, after transplantation. Using Metascape for pathway and process enrichment analysis, we focused on the IL-17 signaling and chemotaxis pathways. ELISA measurements showed significantly elevated IL-17 levels in patients with recurrent FSGS (32.30 ± 9.12 pg/mL) compared to individuals with other glomerular diseases (23.16 ± 2.49 pg/mL; p < 0.01) and healthy subjects (22.28 ± 0.94 pg/mL; p < 0.01), with no significant difference in plasma CCL2/MCP-1 levels between groups. This study explores the molecular dynamics underlying recurrence of FSGS after transplantation, offering insights into potential biomarkers and therapeutic targets for the future development of individualized treatments for transplant patients.

Kidney transplantation in recipient with hyperhomocysteinemia: a case report

Introduction. There is an annual increasing of kidney transplantion all over the world. The number of recipients with hyperhomocysteinemia before and after the operation is also increasing, which increases the risk of cardiovascular complications, graft loss and patients’ death.Materials and methods. A 28-year-old patient with terminal chronic renal desiase in the outcome of chronic glomerulonephritis had underwent an allogeneic kidney transplant from a 52-year-old donor, with confirmed brain death in the outcome of acute hemorrhagic cerebral circulatory disorders.Results. The early postoperative period has complicated by thrombosis.Conclusion. The study of blood homocysteine levels is mandatory when examining patients for kidney transplantation.

Clinical case of recurrent aHUS after allogeneic cadaveric kidney transplantation

Introduction. Atypical hemolytic uremic syndrome (aHUS) is a systemic orphan disease that reproduces as an uncontrolled activation of the alternative pathway of the complement system and is expressed as systemic thrombotic microangiopathy (TMA). The classical triad of aHUS symptoms are hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). Currently, diagnosis of aHUS is a diagnosis of exclusion and has no pathognomonic features. It is established based on the clinical presentation of the disease after excluding other forms of TMA, Objective: to increase physicians’ awareness of this rare disease, the diagnosis and treatment of aHUS using a clinical case study.Conclusion. Early diagnosis of aHUS is extremely important, as timely targeted therapy can significantly improve or completely restore the functions of the affected organ.

IL-21-producing effector Tfh cells promote B cell alloimmunity in lymph nodes and kidney allografts.

Follicular helper T (Tfh) cells have been implicated in controlling rejection after allogeneic kidney transplantation, but the precise subsets, origins, and functions of Tfh cells in this process have not been fully characterized. Here we show that a subset of effector Tfh cells marked by previous IL-21 production is potently induced during allogeneic kidney transplantation and is inhibited by immunosuppressive agents. Single-cell RNA-Seq revealed that these lymph node (LN) effector Tfh cells have transcriptional and clonal overlap with IL-21-producing kidney-infiltrating Tfh cells, implicating common origins and developmental trajectories. To investigate the precise functions of IL-21-producing effector Tfh cells in LNs and allografts, we used a mouse model to selectively eliminate these cells and assessed allogeneic B cell clonal dynamics using a single B cell culture system. We found that IL-21-producing effector Tfh cells were essential for transplant rejection by regulating donor-specific germinal center B cell clonal dynamics both systemically in the draining LN and locally within kidney grafts. Thus, IL-21-producing effector Tfh cells have multifaceted roles in Ab-mediated rejection after kidney transplantation by promoting B cell alloimmunity.

Pharmarcomechanical thrombectomy combined with transluminal balloon angioplasty for treating transplant renal vein thrombosis

Renal vein thrombosis (RVT) is a rare vascular complication that occurs after renal transplantation and usually results in irreversible kidney damage and graft loss. We report the case of a patient who underwent right iliac fossa allogeneic kidney transplantation and developed RVT combined with ipsilateral thrombosis from the popliteal to the femoral veins, with extension to the common iliac veins, 4 months after transplantation. Under unfractionated heparin anticoagulation, an Aegisy (Life Tech Scientific Co., Ltd., Shenzhen, China) vena cava filter was placed to prevent pulmonary embolism. Percutaneous mechanical thrombectomy combined with balloon angioplasty was performed to aspirate the thrombus and successfully dilate the narrow venous lumen. The patient’s renal function was restored postoperatively. Ultrasonography showed the allograft and ipsilateral lower extremity deep veins to be fluent and patent. To conclude, in patients with RVT after renal transplantation, percutaneous mechanical thrombectomy in conjunction with balloon angioplasty can be performed with desirable outcomes and no severe adverse effects. This method reduces the risk of bleeding from exposure to systemic intravenous thrombolysis and avoids surgery-associated trauma.

TFF3 as a Diagnostic Biomarker in Kidney Transplant Patients.

Intestinal trefoil factor 3 (TFF3) is a protein secreted by many cell types, and its serum and urine levels vary in patients with kidney disease. Therefore, the present study aimed to determine the diagnostic value of TFF3 in allogeneic kidney transplant patients included in the one-year follow-up. To analyze the influence of the diagnostic method used, we studied the type of biological material and the time elapsed since renal transplantation on the parameter's value. The study also aimed to investigate the relationship between TFF3 levels and creatinine and estimated glomerular filtration rate (eGFR) values in the serum and urine of the patients studied. The study used blood and urine samples from adult patients (n = 19) 24-48 h, 6 months, and 12 months after kidney transplantation. We collected one-time blood and urine from healthy subjects (n = 5) without renal disease. We applied immunoenzymatic ELISA and xMap Luminex flow fluorimetry to determine TFF3 in serum and urine. There was a significant difference in TFF3 levels in the serum of patients collected on the first one or two days after kidney transplantation compared to the control group (determined by ELISA and Luminex) and six months and one year after kidney transplantation (ELISA). We observed a correlation between creatinine concentration and urinary TFF3 concentration (ELISA and Luminex) and a negative association between eGFR and urinary (ELISA) and serum (Luminex) TFF3 concentration in patients on the first and second days after kidney transplantation. We noted significant correlations between eGFR and TFF3 levels in the serum and urine of patients determined by the two methods six months and one year after transplantation. In women, we observed that urinary TFF3 concentration increased significantly with increasing creatinine and that with increasing eGFR, urinary TFF3 concentration determined by two methods decreased significantly. In the present study, the choice of diagnostic method for the determination of TFF3 in serum and urine significantly affected the concentration of this biomarker. The values of this parameter determined by ELISA were higher than those assessed using the Luminex assay. Based on the presented results, we can conclude that TFF3 has great potential to monitor renal transplant patients. Determination of this protein in parallel with creatinine and eGFR levels in serum and urine may provide helpful diagnostic information.

Research Highlights.

Research Highlights.

#4917 AN EXOME-WIDE STUDY OF RENAL OPERATIONAL TOLERANCE

Abstract Background and Aims Renal operational tolerance is a rare and beneficial state of prolonged renal allograft function in the absence of immunosuppression. The underlying mechanisms are unknown. We hypothesized that tolerance might be driven by inherited protein coding genetic variants with large effect, at least in some patients. Method We set up a European survey of over 218,000 renal transplant recipients and collected DNAs from 40 recipients of an allogeneic kidney transplant who maintained good graft function (serum creatinine &amp;lt;1.7 mg/dL and proteinuria ≤1g/day or /g creatinine) in the absence of immunosuppression for at least one year. We performed an exome-wide association study comparing the distribution of moderate to high impact variants in 36 tolerant patients, selected for genetic homogeneity using principal component analysis, and 192 controls, using an optimal sequence-kernel association test adjusted for small samples. Results We identified rare variants (allele frequency &amp;lt; 1%) of HOMER2 (3/36, FDR 0.0387), IQCH (5/36, FDR 0.0362), and LCN2 (3/36, FDR 0.102) in 10 tolerant patients vs 0 controls. One patient carried a variant in both HOMER2 and LCN2. Furthermore, the three genes showed an identical variant in two patients each. The three genes are expressed at the primary cilium (p0= 0.01), a key structure in immune responses. Both LCN2 variants were located 9 base pairs apart, in the 20 amino-acid long signal peptide of the encoded NGAL protein, suggesting the possibility of a shared functional effect Conclusion Rare protein coding variants in a small set of primary cilium genes are associated with operational tolerance in a sizable portion of patients. Our findings have important implications for a better understanding of immune tolerance in transplantation and other fields of medicine. ClinicalTrials.gov Identifier NCT05124444.

Factors affecting BK polyomavirus infection after kidney transplantation in post-school children and a predictive infection model

Objective: To analyze high-risk factors affecting BK polyomavirus (BKPyV) infection and to construct a prediction model for BKPyV infection in children after renal transplantation. Methods: The clinical data of 332 children who received allogeneic kidney transplantation in the First Affiliated Hospital of Zhengzhou University from January 2014 to March 2022 were retrospectively collected. According to the BKPyV load level, the dynamic change process of lymphocytes at different time points were analyzed. The factors that have potential influence on BKPyV infection were screened by Cox regression analysis, and the receiver operating characteristic curve (ROC) was used to evaluate the sensitivity and specificity of the predictive model of infection. Results: Among the 332 children, there were 215 males and 117 females; the age of transplantation was (12.2±3.9) years old; 37 cases were preschool (1-5 years old), and 295 cases were post-school age (6-18 years old). BKPyV load in 224 urine samples and 30 blood samples of children were detected. There were 9 cases of BKPyV-associated viruria and 3 cases of BKPyV associated viremia in pre-school children, 76 cases BKPyV associated viruria and 14 cases of BKPyV associated viremia in post-school children. Multivariate Cox regression analysis showed that higher body mass index (BMI) (HR=1.105, 95%CI: 1.020-1.197), antithyroglobulin (ATG) application (HR=2.196, 95%CI: 1.335-3.613), and higher tacrolimus concentration (HR=2.484, 95%CI: 1.298-4.753), higher natural killer (NK) lymphocyte count (HR=1.193, 95%CI: 1.009-1.411), higher CD14++CD16-cell count (HR=1.096, 95%CI: 1.024-1.173) were independent risk factors for BKPyV associated viruria in post-school children. Delayed graft function (DGF) (HR=4.993, 95%CI: 1.555-16.038), Acute rejection (AR) (HR=6.021, 95%CI: 1.930-18.787), higher CD14++CD16-cell count (HR=1.227, 95%CI: 1.081-1.392) were independent risk factors for BKPyV associated viremia in post-school children. The results of ROC curve analysis showed that combined BMI, immune induction drugs, tacrolimus concentration, NK cell count, and CD14++CD16-cell count predicted the occurrence of BKPyV associated viruria in post-school children after kidney transplantation at 0.5, 1, 2, and 5 years with area under curve (AUC) of 0.712 (95%CI: 0.626-0.798), 0.708 (95%CI: 0.612-0.804), 0.754 (95%CI: 0.668-0.840) and 0.767 (95%CI: 0.685-0.849). The sensitivity and specificity of the model were 64.9%, 61.4%, 61.6%, 55.8% and 70.9%, 72.4%, 76.0%, 84.0%, respectively. Combined with DGF, AR, and CD14++CD16-cell counts predicted the occurrence of BKPyV-associated viremia at 0.5, 1, 2, and 5 years after renal transplantation in post-school children with AUC of 0.791 (95%CI: 0.631-0.951), 0.744 (95%CI: 0.547-0.936), 0.786 (95%CI: 0.629-0.946) and 0.812 (95%CI: 0.672-0.948). The sensitivity and specificity of the model were 76.1%, 67.1%, 75.0%, 77.9% and 88.9%, 89.0%, 89.9%, 88.0%, respectively. Conclusions: The postoperative CD14++CD16-cell level can be used as an independent predictor of BKPyV infection in post-school children after renal transplantation. Combined BMI, immune induction drugs, tacrolimus concentration, NK cell count, CD14++CD16-cell count and combined DGF, AR, CD14++CD16-cell count show good fitting effect in predicting the occurrence of BKPyV-associated viruria and viremia after transplantation in post-school children respectively.

Lymphocele of the kidney transplant bed: a case report

Lymphocele formation in the kidney transplant bed is the most common postoperative complication after kidney transplantation. The article presents the observation of a clinically significant lymphocele of the kidney transplant bed.Materials and methods. Allogeneic heterotopic kidney transplantation from a post-mortem donor was performed in a 28-year-old patient with a clinical diagnosis of stage 5 chronic kidney disease as a result of a congenital anomaly of kidney development.Results. The early postoperative period was complicated by the development of a clinically significant lymphocele of the kidney transplant bed, which caused compression of the ureter of the kidney graft with impaired passage of urine and expansion of its pelvicalyceal system, as well as compression of the external iliac vein. The treatment carried out in the amount of laparoscopic drainage of the lymphocele into the abdominal cavity by means of capillary drainage under ultrasound control contributed to the elimination of the complication and its consequences.Conclusion. Ultrasound examination is a routine examination that allows timely diagnosis of a kidney transplant bed lymphocele and monitoring the effectiveness of the treatment.

ВОЛЧАНОЧНЫЙ НЕФРИТ: КЛИНИЧЕСКИЙ СЛУЧАЙ С ДВОЙНОЙ ТРАНСПЛАНТАЦИЕЙ. ВКЛАД Ар.А. ДЕМИНА В ИЗУЧЕНИЕ ЗАБОЛЕВАНИЯ

Introduction. Lupus nephritis (LN) is common in systemic lupus erythematosus (SLE), a severe autoimmune disease with a poor prognosis. Restoring the immune system and self-tolerance using high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (AHSCT) is a new approach in the treatment of refractory SLE. The effectiveness of SLE with LN treatment in the long-term follow-up should be the subject for study. Methods. Patient I., 25 years old, with refractory SLE and LN is described. Standard therapy was ineffective, the SLEDAI score remained 22 points, so the patient underwent high-dose immunosuppressive therapy (HIT) with ASCT, and she was included in the registry of the European Group for Blood and Marrow Transplantation of the European League Against Rheumatism (EBMT/EULAR). Results. As a result of ASCT, complete clinical and serological remission was achieved (score on the SLEDAI scale – 0 points) for 3 years. Then there was a relapse with nephrotic syndrome and anti-DNA positivity which led to the end-stage renal failure. Despite therapy, the disease activity persisted, and the patient was on regular hemodialysis for 1 year, then underwent allogeneic kidney transplantation. Currently, 18 years have passed since HIT and AHSCT and 11 years since renal transplantation. The patient receives standard post-transplant immunosuppression, and her condition remains stable, the renal allograft is functioning, the SLEDAI score is 2 points (low titer anti-DNA positivity). Discussion. Modern standards of chemotherapy (hydroxychloroquine, mycophenolate mofetil, cyclophosphamide, corticosteroids), bioactive immunotherapy (rituximab, belimumab, obinituzumab, anifrolumab), “multi-target therapy” (standard + tacrolimus, voclosporin, mycophenolate mofetil), and new approaches (immuno- and nephrotransplantation) for lupus nephritis. Conclusion. The successful long-term results of the first case of immunoablation with high-dose immunosuppressive therapy and double autologous stem cell and allogeneic kidney transplantation for SLE with refractory lupus nephritis and an analysis of the effectiveness of modern treatment approaches are presented.

MiR-155 Derived from Bone Marrow Mesenchymal Stem Cell-Secreted Exosomes Reduces Kidney Rejection in Rat Allogeneic Transplantation Model via SDF-1/CXCR4

Aberrantly expressed miR-155 is associated with renal rejection after allogeneic transplantation. This study mainly explored the mechanism of miR-155 derived from bone marrow mesenchymal stem cell-secreted exosomes (BMSC-exo) in renal rejection after allogeneic transplantation. Thirty Fischer rats and 40 Lewis rats were used as donors and recipients, respectively. The Lewis rats were randomized into 4 groups (10 rats per group): Control group, miR-155 group, positive control group and CXCR4 agonist group. The following indicators were monitored in BMSC-exo: miR-155 expression, serum creatinine level, renal histopathological changes, CADI score, number of cells that were positive for TGF-β, Smad3 and α-SMA, as well as the protein levels of Smad3, TGF-β, CXCR4 and SDF-1. miR-155 expression in BMSC-exo was significantly higher than that in HKb-20 cells. On the 7th day after surgery, the serum creatinine levels of rats in the miR-155 group and positive control group reduced significantly, while decreasing slowly in the control group and CXCR4 agonist group. The CADI scores of rats in the miR-155 group and positive control group were significantly higher than those in the control group and CXCR4 agonist group (P &lt; 0.05). No significant difference was found either between the miR-155 group and positive control group, or between the control group and CXCR4 agonist group (P &gt; 0.05). Rats in the control group and CXCR4 agonist group had more cells that were positive for TGF-β, Smad3 and α-SMA, while those in the miR-155 group and positive control group showed less. The Smad3, TGF-β, CXCR4 and SDF-1 proteins were weakly expressed in the miR-155 group and positive control group, but strongly expressed in the control group and CXCR4 agonist group. No significant difference in the protein levels was found either between the miR-155 group and positive control group, or between the control group and CXCR4 agonist group (P &gt; 0.05). miR-155 derived from BMSC-exo is protective against allogeneic kidney transplantation. Specifically, BMSC-exo-derived miR-155 blocked the activity of SDF-1/CXCR4 and TGF-β/Smad3 pathways, thereby downregulating the expression of α-SMA. As a result, it ameliorated renal fibrosis and alleviated renal dysfunction, ultimately leading to the prevention and reduction of renal rejection following allograft transplantation.

Transcriptionally Distinct B Cells Infiltrate Allografts After Kidney Transplantation.

Following allogeneic kidney transplantation, a substantial proportion of graft loss is attributed to the formation of donor-specific antibodies and antibody-mediated rejection. B cells infiltrate kidney grafts during antibody-mediated rejection; however, the origins, repertoires, and functions of these intrarenal B cells remain elusive. Here, we use murine allogeneic kidney transplant models to study the origins, transcriptional programming and B cell receptor repertoire of intragraft B cells, and in vitro stimulation assays to evaluate the ability of intragraft B cells to promote CD4+ T cell expansion. B cells infiltrate kidney grafts in settings of allogeneic, but not syngeneic, transplantation. Intragraft B cells have characteristics of activation but are transcriptionally distinct from germinal center B cells and resemble innate-like B cells. B cell receptor sequencing demonstrates that the majority of intragraft B cells do not originate from lymph node germinal center B cells and are largely germline. Class-switched intragraft B cells are rare but can be donor-specific and produce IgG capable of binding to the kidney allograft. Lastly, intrarenal B cells are capable of stimulating naive T cells but have an altered ability to promote T follicular helper cell expansion. Together, these data demonstrate that intrarenal B cells during transplant rejection are transcriptionally distinct from lymph node B cells.

Effects of body parameters on renal cortical stiffness measured by shear-wave elastography in patients with kidney transplantation.

The results of elastic imaging in evaluating the function and histopathological changes of allogeneic renal transplantation are contradictory, one of the important reasons may be that there are differences in human parameters related to kidney transplantation among individuals. The purpose of this study is to explore the related human body parameters on shear-wave elastography (SWE) effects on quantitative stiffness of graft cortex. From March 2021 to November 2021, a total of 63 patients with allogeneic kidney transplantation in the Department of Ultrasonography, Third Xiangya Hospital, Central South University, were selected to collect the parameters of two-dimensional, color Doppler and SWE. The subjects were divided into a <20% group and a 20%-30% group according to the variation of cortical hardness measurement. Mann Whitney U test was used to compare the differences in relevant human parameters, and Spearman rank correlation was used to analyze the correlation between relevant human parameters and cortical hardness of transplanted kidney. There was no significant difference between the 2 groups in age, sex, postoperative time, resistance index of interlobar artery, SCr, blood uric acid, ratio of fat layer to muscle layer, and BMI (all P>0.05). Compared with the <20% group, the patients in the 20%-30% group had smaller cortical hardness of the transplanted kidney, greater total distance between the transplanted kidney and the skin surface, and thicker fat layer or muscle layer in front of the transplanted kidney (all P<0.05). The age of patients, the total distance from the transplanted kidney to the skin surface, the thickness of fat layer and muscle layer, the ratio of fat layer to muscle layer, BMI, and the variation of cortical hardness were significantly negatively correlated with the cortical hardness of the transplanted kidney (all P<0.05). Human parameters relevant to kidney transplantation affect the accuracy of SWE in measuring the cortical hardness of the transplanted kidney. It is very important to obtain the highly stabile elastic measurement value and interpret the elastic measurement results according to different levels of human body related parameters in combination with individual conditions.

Blocking CCL8-CCR8-Mediated Early Allograft Inflammation Improves Kidney Transplant Function.

In kidney transplantation, early allograft inflammation impairs long-term allograft function. However, precise mediators of early kidney allograft inflammation are unclear, making it challenging to design therapeutic interventions. We used an allogeneic murine kidney transplant model in which CD45.2 BALB/c kidneys were transplanted to CD45.1 C57BL/6 recipients. Donor kidney resident macrophages within the allograft expanded rapidly in the first 3 days. During this period, they were also induced to express a high level of Ccl8, which, in turn, promoted recipient monocyte graft infiltration, their differentiation to resident macrophages, and subsequent expression of Ccl8. Enhanced graft infiltration of recipient CCR8+ T cells followed, including CD4, CD8, and γδ T cells. Consequently, blocking CCL8-CCR8 or depleting donor kidney resident macrophages significantly inhibits early allograft immune cell infiltration and promotes superior short-term allograft function. Targeting the CCL8-CCR8 axis is a promising measure to reduce early kidney allograft inflammation.

Ophthalmoplegia and Tumor Lysis Syndrome: An Uncommon Presentation of Posttransplant Lymphoproliferative Disorder

A 55-year-old man presented with 1 month of fatigue, nausea, vomiting, and weight loss, and blurry vision in his left eye. He has a history of type 1 diabetes mellitus after allogenic kidney and pancreas transplantation 15 years prior. He was found to have tumor lysis syndrome (TLS), total left-sided ophthalmoplegia and ptosis, and left cavernous, abdomen, and pelvic masses. Biopsy revealed an Epstein-Barr virus–negative diffuse large B-cell lymphoma, a type of posttransplant lymphoproliferative disorder (PTLD). It is essential to consider PTLD in transplant patients who present with TLS and compressive neurologic deficits.

Case report and literature review: A de novo pathogenic missense variant in ACTN4 gene caused rapid progression to end-stage renal disease

BackgroundFocal segmental glomerulosclerosis (FSGS) is a histopathological diagnosis of the sclerosis of glomeruli and the damage to renal podocytes. FSGS affects the filtration function of the kidneys and results in nephrotic syndrome (NS) in children and adults. FSGS is a clinically and genetically heterogeneous disorder. FSGS-1 [OMIM #603278] is one of the progressive hereditary renal diseases. It is caused by heterozygous variants of the actinin alpha 4 (ACTN4) [OMIM*604638] gene on chromosome 19q13.2 in a dominant inheritance (AD) manner. With the recent development of whole-exome sequencing (WES), 22 (including our case) pathogenic or likely pathogenic variants have been identified in ACTN4 gene.Case presentationWe reported a 17-year-old Chinese girl who was hospitalized with foamy urine, nausea and vomiting. Laboratory tests revealed increased levels of serum creatinine and urea nitrogen. Ultrasonography demonstrated bilaterally reduced size of kidneys. The primary diagnoses were NS and chronic kidney disease stage 5 (CKD5). The hemodialysis was initiated in 48 h after admission. After 4 months of treatment, the patient received an allogeneic kidney transplantation from her father. A novel heterozygous missense variant c.494C > T (p.A165V) in the ACTN4 gene was found by WES in the patient. This variant was confirmed by Sanger sequencing. The computational simulation of the stability of mutant protein (p.A165V) was decreased. Interatomic interactions of the p.A165V site were increased, and it might be associated with the increased ubiquitylation in the vicinity of the mutant site.ConclusionAs per the guidelines of the American College of Medical Genetics and Genomics for interpreting sequence variants, the novel heterozygous missense variant was pathogenic (PS2 + PM1 + PM2 + PP3 + PP4). It should be noted that the early onset of severe proteinuria with a poor prognosis is an important and universal symptom for most genetic FSGS. If necessary, genetic screening is recommended.

Drug-induced Fanconi syndrome in patients with kidney allograft transplantation

BackgroundPatients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical.MethodsThis retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis.ResultsThe onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A.ConclusionsFor the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis.

Bone Marrow Mesenchymal Stem Cells (BMSCs)-Exosomes Carrying MicroRNA-965 Attenuates Allogeneic Renal Transplant Rejection Through Regulation of Janus Kinase/Signal Transducers and Activators of Transcription 3 (JAK/STAT3)

This study intends to evaluate the potential effect of BMSC-derived exosomes (exo) on the rejection of allogeneic kidney transplantation in a rat model. BMSCs were cultured and their exos were collected for characterization, in which the expression of miR-965 was detected by PCR. Rats received orthotopic kidney transplantation and treated with exos or PBS followed by analysis of serum creatinine and BUN, inflammatory cell infiltration, renal fibrosis and vascular wall fibrosis by immunohistochemistry staining, JAK2/STAT3 phosphorylation by Western-blot, the inflammatory factor level by ELISA kit, and CD4+ cells differentiation by flow cytometry. miR-965 was enriched in BMSC-derived exo. Treatment with exo ameliorated the allograft rejection, improved renal function, and reduced the histological changes of kidney. In addition, exosomal treatment decreased the level of serum inflammatory cytokines, and altered T cell subpopulations. Meanwhile, fibrosis and neointima formation was reduced as demonstrated by related protein expression and signaling pathways was inactivated in the presence of exos. In conclusion, the miR-965 derived from BMSC-exos mitigated the renal allograft rejection through JAK/STAT3 signaling.