零点活检对活体肾移植术后受体肾功能的预测价值

目的探讨活体肾移植供肾零点活检对受体术后1年内移植肾功能的预测价值。方法 149例活体肾移植受者,根据是否同意活检和活检是否发现异常分为3组：未活检组（63例）,活检正常组（58例）和活检异常组（28例）。受体术后平均随访8个月,比较3组间受体术后移植肾功能恢复情况。结果供肾零点活检异常率为33%,其中肾小管炎7例,肾小管萎缩5例,肾小球硬化8例,肾小球钙化3例,肾小球玻璃样变3例,肾间质炎7例,肾间质纤维化1例,系膜增生2例以及小动脉玻璃样变2例（部分病例有一种以上病理改变）。供者年龄与移植前零点活检异常相关（P〈0.05）。从术后1个月之后至术后1年内,活检异常组各时间点受体血清肌酐均高于未活检组和活检正常组（均为P〈0.05）;术后3个月,活检异常组各时间点受体肾小球滤过率均低于未活检组和活检正常组（P〈0.05）,但术后1年内3组各随访时间点的血尿素氮比较差异无统计学意义（P〉0.05）。术后6个月内重复测量趋势分析显示,与活检正常组比较,活检异常组的血清肌酐和肾小球滤过率的变化趋势差异有统计学意义（均为P〈0.05）,活检异常组的血清肌酐与未活检组比较差异亦有统计学意义（P〈0.05）。结论活体供肾零点活检结果对术后1年内特别是术后6个月内移植肾功能有预测价值,具有临床实用性。     

Real-time contrast-enhanced sonography in renal transplant recipients

Abstract:  Conventional colour Doppler ultrasonography (CDUS) is a well-established and the most frequently used imaging procedure to diagnose kidney allograft dysfunction. Unfortunately, this technique is limited to the estimation of the allograft perfusion in large arteries. Early diagnosis of vascular damage, i.e., chronic allograft nephropathy is essential for an early therapeutic intervention. CDUS is still limited in interpreting vascular integrity. In contrast-enhanced sonography (CES) is a feasible technique for quantitative analysis of kidney perfusion and early diagnosis of biopsy proven chronic allograft nephropathy. CES does not provide only quantitative information on microvascular perfusion of the renal allografts but also represents improved diagnostic significance compared with CDUS for the detection of chronic allograft nephropathy.     

Altered expression of aquaporin-2 in human explants with chronic renal allograft dysfunction

OBJECTIVE: To investigate the distribution of aquaporins, a recently discovered family of transmembrane water channels, in human renal explants, with specific reference to chronic renal allograft dysfunction (CRAD). MATERIALS AND METHODS: Immunohistochemistry for aquaporin-1 and -2 was used in 11 explants, of which five had clinically and histologically confirmed CRAD. Controls were taken from the six explants unaffected by CRAD and from histologically normal areas of six kidneys excised for renal tumours. RESULTS: In the renal tumour control group, aquaporin-1 immunoreactivity was detected in the glomerular endothelium, Bowman's capsule, the proximal convoluted tubules and the thin limb of the loop of Henle, whereas immunoreactivity for aquaporin-2 was detected in the collecting ducts only. Of the explants without CRAD, where architecture was preserved, immunoreactivity for aquaporin-1 and -2 was the same as in the renal tumour controls. In the two explants with no CRAD and loss of collecting ducts, there was no aquaporin-2 immunoreactivity. In five explants with CRAD, immunoreactivity for aquaporin-2 was decreased or absent from the medulla to the cortex. The apparent decreased immunoreactivity of aquaporin-1 in this group was secondary to a decrease in the number of viable proximal tubules. CONCLUSION: There was less aquaporin-2 immunoreactivity in human renal explants diagnosed with CRAD, starting from the medullary region. In explants with no CRAD and viable collecting ducts, or in normal controls, aquaporin-2 immunoreactivity remained unchanged. Aquaporins might be useful as markers for CRAD.     

Association between insulin resistance and endothelial dysfunction in renal transplant recipients

BACKGROUND: Endothelial dysfunction is a common finding in renal transplant recipients (RTR) and is related to impaired local regulation of vasodilative and vasoconstrictive substances, such as nitric monoxide (NO) and endothelin-1 (ET-1). In non-transplanted patients, an association between impaired endothelial function and insulin resistance has been shown. Whether such an association also exists in RTR is unknown. OBJECTIVE: The aim of the present study was to examine whether insulin resistance is associated with endothelial dysfunction in RTR. MATERIAL AND METHODS: A total of 47 RTR in a stable phase six yr post-transplant were included in the statistical analysis. The immunosuppressive therapy was based on cyclosporine and prednisolone. Non-invasive assessment of endothelial function was performed with laser Doppler flowmetry of the forearm skin vasculature after local acetylcholine stimulation. Oral glucose tolerance tests comprising both glucose and insulin measurements were used to calculate insulin sensitivity (IS) indices. NO, ET-1 and von Willebrand factor were measured in fasting plasma samples. RESULTS: Normal glucose tolerance was found in 31 RTR. In these subjects, both IS (r(2) = 0.164, p = 0.044) and plasma NO (r(2) = 0.326, p = 0.002) were significantly correlated with endothelial function. Patients with glucose intolerance (n = 16) had higher plasma ET-1 and lower NO levels, but the association between IS and endothelial function was not significant in these subjects. In the total patient cohort, IS and endothelial function tended to be correlated (p = 0.127). CONCLUSIONS: Endothelial dysfunction is significantly associated with insulin resistance in normoglycemic RTR but explains a rather small part of the variation. In glucose-intolerant recipients, IS appears to be more critically dependent on other factors not revealed in the present study.     

Clinical significance of C4d deposition in stable renal allografts in the early post‐transplantation period

Abstract: The clinical significance of C4d positivity in patients with stable graft function is undetermined. This study evaluated the clinical outcome of protocol biopsy‐proven C4d‐positive renal transplants with stable graft function in the early post‐transplantation period. Protocol biopsies (n = 79) were performed on stable allografts on the 14th post‐transplant day, and indication biopsies (n = 74) were performed on dysfunctioning allografts within one yr after transplantation. Clinical and histological findings, graft function and graft survival rates were compared between C4d‐positive and C4d‐negative grafts in each group. The incidence of C4d positivity was 5.1% in protocol biopsies and 9.5% in indication biopsies. In protocol biopsies, C4d‐positive allografts showed minimal tubulointerstitial inflammation, and the graft function and graft survival rate did not differ from C4d‐negative allografts. All C4d‐positive allografts maintained stable graft function without anti‐rejection therapy, and follow‐up biopsies of two patients showed no C4d deposition or evidence of rejection. On the other hand, C4d‐positive allografts in indication biopsies showed severe tissue injury, and the graft survival rate was significantly lower than C4d‐negative allografts. In conclusion, C4d‐positive allografts with stable graft function in the early post‐transplantation period take an indolent course.     

Evaluation of penile perfusion by color-coded duplex sonography in the management of erectile dysfunction

The etiology of erectile dysfunction is wide ranging. Penile vascular disorders may result in impaired erection or complete impotence. Almost 30% of erectile dysfunction is due to the presence of systemic disease which affects the blood supply to the penis. The intracavernosal injection test with prostaglandin E1 alone offers limited information on the vascular status. In accordance with the increasing demand for less invasive procedures, penile color-coded duplex sonography (CCDS) combined with the pharmaco-erection test represents a first-line noninvasive approach to investigate arterial and veno-occlusive function. Peak systolic velocity and a change in cavernous artery diameter are indicators of arterial inflow, while the pathological end diastolic velocity and resistance index point out veno-occlusive dysfunction. The combined investigation of power and standard color Doppler ultrasound may yield more details of penile vascular anatomy.     

Evaluation of renal allograft function by Doppler spectrum analysis

A decreased renal function is rather common after renal transplantation. The causes of this decreased function are diverse and difficult to differentiate. Yet, duplex examination, and especially quantitative Doppler spectrum analysis of the blood velocities in the renal artery, may be an effective method for differentiating between some of these causes. Forty-five renal transplant recipients were included in this preliminary study. Doppler spectra were recorded from the renal artery to the allograft. Parameters were derived from every Doppler spectrum in order to characterize each spectrum. Renal allograft function was evaluated on the basis of a number of clinical parameters. A significant correlation was found between the clinical parameters and the Doppler spectrum parameters indicative for changes in the peripheral resistance. Patients with a normal renal allograft function showed Doppler spectra with a high diastolic flow, typical of a vascular bed with a low peripheral resistance. Patients with a decreased renal allograft function caused by a stenosis in the renal artery could be distinguished by a low peak velocity and a low pulsatility index. A decreased allograft function caused by allograft rejection or cyclosporin nephrotoxicity also led to characteristic arterial flow disturbances. In these cases, the peripheral resistance was increased, and this was primarily reflected in a decrease in the diastolic blood velocity. We conclude that quantitative analysis of the blood velocities in the renal artery by Doppler spectrum analysis seems to be a useful, noninvasive diagnostic tool that discriminates between some of the causes of a decreased renal allograft function.     

beta6 integrin is up-regulated in chronic renal allograft dysfunction

Up-regulation of beta6 integrin, which is indispensable to the activation of transforming growth factor-beta1 (TGF-beta1), was investigated in chronic renal allograft dysfunction (CAD). A total of 103 renal biopsy samples (normal, 10; acute rejection, 30; CAD, 63) were immunohistochemically evaluated for expression of TGF-beta1 and beta6 integrin. No TGF-beta1 or -beta6 integrin was detected in normal kidney, but both TGF-beta1 and -beta6 integrin reactivity were observed in the distal tubules in acute rejection, and even greater reactivity was observed in the distal tubules in the CAD samples. Semiquantitative analysis revealed that the reactivity of TGF-beta1 and -beta6 integrin was significantly greater in the CAD kidney than in the normal kidney and the kidney in acute rejection. The results suggest that beta6 integrin as well as TGF-beta1 is up-regulated in CAD and that it may serve as an alternative target for the treatment for CAD.     

The quality of function of renal allografts is associated with donor age

The quality of renal allograft function was assessed by prospective measurement of creatinine clearance at 1 year (n=197) and at 3 years (n=115) after cadaveric renal transplantation in a cohort of 268 patients treated with triple therapy immunosuppression. Donor age (P<0.0012) and recipient age (P<0.01) were independently associated with creatinine clearance both at 1 and at 3 years. In patients with donor age above 50 years and recipient age above 45 years, the mean creatinine clearance was 32.7 (SD 10.4) ml/min (n=27). When the donor age was below 30 years and recipient age below 45 years, the mean creatinine clearance was 55.6 (SD 14.4) ml/min (n=47, P<0.001). However, in these patients there was no significant association between graft function and many of the factors known to influence graft survival, such as HLA matching, sensitisation of the recipient, and the occurrence of rejection. In conclusion, the quality of renal allograft function declined with increasing donor and recipient age in our patients, whilst immunological factors were not significantly associated with function in surviving grafts.     

The pulsatility index and the resistive index in renal arteries in patients with hypertension and chronic renal failure

BACKGROUND.: The pulsatility index (PI) and the resistive index (RI) areused as pulsed-wave Doppler measurement of downstream renalartery resistance. Little information is available on theirvalue in chronic renal failure and their correlation to parametersof renal function and haemodynamics. The aim was to comparePI and RI of renal arteries in healthy volunteers and in patientswith hypertension and chronic renal failure, and furthermoreto study the correlation of these indices to measurements ofrenal haemodynamics and function by standard methods in patientswith renal failure and hypertension. METHODS.: Twenty-five hypertensive patients (10 females, 15 males, meanage 52 years (24–74) with a glomerular filtration rate(GFR) less than 50 ml/min and an arterial blood pressure above140 mmHg systolic and 95 mmHg diastolic were included in thestudy. Ten healthy, normotensive volunteers (4 females and 6males, mean age 43 years (30–62)) served as controls inthe Doppler examinations. Doppler examinations were performedin segmental arteries by an Acuson 128. The PI and the RI wascalculated from the blood flow velocities. RESULTS.: Both the PI and the RI were significantly higher in the patientgroup (P) than in the control group (C) (PI, P 1.65 (1.31–1.86),C 1.19 (0.93–1.25), P=0.003; RI, P 0.76 (0.69–0.81),C 0.67 (0.64–0.70), P=0.003). Both PI and RI correlated significantly with effective renalplasma flow (PI: r= –0.5, P=0.02; RI: r=–0.5, P=0.006),renal vascular resistance (PI: r=0.4, P= 0.05; RI: r=0.5, P=0.02),filtration fraction (PI: r=0.6, P=0.005; RI: r=0.5, P=0.01)and clearance of creatinine (PI: r=–0.6, P=0.008; RI:r=–;0.6, P= 0.006). Only RI correlated significantly toGFR (r=–0.5, P=0.02). The indices did not correlate toserum creatinine, or mean arterial blood pressure. CONCLUSION.: PI and RI seems to be closely related to parameters of renalhaemodynamics and clearance of creatinine in patients with chronicrenal failure and hypertension.     

Analysis of allograft biopsy specimens from long-term surviving patients with stable renal function: predictive value of long-term graft prognosis

Abstract: Chronic allograft dysfunction is multi-factorial, and histology of long-term renal allograft shows variable findings. It is important to characterize the pathological features of graft kidneys with normal function to understand the natural course of transplants, which in turn would contribute to elucidate the causes of chronic allograft nephropathy (CAN). To address this issue, we performed 'non-episode' biopsies on well-functioning renal allografts, and evaluated the correlation between clinical outcome and histopathological findings. Patients who underwent a non-episode biopsy had a serum creatinine concentration less than 2.0 mg/dL, urinary protein of less than 500 mg/day and a stable clinical course. In total, 90 such biopsies were performed. Mean follow-up period after biopsy was 29 ± 16 months. We evaluated the histopathological findings and clinical outcome on each finding. Moreover, we compared the findings in the patients on tacrolimus with those of patients taking cyclosporin. Twenty-three biopsy specimens were essentially normal. Graft dysfunction during the follow-up period was recognized more frequently in patients showing more than one pathological process than in those with isolated findings. Graft outcome was not associated with drug-induced nephropathy, but with acute rejection ( P  = 0.0193) and CAN ( P  = 0.0032). Patients found to have CAN-b had a worse outcome than those with CAN-a. CAN-b was less common in the tacrolimus group than in the cyclosporin group. Non-episode biopsy has a predictive value of the long-term outcome of a renal allograft. CAN is associated with graft dysfunction; neither is drug-induced nephropathy. Patients treated with tacrolimus had lower rates of CAN-b than did cyclosporin-treated subjects.     

Significance of subclinical rejection in early renal allograft biopsies for chronic allograft dysfunction

To determine the significance of early subclinical rejection of renal allografts, we reviewed 127 biopsy specimens obtained soon after transplantation. Histological finding was categorized according to a modification of the Banff scheme as: acute rejection (AR), borderline changes (BL); non-specific inflammatory changes, (NI) and no rejection (NR). Subclinical rejection was defined as AR, BL or NI. Patients with BL or NI were divided into two groups; one was treated with high-dose methylprednisolone (MP), the other remained untreated. Freedom from chronic allograft dysfunction (defined as non-doubling of serum creatinine 5 yr after transplantation) was significantly more frequent in the NR group (89%) than in the BL (70%) and AR (64%) groups. At 1 yr after transplantation, mean serum creatinine had increased significantly only in the untreated group (p < 0.05), and re-biopsy showed that interstitial fibrosis had developed to a significantly greater extent in the untreated group than in the treated group (p < 0.01). Subclinical rejection in the early protocol biopsies correlated closely with subsequent allograft dysfunction. High-dose MP treatment for early subclinical rejection may be effective in suppressing the development of interstitial fibrosis at 1 yr after transplantation.     

Benazepril slows progression of renal dysfunction in patients with non-diabetic renal disease

AIM: The present study examined the effects of benazepril, an angiotensin-converting enzyme inhibitor, on the progression of renal insufficiency in patients with non-diabetic renal disease. METHODS: Fifteen patients with non-diabetic renal disease whose serum creatinine (Cr) ranged from 1.5 to 3.0 mg/dL were given either benazepril (2.5-5 mg) or placebo once daily for 1 year in a random crossover manner. In both periods, antihypertensive medications were increased if blood pressure was greater than 130/85 mmHg. Blood sampling and urinalysis were performed bimonthly throughout the study period. RESULTS: Blood pressure was similar when comparing the benazepril and the placebo periods (128+/-12/83+/-6 vs 129+/-10/83+/-7 mmHg). Serum Cr significantly increased from 1.62+/-0.18 to 1.72+/-0.30 mg/dL (P=0.036) during the placebo period, while there was no statistically significant increase in serum Cr during the benazepril period (from 1.67+/-0.17 to 1.71+/-0.27 mg/dL). The slope of decrease of the reciprocal of serum Cr was steeper in the placebo period than in the benazepril period (-0.073+/-0.067 vs-0.025+/-0.096/year, P=0.014). Urinary protein excretion was lower during the benazepril period than during the placebo period (0.57+/-0.60 vs 1.00+/-0.85 g/gCr, P=0.006). Serum K was significantly higher in the benazepril period than in the placebo period (4.4+/-0.5 vs 4.2+/-0.5 mEq/L, P<0.001), but no patient discontinued benazepril therapy as a result of hyperkalemia. CONCLUSION: Long-term benazepril treatment decreased the progression of renal dysfunction in patients with non-diabetic renal disease by a mechanism that is independent of blood pressure reduction.     

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

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

Sirolimus Versus Cyclosporine in Kidney Recipients Receiving Thymoglobulin®, Mycophenolate Mofetil and a 6-Month Course of Steroids

To evaluate the efficacy and tolerance of a calcineurin inhibitor (CNI)-free regimen, 145 renal recipients were prospectively randomized to receive either sirolimus (n = 71) or cyclosporine (CsA; n = 74). All patients received polyclonal antilymphocyte antibodies, mycophenolate mofetil (MMF) and steroids (6 months). The primary endpoint, estimated glomerular filtration rate (eGFR) was not significantly different at 12 months comparing sirolimus- and CsA-treated patients (60 +/- 27 vs. 57 +/- 21 mL/min). At 12 months, patient and graft survival, incidence of biopsy-proven rejection and rates of steroid withdrawal were not statistically different (97% vs. 97%; 90% vs. 93%; 14.3% vs. 8.6% and 82.8% vs. 84.1%, respectively). Delayed and slow graft function (SGF) was not significantly different (18.6% vs. 12.3% and 11.4% vs. 13.7%, respectively). In patients who remained on treatment according to protocol at 12 months, eGFR was significantly higher with sirolimus (69 +/- 19 vs. 60 +/- 14 mL/min, p = 0.01). Overall study drug discontinuation rates were 28.2% with sirolimus and 14.9% with CsA. Adverse events (wound complications, mouth ulcers, diarrhea, hypokalemia, bronchopneumonia) and proteinuria >0.5 g/24h (38.8% vs. 5.6%, p < 0.001) were significantly more frequent in sirolimus-treated patients. Cytomegalovirus (CMV) infections were significantly less frequent with sirolimus (6% vs. 23%, p < 0.01). A CNI-free regimen using sirolimus-MMF can achieve excellent renal function, but patients on sirolimus experienced a high rate of adverse events and study drug discontinuation.     

The effect of angiotensin converting enzyme gene polymorphism on chronic allograft dysfunction in living donor renal transplant recipients

BACKGROUND: Chronic allograft dysfunction (CAD), the major cause of the failure of kidney allografts, may be caused by immunological and non-immunological haemodynamic factors. Renin-angiotensin system has been implicated in the development of intraglomerular hypertension and has a central role on progression in chronic renal disease. Polymorphism in 16th intron of the ACE gene has been reported to predict the circulating angiotensin II levels. The aim of this study was to investigate the effect of the both recipient and donor angiotensin converting enzyme (ACE) genotype on the development of CAD in renal allograft recipients. PATIENTS AND METHODS: A total of 143 renal transplant recipients (95 male, 48 female, mean age 32 +/- 10 yr) were included. In order to exclude the effect of cold ischaemia, only patients transplanted from living donors were selected. Factors analysed in the development of CAD were donor and recipient age, past history of acute rejection, presence of hypertension and hypercholesterolaemia, serum uric acid level and ACE gene polymorphism. RESULTS: Forty of the patients (28%) had CAD. Homozygous deletion type ACE gene polymorphism was detected in 59 renal transplant recipients (42%) and in 31 donors of the patients (37%). On comparing patients with and without CAD, donor age, rate of acute rejection and hypertension and serum uric acid levels were significantly higher in CAD (+) groups. Neither recipient nor donor ACE genotype was associated with time to CAD. Cox regression analysis revealed donor age (p < 0.001), presence of hypertension (p=0.002) and serum uric acid levels (p=0.009), but neither donor nor recipient ACE genotype as independent factors for predicting development of CAD. CONCLUSION: Donor age, presence of hypertension and serum uric acid levels was independent factors. Donor and recipient ACE genotype seemed to have no influence on the development of CAD in living donor transplanted patients.     

Reproducibility of fine-needle aspiration biopsy in the diagnosis of acute rejection of renal allografts

BACKGROUND: Although it has been used as a diagnostic tool in many renaltransplant centres the reproducibility of fine-needle aspirationbiopsy (FNAB) has not been critically evaluated. METHODS: In the present study material sequentially obtained from 15patients (177 aspirations) over a 3-month period following renaltransplantation was evaluated by two independent observers.Intraobserver reproducibility was studied through the analysisof two evaluations by observer 1 performed 8 months apart. Interobserverreproducibility was calculated comparing the second evaluationof observer 1 with the evaluation of observer 2. All evaluationswere performed blindly. Slides and protocols of individual patientswere chronologically arranged and thus interpreted. Representation,total corrected increment (TCI), accuracy, and the percent agreementfor the diagnosis of acute rejection were evaluated. RESULTS: No intraobserver statistically significant differences wereobserved. Differences observed in interobserver evaluation ofTCI either during, or out of acute rejection episodes, wellas the representative quality of the sample and accuracy, werenot statistically significant. The percent of agreement forthe presence or absence of acute rejection was 77.5% for theintraobserver comparison and 76.7% for the interobserver evaluation.Both values showing either a non-significant value for the differenceor a statistical significance for the concordance. CONCLUSION: We concluded that FNAB is an accurate method with fairly goodintra- and interobserver reproducibility for the diagnosis ofacute rejection of renal allografts.     

DTPA renal scan assessment of renal allograft dysfunction in rats

The precise cause of allograft dysfunction after renal transplantation often cannot be established by non-invasive means. In clinical practice, radionuclide scans form an integral part of the clinician's armamentarium in the assessment of these patients [1, 2]. Unfortunately, in the clinical setting more than one pathological process may be responsible for the impaired function, making it difficult to correlate the scan appearances with the pathology. In this study in rats we compared the renal DTPA scan appearances of the various pathological processes which may cause renal allograft dysfunction in the immediate post-transplant period.