Chronic Transplant Nephropathy Research Articles

THE MODERN VIEW ON THE PATHOGENESIS OF THE ISCHEMIA–REPERFUSION SYNDROME IN KIDNEY TRANSPLANTATION

This article highlights the main factors of the pathogenesis of ischemia/reperfusion syndrome of renal allograft. Cellular, humoral, and nonspecific mechanisms of renal damage development are described. The possibilities of effective influence on it are limited by objective difficulties, which are mainly associated with the presence of a variety of alternative ways, which ultimately lead to severe graft damage, the rapid development of chronic transplant nephropathy and increase the risk of graft loss. Further research is needed to develop ways to target the main links of pathogenesis.

Impact of smoking on kidney transplantation outcomes

To investigate the impact of smoking on kidney transplantation outcomes. The materials of 350 patients (including 229 (65.4%) men aged 37.1±0.6 years) who had undergone kidney allotransplantation (KAT) for end-stage renal disease were analyzed. The main outcomes of KAT (patient status (alive or dead); renal allograft (RAG) function or dysfunction; development of chronic transplant nephropathy (CTN)), were studied. There were 52 (14.8%) smoking patients (50 (96.2%) men and 2 (3.8%) women). The survival rate of smokers after KAT was significantly lower (p=0.043), as was the duration of graft function in the smoking patients (p=0.038). There were statistically significant associations of smoking with age, sex, time to normalize post-KAT serum creatinine concentrations, the development of CTN and graft rejection crises, postoperative hypertension, post-KAT serum creatinine, hemoglobin, and albumin levels, pretransplantation alanine aminotransferase concentrations, pre-KAT left ventricular hypertrophy, patient compliance with the prescribed treatment regimen, the presence or absence of a job in the patient after KAT (p<0.05). The investigators built models for predicting the outcome of KAT for a patient's life and the development of CTN from preoperative patient risk factors, as well as a model of a RAG outcome from the factors of the pre-transplantation period and those seen one year after KAT. The impact of smoking on outcomes of KAT was revealed in all models along with other predictors. Smoking is an important predictor of kidney transplantation outcome for both patients' lives and RAG function.

INFLUENCE OF BONE MARROW MSCs ON THE DEVELOPMENT OF POSTTRANSPLANT CHANGES IN KIDNES

Aim:to study of infl uence of various doses of autologous BM MSCs on the development of chronic transplant nephropathy in a decentralized kidney using kidney autotransplantation model (KAT).Materials and methods.Five groups of experiments were performed on 105 Wistar rats. The model of kidney autotransplantation by means of surgical decentralization (denervation – delymphatization) and infl ammation induction with kidney antigen and Freund’s adjuvant was created in groups I, II and III. Group I served as a decentralization control (control 1). In groups II and III autologous BM MSCs were injected intravenously once 35–40 days after surgery – a high dose in group II: 3.0–5.0×106 cells; a low dose in group III: 0.3–0.5×106 cells; group IV served as intact control; group V served as intact control with the injection of the same dose of BM MSCs as in group II. Kidney excretory functions (diuresis, creatinine, urea, protein in blood and urine, sodium excretion) and morphology were examined during months 3, 5 and 7–10.Results.In all five groups over the study duration nitrogen excretion was not disrupted. High doses of BM MSCs after KAT modeling resulted after month 3 in pronounced proteinuria in all rats (3–3.5 times more than in group I) and gradually decreased diuresis; histologically severe focal cell infiltration and the accumulation of protein masses in lumina of glomeruli and tubules were observed. By month 10 glomerular and tubulointerstitial focal sclerosis was developed. Low doses of BM MSCs after KAT modeling led to gradual decrease of proteinuria after month 3 reaching the initial values by months 5 and 7 of observation; histologically rare foci of cellular infiltration around glomeruli were observed.Conclusion.A single application of low doses of BM MSCs is capable of protective desensitizing infl uence on the tissue of decentralized kidney and can prolong the duration of kidney function without signs of pronounced damage, while under the same conditions high doses of autologous BM MSCs lead to accelerated development of severe chronic transplant nephropathy.

The Emerging Role of Mitochondrial Targeting in Kidney Disease.

Renal disease affects millions of people worldwide, imposing an enormous financial burden for health-care systems. Recent evidence suggests that mitochondria play an important role in the pathogenesis of different forms of renal disease, including genetic defects, acute kidney injury, chronic kidney disease, aging, renal tumors, and transplant nephropathy. Renal mitochondrial abnormalities and dysfunction affect several cellular pathways, leading to increased oxidative stress, apoptosis, microvascular loss, and fibrosis, all of which compromise renal function. Over recent years, compounds that specifically target mitochondria have emerged as promising therapeutic options for patients with renal disease. Although the most compelling evidence is based on preclinical studies, several compounds are currently being tested in clinical trials. This chapter provides an overview of the involvement of mitochondrial dysfunction in renal disease and summarizes the current knowledge on mitochondria-targeted strategies to attenuate renal disease.

Nutritional research and intensive nutritional counselling of the chronic kidney disease patients after kidney transplantation

Background: Dietology treatment is the one of the foundation stones in the complex treatment of the chronic kidney disease (CKD) patients together with all other treatments. The dietary intervention plays an important role to determine the effects to a decrease of metabolic abnormalities. Aim: The aim of the long-term study was to monitor nutritional parameters in the post-transplant period. Subjects and methods : We studied 28 clinically stable consecutive nondiabetic kidney transplant patients: 12 males at the age of 42.8 ± 16.1 years, and 16 females at the age of 47.0 ± 14.9 years. Intensive nutritional counselling and dietary consultation by a dietitian were carried out for all the studied patients during one and a half years after the kidney transplantation. Initial data were compared with the results obtained at the end of the study. During the 3-days dietary records analysis and counselling of CKD patients, giving answers to their questions about their food and portion sizes, the dietitian used the standards portion book with many photographs. Results: The consumption of vegetables and fruit was modest compared to Estonian food and nutrition recommendations. The food frequency questionnaire revealed that the patients consumed different foodstuffs at different frequencies, but there was a tendency to excessive consumption of foodstuffs rich in proteins and carbohydrates. To consumption of fat-rich foodstuffs a tendency of decrease was found. Conclusion: An intensive nutritional counselling and healthy diet, avoiding excessive amounts of alcohol as well as regular exercise can help to reduce the chance of developing of chronic transplant nephropathy.

ROENTGENOENDOVASCULAR EMBOLIZATION OF NEPHROTRANSPLANT ARTERIES AS A STAGE OF TRANSPLANTECTOMY

Aim. To improve the results of surgical treatment of patients with chronic transplant nephropathy (CTN) in nephrotransplantectomy (NTE) using preventive endovascular transplant arteries embolization (ETAE). Materials and methods. The results of clinical examination and surgical treatment of 30 patients with chronic transplant nephropathy in the period from 2004 to 2012 were assessed. Patients were divided into two groups: group 1, in which NTE was performed after ETAE and group 2 – NTE without ETAE. Both groups were compared by the hemorrhage volume, surgical complications, medical measures. Results. Intraoperative hemorrhage in group 1 was from 20 to 50 ml, on the average 40±10,5 ml. In group 2 – from 100 to 600 ml, on the average 295±50,4 ml ( p =0,04). No surgical complications, such as vascular damage when performing NTE in group 1 were noted. In group 2 there was registered vascular damage in 15% of cases ( n =3).No intra-and postoperative hemotransfusions connected with hemorrhage were detected in group 1. In group 2 erythrocytic mass infusion was administered in 75% of cases ( n =15). Conclusion. Preventive ETAE permits to significantly reduce the hemorrhage degree (from 295±50,4 ml to 40±10,5 ml) during NTE that is very important for patients with nephrogenic anemia against the background of tCPN transplant. ETAE allows to completely abolish immunosuppression in the early period after this manipulation, to carry out nephrectomy in the delayed terms and to grade the risk of immunological conflict with subsequent allotransplantations to these recipients.

Acute Rejection as Key Predictor for Long-Term Outcomes after Kidney Transplantation?

Introduction: Type, severity, timing, and clinical course of acute rejection each influence the impact of a rejection episode, and if renal function recovers fully, there appears to be no survival disadvantage (CTS-Study, Opelz). With modern immunosuppressive regimens, the overall incidence of acute rejection may no longer be the most accurate surrogate marker for long-term kidney graft survival. We investigated the specificity of (subclinical) chronic inflammatory responses (SCAR) induced either by not successful treated rejection episodes, by using different CNI's or ongoing activated innate immune responses. We used the high sensitive parameter for inflammation, indoleamine 2,3 dioxygenase (IDO), in patients after renal transplantation in correlation to graft survival and graft function. Patients and methods: In a retro- (A, n=224, up to 12 years) and prospective study (B, n=124, up to 3 years) of renal transplant recipients we evaluated the IDO behavior for the long-term run. Both groups were comparable concerning the basic demographic data (age, time on dialysis, PRA and waiting time). Estimation of IDO was performed via kynurenine measurement. Results: IDO in normal controls (n=257) was 2,5±0,4 μmol/L Kyn, in stabile renal transplanted patients (n=248) 5,8 ±1,8μmol/L. We identified in both groups already end of the first week posttransplant a statistically significant difference (A:17,2 vs. 7,0 (week 1, median, p< .005; 8,1vs.4,8 (w.6, median, p< .001; B:12,3 vs. 7,0 (w.1, median, p< .001); 6,7 vs. 4,2 (w.6, median, p< .001)) in the IDO levels between patients with/without acute rejection. Patients with an IDO-level > 5, 5 in the follow up (min.3 weeks) and after rejection treatment showed a significant lower graft survival. In the cohort A (IDO < 5,0) 1/5/10 year graft survival was 98/88/69% compared to 88/57/34% (survival data death censored). There was no difference between both CNI's. Rejection rate in A was allover 18%, in B 19,5 % (BPAR). Patients with induction or polyclonal rejection treatment showed lower IDO levels and a better long-term survival. Conclusion: Supported by recent publications we found that chronic transplant nephropathy may not be related solely to CNI toxicity. Our data supporting the results, that not the rejection episode itself is leading to a reduced long-term outcome but a subclinical ongoing inflammatory processes. Once the rejection episode is treated successfully - meaning the reestablishment of the inflammatory homeostasis - the chance for a long graft survival is still given. IDO monitoring might be a helpful tool to identify very early subclinical acute rejection, the best rejection treatment and the optimization of immunsuppressive regimen in sense of rejection prophylaxis.

Pneumonitis Associated With Mammalian Target of Rapamycin Inhibitors in Renal Transplant Recipients: A Single-Center Experience

Background The mammalian target of rapamycin inhibitors (mTORi) sirolimus (Si) and everolimus (Ev) induce pneumonitis, an unusual but potentially fatal adverse effect. We report 8 cases of suspected mTORi-induced pneumonitis over a 9-years experience from 2000 to 2009. Methods The switch from a calcineurin inhibitor (CNi) was made due to chronic transplant nephropathy, tumors, nephrotoxicity, or for rejection prophylaxis. Results One hundred six patients were switched from CNi to Si ( n = 29) or Ev ( n = 134). Twenty-five additional patients were treated de novo with mTORi. The 8 patients (3 Si, 5 Ev) who developed pneumonitis included 5 females and 3 males of median age, 59.1 years (range, 40–68). The median time from switch to pneumonitis onset was 292 days (range, 60–982). The clinical presentation included fatigue ( n = 6), fever ( n = 7), dyspnea ( n = 6), dry cough ( n = 6), and weight loss ( n = 5). In most cases, imaging tests (chest radiograph, computerized tomography) revealed bilateral lower lobe involvement. Bronchoalveolar lavage showed a lymphocytic alveolitis in 5 subjects with negative cultures. All patients recovered after mTORi withdrawal. All patients were treated with antibiotics and five with steroids. Conclusion mTORi associated pneumonitis is not a rare disease. It is equally induced by Si or Ev. Pneumonitis was not apparently dependent on the drug dose or the blood levels. Discontinuation of mTORi seems to be the safest treatment option to avoid pulmonary fibrosis or a fatal outcome.

Prospective Study on Autoantibodies Against Apolipoprotein H (β2GPI) in Several Clinical Parameters From Patients With Terminal Renal Failure and Functioning Renal Transplants

Renal transplantation is the best therapeutic option for patients with end-stage renal disease. However, long-term results have not been very encouraging because of patient deaths due to cardiovascular disease and chronic transplant nephropathy (CTN), which includes vascular damage similar to arteriosclerosis injury. Several autoantibodies have been related to vasculopathy in the transplant such as anti-beta2GPI IgA, IgG, and IgM autoantibodies. We analyzed the levels of these autoantibodies among a cohort of 176 transplant recipients and a control group of 80 healthy subjects using enzyme-linked immunosorbent assay (ELISA). We collected data concerning the cardiovascular status of the patients, such as age, sex, diabetes mellitus, biopsy-confirmed CTN, schemic cardiopathy, cholesterol, triglycerides, and renal status by Modification of Diet in Renal Disease (MDRD) clearance and proteinuria. We also selected other characteristics, including hepatitis C virus infection and systolic/diastolic arterial pressures. The proportion of patients with high levels of IgG and IgM anti-beta2GPI autoantibodies did not differ from that observed in the control group, whereas the difference became significant in the case of anti-beta2GPI IgA autoantibodies (19.88% vs 1%). These results for the presence of anti-beta2GPI IgA autoantibodies were related to clinical data through a multivariate analysis, where the only parameter influenced by the presence of these autoantibodies seemed to be proteinuria, which in most cases was due to CTN.

Significance of HLA Nondependent Risk Factors of Chronic Transplant Nephropathy for the Development of Endothelial Dysfunction After Kidney Transplantation

More than 40% of renal allografts show chronic transplant nephropathy (CTN) early after renal transplantation. Cardiovascular disease is the leading cause of death in this population. Thus endothelial dysfunction represents an early angiopathy causing CTN and atherosclerosis. We sought to evaluate changes in endothelial dysfunction and vascular wall thickness during the first year posttransplantation as well as their association with HLA nondependent risk factors for CTN. At 3 and 52 weeks after grafting, we studied 25 patients without overt atherosclerotic disease and acute posttransplant complications for von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), big endothelin-1 (ET-1), flow-mediated dilatation (FMD), intimal media thickness (IMT), serum total cholesterol (TC), and triglycerides (TAG). FMD and IMT at 52 weeks showed significant correlations ( P < .05) with recipient age, and the FMD ratios at 3 and 52 weeks correlated with the time on hemodialysis. Recipient age was significantly correlated with TC and PAI-1 with TAG. vWF was the only parameter that significantly correlated with donor age. There were no significant correlations with creatinine clearance. Decreased TAG approached statistical significance ( P = .07) and TC decreased nonsignificantly. The worsening of FMD and ET-1 was not significant. A nonsignificant improvement in IMT was not associated with any analyzed parameters. Our results implied that the time on hemodialysis, the presence of hyperlipoproteinemia, and the recipient age significantly contributed to endothelial dysfunction during the first year after transplantation.

Effectiveness of EUS in Liver Lesions of Unclear Etiology

Endoscopic ultrasound (EUS) has assumed an important role in the diagnosis and staging of malignant GI tumors over the past few decades. EUS has widespread applications in the imaging of the GI tract, but has not been comprehensively studied in characterizing liver lesions. This case report describes the application of EUS in one such case. Case: 24 yo male with hypoplastic kidneys s/p renal transplant × 2 (last being 7 years prior), chronic transplant nephropathy, and chronic pancreatitis presented with a 3-week history of epigastric pain. CT of abdomen without intravenous contrast (due to the patient's renal function) revealed a 3–4 cm mixed density lesion in the anterior segment of the right hepatic lobe which was biopsied under CT-guidance with aspiration of 10–15 ml of serosanguinous fluid. Biopsy cultures grew Enterococcus for which the patient was prescribed intravenous ampicillin/sulbactam for 6 weeks. The patient left the hospital AMA. Two weeks later, he returned to the hospital and underwent an MRI without contrast and a trans-abdominal ultrasound with equivocal findings. A repeat CT-guided biopsy was performed and revealed a bloody aspirate. EUS was performed and showed a 30 × 40 mm vascular structure in the right lobe of the liver with turbulent flow with a doppler characteristic of an arterial structure, consistent with an arterio-venous malformation. Four weeks later, the patient presented with sharp epigastric pain, melena, and icterus. Labs revealed a total bilirubin of 22.5 mg/dL and a significant decrease in hemoglobin (10 to 5.9 g/dL). An EGD revealed esophagitis. Side-view endoscopy (duodenoscope) demonstrated blood-tinged bile from the major papilla. Contrast injection revealed blood clots obstructing the CBD, which was cleared and stented with a 10-Fr 10 cm plastic stent. The cause of the upper GI bleed was determined to be hemobilia. Conclusions: This case report suggests the use of EUS as the imaging modality of choice for the liver prior to any therapeutic endeavor for patients who have contraindications for radiological contrast. Although scant information is available on the use of EUS as a primary imaging modality in cases such as these, this report suggests EUS may serve an important role in identifying liver lesions and preventing potential iatrogenic complications.

A rare case of vascular rejection in a renal transplant recipient with nephrotic range proteinuria

Abstract: In the post‐cyclosporine A era, it has been reported that acute rejection after kidney transplantation is commonly revealed as an asymptomatic increase in the serum creatinine level. Nephrotic range proteinuria is observed in patients with recurrent or de novo glomerulonephritis, or with chronic transplant nephropathy and glomerulopathy in the late phase. Acute rejection occurring with nephrotic range proteinuria without a rise of serum creatinine has been rarely reported. Here, we report a rare case of vascular rejection in a renal transplant recipient with nephrotic range proteinuria. A 34‐yr‐old male renal transplant recipient presented with acute vascular rejection and early‐onset nephrotic syndrome. Severe nephrotic range proteinuria was detected with a minimally elevated level of serum creatinine. Biopsy showed severe glomerulitis and vasculitis, which was relieved by conversion of the immunosupressant regimen. Severe proteinuria was a sign of acute vascular rejection with severe glomerulitis and vasculitis. Careful observation to ensure maintenance of immunosuppression is necessary in such cases.

The Immunological Implications of Renal Transplantation in Diabetes

Over the past years immunosuppressive regimens have been a key component in improving short term outcomes for solidorgan transplantation. However, the prevention and treatment of chronic transplant nephropathy is still an issue. Immunosuppressive agents are given at a cost to patients with renal transplants, increasing the risk of infections and cardiovascular morbidity and mortality. One of the main ways through which these drugs cause harm is through the development of post transplant diabetes or the worsening of previously present diabetes. Corticosteroids and calcineurin inhibitors play major roles in the development of post transplant diabetes, infections and other metabolic complications. Another important immunological implication for renal transplantation occurs with combined kidney and pancreas or islet cell transplantation. Beta cell replacement is an attractive cure for patients with diabetes undergoing renal transplantation. Improvement of blood glucose levels helps reduce development of complications. However an important immunological mechanism may adversely affect this procedure. In patients with Type 1 diabetes a memory autoimmune response to islet autoantigens may occur with re exposure to these antigens. Keeping these issues in mind, we ask, are new drugs improving the lives of these patients? Is there a solution to these problems?

Gene profiling of polycystic kidneys

While the genetic basis of autosomal dominant polycystic kidney disease (ADPKD) has been clearly established, the pathogenesis of renal failure in ADPKD remains elusive. Cyst formation originates from proliferating renal tubular epithelial cells that de-differentiate. Fluid secretion with cyst expansion and reactive changes in the extracellular matrix composition combined with increased apoptosis and proliferation rates have been implicated in cystogenesis. To identify genes that characterize pathogenical changes in ADPKD, we compared the expression profiles of 12 ADPKD kidneys, 13 kidneys with chronic transplant nephropathy and 16 normal kidneys using a 7 k cDNA microarray. RT-PCR and immunohistochemical techniques were used to confirm the microarray data. Hierarchical clustering revealed that the gene expression profiles of normal, ADPKD and rejected kidneys were clearly distinct. A total of 87 genes were specifically regulated in ADPKD; 26 of these 87 genes were typical for smooth muscle, suggesting epithelial-to-myofibroblast transition (EMT) as a pathogenetic factor in ADPKD. Immunohistology revealed that smooth muscle actin, a typical marker for myofibroblast transition, and caldesmon were mainly expressed in the interstitium of ADPKD kidneys. In contrast, up-regulated keratin 19 and fibulin-1 were confined to cystic epithelia. Our results show that the end stage of ADPKD is associated with increased markers of EMT, suggesting that EMT contributes to the progressive loss of renal function in ADPKD.

Paediatric kidney transplantation in small children - a single centre experience

Kidney transplantation (KTx) remains a challenging procedure in small children. This study presents our centre results. From 1983 to 2004, 40 of 442 paediatric KTx were performed in children with a body weight <11 kg. Median body weight was 9.2 kg (range: 7.2-10.9), median age was 2.7 years (range: 0.9-5.9). Preoperative dialysis was performed in 87.5%. In 24 cases (60%) grafts came from cadaveric (CAD) and in 16 cases (40%) from living related donors (LRD). Median donor age of CAD was 8 years (range: 1-40). The overall 1-, 5-, 10-, 15-year patient survival was 93%, 90%, 90% and 87% respectively. The overall 1-, 5-, 10-, 15-year graft survival was 90%, 80%, 66% and 56% respectively. There was no significant difference in survival of CAD or LRD grafts. Median follow-up was 13.7 years. Initial graft function rate was 100% for LRD and 79% for CAD. The relative glomerular filtration rate (GFR) showed no statistical difference between CAD and LRD. Main reasons for graft loss were chronic transplant nephropathy. Paediatric KTx is the treatment of choice even in very small children. Living donor KTx is the preferable donor source in terms of primary graft function and timing to transplantation.

Impact of the new drugs in the cost of maintenance immunosuppression of renal transplantation. Is it justified?

The new immunosuppressive drugs control acute rejection better, and have potentially short-term economic advantages. However, their long-term cost-effectiveness must still be determined. The Spanish study of chronic transplant nephropathy provides data that facilitates the assessment of the economic importance of maintenance immunosuppression (MI). We determined the frequency of use of the different MI drugs and their combinations in three renal transplantation cohorts performed in 1990, 1994 and 1998 (total: 3279), and their evolution over time. Based on the real costs found in a medium-sized service in our country at the end of 2000, the mean annual costs of MI drugs were calculated. We performed a multivariate analysis of graft survival in the 1998 cohort. In 1990 and 1994, cyclosporine (CsA) with or without azathioprine (AZA) was used almost exclusively as the initial MI drug. In 1998, 76% received mycophenolate mofetil (MMF) and 20% tacrolimus (TAC). During their follow-up, a growing number of patients from the 1990 and 1994 groups were converted to MMF (12 and 17%) and TAC (4 and 8%), while the treatment of those from 1998 remained stable. Using prices from the year 2000, the mean cost of the MI at the end of the first year in 1998 (5380) was almost double that of 1994 (2902) and 1990 (2855). In these two groups, the mean cost remained stable until 1996; afterwards, it increased in both, more rapidly in the 1994 (24.8%) than in the 1990 (17.3%) group, although it remained significantly inferior to that of 1998. Correction for the evolution of the drug prices and the peseta purchasing value lessened these changes in an important way. The new regimens allowed for the withdrawal of steroids in a greater proportion of cases; TAC was associated with a less frequent use of lipid-lowering drugs and antihypertensive drugs. In the whole patient group, the regimens with MMF and/or TAC showed a tendency to greater mean life of the organs, but without reaching statistical significance in the multivariate analysis of patients in 1998. The introduction of new drugs in the MI applied in Spain has had an important economic impact since 1996. Their cost-effectiveness is still pending confirmation in our country.

Cyclosporine nephrotoxicity

The introduction of cyclosporine (CSA) into organ transplantation was a landmark achievement leading to a substantial improvement of the early transplant results. It was particularly the reduction in early severe acute rejections that accounted for this improvement. However, on a long-term basis development of chronic transplant nephropathy did not seem to become counteracted by CSA. Conversely, CSA may cause both acute and chronic nephrotoxicity, with reduced renal transplant function along with arteriolopathy and interstitial fibrosis. This is the shortcoming of CSA as well as other calcineurin inhibitors (CNIs) such as tacrolimus (TAC). Other immunosuppressive agents were developed subsequently, including Target of Rapamycin (ToR) blockers and mycophenolate mofetil (MMF), which were not nephrotoxic. Current strategies to overcome CNI toxicity include reduction or even stopping administration of CSA or TAC along with switching to a sirolimus, everolimus or MMF based regimen. This strategy has been documented (and there are currently additional ongoing studies) to cause an improvement in renal transplant function or to reduce the deterioration rate. These measures to deal with CSA toxicity need further documentation, since a preserved good renal function seems to not only have an important impact on graft survival but also on patient survival.

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.

The Remission of Post-Transplant Nephrotic Syndrome Clinicopathologic Characterization

Among 67 renal transplant recipients with nephrotic syndrome (NS), nine episodes were reversible in eight patients. Biopsies showed minimal-change disease, focal segmental membranous glomerulonephritis and acute glomerulitis, IgA nephropathy and acute glomerulitis or thrombotic microangiopathy, and chronic transplant nephropathy with or without acute glomerulitis. NS developed 1-4 months post transplant in the four patients with minimal-change disease, but later (33-151 months) in the others. At onset, serum creatinine was normal or elevated. Treatment included calcium-channel blockers, angiotensin-converting enzyme inhibitors, or both, together with routine antirejection therapy. Remission was achieved 4-12 months after onset, when renal function remained normal in four, improved in four, and worsened in one. At last follow-up, six patients still had remission and functional grafts. One lost graft to chronic transplant nephropathy while NS remained in remission. In the remaining patient, proteinuria, which was due to chronic transplant glomerulopathy unrelated to the initial minimal-change disease-associated NS, recurred 50 months post transplant. Remission of post-transplant NS is possible. It is often associated with minimal-change diseases and less frequently with other glomerular lesions, including acute glomerulitis. Reversible post-transplant NS does not have an adverse effect on the renal allografts.

Combination treatment with an ET(A)-receptor blocker and an ACE inhibitor is not superior to the respective monotherapies in attenuating chronic transplant nephropathy in a 'Fisher-to-Lewis' rat model.

Specific endothelin A (ET(A))-receptor blockade and ACE inhibition attenuate chronic transplant nephropathy (CTN) in the 'Fisher-to-Lewis' rat model. It is unknown (i) which of both pharmacological interventions attenuates CTN more effectively and (ii) whether combination therapy exerts additive nephroprotection. We compared (i) the effects of specific ET(A)-receptor blockade with LU 302146 (30 mg/kg bw/day) and ACE inhibition with trandolapril (0.3 mg/kg bw/day) and (ii) the effect of a combination therapy of both drugs on the development of CTN. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Untreated 'Fisher-to-Lewis' allografts served as controls (TX). All animals received low-dose cyclosporin A (1.5 mg/kg body weight) for 10 days post-transplant to inhibit early acute rejection episodes. The duration of the experiment was 36 weeks. Blood pressure (BP) was measured every other week by tail plethysmography. Indices of glomerulosclerosis (GS), tubulointerstitial and vascular damage, number of glomeruli, total glomerular volume and mean glomerular volume were measured using morphometric and stereological techniques, respectively. Albuminuria, blood chemistry and haematology were measured at the end of the experiment. LU 302146 did not affect systolic BP. In contrast, trandolapril and combination treatment significantly reduced systolic BP. Histological signs of CTN were almost completely prevented by LU 302146 and trandolapril as compared to TX, e.g. GS=0.8+/-0.08 and 0.9+/-0.20 vs 1.8+/-0.21* (arbitrary unit; *P<0.001 vs treated groups). Allograft weight was significantly lower in treated vs TX animals. Trandolapril and combination therapy, but not LU 302146 alone, abrogated glomerular hypertrophy, i.e. mean glomerular volume: TX 2.22+/-0.43, trandolapril 1.61+/-0.38**, LU 302146 2.22+/-0.11, trandolapril+LU 302146 1.78+/-0.28* (microm(3); *P<0.05 vs control and LU 302146, **P<0.01 vs control and LU 302146). Albuminuria was lower in treated compared to TX animals. Combination therapy did not confer additional benefit compared to the respective monotherapies. We conclude that ET(A)-receptor blockade abrogates GS, tubulointerstitial and vascular damage in the 'Fisher-to-Lewis' model of CTN to a similar extent as ACE inhibition. However, only ACE inhibition inhibits glomerular hypertrophy. In contrast to ACE inhibition, the effect of ET(A)-receptor blockade is independent of BP. This finding is consistent with the notion that ET(A)-receptor mediated events play a partly BP-independent role in the genesis of CTN. Combination therapy exerts no additive nephroprotection.