Expression and role of matrix metalloproteinase in injury related renal transplantation / 器官移植

Matrix metalloproteinase (MMP) is a large class of proteases which can cut or reshape extracellular matrix (ECM) and cell surface proteins. The activity of MMP is regulated by a variety of cytokines, including tissue inhibitor of metalloprotease (TIMP), signal transduction molecules and cell adhesion molecules. The latest research shows that MMP has a role in the pathophysiology process of many acute and chronic kidney diseases. In this article, the classification, expression and distribution in the kidney of MMP and its role in injury related renal transplantation was reviewed.

Clinical efficacy of Shuxuening injection combined with compound coenzyme in treatment of chronic allograft nephropathy / 实用医学杂志

Objective To observe the clinical efficacy of Shuxuening injection combined with compound coenzyme in the treatment of chronic allograft nephropathy (CAN). Methods A retrospective analysis of 108 patients with chronic allograft nephropathy (CAN) admitted to our hospital from June 2014 to May 2018 were divided into two groups according to different treatments. The 43 cases in the experimental group were given Shuxuening injection combined with compound coenzyme, and the 65 cases in control group were given non-Shu Xuening + compound coenzyme. The original immunization protocol was maintained in both groups. After 4 weeks of treatment, the changes of hemodynamic parameters, clinical efficacy, biochemical parameters, coagulation function and adverse reactions were observed before and after treatment. Results There was no significant difference in baseline data between the two groups before treatment (P> 0.05). After treatment, the peak systolic velocity of the intersegmental artery and cortical arteriole in the experimental group were significantly higher than that the control group (P < 0.05) , and the resistance index was lower than that in the control group (P < 0.05). After treatment, serum creatinine, 24 h urine protein quantitation, urinary microalbumin, total cholesterol and triglycerides were lower than that before treatment (P < 0.05) , and estimated glomerular filtration rate (eGFR) and serum. Albumin increased significantly (P < 0.05) , but the 24 h urine protein quantitation and urinary albumin decreased significantly in the experimental group compared with the control group (P < 0.05). After treatment, the total amount of cholesterol, triglycerides showed no significant difference (P> 0.05). After treatment, the platelet count, fibrinogen and D-dimer of the experimental group were significantly lower than those before treatment (P < 0.05) , and the activated partial thrombin time (APT) was significantly higher than that before treatment (P < 0.05). Significant difference in platelet count, fibrinogen, D-dimer and APTT was found after treatment (P < 0.05). After 4 weeks of treatment, the values of urea nitrogen and serum creatinine were significantly lower than those of the control group (P < 0.05). The recovery of transplanted kidney function in the experimental group was higher than that in the control group (P < 0.05). The experimental group reported 2 cases of fatigue complain and 1 case of dizziness, but no special treatment was given to them and their condition improved after symptomatic treatment; 1 case of mild phlebitis which was cured after given slowed drip rate and local hot compress therapy. The incidence of adverse events was 9.3％ (4/43). The control group reported 2 cases of fatigue complain, 1 case of nausea, 1 case of facial flushing, and all cured with no special treatment was given; 1 case of mild phlebitis, and cured after slowed the i.v. drip rate and ocal hot compress; The adverse events rate was 7.7％ (5/65). No serious adverse reactions occurred during the entire clinical trial. There was no significant difference in the incidence of adverse events between the experimental group and the control group (χ2=0.054, P=0.732). Conclusion Combined with Shuxuening injection and compound coenzyme can improve blood flow of transplanted kidney, reduce proteinuria, reduce blood urea nitrogen and creatinine in patients with CAN after renal transplantation and effectively improve patient's hemodynamic parameters and safety.

The value of diffusion tensor imaging in early diagnosis of chronic allograft nephropathy and monitoring graft fibrosis in rats / 中华放射学杂志

Objective To estimate the value of diffusion tensor imaging (DTI) in early diagnosis of chronic allograft nephropathy (CAN) and monitoring of graft fibrosis in rat models . Methods Thirty CAN rat models were established as experimental group by transplanting Fisher donor kidneys into Lewis recipients. Thirty Lewis rats that received Lewis kidneys served as control group. Serum creatinine (SCr) was monitored regularly every two weeks from 14 days after transplantation. Eight rats were randomly selected by random number table method and underwent DTI examination at 4, 12, 20 weeks after modeling. DTI scans were performed on the renal cortex and medulla to measure apparent diffusion coefficient (ADC) and fractional anisotropy (FA). From the remaining 22 rats in each group, 6 rats were randomly selected and underwent pathological analysis at 4, 12, 20 weeks after modeling. Histological changes in the kidney were evaluated by chronic allograft damage index (CADI) scores. The expression of alpha-smooth muscle actin (α-SMA) and Vimentin were quantitatively measured. The differences in creatinine, DTI parameters, CADI score, α-SMA, Vimentin expression level were analyzed by two independent samples t test in two groups, the differences among CADI score, α-SMA, Vimentin expression level of the experimental group were compared using ANOVA. The correlations among DTI parameters and CADI score, α-SMA and Vimentin expression level were analyzed using Pearson analysis. Results The creatinine in the experimental group increased continuously, and the creatinine in the control group showed no significant increase. The difference in creatinine between the two groups was statistically significant from 8th week after operation (P＜0.01). There was no obvious difference in the size and signal intensity of transplanted kidneys in control group at different time points. Compared with the control group, the graft kidney in the experimental group at the 4 weeks demonstrated increased signal intensity with mild increased volume of kidney, and the boundaries between cortex and medulla were not clear. The cortex and medulla showed gradually increased signal intensity, heterogeneous signal distribution and marginal haziness over time. The ADC and FA value of renal cortex and medulla in experimental group were significantly lower than those in control group at 4, 12, 20 weeks (P＜0.05). The ADC and FA values of the cortex and medulla gradually decreased in the experimental group over time, while the values of the parameters in the control group did not show a significant decrease. The ADC and FA values of the cortex and medulla were negatively correlated with the scores of CADI, and the expression level of α-SMA, Vimentin in the experimental group(r=－0.50 to －0.85, P＜0.01).Conclusion DTI can be an effective technique for early diagnosis of CAN and monitoring of graft fibrosis process.

Clinical effect of conversion to Rapamycin on chronic allograft nephropathy / 中华器官移植杂志

Objective To study the effect and safety of conversion from calcineurin inhibitors to rapamycin in kidney transplantation recipients with chronic allograft nephropathy.Methods In 82 kidney transplant recipients enrolled in this study,72 cases were diagnosed as having chronic allograft nephropathy by biopsy.Recipients (SRL group) were administered with rapamycin after withdrawal of calcineurin inhibitors.The doses of CNI in other recipients (non-SRL group) were not changed.Renal function,proteinuria,blood pressure,blood fat,hepatic function and hemogram were observed for 24 months in each group.Results During the follow-up period,serum creatinine level was dropped significantly in SRL group (P＜0.05),but it was increased in non-SRL group (P＜0.05).SRL group showed increased proteinuria,serum cholesterol and triglycerides (P＜0.05),and reduced Plt (P＜0.05).According to the renal function before conversion,the recipients who were administered rapamycin divided into four groups.In group A (Scr ＜ 120 μmol/L),there was no significant difference in diverse variables before and after conversion.In group B (Scr 120-200 μmol/L and Banff Ⅰ-Ⅱ),renal function was improved,and proteinuria alleviated.In group C (Scr 120-200 μmol/L and Banff ＞ Ⅱ),and group D (Scr ＞200 μmol/L),renal function was damaged to varying degrees and proteinuria was deteriorated.Conclusion It is safe and effective for patients with chronic allograft nephropathy to convert from calcineurin inhibitors to rapamycin.

Influence of immunosuppressants on C4d deposition in renal allografts of rats with chronic allograft nephropathy / 第二军医大学学报

Objective To observe C4d deposition in renal allografts of rats undergoing chronic allograft nephropathy (CAN), and to analyze the effects of immunosuppressants on deposition of C4d in peritubular capillaries. Methods The renal grafts of Fisher 344 rats were ortho topically transplanted into Lewis rats to create CAN models, and all the recipients were given cyclosporine A (CsA) 10 mg/(kg �� d) X10d after operation. The models were then divided into 5 groups (each n=9): Group A was normal saline control group, only receiving vehicle orally; Group B, C, D, and E received CsA 6 mg/(kg �� d), RAPA0. 8 mg/(kg �� d), FK506 0. 15 mg/(kg �� d), and MMF 20 mg/(kg �� d), respectively. The renal allografts were harvested after three rats were sacrificed at the 4th, 8th and 12th weeks post-transplantation. The histological changes were assessed according to Banff 97 standard. The deposition of C4d was detected by immunofluorescence method. Results C4d deposition in peritubular capillary (PTC) was found in all the allografts at the 4th week after transplantation, while there were no obvious clinical pathological changes of CAN in all groups, and the Banff scores were not significantly different among different groups (P > 0. 05). CAN manifestations of different degrees were observed 8 weeks after operation, with increased C4d deposition in the PTC. Severest CAN was observed at the 12th week after operation, accompanied by the most C4d deposition in the PTC. C4d deposition was positively correlated with the severity of CAN (r=0. 894, P = 0. 000). Compared with the control group, CsA and FK506 showed no significant effect on C4d deposition (P>0. 05); however, MMF and RAPA significantly decreasedC4d deposition (P<0. 05). Conclusion Deposition of C4d in PTC may appear in allografts earlier than the pathological changes of CAN, and the deposition is associated with the progression of CAN. MMF and RAPA can inhibit the progression of CAN, while CsA and FK506 can not.

Initial application of virtual touch tissue quantification in diagnosis of chronic allograft nephropathy / 中华超声影像学杂志

Objective To investigate the feasibility of virtual touch tissue quantification(VTQ) for the assessment of chronic allograft nephropathy(CAN).Methods 48 patients with normal renal function and 50 patients with CAN were checked by color Doppler and VTQ technique.All the results were compared　between two groups.Results Mean VTQ-values were significantly different between the two groups( P ＜ 0.05).ROC curve displayed that VTQ value of 2.51 m/s could be used to diagnose CAN,the sensitivity,specificity,positive predictive value and negative predictive value were 76.0％,52.1％,60.3％ and 65.7％,respectively.The diagnostic efficiency was 62.2％.Conclusions Parenchymal stiffness measured by VTQ is stable and repeatable,which can be used to diagnose patients with CAN and to monitor renal function.

Significance of CD20-positive lymphocytes infiltrating in renal allograft biopsies with chronic allograft nephropathy / 中华器官移植杂志

ObjectiveTo investigate the action mechanism of CD20 lymphocyte infiltration in the renal allograft biopsy with chronic allograft nephropathy (CAN).MethodsCAN cases confirmed by renal biopsy within 2 years after renal transplantation served as study subjects. By using immunohistochemistry,the deposition of C4d and the CD20-positive lymphocytes infiltration in the renal grafts were examined.The clinical follow-up data were analyzed.ResultsForty-four cases of CAN were enrolled in the study, including 13 cases (29.5％ ) of CD20-positive lymphocytes infiltration,and 31cases (70.5％ )of CD20-negative lymphocytes infiltration. CD20-positive lymphocytes in biopsy showed nodular and scattered lymphocytes infiltration.There were 5 (26.3％)cases of CAN Ⅰ,4 cases (25.0％) of CAN Ⅱ,and 4 (44.4％) of CAN Ⅲ in CD20-positive group.There was no statistically significant difference between the only CAN group and CAN with AR group in CD20-positive rate.Immunohistochemical staining showed there were 12 cases (27.3％) with C4d linear deposition in peritubular capillary endothelial cells (PTC).C4d positive rate had no significant difference among the CAN classifications. There was no significant relationship between C4d deposition and CD20-positive lymphocytic infiltration.The average serum creatinine in CD20-negtive group and CD20-posigtive group was 140.8 ± 22.0 and 183.5 ± 25.5μmol/L before biopsy,and 165.6 ± 37.6 and 242.2 ± 59.1 μmol/L one year after biopsy.The average serum creatinine level in CD20-positive group was higher than in CD20-negtive group before and after biopsy.ConclusionProgressive chronic humoral immunity is high risk in the process of CAN. The CD20-positive lymphocyte infiltration has no relevance with CAN grade and C4d deposition in PTC,but is associated with circulating antibody PRA and allograft long-term outcome. Pathogenetic mechanism may not contribute to chronic humoral immune,but B cells presenting donor antigens,are recognized and activated by T cells as antigen-presenting cells.

TMP combined with salvia miltiorrhiza delays the progression of chronic allograft nephropathy in rats / 中华器官移植杂志

Objective To investigate the effects of ligustrazine (TMP) combined with salvia miltiorrhiza on the progression of chronic allograft nephropathy (CAN) in rats and the action mechanism.Methods Fischer 344 rats and Lewis rats were used as renal transplant recipients and donors for ortlotopic kidney transplantation. The CAN model was established.By using random number table,the kidney transplant recipients were divided into five groups:cyclosporine A (CsA) group (A),TMP + CsA group (B),Salvia + CsA group (C),TMP + Salvia + CsA group (D) and blank control group (E,receiving no treatment).At 2nd,4th,6th,8th and 12th week after operation,5 mice in each group were sacrificed,and the transplanted kidney was removed for examination of renal histopathological changes. The immunohistochemistry was used to detect the expression of transforming growth factor β1 (TGF-β1) in the renal allograts,and by using fluorescent quantitative polymerase chain reaction,TGF-β1 mRNA expression in the renal allograts assayed.Results In blank control group,the survival time was no more than two weeks.In group A,the CAN pathological changes occurred at 4th week postoperation,those in group B and group C occurred later than in group A,and latest in group D with mild pathological lesions.In all groups after operation,Banff scores showed an upward trend,and at the same time point,those in group A were significantly higher than groups B,C and D ( P＜0.05 and P＜0.01 ).and those in group D was significantly lower than in group B and group C (P＜0.05),but no significant difference was found between group B and group C (P＞0.05).With time over,the TGF-β1 expression intensity showed an increasing trend.At the same time point,TGF-β1 expression intensity in group A was strongest among groups A,B,C and D (P＜0.05 and P＜0.01 ),and that in group D was significantly lower than in group B and group C (P＜0.05),but no significant difference was found between group B and group C (P＞00.05).The changes of TGF-β1mRNA expression pattem in each group showed the same trends as TGF-β1 protein expression.Conclusion TMP or salvia miltiorrhiza can delay the progression of CAN in kidney transplant rats by down-regulating the TGF-β1 expression,and the combined use of them exerts synergic effects.

Efficacy of the program of rapamycin combined with CNI in chronic allograft nephropathy / 中华器官移植杂志

ObjectiveTo investigate the efficacy of rapamycin combined with CsA/Tacrolimus (Tac) in chronic allograft nephropathy (CAN).MethodsFifty-three cases of CAN accepted the quadruple immunosuppressive drug program,which contained rapamycin combined with CsA/Tac and MMF and prednisone,and CsA/Tac and MMF were reduced to the original amount of 25％ to 50％.After treatment for 12 months,more relevant indicators,including serum creatinine,glomerular filtration rate,serum cholesterol,triglycerides,urinary protein,GPT and bilirubin and other changes were observed.ResultsIn the patients receiving quadruple regimen of rapamycin during 12 months,the blood Ccr was decreased from (161.51 ± 106.48)μmol/L before treatment to (126.51 ± 56.2)μmol/L after treatment for 6 months (P＜0.05) and to (123.43 ± 54.18)μmol/L after for 12 months (P＜0.01).The GFR was increased from (0.754 ± 0.302) ml/s before treatment to (0.952 ± 0.347)ml/s after treatment for 6 months (P＜0.05) and to (1.007 ± 0.394) ml/s after treatment for 12 months (P＜0.01).Cholesterol and triglycerides in patients had no significant change before and after treatment.The positive rate of proteinuria after treatment showed an increasing trend from 9.4％ before treatment to 26.4％ after treatment for 12 months.ConclusionThe quadruple program of rapamycin combined with CsA/FK506 and MMF can significantly improve Ccr and GFR in patients with CAN,but it can increase the incidence of proteinuria in patients:

Biomarkers for long-term survival of renal graft: Recent progress / 第二军医大学学报

How to maintain a good long-term graft function is currently the most prominent problem in renal transplantation. Due to inefficiency of the existing diagnostic tools, extensive studies have been made to search for novel biomarkers and have made rapid progression. Here we aimed to make a brief review of important biomarkers that have been shown relevant to the long-term outcome of renal graft.

Establishment of rat experiment model of chronic allograft nephropathy / 中华器官移植杂志

Objective To summarize the experience of establishing the stable rat model of chronic allograft nephropathy. Methods We used Fisher rats as donors and Lewis rats as recipients.After the left kidney of the donor perfused in situ under hypothermic condition, the left renal vein,abdominal aorta and bladder flap of the donor was anastomosed with the left renal vein, renal artery and bladder of the recipient, respectively. The recipients were given cyclosporin oral solution 10 mg/kg every day by gavage for 10 days after transplantation. The blood and urine samples were collected 1 month, 2 months and 4 months after transplantation and renal function and total urine protein were examined. The pathological changes of the renal allograft were observed 2 and 4 months after transplantation. Results Forty-five rats received operation and achievement ratio was 85%. The renal transplantations were finished in 120 ± 20 min. The Scr, BUN, Cycs and total urine protein demonstrated a significant increase one month after transplantation. On the second and fourth month,with the exception of urine protein continued to increase, the other indicators did not change significantly. Two months after transplantation renal pathology demonstrated light to moderate interstitial fibrosis, infiltration of lymphocytes and plasma cells. At 4th month the renal allografts showed extensive interstitial fibrosis, a large number of infiltrating interstitial cells, thickening,hardening, occlusion of glomerular basement membrane, and renal tubular atrophy that were consistent with pathological changes of chronic allograft nephropathy. Conclusion Through adequate surgical training and improvement, and specification for rat nephrectomy, transplantation surgery,and postoperative management in every detail, the model with high success rate and stability can be achieved.

Expression of Osteopontin and molecules in EMT of rats with chronic allograft nephropathy / 中华器官移植杂志

Objective To investigate the expression of OPN, α-SMA, E-cadherin and their correlation in the chronic allograft nephropathy (CAN) rat model, and to explore the possible role of OPN in CAN.Methods Orthotopic renal-transplantation using Fisher rats as donors and Lewis rats as recipients was done to establish CAN group, and Lewis to Lewis rats as control group. Rats in each group were sacrificed 12 weeks after the surgery. Blood and urine were collected for further test. Allograft samples were collected and sectioned for HE, Sirus-red staining, immunohistochemistry and Western blot.Results There were CAN morphological changes of the allograft in CAN group. As compared with control group, immunohistochemistry and Western blot revealed that the expression of OPN and α-SMA in CAN group was significantly increased, and that of E-Cadherin reduced. Its trend was correlated with the inflammatory response and the EMT of tubule epithelial cells.Conclusions OPN expression in rat CAN model is significantly up-regulated. OPN may play a role in CAN. OPN might affect the CAN by promoting EMT of tubule epithelial cells.

Effect of conversion from cyclosporine A to tacrolimus on the patients with chronic allograft nephropathy / 中华器官移植杂志

Objective To investigate the effect of conversion from cyclosporine A (CsA) to tacrolimus (Tac) on chronic allograft nephropathy (CAN). Methods 153 CAN patients undergoing kidney transplantation received CsA, mycophenolate mofetil (MMF) and prednisone (CsA-MMF-Pred) regimen after kidney transplantation, and divided into 2 groups according to whether CsA were maintained in the immunosuppressive regimen: CsA + MMF + Pred group (CsA group, n = 45); Tac + MMF + Pred group (Tac group, n = 108). The patients were followed up with patient/kidney survival rate, acute rejection incidence, renal function, 24-h proteinuria and adverse events of immunosuppressive drugs for 12 months. Results Compared with CsA group, the transplanted kidney survival rate was significantly higher in Tac group (93. 5 % vs 86.6 %, P＜0. 05). Acute rejection (AR) was diagnosed in 4. 4 % (2/45) of recipients in CsA group and 3. 7 % (4/108) in Tac group (P＞0. 05) respectively. Acute rejection (2 cases in CsA group and 4 in Tac group) was reversed by 500 mg of methylprednisolone for consecutive 3 days, and the patients in Tac group showed a significantly lower degree of interstitial fibrosis and tubular atrophy (IF/TA) (P＜0. 05).Renal allograft functions and 24-h proteinuria during a follow-up period of 12 months were significantly improved in Tac group (P ＜ 0. 05). Incidence of mild hyperglycemia in Tac Group (13.8 %, 15/108) was significantly higher than in CsA group (4.4 %, 2/45), and that of hypertension in Tac group (22. 2 %, 24/108) was significantly lower than in CsA group (55.6 %,25/45). CsA-related side effects (such as hirsutism and gingival hypertrophy) in 17 patients were greatly improved after conversion from CsA to Tac treatment. Conclusion The conversion from CsA to Tac on the patients with CAN can improve renal allograft function, retard the progression of renal allograft dysfunction, reduce the incidence of CsA-related side effects and not generate serious adverse effects of Tac.

Role and mechanism of phosphate myosin light chain in chronic allograft nephropathy of rats / 中华器官移植杂志

Objective To investigate the role and mechanism of phosphate myosin light chain (pMLC) in the rat kidney of chronic allograft nephropathy (CAN) model. Methods The left donor kidneys from Fisher (F344) rats were orthotopically transplanted into Lewis recipients. Meanwhile, the F344 rats and LEW rats with resection of the right kidney served as control groups. Animals were harvested respectively at the 4th, 8th and 12th week after transplantation. The creatinine clearance rate (CCr) was calculated by urine creatinine of 24-h urine. Blood samples were collected from rats for determination of serum creatinine. The expression of pMLC was detected by using Western blotting and immunohistochernistry, and that of integrin-linked kinase (ILK) by using immunohistochemistry. Results Mononuclear cells infiltration of allografts was markedly aggravated as compared to the controls. Allografts got severe interstitial fibrosis and tubular atrophy at 12th week after transplantation. The expression of pMILC and ILK was up-regulated in the kidney of CAN rats after transplantation, and increased more significantly as the time went on. The expression of pMILC was significantly correlated with 24-h urine protein excretion (r= 0. 273, P＜0. 05), serum creatinine levels (r = 0. 434, P＜0. 01 ), the number of tubulointerstitial infiltrated mononuclear cells (r = 0. 525, P＜0. 01 ), the number of smooth muscle cells (SMC) in vascular wall (r= 0. 676, P＜0. 01 ) and the extent of interstitial fibrosis (r= 0. 570, P＜0. 01 ).There was a significantly positive correlation between ILK and pMLC in CAN rats at the 4th week after transplantation (r= 0. 778, P＜0. 01 ). Conclusion pMLC might play an key role in CAN, and the over-expression of ILK might be involve in the pathogenesis of CAN.

Role of glucogen synthase kinase-3β in a rat kidney model of chronic allograft nephropathy / 中华器官移植杂志

Objective To investigate the expression and significance of glucogen synthase kinase-3β (GSK-3β) in the pathogenesis of chronic allograft nephropathy (CAN) in rats.Methods Kidneys of Fisher (F344) rats as donors were orthotopically transplanted into Lewis (LEW) rats as recipients.The renal function and histopathological changes were observed at 4,8,12,16,and 24week post-transplantation.Phosphorylated GSK-3β (p-GSK-3β) protein and mRNA expression was determined by using immunohistological assays and RT-PCR respectively.Results Our data showed that 24-h urinary protein excretion in CAN rats was increased significantly at week 16 as compared with F344/LEW controls.Allografts showed markedly increased mononuclear cells infiltration and presented with severe interstitial fibrosis and tubular atrophy at 16 and 24 week post-transplantation.p-GSK-3β expression (protein/mRNA) was down-regulated in rat kidneys with CAN,and the decrease became more significant over time after transplantation.p-GSK-3β expression was correlated significantly with 24-h urinary protein excretion,serum creatinine levels,tubulointerstitial mononuclear cells infiltration,smooth muscle cells migration in vascular wall,and interstitial fibrosis.Conclusion It was concluded that GSK-3β down-regulation was the key event that may be involved in mononuclear cells infiltration and vascular SMCs migration at early stage,and interstitial fibrosis and allograft nephroangiosclerosis at later stage of CAN pathogenesis in rats.

Glomerular damage as a predictor of renal allograft loss

Interstitial fibrosis and tubular atrophy (IF/TA) are the most common cause of renal graft failure. Chronic transplant glomerulopathy (CTG) is present in approximately 1.5-3.0 percent of all renal grafts. We retrospectively studied the contribution of CTG and recurrent post-transplant glomerulopathies (RGN) to graft loss. We analyzed 123 patients with chronic renal allograft dysfunction and divided them into three groups: CTG (N = 37), RGN (N = 21), and IF/TA (N = 65). Demographic data were analyzed and the variables related to graft function identified by statistical methods. CTG had a significantly lower allograft survival than IF/TA. In a multivariate analysis, protective factors for allograft outcomes were: use of angiotensin-converting enzyme inhibitor (ACEI; hazard ratio (HR) = 0.12, P = 0.001), mycophenolate mofetil (MMF; HR = 0.17, P = 0.026), hepatitis C virus (HR = 7.29, P = 0.003), delayed graft function (HR = 5.32, P = 0.016), serum creatinine ≥1.5 mg/dL at the 1st year post-transplant (HR = 0.20, P = 0.011), and proteinuria ≥0.5 g/24 h at the 1st year post-transplant (HR = 0.14, P = 0.004). The presence of glomerular damage is a risk factor for allograft loss (HR = 4.55, P = 0.015). The presence of some degree of chronic glomerular damage in addition to the diagnosis of IF/TA was the most important risk factor associated with allograft loss since it could indicate chronic active antibody-mediated rejection. ACEI and MMF were associated with better outcomes, indicating that they might improve graft survival.

Retrospective study of the effect of C4d deposition in peritubular capillary in chronic allograft nephropathy on the prognosis of renal allografts / 中华器官移植杂志

Objective To investigate the effect of C4d deposition in peritubular capillary (PTC)in chronic allograft nephropathy (CAN) on prognosis and intervention of renal transplantation recipients. Methods All the cases who received the renal graft biopsy due to diagnosis of CAN from January 2000 to August 2008, and had the 2-year follow-up data were included in the study. The clinical data were analyzed according to the C4d deposition in PTC. Results Among 86 cases 39 cases were C4d positive (C4d+ group) and the remaining 47 cases were negative (C4d group). There was no significant difference in sex, age, donor source, transplant times, time after biopsy, the panel reactive antibodies (PRA) level between two groups (P＞0. 05). Before intervention, there was no significant difference in serum creatinine (Scr) and 24 h urinary protein between two groups (P＞0. 05). At the end of 2-year followed-up period, graft loss rate and urinary protein levels in C4d+group were significantly higher than in C4d- group (P＜0. 05). Before intervention, the incidence of blood lipid disorder and hypertension was higher in C4d- group (P ＜ 0. 05 ), but no significant difference was found in uric acid and blood sugar levels (P＞0. 05). At the end of 2-year followed-up period, there was no significant difference in blood glucose, uric acid, blood pressure and lipid profile (eliminating renal lost cases) between two groups (P＞0. 05). Conclusion The patients with CAN and C4d+ means the involvement of chronic humoral rejection and have poor clinical results. Effective intervention against humoral immune response can improve renal allograft survival.

Expression of E-cadherin, Heat Shock Protein 47, Transforming Growth Factor beta1 and C4d in Chronic Allograft Nephropathy / 대한이식학회지

BACKGROUND: Chronic allograft nephropathy (CAN), which causes graft failure, is related to tubular atrophy and interstitial fibrosis. E-cadherin is a well-known epithelial marker and heat shock protein (HSP)-47 is a collagen-specific molecular chaperone that regulates collagen synthesis. Transforming growth factor (TGF)-beta1, a profibrotic cytokine, downregulates E-cadherin and induces expression of mesenchymal markers in an in vitro model. C4d expression is considered a poor prognostic marker for graft survival. This study evaluated the relationship between the expression of E-cadherin, HSP47, TGF-beta1, and C4d with the prognosis for CAN. METHODS: Between March 1991 and August 2007, we performed renal allograft biopsies on 42 recipients with deteriorating renal function. CAN was diagnosed according to the chronic allograft damage index (Banff classification). Renal allograft biopsies were examined for the expression of E-cadherin, HSP47, TGF-beta1, or C4d by immunohistochemistry. The HSP47, TGF-beta1, and E-cadherin staining was scored semiquantitatively by analyzing ten different fields of cortical interstitium and tubules. Biopsies with endothelial C4d staining in peri-tubular capillaries (> or =25%) were designated as C4d-positive. RESULTS: Of 42 recipients, 17 (40.5%) were in the graft survival group (GS) and 25 (59.5%) were in the graft failure group (GF). E-cadherin expression in tubular cells of the GS was much higher than that of the GF (94.1% vs 52%, P=0.04). HSP47 expression in tubular cells and interstitium in the GF was much higher than that in the GS (84% vs 35.3%, P=0.001). TGF-beta1 expression in tubular cells and interstitium in the GF was much higher than that in the GS (72% vs 23.5%, P=0.02). CONCLUSIONS: E-cadherin, HSP47, and TGF-beta1 expression was strongly correlated with the CAN prognosis.

Proximal tubular dysfunction as an indicator of chronic graft dysfunction

New strategies are being devised to limit the impact of renal sclerosis on graft function. Individualization of immunosuppression, specifically the interruption of calcineurin-inhibitors has been tried in order to promote better graft survival once chronic graft dysfunction has been established. However, the long-term impact of these approaches is still not totally clear. Nevertheless, patients at higher risk for tubular atrophy and interstitial fibrosis (TA/IF) development should be carefully monitored for tubular function as well as glomerular performance. Since tubular-interstitial impairment is an early event in TA/IF pathogenesis and associated with graft function, it seems reasonable that strategies directed at assessing tubular structural integrity and function would yield important functional and prognostic data. The measurement of small proteins in urine such as α-1-microglobulin, N-acetyl-beta-D-glucosaminidase, alpha/pi S-glutathione transferases, β-2 microglobulin, and retinol binding protein is associated with proximal tubular cell dysfunction. Therefore, its straightforward assessment could provide a powerful tool in patient monitoring and ongoing clinical assessment of graft function, ultimately helping to facilitate longer patient and graft survival associated with good graft function.

Patologia do transplante renal: achados morfológicos principais e como laudar as biópsias / Renal transplant pathology: main morphological findings and how to sign out biopsies

O transplante renal alcançou expressivos e crescentes índices de sucesso desde sua implantação, constituindo atualmente uma terapia substitutiva de larga escala. É cada vez mais freqüente o encontro de biópsias de enxerto renal na rotina dos laboratórios de patologia, cujos achados são os mais variados. Este artigo resulta da experiência dos membros do Clube do Rim (da Sociedade Brasileira de Patologia) e apresenta um panorama geral da patologia do transplante renal, enfatizando a atual classificação de Banff, com suas principais categorias e entidades de diagnóstico problemático.

Renal transplant has reached remarkable and growing rates of success since its introduction; nowadays it is a widely used replacement therapy. Renal allograft biopsies are increasingly more frequent in the routine of pathology laboratories, whose histological findings are varied. This paper results from the expertise of the members of the Kidney Club of Sociedade Brasileira de Patologia, and presents a general overview of renal allograft pathology, focusing on the current Banff classification, its main categories and cases of difficult diagnosis.