Chronic Renal Allograft Nephropathy Research Articles

Long-Term Outcome of Kidney Retransplantation in Comparison With First Transplantation: A Propensity Score Matching Analysis

BackgroundAdvances in renal transplantation have improved graft survival. However, many patients experience graft failure due to chronic renal allograft nephropathy. Although renal retransplantation is increasingly performed, its outcome is controversial. The aim of this study was to evaluate outcomes of renal retransplantation compared with those of first renal transplantation. MethodsFrom March 1969 to August 2018, there were 3000 cases of renal transplantation performed at Seoul St. Mary’s Hospital, Korea. Because the number of third renal transplantation was too small, only first and second renal transplantation groups were compared using propensity score matching. Outcomes of the third renal transplantation were then added. Graft survival rates were determined using Kaplan-Meier survival curves and assessed for significance using log-rank test. ResultsFive- and 10-year patient-graft survival rates for the first renal transplantation were 82.6% and 72.8%, respectively. Those for the second renal transplantation were 78.4% and 73.9%, respectively (P = .588). Five- and 10-year patient survival rates were 91.2% and 85.1%, respectively, for the first renal transplantation. These were 87.8% and 85.5%, respectively, for the second renal transplantation (P = .684). Five- and 10-year death-censored graft survival rates were 88.8% and 80.6%, respectively, for the first renal transplantation. These were 84.6% and 80.5%, respectively, for the second renal transplantation (P = .564). ConclusionsThis study showed that graft survival of second renal transplantation was not significantly different from that of first renal transplantation. Therefore, renal retransplantation might be a reasonable option for patients who lost the first renal graft.

Role of bone marrow-derived stem cells, renal progenitor cells and stem cell factor in chronic renal allograft nephropathy

IntroductionChronic allograft nephropathy (CAN) is a poorly understood clinico-pathological entity associated with chronic allograft loss due to immunologic and non-immunologic causes. It remains the leading cause of late allograft loss. Bone marrow derived stem cells are undifferentiated cells typically characterized by their capacity for self renewal, ability to give rise to multiple differentiated cellular population, including hematopoietic (HSCs) and mesenchymal stem cells (MSCs). Characterization of HSCs includes their multipotency, expression of typical surface markers such as CD34 and CD45, while characterization of MSC includes their multipotency, expression of typical surface markers such as CD90 and CD105, and the absence of hemopoietic lineage markers. Aim & methodsThe aim of the present work was to study the role of bone marrow-derived HSCs and MSCs, renal progenitor cells and SCF in chronic renal allograft nephropathy in relation to renal hemodynamics and histopathological changes. We studied 30 patients with kidney transplantation for more than 6 months, divided into 15 patients with stable serum creatinine and 15 patients who developed CAN. Detection of HSCs and MSCs in the peripheral blood using flow cytometry via detection of CD34, CD45, CD117 and CD106, as well as immunohistochemical detection of CD34, CD133, VEGF and αSMA in transplanted kidney biopsies of patients with CAN were done. ResultsThere was a significant increase in the levels of SCF, number of peripheral blood HSCs and MSCs in both transplanted patient groups than the controls and they were higher in patients of group Ia than patients of group Ib, (F = 39.73, P < 0.001), (F = 13.28, P < 0.001), (F = 11.94, P < 0.001), respectively and this was accompanied by evident expression of markers of renal repair. ConclusionStem cells might have a role in renal regeneration in CAN and this may pave the way toward the use of stem cells in correction of CAN.

Elevated Urine Heparanase Levels Are Associated with Proteinuria and Decreased Renal Allograft Function

Heparanase is an endo-β-glucuronidase that cleaves heparan sulfate side chains, leading to structural modifications that loosen the extracellular matrix barrier and associated with tumor metastasis, inflammation and angiogenesis. In addition, the highly sulfated heparan sulfate proteoglycans are important constituents of the glomerular basement membrane and its permselective properties. Recent studies suggest a role for heparanase in several experimental and human glomerular diseases associated with proteinuria such as diabetes, minimal change disease, and membranous nephropathy. Here, we quantified blood and urine heparanase levels in renal transplant recipients and patients with chronic kidney disease (CKD), and assessed whether alterations in heparanase levels correlate with proteinuria and renal function. We report that in transplanted patients, urinary heparanase was markedly elevated, inversely associated with estimated glomerular filtration rate (eGFR), suggesting a relationship between heparanase and graft function. In CKD patients, urinary heparanase was markedly elevated and associated with proteinuria, but not with eGFR. In addition, urinary heparanase correlated significantly with plasma heparanase in transplanted patients. Such a systemic spread of heparanase may lead to damage of cells and tissues alongside the kidney.The newly described association between heparanase, proteinuria and decreased renal function is expected to pave the way for new therapeutic options aimed at attenuating chronic renal allograft nephropathy, leading to improved graft survival and patient outcome.

Nephron number determines susceptibility to renal mass reduction-induced CKD in Lewis and Fisher 344 rats: implications for development of experimentally induced chronic allograft nephropathy

The Fisher 344 (F344) rat kidney transplanted to a Lewis rat recipient is a common model of chronic renal allograft nephropathy (CAN); however, CAN does not develop when the Lewis kidney is grafted into a F344 recipient. In this study we investigated whether a difference in nephron number/glomerular volume exists between the strains that could contribute to a greater susceptibility to development of kidney disease in the F344. Separate animals, male F344 and Lewis rats, were subjected to either sham surgery or right uni-nephrectomy and infarction of 2/3 of the left kidney, to produce a 5/6 ablation/infarction injury (5/6 A/I). Serial urinary protein excretions were measured, a terminal 24-h creatinine clearance was obtained and rats were killed 11 weeks after surgery and kidneys were harvested for pathology. Glomerular volumes were measured in the sham controls of each strain. Glomerular number was counted in separate, normal rats of each strain. The normal F344 had approximately 30% fewer glomeruli than Lewis rats that were larger in volume. The sham F344 had similar creatinine clearance and glomerular structure to the Lewis shams, although BP and urine protein excretion were higher. After 5/6 A/I the F344 developed more severe proteinuria and structural kidney damage. When factored for kidney weight, the F344 rats exhibited a greater compensatory hyperfiltration in response to 5/6 A/I, compared to Lewis. The F344 strain is more vulnerable to development of progressive kidney damage due to 5/6 A/I, compared to the Lewis. This is likely due to the lower nephron number/greater glomerular volume of the F344 that may also account for the greater susceptibility to CAN exhibited by this strain.

Evolution of the Renal Function is a Better Predictor of Long-Term Survival Than Serum Creatinine

Background In recent years acute rejection has decreased to 10% to 20%. Therefore it is necessary to look for new endpoints in renal transplantation. Serum creatinine and changes in creatinine have been reported to be powerful predictors of long-term kidney transplant survival. Chronic renal allograft nephropathy is the primary cause of long-term graft failure but may appear at any stage in the evolution. Methods Data from 315 patients receiving cadaver donor renal transplants between February 1987 and March 2001 that functioned for 1 year were examined for the influence of demographic characteristics and transplant variables. Creatinine clearance was estimated using the Cockroft-Gault formula. Survival was assessed with the actuarial method. The multivariate analyses were performed using Cox proportional hazard models. Results The 10-year graft survival showed a relative risk of 2.5 in the univariate analysis when there was more than 10% decrease in renal function at 3 months compared with nadir values. When the decrease was more than 25% of creatinine clearance at the third month, during the evolution and serum creatinine at 3 months introduced in the multivariate model, the latter was not significant, while the other variables had a RR of 4.4 and 10, respectively. Conclusion The evolution of renal function at 3 months and throughout the evolution were better predictors of graft failure than an isolated serum creatinine value.

Compartment-specific quantitative gene expression analysis after laser microdissection from archival renal allograft biopsies

Various immunological and non-immunological pathomechanisms are responsible for the cellular damage in renal allografts. Since the kidney is an anatomically complex organ with functional and morphological heterogeneous compartments (interstitium, tubuli, vessels, glomeruli), the local response to injury maybe variable, therefore, the identification of local pathomechanisms is important. To elucidate any discrepancies in quantitative mRNA expression profiles between a total specimen analysis and a cell-specific evaluation after laser microdissection. Real-time RT-PCR was performed for complement component C3 and heme oxygenase-1 (HO-1) genes compared to the housekeeping gene beta-actin using whole section RNA extracted from formalin-fixed and paraffin-embedded archival material of 16 explanted, rejected renal allografts. Ten non-transplant nephrectomies served as controls. For five cases from each group, five different compartments of the organs (interstitium, proximal tubuli, distal tubuli, vessels, glomeruli) were microdissected and quantitative analysis for C3 and HO-1 was performed identically. Whole section mRNA expression analysis: the data showed a constant expression of the housekeeping gene beta-actin, a 7-fold increased expression of C3 and a 3-fold decreased expression of HO-1 in the allograft group as compared to the control group. mRNA expression results from microdissected compartments: in the control group, C3 and HO-1 expression could only be detected in the proximal tubuli of all cases whereas all five compartments analyzed from the rejecting kidneys showed expression of the two genes. In the allografts, expression levels of the investigated genes varied considerably not only among the different compartments but between individual cases as well. Laser microdissection combined with real-time RT-PCR is a feasible approach for retrospective quantitative gene expression analysis in formalin-fixed and paraffin-embedded renal allograft specimens. As shown for C3 and HO-1, cell-specific expression patterns ofpathogenetically relevant genes vary considerably between individual cases. A close correlation of morphology and cell-specific gene expression analysis will contribute to the elucidation of the complex pathogenesis of chronic renal allograft nephropathy.

A PILOT STUDY OF SWITCHING CSA TO LOW DOSE OF TACROLIMUS ON CHRONIC ALLOGRAFT NEPHROPATHY AFTER KIDNEY TRANSPLANTATION

P178 Aims: The two principal factors implicated in late kidney allograft failure are chronic allograft nephropathy(CAN) and death of the patient with a functioning graft (mainly from cardiovascular causes). CAN is the leading cause of graft failure. Both nonimmunological and immunological mechanisms contribute to this pathology. Tacrolimus is a new, high-potential immunosuppressive agent, possible strategies to stabilize or improve allograft function in patients with already established CAN are the addition of mycophenolate mofetil and conversion from cyclosporine to tacrolimus. Methods: A total of 58 cadaveric kidney transplants were performed at CHAO YANG HOSPITAL from 1998-2000,these patients were first grafts. All recipients received CsA-based triple immunosuppressive regimen. The mean age was 36±14 years, 0.5 to 7.5years after operation. The patients with abnormal grafted renal function after operation and chronic renal allograft nephropathy proved pathologically were collected. A cyclosporine based regimen was converted to a tacrolimus-based regimen. Recipients began to received tacrolimus-based triple immunosuppressive regimen (tacrolimus + MMF +prednisone) after 12 hours discontinuation of CsA. The initial dosage of tacrolimus ranged from 0.04 mg/kg/d to 0.07mg/kg/d,. Dosage adjustments were based on whole blood trough levels. The targeting whole blood trough levels was 8-10ng/ml within 6 months after operation, 5-7 ng/ml after 6 months operation. The dosage of MMF was 1500mg/day. Fellow up at least twelve months. Monitoring the slope of serum creatinine and GFR(ml/min/1.73m2) and 24-hours urine protein output and blood pressure and lipid before and after twelve months of switching CsA to Tacrolimus. Results: The result are shown in Fig 1, 2 and Table 1. The 58 patients of serum creatinine level decreased from 387.5 ±49.7mmol/l to 165.1±56.2mmol/L(p<0.01), 185.1±48.2mmol/L, 180.1±51.2mmol/L. The slope of serum creatinine were from-1.35±1.3 to 2.43±1.7(p<0.05), 2.33±1.5, 2.45±1.5,The result are shown in Fig 2. GFR (ml/min/1.73m2) were from 38.79±2.25 to 49.21±3.19 (p<0.05), 47.21±3.38, 43.37±2.54,24-hours urine protein output were from 4.3±0.8g to 1.9±0.5g(p<0.05), 1.7±0.8g,1.8±0.6g,Cholesterol were from 288±46 mg/dL to 159±55 mg/dL, 169±39 mg/dL,152±47mg/dL, Triglyceride were from 308±56 mg/dL to 217±48 mg/dL, 197±52 mg/dL, 201±43 mg/dL,MAP were from 126±39 mmHg to 90±25 mmHg, 95±38 mmHg, 87±40 mmHg before and after 12,24,36 months of switching CsA to Tacrolimus. The patients survival rates were 100%(58/58),96.5%(56/58), 94.8%(55/58) at 1 year,2 year,3 year respectively. Graft function recovered in 38 cases,improved in 11 recipients, stabilized in 6 patients. Therapy failed in 3 cases and begin hemodialysis. 3 recipients withdrawn from the study because of liver toxicity. The incidence of acute rejection in our study was 10.34%(6/58) after 1 years fellow up. Adverse events in our study were bilirubinemia3.45% (2/58), tremor17.24%(10/58). None of all the patients developed new-onset insulin-dependent Diabetes Mellitus. Conclusions: Many investigators have noted that CAN is the mainly factor of the late kidney allograft failure. Our reports cited that Tacrolimus+MMF is better than CsA in delaying kidney transplant function,(1) Combine Tacrolimus and MMF treatment results in a low incidence of biopsy-confirmed rejection.(2) Tacrolimus reduced TGF-β transforming.(3)Tacrolimus requred less antihypertension,antihyperlipid therapy.(4)To the extent that MMF gives clinicans confidence to reduce the CNI (calcineurin inhibitor) this minimized drug-related toxicities.(5)Mycophenolate mofetil is more bioavailable when used with tacrolimus, compared with cyclosporine, probably because cyclosporine reduces MMF’s bioavailability. The use of a lower dose of MMF in combination with Tacrolimus as maintenance therapy may decrease the incidence of adverse effects while maintaining efficacy. In summary, in this study we demonstrated that conversion from cyclosporine to tacrolimus based regimen was an effective and safe alternative for delaying the course of renal function induced by Chronic Allograft Nephropathy after kidney transplantation.

Plasma levels of transforming growth factor-β1 in renal transplant recipients receiving different immunosuppressive regimens

Experimental and clinical evidence support the role of transforming growth factor beta-1 (TGF-β1), a cytokine with complex immune and nonimmune effects, on the development of chronic renal allograft nephropathy (CAN). We investigated the effects of different immunosuppressive regimens on circulating TGF-β1 plasma levels in stable kidney transplant (KTx) recipients. Two hundred ninety-nine TGF-β1 plasma levels were measured in 125 kidney transplant (KTX) recipients exhibiting stable renal function, immunosuppressed with cyclosporine (CsA), tacrolimus (TAC), or sirolimus (SIR), and in 18 normal healthy volunteers (C). Activated immunoreactive TGF-β1 was detected in platelet-depleted plasma by an enzyme-linked immunoadsorbent assay. Multivariate analyses correlated immunosuppressive regimens with TGF-β1 levels. KTX recipients displayed significantly higher TGF-β1 levels compared to C (P = .0005). Patients receiving CsA had significantly higher TGF-β1 plasma levels compared to those receiving TAC or SIR (P = .0384). Multivariate analyses showed no correlation between TGF-β1 levels and immunosuppressive drug trough blood levels or doses, but only correlations with the main immunosuppressive drug. These data show that: (1) TGF-β1 production is activated in kidney transplant recipients; (2) CsA patients display significantly higher plasma TGF-β1 levels. Follow-up studies seek to assess the possible relationship with clinical events.

Surveillance biopsies are superior to functional studies for the diagnosis of acute and chronic renal allograft pathology in children.

In this report of our 3-yr protocol biopsy program, we describe the evolution of acute rejection (AR) and chronic renal allograft nephropathy (CAN) in a cohort of 21 children treated with antibody induction, tacrolimus, mycophenolate mofetil, and prednisone. The aims of this study were to compare the pathogenicity of clinical acute rejection (CAR) and subclinical acute rejection (SAR), and to determine whether functional studies accurately represent acute and chronic renal allograft pathology in pediatric recipients with disproportionately large grafts. Using concurrent biopsies, we evaluated: (i) the utility of changes in the baseline sCr (DeltasCr) to predict both the onset of AR and the response to immunosuppressive therapy; and (ii) the relationship of the calculated creatinine clearance and the presence of pathologic proteinuria to the severity of CAN. We performed 112 biopsies: 11 donor, 73 protocol, 16 acute graft dysfunction and 12 1-month follow-up AR therapy. CAR and SAR were similar in incidence, timing and histologic severity. Progression of CAN was associated with the first episode of CAR (p < 0.02) and the cumulative number of episodes of CAR (p < 0.01), SAR (p < 0.05), CAR plus SAR (p < 0.002) and borderline SAR (B-SAR) (p < 0.006). One-month post-treatment DeltasCrs could not distinguish 1-month follow-up biopsies with histologically confirmed worsened or unchanged AR from those with improved histology (35.2 +/- 74.8% vs. 23.8 +/- 24.9%, p = NS). These findings led to the addition of anti-lymphocyte antibody therapy in five of 10 (50%) cases. Despite 100% 3-yr actuarial graft survival and excellent function (GFR = 111 +/- 36 mL/min/1.73 m(2)), 18 of 21 (86%) patients had grade I CAN or greater chronic histology at a mean +/- sd follow-up period of 18.2 +/- 13.1 months. Thirteen of 21 (62%) patients progressed to grade I CAN at 5.2 +/- 3.6 months and five (38%) of these patients progressed to grade II CAN at 17.8 +/- 11.3 months. Schwartz GFR did not differ between patients with or without CAN (108 +/- 38 mL/min/1.73 m(2) vs. 127 +/- 8 mL/min/1.73 m(2), p = NS). In biopsies with CAN and no associated AR, neither the Banff chronic tubulointerstitial (Banff ci) score nor the Banff chronic grade correlated with the GFR. Proteinuria was not associated with CAN. Clinical AR and SAR are similar histologic lesions with a capacity for CAN progression. In pediatric renal transplant recipients, longitudinal protocol biopsies are superior to functional studies for the diagnosis and post-therapeutic monitoring of AR and for the surveillance of CAN.

Effect of valsartan on urinary protein excretion and renal function in patients with chronic renal allograft nephropathy

Chronic allograft nephropathy (CAN) remains a significant cause of late renal allograft loss. Although many factors may be involved in pathogenesis, the hemodynamic and fibrogenic consequences of long-term therapy with cyclosporine (CsA) have been implicated as important potentially reversible causes. CsA's effect on CAN is mediated in part through increased renal expression of TGF-β, which can be modified by administration of angiotensin receptor blockers (ARBs). A pilot study was undertaken to evaluate the safety and efficacy of the ARB valsartan on renal function and proteinuira in patients with CAN. Ten patients on CsA-based therapy with evidence of CAN received valsartan in an initial dose of 80 mg/d, force titrated to 160 mg/d after 4 weeks, for a total of 52 weeks. Renal function was evaluated by serum creatinine, 24-hour creatinine clearance (CrCl), and isotope, GFR and urinary protein by 24-hour protein excretion. The 10 patients were aged 20 to 71 years and had been transplanted for 88.2 ± 64.8 months at the time of study. After 52 weeks of valsartan therapy mean blood pressure (BP) fell from 152/88 mm Hg to 138/77 mm Hg ( P = .06); serum creatinine rose from 206 ± 55 μmol/L to 238 ± 81 μmol/L ( P = .22.); GFR fell from 39.8 ± 17.6 to 31.9 ± 19 mL/min ( P = .23); and urine protein fell from 2.16 ± 2.7 to 1.12 ± .095 g/24 hours ( P = .13). Side effects of valsartan therapy were few and included transient hyperkalemia in 2/10 patients. The small rise in serum creatinine and fall in GFR observed were not statistically significant. Urine protein fell by more than 50%, though the small patient numbers in this pilot study prevent this from achieving statistical significance. It is concluded that valasartan reduces BP and proteinuria in CAN patients without inducing a serious worsening in renal function. Valsartan may have a role to play in the management of patients with CAN.

Oxidative stress in chronic renal allograft nephropathy in rats: effects of long-term treatment with carvedilol, BM 91.0228, or alpha-tocopherol.

Oxidative stress is markedly increased after kidney transplantation and may participate in the development and/or progression of chronic renal allograft nephropathy. In the present study we sought to assess the nephroprotective potential of antioxidative treatment in renal allograft recipients. Experiments were performed in the Fisher-Lewis rat model of chronic renal allograft nephropathy, with isografted Lewis rats serving as controls. Allografted rats were orally treated with carvedilol, an antihypertensive drug with antioxidative properties (25 mg/kg/d), its purely antioxidative derivative BM 91.0228 (5 mg/kg/d), alpha-tocopherol (100 mg/kg/d), a combination of propranolol/doxazosine (10/5 mg/kg/d), or vehicle for 24 weeks. At the end of the study, oxidative status and influence of antioxidative treatment were assessed in transplanted animals. Chronic allograft nephropathy was characterized by a marked increase of markers for oxidative stress (increased plasma and kidney levels of malondialdehyde, reduced glutathione, and tocopherol levels in renal allografts). Treatment with carvedilol, BM 91.0228, and tocopherol significantly improved antioxidative status of allograft kidney recipients. In addition, carvedilol reduced elevated blood pressure in allografted rats. However none of the drugs had a beneficial influence on functional and morphologic renal changes. Our data thus demonstrate that long-term treatment with the antioxidants carvedilol, BM 91.0228, or alpha-tocopherol does not prevent development of chronic transplant nephropathy, despite an improvement of antioxidative status.

Tacrolimus in induction immunosuppressive treatment in renal transplantation: comparison with cyclosporine

The aim of the study was to compare the efficacy and safety of induction immunosuppression therapies based on tacrolimus or cyclosporine (CsA) in kidney transplantation. The 240 kidney allograft recipients were divided into two groups: group 1 (n = 94) received tacrolimus (.01 mg/kg per day), mycophenolate mofetil (MMF, 2 g/d), and steroids (30 mg/d); and group 2 (n = 146) CsA (6 mg/kg per day), MMF (2 g/d), and steroids (30 mg/d). Antilymphocyte serum was administered in cases of acute tubular necrosis. The acute rejection rate was higher among group 2 (30.6%) compared with group 1 patients (12.2%) ( P = .001). There were no significant differences between the groups in terms of age, gender, body surface area, serologic virus markers (in donor and recipient), baseline creatinine levels, cause of death, HLA incompatibilities, response to acute tubular necrosis, and number of dialysis sessions. We conclude that both immunosuppressive regimens are effective and safe in kidney transplantation. The survival rates of patients and grafts were similar, but the incidence and degree of acute rejection events were reduced in group 1; this finding may forecast a decreased incidence of chronic renal allograft nephropathy.

Renal transplant fibrosis correlates with intragraft expression of tissue inhibitor of metalloproteinase messenger RNA.

Chronic renal allograft nephropathy is characterized by an abnormal accumulation of extracellular matrix proteins in the glomeruli and tubulo-interstitium. The aim of this study was to determine the relationship between intragraft expression of the genes controlling the accumulation of extracellular matrix and the development of chronic renal allograft nephropathy in human renal transplants. Forty renal allografts with stable renal function were biopsied 6 months after transplantation. Single glomeruli were plucked from the surface of these protocol biopsies and total messenger RNA (mRNA) was extracted. Reverse transcriptase-polymerase chain reaction was used to study the intragraft expression of several fibrosis-associated genes (collagen III, collagen IValpha2, matrix metalloproteinase (MMP) 2, tissue inhibitors of metalloproteinases (TIMPs) 1 and 2, tenascin and transforming growth factor (TGF) beta1). The level of tubulo-interstitial fibrosis was measured by quantitative immunostaining of collagen III. There were positive correlations between the level of tubulo-interstitial collagen III immunostaining and intragraft expression of the genes for TIMP-1 (rs= 0.70, P < 0.02) and TIMP-2 (rs = 0.59, P < 0.02). Interstitial fibrosis was also strongly correlated with the levels of TGF-beta mRNA (rs = 0.67, P < 0.002). Finally, TIMP-1 expression increased with TGF-beta expression (rs = 0.77, P < 0.002). Failure of extracellular matrix degradation may be an important molecular mechanism in the pathogenesis of chronic renal allograft damage.

Intercept and Slope Analysis of Risk Factors in Chronic Renal Allograft Nephropathy

Intercept and Slope Analysis of Risk Factors in Chronic Renal Allograft Nephropathy

Involvement of platelet-derived growth factor and histocompatibility of DRB 1 in chronic renal allograft nephropathy.

The role of activated T cells in graft arteriosclerosis, which is observed in chronic renal allograft nephropathy, and the involvement of major histocompatibility complex (MHC) incompatibility remain to be determined. We examined the effect of T lymphocytes that were obtained from renal transplant patients undergoing chronic rejection treated with cyclosporine (CsA) on platelet-derived growth factor (PDGF)-induced proliferation of cultured human vascular smooth muscle cells (SMC) and compared the proliferation activity of T lymphocytes with MHC incompatibility, especially DRB 1 mismatch. Renal transplant patients with continued allograft function, who survived more than 1 year after transplantation, were recruited. Chronic rejection was documented by graft-biopsy findings together with increasing serum creatinine levels (10-20% per year). After the incubation of supernatant (conditioning medium) of cultured T cells from CsA-treated renal transplant patients with chronic rejection (n=18) and with normal renal function (n=14) as control, normal subjects (n=11) and chronic hemodialysis (HD) patients (n=5) with cultured SMC in the presence or absence of PDGF, DNA synthesis (3H-thymidine uptake) of SMC was examined. The in vitro effects of CsA on DNA synthesis of cultured SMC were also evaluated. The supernatant of cultured T cells from renal transplant patients with chronic rejection stimulated PDGF-induced DNA synthesis of SMC in a dose-dependent manner, showing significant enhancement as compared with control transplant patients, normal subjects, and chronic HD patients. The supernatant itself did not significantly stimulate DNA synthesis of SMC. No significant in vitro stimulation of CsA on DNA synthesis was observed. The supernatant of T cells obtained from recipients undergoing chronic rejection with two DRB 1 mismatches showed significantly higher enhanced activity of PDGF-induced DNA synthesis than the supernatant from those recipients without mismatch of DRB 1. On the other hand, no significant correlation of the enhanced activity by T cell supernatant to HLA A and B mismatch numbers was observed. Growth factor-promoting factors(s) derived from activated T cells associated with MHC class II DR expression, which promotes PDGF-induced proliferation of SMC, exists in renal transplant patients with chronic renal allograft nephropathy, and is probably involved in arteriosclerosis of the graft kidney.

Injury of peritubular capillaries correlates with graft function in chronic renal allograft nephropathy

Injury of peritubular capillaries correlates with graft function in chronic renal allograft nephropathy

The expression of endothelin and inducible nitric oxide synthase in human renal allografts and their role in chronic renal allograft nephropathy

The expression of endothelin and inducible nitric oxide synthase in human renal allografts and their role in chronic renal allograft nephropathy

Treatment with a combined endothelin A/B-receptor antagonist does not prevent chronic renal allograft rejection in rats.

A markedly increased expression of endothelin (ET)-1 has been observed in renal allografts with chronic rejection, one of the most common causes of kidney graft loss. In this study we investigated the effect of treatment with a combined ET-A/B-receptor antagonist on the course of chronic renal allograft rejection. Experiments were performed in the Fisher-to-Lewis rat model of chronic rejection. Lewis-to-Lewis isografts and uninephrectomized Lewis rats served as controls. Animals were treated with either the oral combined ET-A/B-receptor antagonist LU224332 (20 mg/kg/day) or vehicle. Animal survival, blood pressure, creatinine clearance, proteinuria, and urinary ET excretion were investigated for 24 weeks. Kidneys were removed for light-microscopic evaluation and immunohistochemical assessment of cell-surface markers. Treatment with LU224332 did not improve survival after 24 weeks (0.47 vs. 0.38; p > 0.05 by log-rank test), nor did it have an influence on blood pressure, creatinine clearance, or proteinuria. Combined ET-A/B-receptor blockade was associated with a reduction of expression of cell-surface markers for macrophages (EDI), T-cells (R73), and major histocompatibility complex (MHC) II (F17-23-2), but did not lead to an improvement of histologic changes of chronic allograft rejection. Our data show that blocking both ET-A- and -B receptors, in opposition to a previously published beneficial effect of selective ET-A blockade, does not prevent the progression of chronic renal allograft rejection and does not prolong survival in this model. Functional integrity of the ET-B receptor therefore seems to play an important role in the nephroprotection provided by selective ET-A-receptor antagonists in chronic renal allograft nephropathy.

The role of transforming growth factor beta in chronic renal allograft nephropathy.

The role of transforming growth factor beta in chronic renal allograft nephropathy.

THE EFFECT OF MYCOPHENOLATE MOFETIL AND POLYPHENOLIC BIOFLAVONOIDS ON RENAL ISCHEMIA REPERFUSION INJURY AND REPAIR

Chronic renal allograft nephropathy is associated with both immune and ischemic injury which may act synergistically to promote an inflammatory response. The immunosuppressant mycophenolic acid and the polyphenolic agents curcumin and quercetin possess properties that might ameliorate such injury. We studied the effects of these agents in models of ischemic renal injury and skin allograft rejection. Ischemic acute tubular necrosis was produced in rats by renal pedicle occlusion with contralateral nephrectomy. Animals were treated with mycophenolic acid, quercetin and curcumin, or a combination of agents. Animals were killed on days 2 and 7 after operation and tissue samples were collected. Renal tubular apoptosis and cellular proliferation were assessed by immunohistochemistry. Expression of the cytokines RANTES and AIF were evaluated by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Treatment with the polyphenolic compounds alone or in combination with mycophenolic acid was associated with less tubular damage, attenuation of renal inflammation, and prolongation of skin graft survival. A combination of agents decreased serum creatinine on day 2 from 4.5 to 0.9 mg./dl. (p< or =0.01) and at day 7 from 3.8 to 0.6 mg./dl. (p< or =0.01). Treatment with the polyphenolic compounds inhibited apoptosis at day 2. By RT-PCR, RANTES and AIF were detected at high levels on days 2 and 7. Treatment with these agents alone or in combination strongly attenuated this increased expression. The combination of mycophenolic acid with curcumin and quercetin reduces renal injury and facilitates repair. These agents may have a role in therapeutic regimens that are both immunosuppressive and renoprotective.