Chronic Renal Allograft Injury Research Articles

Renal Allograft Macrophage Infiltration in Antibody-Mediated Renal Allograft Rejection

Abstract Introduction/Objective Macrophages are involved in the pathogenesis and contribute to acute and chronic renal allograft injury. We evaluated CD163+ (M2) macrophage graft tissue infiltration and its correlation with clinical and histological prognostic factors. Urinary soluble CD163, circulating total, and monocyte-derived microparticles (MMPs) in plasma were also estimated and correlated with tissue M2 macrophage infiltration. Methods/Case Report The study included forty-five renal allograft recipients with for-cause graft biopsy, with Antibody-mediated Rejection (ABMR) (n=30) or no evidence of rejection (NER) (n=15), from Jan 2021-Dec 2023, along with fifteen age-matched healthy controls (HC). On immunohistochemistry, CD163 positive cells were counted in glomeruli and tubulointerstitium. Urinary sCD163 was done by ELISA. Flow cytometry quantified plasma MPs (AnnexinV+) and MMPs (CD14+/ AnnexinV+). Results (if a Case Study enter NA) The mean age of renal allograft recipients was 35±9yrs (all males). Mean s.creatinine in ABMR and NER was 3±2.6 and 2±0.5 mg/dl, respectively. ABMR had significantly more glomerular (16.2±13.7/10 glomeruli) and tubulointerstitial (183±108/10hpf) M2 macrophage (CD163+) cell infiltration than NER (4.8±4.7/10 glomeruli; 133.5±108/10hpf). Urinary sCD163 in ABMR was also significantly raised (0.89±0.63ng/ml) than in NER. It was not detectable in HC. Plasma MMPs were elevated in ABMR [25% of total MPs (1.62x104)] as compared to NER [8.2 % of total MPs (1.4x104)] and HC [7.8% of total MPs (1.2x104)]. In ABMR, the glomerular CD163+ cells correlated with urinary sCD163 levels (r=0.350, p=0.050) and circulating MMPs (r=0.526, p=0.002). Conclusion We found that in renal allograft recipients with ABMR, there is significantly higher graft biopsy glomerular CD163+ (M2) macrophage infiltration and elevated urinary sCD163 levels as compared to NER. The plasma circulating MMPs were also elevated in ABMR. Our findings suggest that monocyte activation plays a significant role in the pathogenesis and injury in ABMR. Non-invasive markers of monocyte activation can distinguish ABMR from NER in allograft recipients presenting with allograft dysfunction.

Role of Shear Wave Elastography for Assessment of Renal-Allograft Fibrosis and its Correlation With Histopathology.

To investigate whether shear wave elastography (SWE) can accurately identify interstitial fibrosis and tubular atrophy (IFTA) in chronic renal allograft injury (CRAI) and whether it can differentiate between different grades of IFTA. Prospective observational study on renal transplant recipients who presented with CRAI. Patient selection was done on the basis of clinical presentation, serum creatinine, and eGFR levels. Biopsy and SWE were performed and SWE values were correlated with histopathological findings according to Banff schema. Receiver operating characteristic (ROC) was also analyzed to assess the diagnostic efficacy of SWE. Sxity-one patients were evaluated. Ten patients had no IFTA, 33 patients had mild IFTA, 16 patients had moderate IFTA, and 2 patients had severe IFTA. Mean parenchymal stiffness values in no IFTA, mild IFTA, moderate IFTA and severe IFTA were 39.86 ± 2.17 kPa (3.64 ± 0.09 m/s), 41.59 ± 3.36 kPa (3.71 ± 0.15 m/s), 47.59 ± 3.34 kPa (3.98 ± 0.14 m/s), and 53.83 ± 1.41 kPa (4.25 ± 0.03 m/s), respectively. SWE values of parenchymal stiffness reached statistical significance to differentiate between mild, moderate, and severe IFTA. ROC analysis revealed cut-off values of 45.09 kPa (3.89 m/s) to differentiate between mild IFTA and moderate IFTA, 52.06 kPa (4.18 m/s) to differentiate between moderate IFTA and severe IFTA with acceptable sensitivity and specificity. SWE is a non-invasive and cost-effective imaging tool to evaluate the disease status of renal allografts affected by CRAI. Thus, it can be of paramount importance if added to the regular follow-up imaging protocol of renal allograft along with grayscale and Doppler imaging.

#5095 THE CURIOUS CASE OF GAS IN THE GRAFT KIDNEY

Abstract Background and Aims Emphysematous pyelonephritis (EPN) denotes a severe infection of renal parenchyma resulting in necrosis and gas accumulation in the renal and perirenal tissue. Risk factors for urinary tract infections in renal transplant recipients include advanced age, female gender, reflux nephropathy prior to transplantation, diabetes mellitus, deceased donor kidney, kidney–pancreas transplant, retransplantation, antibody induction for immunosuppression, urinary bladder catheterisation, history of allograft rejection with subsequent escalation of immunosuppressive therapy and use of ureteral stents. There are no definite guidelines for management of EPN in renal allografts. If unstable and deteriorating, graft nephrectomy should be undertaken as soon as possible. Any delay in surgical intervention, be it percutaneous drainage or nephrectomy may result in death. Method A 25-year old male, diagnosed with IgA Nephropathy (IgAN) received a living donor renal transplant from his mother in 2013 after a dialysis vintage of 3 years. He received Basiliximab induction followed by maintenance immunosuppression with Tacrolimus, Mycophenolate mofetil and Prednisolone. He had no history of UTI in the immediate post-transplant period. His blood glucose levels were within normal limits and he had not had any urological intervention. In 2019, patient was diagnosed with IgAN recurrence as a cause of chronic renal allograft injury. His Creatinine at last follow up in July 2022 was 4.1 mg/dL. He presented in September 2022 with fever, chills, vomiting, pain in the right iliac fossa and inability to extend his right leg. At presentation, his BP was 86/60mmHg, with pyrexia and tachycardia. Ultrasonography revealed an ill-defined collection superomedial to the graft kidney with doubtful posterior extension and air foci. Non-contrast CT study revealed a large subcapsular collection, extending posteriorly into the right iliac fossa involving the right psoas major and inferiorly into the pelvis, with air foci and no evidence of any urinary tract obstruction suggestive of Acute Emphysematous pyelonephritis with ruptured abscess. He was started on broad-spectrum iv antibiotics- Meropenem and Levofloxacin. Immunosuppression was reduced. Laboratory investigations revealed total leucocyte count of 37,000 cells/mm3, Creatinine of 11 mg/dL, urine routine microscopy revealed field full of pus cells. Blood and urine cultures grew ESBL Escherichia coli. He was taken up for urgent urological intervention in the form of percutaneous drain insertion. Frank pus was aspirated and 200mL drained instantaneously, cultures of which demonstrated the same organism. Within 24 hours of pus drainage, patient became afebrile and had pain relief. He was given 3 weeks of culture-appropriate iv antibiotics, to continue another 3 weeks of oral Carbapenem. However, his graft dysfunction persisted, with no recovery and he became dialysis-dependent. Discussion EPN of the renal allograft is a rare occurrence. A study of EPN in renal transplant recipients by Alexander et al from 2012 revealed 18 out of 22 patients were diabetics, 9 necessitated graft nephrectomy and 7 required percutaneous drainage in addition to antibiotics4. Till date, up to 30 cases of graft EPN have been reported in English literature. The striking feature is that more than 90% of these cases were diabetic. Conclusion The complete pathogenesis of renal allograft EPN, especially in patients with no apparent traditionally described risk factors remains yet to be understood. A high degree of suspicion and early intervention may help to save the allograft.

Macrophage to Myofibroblast Transition in Diastolic Dysfunction Development

Heart failure is the top killer in the U.S and worldwide, often caused by hypertension, aging, or cardiac toxicity. Diastolic Dysfunction (DD), the often the first step of heart failure, occurs when the chambers of the heart are not able to expand during the filling phase. In addition, hypertension is the leading cause of DD. Though this is known, the progression of hypertension into DD remains poorly understood. Of note is the ability of M2 macrophages to differentiate into a myofibroblast-like phenotype, known as macrophage to myofibroblast transition (MMT). This transition has been observed in interstitial fibrosis in chronic renal allograft injury. The researchers noted that MMT account for 50% of the myofibroblast population. To our knowledge, the extent of fibrotic remodeling due to MMT in the heart has not been ardently investigated. Therefore, we aim to answer whether MMT plays a causal role in the progression of hypertension to DD and the pathogenesis of heart failure.Utilizing the uninephrectomized, DOCA-salt model, mice were subjected to this treatment and hypertension was induced. As a negative control, another group of mice received a uninephrectomy and the same salt in their drinking water, however, DOCA was not administered (Sham group). MMT prevalence, identified as CD68+ α-SMA+ expressions, was observed inside the hearts of DOCA and Sham mice. The hearts were isolated and homogenized via gentleMACS tissue Dissociator, the monocytes were purified via Percoll isolation, and flow cytometry was used to identify the population of CD68+ α-SMA+ expressing cells.As soon as 10 days post DOCA implantation, the DOCA group exhibited worsening diastolic function as it took longer for the pressure to change in the hearts of DOCA mice than in Sham (-dp/dt). These data were gathered via left ventricular (LV) catheter insertion. At a later time, utilizing a different cohort of mice preliminary data show an increase of monocyte (CD68+) and fibroblast (α-SMA+) double-positive expressing cells in the hearts of hypertensive mice.MMT has been observed in the hearts of hypertensive mice. This transition may exacerbate Diastolic Dysfunction. More research must be performed to investigate the wide variety of functions of macrophages (i.e., M1 to M2 ratio and transition, macrophage residence or infiltration, and macrophage stimulation of myofibroblasts), as well as the specific interactions between macrophages and cardiomyocytes, or other immune cells, that might mediate this transition. These data provide a preliminary, but interesting glimpse, into the role of macrophages in exacerbating Diastolic Dysfunction and mediating Heart Failure. NIH RO1-HL146713 and AHA 15BGIA25730047 (Shengyu Mu) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Prognostic and Diagnostic Value of Endocan in Kidney Diseases.

Endocan, previously called endothelial cell-specific molecule-1, is a soluble proteoglycan that is predominantly expressed in vascular endothelial cells of the lungs and kidneys. It is upregulated by proinflammatory cytokines and plays a critical role in inflammatory, proliferative, and neovascularization processes. The utility of endocan as a biomarker in a wide spectrum of diseases is being increasingly acknowledged. In this review, we summarize the current evidence concerning the role of endocan in kidney diseases, with emphasis on its prognostic and diagnostic value. It seems that the determination of plasma endocan levels may provide useful prognostic information in many types of renal failure such as chronic kidney disease, IgA nephropathy, and diabetic nephropathy. Endocan could additionally improve the early diagnostic evaluation of acute kidney disease, chronic renal allograft injury, and acute rejection after kidney transplantation, thus contributing to endothelial cell injury monitoring in a timely manner.

Curcumin Blunts IL-6 Dependent Endothelial-to-Mesenchymal Transition to Alleviate Renal Allograft Fibrosis Through Autophagy Activation.

Fibrosis contributes to graft loss in chronic renal allograft injury. Endothelial‐to‐mesenchymal transition (EndMT) plays an important role in the development of fibrosis following kidney transplantation. Autophagy plays an important role in the homeostasis of diverse cell types including endothelial cells. Here we demonstrate that inhibition of autophagy by treatment with 3-methyladenine (3-MA) or by silencing autophagy-related (ATG)5 promoted interleukin (IL)-6–dependent EndMT in human umbilical vein endothelial cells (HUVECs) and human renal glomerular endothelial cells (HRGECs), and autophagy inactivation was associated with EndMT in patients with chronic allograft dysfunction. IL-6 level was significantly higher in the culture medium of HUVECs transfected with ATG5 siRNA or treated with 3-MA compared to the respective control groups. IL-6 application induced EndMT in HUVECs and HRGECs, whereas antibody-mediated neutralization of IL-6 suppressed EndMT induced by ATG5 silencing. The protective role of curcumin (Cur) against allograft fibrosis was confirmed in a rat kidney transplantation model of F344 donors to Lewis recipients. Curcumin—a natural polyphenol compound with known antifibrotic effects in various tissues—alleviated IL-6–induced EndMT and promoted autophagy in the allografted organ and in HUVECs. This is the first demonstration of the role of autophagy in renal allograft fibrosis; our findings indicate that curcumin can alleviate chronic renal allograft injury by suppressing IL-6–dependent EndMT via activation of autophagy.

Lymphotoxin expression in human and murine renal allografts.

The kidney is the most frequently transplanted solid organ. Recruitment of inflammatory cells, ranging from diffuse to nodular accumulations with defined microarchitecture, is a hallmark of acute and chronic renal allograft injury. Lymphotoxins (LTs) mediate the communication of lymphocytes and stromal cells and play a pivotal role in chronic inflammation and formation of lymphoid tissue. The aim of this study was to assess the expression of members of the LT system in acute rejection (AR) and chronic renal allograft injury such as transplant glomerulopathy (TG) and interstitial fibrosis/tubular atrophy (IFTA). We investigated differentially regulated components in transcriptomes of human renal allograft biopsies. By microarray analysis, we found the upregulation of LTβ, LIGHT, HVEM and TNF receptors 1 and 2 in AR and IFTA in human renal allograft biopsies. In addition, there was clear evidence for the activation of the NFκB pathway, most likely a consequence of LTβ receptor stimulation. In human renal allograft biopsies with transplant glomerulopathy (TG) two distinct transcriptional patterns of LT activation were revealed. By quantitative RT-PCR robust upregulation of LTα, LTβ and LIGHT was shown in biopsies with borderline lesions and AR. Immunohistochemistry revealed expression of LTβ in tubular epithelial cells and inflammatory infiltrates in transplant biopsies with AR and IFTA. Finally, activation of LT signaling was reproduced in a murine model of renal transplantation with AR. In summary, our results indicate a potential role of the LT system in acute renal allograft rejection and chronic transplant injury. Activation of the LT system in allograft rejection in rodents indicates a species independent mechanism. The functional role of the LT system in acute renal allograft rejection and chronic injury remains to be determined.

Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury.

Interstitial fibrosis is an important contributor to graft loss in chronic renal allograft injury. Inflammatory macrophages are associated with fibrosis in renal allografts, but how these cells contribute to this damaging response is not clearly understood. Here, we investigated the role of macrophage-to-myofibroblast transition in interstitial fibrosis in human and experimental chronic renal allograft injury. In biopsy specimens from patients with active chronic allograft rejection, we identified cells undergoing macrophage-to-myofibroblast transition by the coexpression of macrophage (CD68) and myofibroblast (α-smooth muscle actin [α-SMA]) markers. CD68+/α-SMA+ cells accounted for approximately 50% of the myofibroblast population, and the number of these cells correlated with allograft function and the severity of interstitial fibrosis. Similarly, in C57BL/6J mice with a BALB/c renal allograft, cells coexpressing macrophage markers (CD68 or F4/80) and α-SMA composed a significant population in the interstitium of allografts undergoing chronic rejection. Fate-mapping in Lyz2-Cre/Rosa26-Tomato mice showed that approximately half of α-SMA+ myofibroblasts in renal allografts originated from recipient bone marrow-derived macrophages. Knockout of Smad3 protected against interstitial fibrosis in renal allografts and substantially reduced the number of macrophage-to-myofibroblast transition cells. Furthermore, the majority of macrophage-to-myofibroblast transition cells in human and experimental renal allograft rejection coexpressed the M2-type macrophage marker CD206, and this expression was considerably reduced in Smad3-knockout recipients. In conclusion, our studies indicate that macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. Moreover, the transition of bone marrow-derived M2-type macrophages to myofibroblasts in the renal allograft is regulated via a Smad3-dependent mechanism.

Genomic Analysis of Kidney Allograft Injury Identifies Hematopoietic Cell Kinase as a Key Driver of Renal Fibrosis.

Renal fibrosis is the common pathway of progression for patients with CKD and chronic renal allograft injury (CAI), but the underlying mechanisms remain obscure. We performed a meta-analysis in human kidney biopsy specimens with CAI, incorporating data available publicly and from our Genomics of Chronic Renal Allograft Rejection study. We identified an Src family tyrosine kinase, hematopoietic cell kinase (Hck), as upregulated in allografts in CAI. Querying the Kinase Inhibitor Resource database revealed that dasatinib, a Food and Drug Administration-approved drug, potently binds Hck with high selectivity. In vitro, Hck overexpression activated the TGF-β/Smad3 pathway, whereas HCK knockdown inhibited it. Treatment of tubular cells with dasatinib reduced the expression of Col1a1 Dasatinib also reduced proliferation and α-SMA expression in fibroblasts. In a murine model with unilateral ureteric obstruction, pretreatment with dasatinib significantly reduced the upregulation of profibrotic markers, phosphorylation of Smad3, and renal fibrosis observed in kidneys pretreated with vehicle alone. Dasatinib treatment also improved renal function, reduced albuminuria, and inhibited expression of profibrotic markers in animal models with lupus nephritis and folic acid nephropathy. These data suggest that Hck is a key mediator of renal fibrosis and dasatinib could be developed as an antifibrotic drug.

Evolution of the Concept and Pathogenesis of Chronic Renal Allograft Injury: An Updated Review.

The advantages conferred by renal transplant, such as the improved quality of life and survival, are compromised by the reduced half-life of the transplanted kidney to a decade because of chronic allograft injury, which is the leading cause of transplant loss. There has been a significant evolution in the concept of the nomenclature, grading of histologic changes, diagnostic markers, and the theories of the pathogenesis of chronic allograft injury in the past decade. This review sought to consolidate the published literature that contributes toward understanding the changing concepts and pathogenesis of the chronic allograft injury, which has implications to managing and preventing chronic allograft injury in experimental and clinical settings.

Fibroblast growth factor-23 and chronic allograft injury in pediatric renal transplant recipients: a Midwest Pediatric Nephrology Consortium study.

The chronic kidney disease-mineral bone disorder (CKD-MBD) produces fibroblast growth factor-23 (FGF-23) and related circulating pathogenic factors that are strongly associated with vascular injury and declining kidney function in native CKD. Similarly, chronic renal allograft injury (CRAI) is characterized by vascular injury and declining allograft function in transplant CKD. We hypothesized that circulating CKD-MBD factors could serve as non-invasive biomarkers of CRAI. We conducted a cross-sectional, multicenter case-control study. Cases (n = 31) had transplant function >20 mL/min/1.73 m(2) and biopsy-proven CRAI. Controls (n = 31) had transplant function >90 mL/min/1.73 m(2) and/or a biopsy with no detectable abnormality in the previous six months. We measured plasma CKD-MBD factors at a single time point using ELISA. Median (range) FGF23 levels were over twofold higher in CRAI vs. controls [106 (10-475) pg/mL vs. 45 (8-91) pg/mL; p < 0.001]. FGF23 levels were inversely correlated with transplant function (r(2) = -0.617, p < 0.001). Higher FGF23 levels were associated with increased odds of biopsy-proven CRAI after adjusting for transplant function, clinical, and demographic factors [OR (95% CI) 1.43 (1.23, 1.67)]. Relationships between additional CKD-MBD factors and CRAI were attenuated in multivariable models. Higher FGF23 levels were independently associated with biopsy-proven CRAI in children.

Computational Biology: Modeling Chronic Renal Allograft Injury.

New approaches are needed to develop more effective interventions to prevent long-term rejection of organ allografts. Computational biology provides a powerful tool to assess the large amount of complex data that is generated in longitudinal studies in this area. This manuscript outlines how our two groups are using mathematical modeling to analyze predictors of graft loss using both clinical and experimental data and how we plan to expand this approach to investigate specific mechanisms of chronic renal allograft injury.

Monocytic Tissue Transglutaminase in a Rat Model for Reversible Acute Rejection and Chronic Renal Allograft Injury.

Acute rejection is a major risk factor for chronic allograft injury (CAI). Blood leukocytes interacting with allograft endothelial cells during acute rejection were suggested to contribute to the still enigmatic pathogenesis of CAI. We hypothesize that tissue transglutaminase (Tgm2), a multifunctional protein and established marker of M2 macrophages, is involved in acute and chronic graft rejection. We focus on leukocytes accumulating in blood vessels of rat renal allografts (Fischer-344 to Lewis), an established model for reversible acute rejection and CAI. Monocytes in graft blood vessels overexpress Tgm2 when acute rejection peaks on day 9 after transplantation. Concomitantly, caspase-3 is activated, suggesting that Tgm2 expression is linked to apoptosis. After resolution of acute rejection on day 42, leukocytic Tgm2 levels are lower and activated caspase-3 does not differ among isografts and allografts. Cystamine was applied for 4 weeks after transplantation to inhibit extracellular transglutaminase activity, which did, however, not reduce CAI in the long run. In conclusion, this is the first report on Tgm2 expression by monocytes in vivo. Tgm2 may be involved in leukocytic apoptosis and thus in reversion of acute rejection. However, our data do not support a role of extracellular transglutaminase activity as a factor triggering CAI during self-limiting acute rejection.

Relationship between the quantitative analysis of tissue diffusion and the level of serum creatinine in chronic renal allograft injury

Objective To investigate the quantitative analysis of tissue diffusion of real-time elastography(RTE) in chronic renal allograft injury(CRAI) and the relationship between RTE and the level of serum creatinine(Cr).Methods Sixty-nine cases of allograft renal transplantation patients were detected by conventional ultrasound and RTE.According to the time after operation and Cr,they were divided into three groups:group A (in three months after operation and normal Cr,25 cases),group B (more than three months after operation and normal Cr,23 cases),and group C (more than three months after operation and high Cr,21 cases).The results were compared and analyzed.Results ①Contrast between group A and group B,there were differences on Cr and average ralative strain value(MEAN),area ratio of low-strain region (％ AREA),complexity (COMP),skewness (SKEW),(P ＜ 0.05).② In group B,there was correlation between Cr and ％AREA,MEAN,SKEW (r =0.682,P ＜0.05; r =0.628,P ＜0.05; r =-0.481,P ＜0.05).③To make ROC curve,MEAN has higher sensitivity (90.9％),COMP has higher specificity and accuracy (68.0％,81.8％).④ To apply the third result in group C,4 or 5 cases in 21 were abnormal.Conclusions There is a good correlation between the quantitative analysis of tissue diffusion and the level of serum creatinine.RTE can indirectly reflect CRAI,and it is a new method of ultrasonic to evaluate renal allograft function. Key words: Ultrasonography; Kidney transplantation; Creatinine; Elasticity imaging techniques

Renal dysfunction and intragraft proMMP9 activity in renal transplant recipients with interstitial fibrosis and tubular atrophy.

Chronic renal allograft injury is reflected by interstitial fibrosis and tubular atrophy (IF/TA) and by the accumulation of extracellular matrix (ECM). Metalloproteinases (MMPs) are renal physiologic regulators of ECM degradation. Changes in MMPs expression or activity may disturb ECM turnover leading to glomerular scarring and worsening renal function. Our goal was to investigate intragraft MMP2 and MMP9 activities and their correlation with renal dysfunction. Plasma MMP2 and MMP9 activities were analyzed as noninvasive markers of renal allograft deterioration. Transplanted patients were biopsied and histopathologically characterized as IF/TA+ or IF/TA-. Renal function was evaluated by serum creatinine, glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease equation and urinary protein/creatinine ratio. Kidney and plasma MMP2 and MMP9 activities were analyzed by zymography. A significant renal dysfunction was observed in IF/TA+ patients. Intragraft proMMP9 showed a significant higher activity in IF/TA+ than in IF/TA- samples and was inversely correlated with the GFR. Intragraft proMMP2 activity tended to increase in IF/TA+ samples, although no statistic significance was reached. Circulating proMMP2 and proMMP9 activities did not show significant differences between groups. Our data provide evidence that correlates intragraft proMMP9 activity with the fibrotic changes and renal dysfunction observed in IF/TA.

Through a glass darkly: seeking clarity in preventing late kidney transplant failure.

A common lament is that long-term kidney transplant outcomes remain the same despite improvements in early graft survival. To be fair, progress has been made-in both our understanding of chronic injury and modestly, graft survival. However, we are still a long way from actually solving this important and difficult problem. In this review, we outline recent data supporting the existence of several causes of renal allograft loss, the incidences of which peak at different time points after transplantation. On the basis of this broadened concept of chronic renal allograft injury, we examine the challenges of clinical trial design in long-term studies, including the use of surrogate end points and biomarkers. Finally, we suggest a path forward that, ultimately, may improve long-term renal allograft survival.

Serum Endocan Correlated With Stage of Chronic Kidney Disease and Deterioration in Renal Transplant Recipients

Earlier detection and intervention for chronic renal allograft injury (CRAI) remain major challenges for transplantation physicians. Endocan plays a key role in the regulation of cell adhesion, inflammatory disorders, and tumor progression. We conducted this cross-sectional study of 97 renal transplant (RT) recipients with mean RT duration of 7.0 ± 5.7 years to determine whether Endocan could be a diagnostic and prognostic marker. The patients' mean age was 43.6 ± 13.2 years, and 55.7% (54/97) were male. Higher Endocan levels were found in more advanced chronic kidney disease (CKD) stages in a dose-dependent manner. Interestingly, the Endocan ≥643.19 pg/mL group had higher creatinine (Cr; 1.2 ± 0.4 vs 1.6 ± 1.1 mg/dL; P = .029) and lower estimated glomerular filtration rate (eGFR; 67.8 ± 23.8 mL/min vs 54.4 ± 22.0; P = .006) than the Endocan <643.19 pg/mL group after 3 months of follow-up, respectively. Linear regression analysis found tumor necrosis factor (TNF)-α correlated well with Endocan. To elucidate the response of endothelium activation, we stimulated human umbilical vein endothelial cells (HUVECs) with TNF-α in vitro, and found the levels of Endocan (P = .022) and transforming growth factor (TGF)-β1 (P = .034) increased with time, but interleukin (IL)-10 decreased (P = .013). In summary, Endocan may reflect the degree of endothelial cell injury in renal allografts, and showed a trend of elevation in late-stage CKD. An in vitro study demonstrated TNF-α–activated HUVECs secreted high levels of Endocan and TGF-β1, which could lead to a better understanding of the role of endothelium in immune balance. In conclusion, Endocan may have potential as a useful long-term indicator of CRAI in RT recipients, but further study is needed to verify our findings.

Urinary Connective Tissue Growth Factor (CTGFu) as a Marker and Early Predictor of Chronic Renal Allograft Injury

Urinary Connective Tissue Growth Factor (CTGFu) as a Marker and Early Predictor of Chronic Renal Allograft Injury

Subclinical Inflammation and Chronic Renal Allograft Injury in a Randomized Trial on Steroid Avoidance in Pediatric Kidney Transplantation

Steroid avoidance is safe and effective in children receiving kidney transplants in terms of graft function and survival, but the effects on allograft histology are unknown. In this multicenter trial, 130 pediatric renal transplant recipients were randomized to steroid-free (SF; n = 60) or steroid-based (SB; n = 70) immunosuppression, and underwent renal allograft biopsies at the time of graft dysfunction and per protocol at implantation and 6, 12 and 24 months after transplantation. Clinical follow-up was 3 years posttransplant. Subclinical acute rejection was present in 10.6% SF versus 11.3% SB biopsies at 6 months (p = 0.91), 0% SF versus 4.3% SB biopsies at 1 year (p = 0.21) and 0% versus 4.8% at 2 years (p = 0.20). Clinical acute rejection was present in 13.3% SF and 11.4% SB patients by 1 year (p = 0.74) and in 16.7% SF and 17.1% SB patients by 3 years (p = 0.94) after transplantation. The cumulative incidence of antibody-mediated rejection was 6.7% in SF and 2.9% in SB by 3 years after transplantation (p = 0.30). There was a significant increase in chronic histological damage over time (p < 0.001), without difference between SF and SB patients. Smaller recipient size and higher donor age were the main risk factors for chronic histological injury in posttransplant biopsies.

Chronic renal allograft injury: early detection, accurate diagnosis and management

Chronic renal allograft injury (CRAI) is a multifactorial clinical/pathological entity characterised by a progressive decrease in glomerular filtration rate, generally associated with proteinuria and arterial hypertension. Classical views tried to distinguish between immunological (sensitization, low HLA compatibility, acute rejection episodes) and non-immunological factors (donor age, delayed graft function, calcineurin inhibitors [CNI] toxicity, arterial hypertension, infections) contributing to its development. Defining it as a generic idiopathic entity has precluded more comprehensive attempts for therapeutic options. Consequently, it is necessary to reinforce the diagnostic work-up to add etiopathogenetic diagnosis in any case of graft dysfunction, specially transplant vasculopathy and transplant glomerulopathy, reserving the term interstitial fibrosis and tubular atrophy (IFTA) when a case of CRAI is unspecific and no clear contributing factors or a specific etiology is possible in diagnosis. Earlier detection and intervention of CRAI remain as key challenges for transplant physicians. Changes in SCr levels and proteinuria often occur late in disease progression and may not accurately represent the underlying renal damage. Deterioration of renal function over time, determined through slope analysis, is a more accurate indicator of CRAI, and earlier identification of renal deterioration may prompt earlier changes in immunosuppressive therapies. The crucial point is probably to distinguish between nonimmunological or toxic CRAI and immunological-derived CRAI cases. Conversion to nonnephrotoxic immunosuppressants, such as mTOR inhibitors, holds promise in reducing the impact of toxic CRAI by both avoiding and reducing the impact of CNIs and reducing smooth muscle cell proliferation in the kidney. CRAI due to chronic antibody mediated rejection is an important entity, better and better defined that carries a bad prognosis and is associated with graft loss. The best prevention is adequate immunosuppression and tight patient monitoring, from the clinical, analytical and histological standpoint. While clinical trial evidence is needed for early detection and intervention in patients with CRAI, this review represents the current knowledge upon which clinicians can base their strategies. New prospective, ideally well-controlled trials are needed to establish the usefulness of different potentially therapeutic regimens. These evidences should demonstrate the benefits before extended uncontrolled use of drugs such as rituximab, bortezomib or eculizumab, which are expensive and frequently iatrogenic.