Renal Allograft Dysfunction Research Articles

A novel simple noninvasive index to predict renal transplant acute rejection by contrast-enhanced ultrasonography.

This study aimed to evaluate the application of quantitative contrast-enhanced ultrasonography (CEUS) in the assessment of renal allograft dysfunction and to establish a new noninvasive index to predict acute rejection (AR). Fifty-seven renal transplant recipients were enrolled in this prospective study. Before renal allograft biopsy, CEUS examinations were performed.The biopsy results proved 23 cases of AR (AR group), 10 cases of acute tubular necrosis (ATN group), and 24 with normal evolution (stable group). Contrast-enhanced ultrasonography parameters including rising time (RT), time to peak (TTP), and the delta-time among regions of interest (ΔRT and ΔTTP) were analyzed. In the AR group, RT and TTP of interlobar artery and medulla (RTi, RTm, TTPi, and TTPm) as well as ΔRT and ΔTTP between medulla and cortex (ΔRTm-c and ΔTTPm-c) were significantly higher compared with those in the stable group. RTm and TTPm as well as ΔRTm-c and ΔTTPm-c were remarkably higher compared with those in the ATN group. ΔRTm-c and estimated glomerular filtration rate (eGFR) were identified as independent predictors by multivariate analysis (P = 0.008 and P = 0.024). On the basis of the multivariate analysis results and area under the receiver operating characteristic curves of individual markers, we constructed a new simple index, P = -0.587 + 0.286 ×ΔRTm-c − 0.028 × eGFR; new index = e(P)/(1 + e(P)), to discriminate AR, which had better area under the receiver operating characteristic curves than eGFR or individual CEUS parameters. Contrast-enhanced ultrasonography parameters are reliable markers for differentiating the perfusion status of transplanted kidneys. Furthermore, the new simple index can easily predictAR with a high degree of accuracy.

BK Virus Infeksiyonunda Idrar Sitokin Yaniti

Objective: Human BK virus (BKV) is a member of the polyomavirus family. In renal transplant recipients, reactivation of BKV may cause the renal-allograft dysfunction. Primary BKV infection usually occurs asymptomatically during childhood. After primer infection, BKV persists latently especially in the urogenital system. Cellular immunity plays an important role in the pathogenesis of BKV infection. The aim of this study was to determine the urinary cytokine responses in patients with BKV infection and associated levels of urinary cytokines and BK viruria. Methods: Urine samples of 72 patients with BKV infection were included in this study. BKV DNAs were detected by using quantitative real-time polymerase chain reaction. The levels of cytokines in urine samples were determined by ELISA. Results: The levels of urinary proinflammatory cytokines in BKV DNA positive patients were significantly higher than those of patients who were BKV DNA negative. In addition, urinary proinflammatory cytokines were also higher in BKV DNA positive patients with high viral load than in patients with low viral load. Conclusion: According to our results, it is suggested that proinflammatory cytokines may play an important role in the pathogenesis of BKV infections. A better understanding of cytokine responses in BKV infections may help to provide new therapeutic approaches to the treatment of BKV infection especially in transplantation patients.

An interesting case of renal allograft dysfunction with multiple renal arteries of the transplanted kidney

An interesting case of renal allograft dysfunction with multiple renal arteries of the transplanted kidney

Resistance Index Determination in the Pre and Post Kidney Transplantation Time Points in Graft Dysfunction Diagnosis

BackgroundDonor shortage necessitates the development of tools capable of objectively assessing kidney graft quality from expanded criteria donors and kidneys donated after cardiac death. The deteriorating donor profile is leading to a shift from cold storage toward machine perfusion preservation. Several authors found that renal resistance (RR) at the end of machine perfusion was an independent risk factor for the development of delayed graft function (DGF). In contrast, Doppler ultrasonography in the posttransplant period reveals renal hemodynamics and is useful in diagnosing renal allograft dysfunction. We sought to determine concordance between RR and the resistance index (RI) and their diagnostic value in the assessment of graft viability. MethodsRR was determined at the end of perfusion during hypothermic machine preservation and RI was measured by Doppler ultrasonography in the early posttransplant period. Agreement between these 2 measures was established by means of the intraclass correlation coefficient (ICC). Diagnostic validity for RR and RI was determined by sensitivity, specificity and positive and negative predictive values. ResultsThe ICC was 0.135, which indicates a slight agreement. RR and RI had limited value in the prediction of DGF for a specific kidney as reflected by a c-statistic of 0.58 and 0.66, respectively. ConclusionsThere is no agreement between the RR and RI, which may be owing to the different conditions under which measurements are made. The poor predictive power of RR for DGF indicates that kidneys should not be discarded based on RR criteria alone.

Utility of Iron Staining in Identifying the Cause of Renal Allograft Dysfunction in Patients with Sickle Cell Disease.

Sickle cell nephropathy (SCN) is associated with iron/heme deposition in proximal renal tubules and related acute tubular injury (ATI). Here we report the utility of iron staining in differentiating causes of renal allograft dysfunction in patients with a history of sickle cell disease. Case 1: the patient developed acute allograft dysfunction two years after renal transplant. Her renal biopsy showed ATI, supported by patchy loss of brush border and positive staining of kidney injury molecule-1 in proximal tubular epithelial cells, where diffuse increase in iron staining (2+) was present. This indicated that ATI likely resulted from iron/heme toxicity to proximal tubules. Electron microscope confirmed aggregated sickle RBCs in glomeruli, indicating a recurrent SCN. Case 2: four years after renal transplant, the patient developed acute allograft dysfunction and became positive for serum donor-specific antibody. His renal biopsy revealed thrombotic microangiopathy (TMA) and diffuse positive C4d stain in peritubular capillaries. Iron staining was negative in the renal tubules, implying that TMA was likely associated with acute antibody-mediated rejection (AAMR, type 2) rather than recurrent SCN. These case reports imply that iron staining is an inexpensive but effective method in distinguishing SCN-associated renal injury in allograft kidney from other etiologies.

Intravenous Immunoglobulin in BK Virus Nephropathy

The incidence of post transplant viral infections has increased with the use of more potent immunosuppressive regimens. Consequently, BK virus nephropathy (BKVN) has arisen as a significant cause of graft dysfunction and loss. Reduction of immunosuppression is the first line management of post-transplant viral infections. Other therapies such as intravenous immunoglobulin (IVIg), cidofovir, leflunomide and fluoroquinolones have been tried with varying degrees of success. We report our experience with IVIg in three pediatric renal transplant recipients who presented with allograft dysfunction. First, we describe two cases of biopsy proven BKVN, one diagnosed with undetectable viral titers in plasma, demonstrating that BKVN can occur even at low viral loads. We also present a pediatric renal transplant recipient with persistent BK viremia and allograft dysfunction who responded to therapy with recovery of renal function and clearance of viremia. Therefore we conclude that IVIg is efficacious in the treatment of persistent BK viremia and BKVN. The appropriate dose, frequency and duration of therapy require further study.

Treatment of Presumptive BK Nephropathy with Ciprofloxain in Kidney Transplant Recipients: Three Case Reports

BK virus nephropathy has emerged as an important cause of renal allograft dysfunction. Reduction in immunosuppression is the mainstay of BK virus nephropathy treatment. However, decreasing immunosuppressive medications is not sufficient for treatment of BK virus nephropathy. Therefore, there is a need for other treatment strategies such as cidofovir, leflunomide, and intravenous immunoglobulin in combination with immunosuppression reduction. Ciprofloxacin has recently been reported to have antiviral activity and decrease BK viral load in kidney transplant recipients. These findings suggest that the use of ciprofloxacin represents a valuable treatment strategy in patients with BK virus nephropathy. Here, we report on our experience with three patients who developed presumptive BK virus nephropathy after kidney transplantation, who, after 2 months of ciprofloxacin treatment, showed disappearance of BK viremia and improvement in the estimated glomerular filtration rate. Ciprofloxacin may be consid- ered an effective treatment option for BK viremia in kidney transplant recipients.

Belatacept in kidney transplantation.

Calcineurin inhibitors (CNIs) play a major role in long-term renal allograft dysfunction because of their nephrotoxic side-effects. Belatacept, a selective costimulation blockade agent, is the first biological agent approved for maintenance immunosuppression in renal transplantation. Studies have shown better preservation of glomerular filtration rate and improved metabolic end points with belatacept when compared with CNIs. More recent studies have shown that belatacept can be an effective first-line immunosuppressive agent with complete avoidance of CNIs and corticosteroids. Newer biological agents like belatacept may replace CNIs/corticosteroids in renal transplant recipients, with a benefit of better short-term and long-term renal function, better compliance, and ultimately a possible improvement in long-term renal allograft survival.

Renal expression of Toll-like receptor 2 and 4: Dynamics in human allograft injury and comparison to rodents

Activation of the innate immunity through Toll-like receptors (TLRs) has been postulated to play an important role in the pathophysiology of renal allograft dysfunction. TLR2 and TLR4 dynamics in different human post-transplant pathological entities has never been studied. Therefore, we evaluated pre- and post-transplantation protein expression of TLR2 and TLR4 in human kidney biopsies.Human kidney biopsies obtained from living kidney donors and patients with acute tubular necrosis, acute cellular and vascular rejection and interstitial fibrosis/tubular atrophy (IF/TA) were used. Translating results from animal studies to the clinical situation is highly important considering the upcoming clinical studies with TLR inhibitors in human renal transplantation. Hence, the TLR2 and TLR4 expression in healthy mouse and rat kidneys was analyzed and compared with human kidneys. In healthy human kidneys, TLR2 is expressed on the endothelium and Bowman's capsule, while TLR4 is expressed on the endothelium only. No tubular staining was found for both receptors in human kidneys. In contrast to human biopsies, TLR2 and TLR4 expression in rodents was observed on tubular epithelial cells. In all acute rejection human biopsies, increased infiltration of TLR4+ leukocytes was observed. In conclusion, a discrepancy exists between human and rodent renal TLR expression, which suggests careful attention when translating results from rodent studies to the human situation. Additionally, this study revealed human TLR2 and TLR4 expression dynamics in human biopsies pre- and post-transplantation.

Effect of Transient BK Viremia and Viruria on Long-term Renal Allograft Survival and Function

IntroductionThe purpose of this study is to present the five-year survival and function of the renal allograft of recipients who were diagnosed with BK viremia and viruria during the first year after renal transplantation. Patients and MethodsBK virus was studied in 32 new renal allograft recipients, from the first postoperative day until 18 months after the transplantation. Real-time polymerase chain reaction was used to detect and quantitate BK viral load in serum and urine samples. ResultsQualitative analysis with PCR for the DNA of BK virus showed 31 (31/228, 14%) positive serum samples originating from 20 (20/32, 62%) renal allograft recipients and 57 (57/228, 25%) positive urine samples originating from 23 (23/32, 72%) recipients. During the follow up period of 5 years, renal allograft function remained stable (eGFR 18th month: 53.9 ± 23.9 mL/min/1.73 m2 and eGFR 5th year: 52.6 ± 20.6 mL/min/1.73 m2). Comparison of recipients that presented with either BK viremia or viruria with a group that did not present viral reactivation did not reveal a statistically significant difference in eGFR. Furthermore, recipients with significantly high viral load in serum or urine did not present renal allograft dysfunction. ConclusionBK virus is potentially pathogenic in renal allograft recipients. It is certain that there is a reactivation of the virus in a high percentage of transplanted patients mostly in the first year after the surgery, without however a negative effect of the transient viremia and viruria in renal allograft function.

Blood Stream Infections in Renal Transplant Recipients: A Single-Center Study

IntroductionBacteremias among renal transplant recipients are more frequent as a result of immunosuppression. They are considered extremely high-risk because they are correlated with decreased allograft and recipient survival. Patients and MethodsAll episodes of bacteremia among renal transplant recipients were documented following review of medical records, from January 2010 to May 2013. ResultsIn total 26 episodes of bacteremia were observed in 22 patients. Gram negative bacteremia was identified in 73% (19/26) cases. Pathogens according to their frequency were the following Escherichia coli (6/26, 23%), Klebsiella pneumonia (5/26, 19%), Pseudomonas aeruginosa (3/26, 11%), Staphylococcus epidermidis (3/26, 11%), Acinetobacter baumanni (2/26, 7.7%), Enterococcus faecalis (2/26, 7.7%). The first trimester post renal transplantation 18 episodes (69%) of bacteremia were presented that were not correlated to indwelling urinary catheter or stent. Positive urinary culture with the same pathogen was recognized in 13 patients. All recipients manifested fever, eight recipients had leucocytosis and three cases were complicated by septic shock. Immediate resuscitation with intravenous fluids and non-nephrotoxic antibiotic regimen was initiated. Acute renal allograft dysfunction (defined as an increase in serum creatinine more than 0.5 mg/dL from baseline) was observed in five patients and was restored following infection resolution. ConclusionIncreased prevalence of bacteremia in renal transplant recipients is attributed to immunosuppression and usually bacteremic episodes follow urinary tract infection. The commonest pathogens are Gram negative bacteria with E. coli the most frequent. Early detection and proper management are important as bacteremia affects renal allograft and recipient survival.

Assessment of early renal allograft dysfunction with blood oxygenation level-dependent MRI and diffusion-weighted imaging

PurposeTo investigate blood oxygenation level-dependent (BOLD) MRI and diffusion-weighted imaging (DWI) at 3T for assessment of early renal allograft dysfunction. Materials and methods34 patients with a renal allograft (early dysfunction, 24; normal, 10) were prospectively enrolled. BOLD MRI and DWI were performed at 3T. R2* and apparent diffusion coefficient (ADC) values were measured in cortex and medulla of the allografts. Correlation between R2* or ADC values and estimated glomerular filtration rate (eGFR) was investigated. R2* or ADC values were compared among acute rejection (AR), acute tubular necrosis (ATN) and normal function. ResultsIn all renal allografts, cortical or medullary R2* and ADC values were moderately correlated with eGFR (P<0.05). Early dysfunction group showed lower R2* and ADC values than normal function group (P<0.05). AR or ATN had lower R2* values than normal allografts (P<0.05), and ARs had lower cortical ADC values than normal allografts (P<0.05). No significant difference of R2* or ADC values was found between AR and ATN (P>0.05). ConclusionBOLD MRI and DWI at 3T may demonstrate early functional state of renal allografts, but may be limited in characterizing a cause of early renal allograft dysfunction. Further studies are needed.

Chronic Allograft Dysfunction in Kidney Transplant Recipients: Long-term Single-center Study

ObjectiveThe aim of this study was to determine the prevalence and risk factors responsible for the occurrence and progression of chronic allograft dysfunction (CAD) among patients treated in our transplant center. Material and MethodsRetrospective analysis included 637 kidney allograft recipients transplanted between 1990 and 2003 with functioning graft for at least 1 year. CAD was diagnosed based on increased creatinine concentration ≥ 2 mg/dL, occurrence of proteinuria, and worsening of arterial hypertension. In immunosuppressive treatment, 50% of patients received cyclosporine A (CsA), azathioprine, and prednisone; 25% received CsA, mycophenolate mofetil (MMF), and prednisone; whereas 20% received tacrolimus, MMF, and prednisone. The influence of immune and non-immune factors before and after transplantation on the occurrence and progression of CAD was analyzed. ResultsCAD was diagnosed in 43.1% of patients within 10 years after kidney transplantation. CAD development considerably worsened the actual 10-year survival rate of patients (80% versus 92%) and the graft (42% versus 92%). The following factors had the greatest influence (as confirmed with multivariate regression analysis) on CAD progression: proteinuria (odds ratio [OR]: 11.3; P < .0001), serum creatinine concentration > 1.5 mg/dL at 12th month (OR: 3.5; P < .0001) and 24th month (OR: 6.69; P < .0001), cytomegalovirus (CMV) infections (OR: 3.15; P < .0001), and male gender of recipients (OR: 1.48; P < .04). In the CAD patients, acute rejection episodes, delayed graft function, urinary tract infections, and hepatitis C virus (HCV) infections were statistically significantly more often observed compared with the group of patients with stable renal function (reference group). Moreover, in the CAD group, donors were older and recipients younger. The CAD patients had higher arterial pressure and uric acid concentration. ConclusionsDuring the 10-year follow-up, chronic renal allograft dysfunction developed in 43.1% of patients. Proteinuria, serum creatinine level >1.5 mg/dL at 12th and 24th month, and CMV infections were identified as the most significant CAD progression factors. CAD had detrimental effects both on graft and patient survival rates.

P042 : PREVALENCE AND CLINICAL SIGNIFICANCE OF C1q BINDING DONOR SPECIFIC ANTIBODIES IN RENAL TRANSPLANTATION

Antibody-mediated injury is a major cause of renal allograft dysfunction and loss. In this study, we aimed to determine the prevalence and clinical significance of complement binding donor-specific antibodies (C1q + DSA) in renal transplant recipients with functioning allografts after 3–30 years post-transplantation. A total of 405 patients who received renal transplantation at our center from 1982 to 2009 were enrolled in this study. HLA-A, B, C, DR and DQ typing information was available for all patient and donor pairs. All patients were transplanted based on a negative crossmatch and had current serum samples available for DSA testing. Serum IgG- and C1q-binding HLA antibodies were tested using the Single Antigen Bead assay. Based on DSA status, 3 distinct groups were identified in our patient population: 33 patients (8%) with C1q + DSA, 44 patients (11%) with C1q- DSA and 328 patients (81%) without DSA. There were no differences between the groups in terms of gender, race, previous transplantation and induction therapy. However, age and transplant type were significantly different between the groups, with C1q + DSA + patients receiving transplantation at a younger age and more frequently from deceased donors than the other groups ( p p Conclusion Our results indicate that C1q + DSA occured at a frequency of 8% in patients with functioning renal allografts 3–30 years after transplantation. Such antibodies occured more frequently in younger patients and those who received deceased donor allografts. C1q + DSA were associated with an increased incidence of acute and chronic antibody mediated rejection. Thus, monitoring of high-strength/complement binding DSA may assist in the identification of patients at risk for graft loss late after transplantation.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

Chronic Renal Allograft Dysfunction Antibody-Mediated: An Update

This paper reviews the most important studies on chronic antibody-mediated rejection (cABMR), which is an important cause of late graft dysfunction after renal transplantation. Several antibodies seem to be responsible for chronic rejection; new techniques have allowed us to identify these antibodies in circulation. The pathogenetic role of the antibodies generally includes the complement pathway, but may also be complement-independent. This paper also examines the pathogenesis of chronic endothelial lesions, as well as the histopathological aspects. Antibodies responsible for chronic rejection may preexist before transplantation or may develop after transplantation. The possible therapeutic approaches are poor and principally based on early identification and desensitisation techniques. New B cell targeting drugs are aimed at an improved control of the relevant condition.

Low-Dose Interleukin-2 Therapy: Effects in Chronic Renal Allograft Dysfunction.

Immune modulating therapies gain increasing importance in treatment of patients with autoimmune diseases and organ transplantation. Daily low-dose interleukin-2 therapy has been shown to expand regulatory T-cells with clinical improvement in patients with HCV-induced vasculitis or chronic graft-versus-host disease. Here, we studied safety, immunologic effects, and impact on chronic allograft dysfunction of the administration of low-dose interleukin-2 in kidney transplant recipients (KTRs) with end-stage allograft dysfunction. 3 KTRs with chronic renal allograft dysfunction who were refractory to conventional therapy, and who were receiving triple-drug maintenance immunosuppression, received one course of interleukin-2 (1.5 million IU per day) for 5 days, followed by repetition at week 3. Safety and effectiveness of the treatment were evaluated by monitoring lymphocyte subpopulations, gene expression profiles of 13 selected tolerance-associated genes, and the development of HLA- and non-HLA-antibodies. CMV-specific, BKV-specific and alloreactive T-cells were measured using an interferon-γ Elispot assay. No serious adverse events were observed. Interleukin-2 therapy didn't induce effector T-cell activation, acute cellular or antibody-medicated rejection, or reactivation of latent viruses as CMV or BKV. We observed an improvement of allograft function in all KTRs after 2 courses of interleukin-2 with a reduction of serum creatinine levels from 4.37 to 3.35, 4.44 to 3.39, and 2.88 to 2.09mg/dl. However, all KTRs showed a return to baseline serum creatinine levels after discontinuation of interleukin-2 therapy. Administration of low-dose interleukin-2 was followed by an increase in the percentage of CD4+CD25+FOXP3+ Tregs [maximum value ÷ baseline value × 100 = 350%]. Low-dose IL-2 had minimal effects on other T-cell subpopulations, NK-cells, or B-cells. Gene expression patterns of FOXP3 and MAN1a1 were upregulated by interleukin-2 therapy. Low-dose interleukin-2 therapy was safe and led to expansion of regulatory T-cells and temporary improvement of allograft function in KTRs with chronic renal allograft dysfunction.

Early Versus Late Acute Antibody-Mediated Rejection in Thai Kidney Transplant Patients: The Two Distinct Clinical Syndromes.

Background: Acute antibody-mediated rejection (AMR) is the leading cause of early and late renal allograft dysfunction. The purpose of this study was to compare the clinico-pathological features between early and late acute AMR in Thai kidney transplant patients. Method: We examined our kidney transplant recipients for acute AMR demonstrated on biopsy between January 2005 and December 2013. Patients who had glomerulitis and/or peritubular capillaritis were enrolled and stratified by early (≤ 3 months) and late acute AMR (> 3 months after transplantation). Results: Of 64 patients with biopsy-proven acute AMR, 27 cases of early acute AMR were analyzed for associated factors compared with 37 cases of late acute AMR. Early acute AMR was more common in older patients (46.5 ± 10.0 vs. 34.9 ± 9.8; p < 0.001), female recipients (66.7% vs. 32.4%; p = 0.007), deceased donor allografts (70.4% vs. 37.8%; p = 0.01), and highly sensitized patients (74.1% vs. 13.5%; p = 0.01). Non-adherence was observed in 9 cases (24.3%) with late acute AMR whereas none with early acute AMR (p = 0.01). Endothelialitis was more prevalent in early acute AMR (77.8% vs. 10.8%; p < 0.001). Transplant glomerulopathy and interstitial fibrosis/tubular atrophy, the pathological features of chronic changes, were already demonstrated in late acute AMR (70.3% and 13.5%, respectively) but none in early acute AMR (p < 0.001 and 0.05, respectively). Peritubular capillary C4d deposition were commonly revealed in late acute (70.3% vs. 25.9%; p <0.001, respectively). Donor specific antibodies (DSA) were significantly evidenced in late acute AMR (67.6% vs 37%; p = 0.01). Anti-HLA class II (mostly anti-HLA DQ) was more common than class I (62.2% vs 21.6%; p = 0.003) in late acute AMR while anti-HLA class I (mostly anti-HLA A) was more prevalent than class II (29.6% vs 11.1%; p = 0.09) in early acute AMR. The patients with stable graft function at one year after anti-humoral treatment were observed in 21 cases (77.8%) with early acute AMR but only 13 cases (35.1%) with late acute AMR (p = 0.001). Conclusion: Despite similar pathological findings, early and late acute AMR are distinct clinical syndromes. Late acute AMR has worse prognosis than early acute AMR.

Changes in Successive Measures of De Novo DSA Intensity Predict Development of Renal Allograft Dysfunction.

Changes in Successive Measures of De Novo DSA Intensity Predict Development of Renal Allograft Dysfunction.

Renal transplant vascular complications: the role of Doppler ultrasound.

Improvements in the care of kidney transplant recipients and advances in immunosuppressive therapy have reduced the incidence of graft rejection. As a result, other types of kidney transplant complications, such as surgical, urologic, parenchymal, and vascular complications, have become more common. Although vascular complications account for only 5-10% of all post-transplant complications, they are a frequent cause of graft loss. Ultrasonography, both in B-mode and with Doppler ultrasound, is a fundamental tool in the differential diagnosis of renal allograft dysfunction. Doppler ultrasound is highly specific in cases of transplanted renal artery stenosis, pseudoaneurysms, arteriovenous fistulas, and thrombosis with complete or partial artery or vein occlusion. A single measurements of color Doppler indexes display high diagnostic accuracy and in particular cases are more useful during the post-transplantation follow-up period. More recent techniques, such as contrast-enhanced ultrasound, undoubtedly increase the accuracy of ultrasonography in the diagnosis of vascular complications involving the transplanted kidney.