Meta‐Analyses Qualify Metzincins and Related Genes as Acute Rejection Markers in Renal Transplant Patients

Definition of acute renal allograft rejection (AR) markers remains clinically relevant. Features of T‐cell–mediated AR are tubulointerstitial and vascular inflammation associated with excessive extracellular matrix (ECM) remodeling, regulated by metzincins, including matrix metalloproteases (MMP). Our study focused on expression of metzincins (METS), and metzincins and related genes (MARGS) in renal allograft biopsies using four independent microarray data sets. Our own cases included normal histology (N, n = 20), borderline changes (BL, n = 4), AR (n = 10) and AR + IF/TA (n = 7). MARGS enriched in all data sets were further examined on mRNA and/or protein level in additional patients. METS and MARGS differentiated AR from BL, AR + IF/TA and N in a principal component analysis. Their expression changes correlated to Banff t‐ and i‐scores. Two AR classifiers, based on METS (including MMP7, TIMP1), or on MARGS were established in our own and validated in the three additional data sets. Thirteen MARGS were significantly enriched in AR patients of all data sets comprising MMP7, ‐9, TIMP1, ‐2, thrombospondin2 (THBS2) and fibrillin1. RT‐PCR using microdissected glomeruli/tubuli confirmed MMP7, ‐9 and THBS2 microarray results; immunohistochemistry showed augmentation of MMP2, ‐9 and TIMP1 in AR. TIMP1 and THBS2 were enriched in AR patient serum. Therefore, differentially expressed METS and MARGS especially TIMP1, MMP7/‐9 represent potential molecular AR markers.     

Renal Allografts with IF/TA Display Distinct Expression Profiles of Metzincins and Related Genes

Chronic renal allograft injury is often reflected by interstitial fibrosis (IF) and tubular atrophy (TA) without evidence of specific etiology. In most instances, IF/TA remains an irreversible disorder, representing a major cause of long-term allograft loss. As members of the protease family metzincins and functionally related genes are involved in fibrotic and sclerotic processes of the extracellular matrix (ECM), we hypothesized their deregulation in IF/TA. Gene expression and protein level analyses using allograft biopsies with and without Banff'05 classified IF/TA illustrated their deregulation. Expression profiles of these genes differentiated IF/TA from Banff'05 classified Normal biopsies in three independent microarray studies and demonstrated histological progression of IF/TA I to III. Significant upregulation of matrix metalloprotease-7 (MMP-7) and thrombospondin-2 (THBS-2) in IF/TA biopsies and sera was revealed in two independent patient sets. Furthermore, elevated THBS-2, osteopontin (SPP1) and β-catenin may play regulatory roles on MMP. Our findings further suggest that deregulated ECM remodeling and possibly epithelial to mesenchymal transition (EMT) are implicated in IF/TA of kidney transplants, and that metzincins and related genes play an important role in these processes. Profiling of these genes may be used to complement IF/TA diagnosis and to disclose IF/TA progression in kidney transplant recipients.     

Matrix metalloproteinases and mesangial remodeling in light chain-related glomerular damage

BACKGROUND: Matrix metalloproteinases (MMPs) belong to the zinc endopeptidase subgroup of the metalloproteinase superfamily and are primarily involved in extracellular matrix (ECM) remodeling. Alterations of the mesangial ECM in AL-amyloidosis (AL-Am) and light chain deposition disease (LCDD) are crucial in their pathogeneses as two divergent entities. METHODS: Protein expression patterns of five MMPs (MMP-1, 2, 3, 7, and 9) in renal tissues obtained from autopsies and kidney biopsies, and cultured human mesangial cells (HMCs) treated with light chains obtained from the urines of patients with AL-Am and LCDD were analyzed. MMP mRNA expressions were determined in glomeruli following laser capture microdissection and selective MMP microarray. Zymography was used to assess MMP activity. RESULTS: The average glomerular MMP expression was 6 times greater in AL-Am than LCDD and negative control renal tissues with different expression profiles: MMP-1, 7 > 9 > 3 > 2, MMP-1 > 2, 9 > 3 > 7, and MMP-2, 3, 7 > 9 > 1, respectively. Microdissected glomeruli and HMCs treated with light chains expressed higher levels of MMP mRNA and proteins in AL-Am than LCDD. Zymography was used to assess activity demonstrating increased MMP-2 in AL-Am. CONCLUSION: Altered expressions of MMPs play a key role in the pathogenesis of AL-Am and LCDD. MMPs were more highly expressed in AL-Am compared to LCDD.     

Intragraft Regulatory T Cells in Protocol Biopsies Retain Foxp3 Demethylation and Are Protective Biomarkers for Kidney Graft Outcome

Presence of subclinical rejection (SCR) with IF/TA in protocol biopsies of renal allografts has been shown to be an independent predictor factor of graft loss. Also, intragraft Foxp3+ T_reg cells in patients with SCR has been suggested to differentiate harmful from potentially protective infiltrates. Nonetheless, whether presence of Foxp3 T_reg cells in patients with SCR and IF/TA may potentially protect from a deleterious graft outcome has not yet been evaluated. This is a case‐control study in which 37 patients with the diagnosis of SCR and 68 control patients with no cellular infiltrates at 6‐month protocol biopsies matched for age and time of transplantation were evaluated. We first confirmed that numbers of intragraft Foxp3‐expressing T cells in patients with SCR positively correlates with Foxp3 demethylation at the T_reg‐specific demethylation region. Patients with SCR without Foxp3+ T_reg cells within graft infiltrates showed significantly worse 5‐year graft function evolution than patients with SCR and Foxp3+ T_reg cells and those without SCR. When presence of SCR and IF/TA were assessed together, presence of Foxp3+ T_reg could discriminate a subgroup of patients showing the same graft outcome as patients with a normal biopsy. Thus, presence of Foxp3+ T_reg cells in patients with SCR even with IF/TA is associated with a favorable long‐term allograft outcome.     

Risk Factors for Banff Borderline Acute Rejection in Protocol Biopsies and Effect on Renal Graft Function

Introduction

The interpretation and handling of Banff borderline acute rejection observed in protocol biopsies from patients with stable renal function continues to be controversial. Our objective was to identify the risk factors for borderline acute rejection on 1-year protocol biopsies and to evaluate their effect on renal graft function after 2 years' follow-up.

Methods

We included 82 kidney transplant recipients (KTR), who underwent 1-year protocol biopsies with normal or stable graft function. All KTR had follow-up of at least 2 years posttransplantation. We formed three groups: (1) KTR with a normal biopsy, (2) KTR with borderline changes, and (3) KTR with interstitial fibrosis/tubular atrophy (IF/TA). We searched for risk factors related to borderline injury. The main outcome to evaluate was renal function at 1 month, at protocol biopsy, and 2 years posttransplant.

Results

The 82 patients included in this study showed no differences in immunosuppression, gender, etiology of renal failure, or percentage of panel-reactive antibodies. The risk factors associated with borderline lesions were: at least one biopsy due to allograft dysfunction and acute rejection events during the first year posttransplant (P = .011 and P = .021, respectively). Increased serum creatinine and estimated glomerular filtration rate decline were greater among the borderline lesion than the normal group, but similar to patients with IF/TA.

Conclusion

Renal function decline was greater among borderline and IF/TA groups. However, the sum of insults, and not only the borderline injury itself, produces greater declines in renal function with greater risk for graft loss.     

Correlation of serum and urinary matrix metalloproteases/tissue inhibitors of metalloproteases with subclinical allograft fibrosis in renal transplantation

Progressive interstitial fibrosis and tubular atrophy (IF/TA) is a leading cause of chronic allograft dysfunction. Increased extracellular matrix remodeling regulated by matrix metalloproteases (MMPs) and their inhibitors (TIMPs) has been implicated in the development of IF/TA. The aim of this study was to investigate whether urinary/serum MMPs/TIMPs correlate with subclinical IF/TA detected in surveillance biopsies within the first 6 months post-transplant. We measured eight different MMPs/TIMPs simultaneously in urine and serum samples from patients classified as normal histology (n = 15), IF/TA 1 (n = 15) and IF/TA 2–3 (n = 10). There was no difference in urinary MMPs/TIMPs among the three groups, and only 1/8 serum MMPs/TIMPs (i.e. MMP-1) was significantly elevated in biopsies with IF/TA 2–3 (p = 0.01). In addition, urinary/serum MMPs/TIMPs were not different between surveillance biopsies demonstrating an early development of IF/TA (i.e. delta IF/TA ≥ 1 compared to a previous biopsy obtained three months before; n = 11) and stable grade of IF/TA (i.e. delta IF/TA = 0; n = 20). Next, we investigated whether urinary/serum MMP/TIMP levels are elevated during acute subclinical tubulitis in surveillance biopsies obtained within the first 6 months post-transplant (n = 25). Compared to biopsies with normal histology, serum MMPs/TIMPs were not different; however, all urinary MMP/TIMP levels were numerically higher during subclinical tubulitis (MMP-1, MMP-7, TIMP-1 with p ≤ 0.04). We conclude that urinary/serum MMPs/TIMPs do hardly correlate with existing or early developing IF/TA in surveillance biopsies obtained within the first 6 months post-transplant. This could be explained by the dynamic process of extracellular matrix remodeling, which seems to be active during acute tubulo-interstitial injury/inflammation, but not in quiescent IF/TA.     

Independent risk factors and natural history of renal dysfunction in liver transplant recipients

Renal dysfunction is common after liver transplantation. However, there are only limited data on the predictors and natural history of renal dysfunction after liver transplantation. In this study, we determined independent predictors and the natural history of renal dysfunction in 172 consecutive liver transplant recipients. Survival and time to development of permanent renal dysfunction (renal dysfunction defined as a sustained decrease in estimated glomerular filtration rate (GFR) of > 30 mL/min/1.73 m² from baseline for at least 6 months, severe renal failure defined as absolute GFR <30 mL/min/1.73 m² for at least 6 months) were determined using the Kaplan-Meier method. Cox regression analysis was used to test the independent effect of a given set of variables on time to development of such an event. Nine percent of patients required immediate dialysis, 35% developed permanent renal dysfunction, and 7% developed severe renal failure. The rate of decline in renal dysfunction was maximal, 6.5 mL/min/1.73 m² /mo, at 1 month after liver transplantation. Pre-existing diabetes mellitus, major surgical infection, and waiting time on the transplant list were independent risk factors for immediate dialysis. Presence of serum creatinine > 1.2 mg/dL at any time before liver transplantation and a baseline GFR <70 mL/min/1.73 m² were independent predictors of permanent renal dysfunction. Diabetes mellitus, coronary artery disease, and primary graft nonfunction predicted the development of severe renal failure. GFR stabilized around 9 months, and presence of decreased GFR > 30mL/min/1.73 m² from baseline at 9 months predicted development of permanent renal dysfunction. An absolute GFR of <30mL/min/1.73 m² occurring as early as 3 months after liver transplantation predicted severe renal failure. Severe renal failure was associated with a significantly lower survival by Cox regression analysis. We have identified risk factors and the natural history of permanent renal dysfunction and severe liver failure in liver transplant recipients. These observations may be useful in the development of nonnephrotoxic immunosuppressive regimens for high-risk liver transplant recipients. (Liver Transpl 2003;9:741-747.)     

Cystatin C does not detect acute changes in glomerular filtration rate in early diabetic nephropathy

BACKGROUND: The measurement of renal functional reserve (acute change in glomerular filtration rate [GFR] after protein load) allows the detection of sub-clinical renal dysfunction and has prognostic implications in diabetes. Our aim was to test cystatin C as an index of GFR and renal functional reserve. METHODS: GFR was measured by C(Sinistrin) at baseline and after protein load in 28 diabetic patients with serum creatinine <1.2 mg/dL. The C(Sinistrin) was compared with cystatin C, serum creatinine, creatinine clearance, and Cockcroft-Gault formula. RESULTS: Baseline C(Sinistrin) ranged from 67-172 mL/min. Regression analysis showed an overall low relationship between C(Sinistrin) and the indirect markers of GFR. The highest correlation with C(Sinistrin) was obtained for cystatin C clearance (R(2) = 0.58, r = 0.76, p < 0.001), the 1/serum cystatin C (R(2) = 0.58, r = 0.76, p < 0.001), and serum cystatin C (R(2) = 0.52, r = 0.72, p < 0.001). Renal functional reserve was preserved in 6 of 28 patients. There was no significant change in cystatin C in response to protein load. CONCLUSION: Wide variation in baseline GFR emphasizes the need for the early detection of renal dysfunction. Cystatin C correlated best with C(Sinistrin) at baseline, but did not detect renal functional reserve.     

Determination of glomerular filtration rate in advanced renal insufficiency.

The glomerular filtration rate (GFR) has been determined in 17 patients with advanced renal insufficiency (GFR less than 15 ml/min) by different clearance techniques using creatinine, inulin and 51Cr-EDTA as filtration markers. With renal inulin clearance as reference method for GFR, endogenous renal creatinine clearance overestimated GFR by an average of 30%. Renal clearance of 51Cr-EDTA and inulin were closely correlated and thus 51Cr-EDTA is a suitable GFR marker even at low filtration rates. However, it was found that the plasma clearance of 51Cr-EDTA overestimated the GFR often by more than 100% in the range 2.6--11.2 ml/min. Renal clearance measured during 24 h was lower than 4 h renal clearance with the patient well hydrated and resting in bed. It is concluded that the precise measurement of low glomerular filtration rates requires the use of renal clearance techniques. Four-hour 51Cr-EDTA renal clearance is a suitable method for measuring and following the development of renal function in advanced renal insufficiency.     

发生慢性移植肾功能不全者以西罗莫司替换环孢素A的临床疗效

目的 对采用以环孢素A(CsA)为基础免疫抑制剂的慢性移植肾功能不全(CRAD)患者,将CsA转换为西罗莫司(SRL),观察转换后的临床效果和安全性.方法 20例肾移植后出现CRAD的患者,采用突然转换法将CsA替换为SRL(3 mg/d),霉酚酸酯(MMF)和泼尼松(Pred)的剂量维持不变.另随机选取9例仍然使用CsA、MMF和Pred的CRAD患者作为对照.观察血肌酐(Cr)、肾小球滤过率(GFR)和24 h尿蛋白定量的变化情况以及SRL的不良反应.结果 对照组与转换组在患者年龄、性别构成比、移植后时间、转换时的血Cr水平和转换时免疫抑制剂用量等方面的差异均无统计学意义.随访1年,转换组有18例完成观察,其中11例(61.1%,11/18)转换有效,7例(38.9%,1/18)转换无效.转换有效者和转化无效者在转换时的血Cr、移植后时间、GFR及24 h尿蛋白定量等方面的差异有统计学意义.转换有效者的血Cr明显下降,GFR明显升高,而转换无效者的血Cr呈进行性升高,GFR呈进行性下降.转换治疗期间,1例出现急性排斥反应,经冲击治疗后逆转.完成随访的18例中,2例发生感染,3例出现皮疹,3例出现腹泻,2例出现口腔溃疡,8例出现骨髓抑制,6例转氨酶升高,10例出现高血脂,4例出现低血钾,没有患者因为上述不良反应而退出观察.结论 肾移植后采用以CsA为基础的免疫抑制方案者,若出现CRAD,可以将CsA替换为SRL,部分患者的肾功能得到改善,但转换应在移植肾功能发生严重损害前进行.     

Utility of Estimated Glomerular Filtration Rate Equations in Assessing Renal Allograft Function: Are They Accurate?

Creatinine clearance (CrCl) is more accurate than other methods when assessing renal allograft function, but it is inconvenient for patients. In clinical practice, renal allograft function is often estimated using estimated glomerular filtration rate (GFR) equations. This cross-sectional study compared agreement between CrCl and serum creatinine–based equations among renal transplant recipients (RTRs) attending a transplant clinic in a tertiary center. Six equations (Cockcroft-Gault, Walser's, Nankivell, abbreviated Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI], and European Kidney Function Consortium[EKFC]) were included in the analysis. The bias, precision, and accuracy of each equation were determined. Correlation analysis was performed by determining the correlation coefficient and plotting Bland-Altmann plots. A total of 165 subjects were included in this study. Mean serum creatinine was 112.03 ± 38.67 µmol/L, and mean CrCl was 58.44 ± 21.24 mL/min/1.73 m². Walser's equation showed strongest correlation, lowest bias, and highest accuracy of the proportion of estimated GFR falling within ±30% of CrCl, followed by the 4-variable MDRD equation. All 6 equations systematically underestimated GFR among RTRs. Walser's equation showed the best estimation of GFR, suggesting that it may be the formula of choice to estimate GFR among RTRs.     

Clinical Impact of Subclinical Interstitial Fibrosis or Tubular Atrophy in 1-Hour Allograft Biopsy for Remnant Renal Function in Living Kidney Donors: A Prospective Observational Study

BackgroundPreservation of remnant renal function (RRF) is one of the major concerns among living kidney donors (LKDs). A comprehensive assessment is needed to predict the RRF. In this prospective study, we investigated the roles of histologic findings from a 1-hour allograft biopsy in predicting the RRF.MethodsOur prospective study included 116 LKDs who underwent donor nephrectomy (DN) at our institute. Clinical and radiographic data were obtained from their medical charts. Renal volume parameters were calculated using the preoperative computed tomographic images in the volume analyzer SYNAPSE VINCENT image analysis system. Tissues obtained from allograft biopsy were examined. RRF was defined as the estimated glomerular filtration rate (eGFR) 12 months after DN.ResultsOf 116 LKDs, 95 were finally evaluated. The median age of the LKDs at DN and the preoperative eGFR were 57 years and 80.0 mL/min/1.73 m², respectively. In the histologic analysis, 68 allografts (71.6%) had nonspecific findings involving the glomerulus, vessel, and tubulointerstitium. Interstitial fibrosis or tubular atrophy (IF/TA) was the only significant predictive factor for RRF (P = .039). No significant association was found between renal volume parameters and IF/TA, whereas remnant renal volume adjusted by body weight (RRV/BW) tended to be relatively correlated with IF/TA (P = .072). Furthermore, LKDs with subclinical IF/TA tended to have decreased RRV/BW compared with those without subclinical IF/TA (P = .088).ConclusionsOur findings suggested that the presence of IF/TA could be a predictive factor for RRF after DN. Further research establishing the predictive model for RRF is warranted to improve the outcomes of LKDs.     

Cystatin C, an easy and reliable marker for assessment of renal dysfunction in children with liver disease and after liver transplantation.

Renal dysfunction of variable severity is being increasingly recognized as a major complication of calcineurin inhibitors (CI), in some patients even necessitating renal transplantation. Close and effective monitoring of the renal function is indicated. Current methods for this monitoring are calculation of the glomerular filtration rate (GFR) based on creatinine or exogenous substances like 51Cr-EDTA. The first method is unreliable in children and the second is expensive and cumbersome. Cystatin C has been shown to be an accurate marker of glomerular filtration but has not been evaluated in a large cohort of pediatric patients before and after liver transplantation (LT). We evaluated the accuracy of cystatin C in 62 children (30 male) with LT, who had their 51Cr-EDTA measured on 40 occasions prior to LT and on 47 occasions after LT. The reciprocal of cystatin C correlated better with 51Cr-EDTA GFR (r = .78) than the reciprocal of creatinine (r = .40). Diagnostic accuracy in the identification of reduced GFR was assessed by ROC analysis. Cystatin C yielded the highest area under the ROC curve (AUC) in all groups assessed. From these data a cutoff level of cystatin C predicting 51Cr-EDTA GFR < 80 ml/min/1.73 m2 was calculated. A level of 1.06 mg/L was found to have a sensitivity of 91% and a specificity of 81%. Applying this cutoff level in our patient group would have avoided 51Cr-EDTA GFR estimation in 43 of the 87 estimations. In conclusion, the use of this simple test could be recommended as screening of renal dysfunction in children with liver disease and after LT.     

Is cystatin C useful for the detection and the estimation of low glomerular filtration rate in heart transplant patients?

Although previously studied in patients with chronic kidney disease, there is less data for the use of cystatin C and cystatin C-based formulas in heart transplant recipients. The ability of creatinine and cystatin C to detect renal failure (glomerular filtration rate [GFR] below 60 mL/min/1.73 m(2)) in heart transplant patients has been compared. The accuracy and precision of a creatinine-based formula (Modification of Diet in Renal Disease [MDRD]) versus a cystatin C-based formula (Rule's formula) to estimate GFR have also been studied. GFR was measured using the (51)Cr-ethylenediamine tetraacetic acid tracer in 27 patients. There was no significant difference between GFR and the reciprocal of creatinine or cystatin C. Receiver operating characteristic curves for cystatin C and creatinine were similar. Both formulas were well correlated with the GFR. The bias of the cystatin C-based was significantly better than one of the MDRD formula, but the standard deviation appeared better for the MDRD formula (bias of +3.9 mL/min/1.73 m(2) versus +12 mL/min/1.73 m(2) and SD of 8.5 versus 11.6, respectively). Plasma cystatin C has no clear advantage over serum creatinine to detect renal failure in heart transplanted patients.     

Revisiting the Natural History of IF/TA in Renal Transplantation

Despite the decrease in incidence of early clinical and subclinical rejection and increased 1‐year graft survival in renal transplant patients, the rate of graft loss after the first year has been only moderately improved. Protocol biopsies obtained in the first year have shown rapid increase in the prevalence of IF/TA. This finding has been correlated with later allograft dysfunction and loss, mostly in cases of concomitant interstitial inflammation and fibrosis ( 1 ). The landmark study by Nankivell et al., performed in recipients of organs from deceased young donors under early cysclosporin‐based immunosuppression, suggested two distinct phases of injury involved in IF/TA: an early tubulo‐interstitial damage from ischemic injury and allograft rejection and, beyond 1 year, microvascular, glomerular and additional tubulo interstitial injury interpreted as secondary CsA toxicity ( 2 ). Since this publication, chronic antibody‐mediated rejection has been better identified as leading causes of late graft dysfunction. Moreover, a recent study showed that most cases of kidney graft loss have an identifiable cause that is not idiopathic IF/TA or CNI toxicity and that alloimmunity remains the most common mechanism leading to failure ( 3 ). Thus, with the current immunosuppressive regimens and the input of molecular phenotyping, one may question the natural history of IF/TA.     

Human allograft arterial injury is ameliorated by sirolimus and cyclosporine and correlates with suppression of interferon-gamma

BACKGROUND: Chronic allograft dysfunction may result from arterial injury, manifest as transplant arteriosclerosis (TA). This represents an important factor limiting long-term outcomes after heart and kidney transplantation; a relationship between acute allograft arterial injury and TA has been suggested. We have used SCID/bg mice bearing transplanted human artery, inoculated with allogeneic human PBMC to study arteriopathy in human vessels. Earlier work demonstrated arteriopathy similar to that observed clinically, and identified interferon-gamma as a mediator of the process. This study evaluated whether sirolimus (SRL), with cyclosporine A (CsA) or alone, affects TA, and examined possible mechanisms of action. METHODS: CB17/SCID/bg mice were transplanted with human arteries replacing the abdominal aorta; reconstituted with allogeneic human PBMC. Controls received vehicle alone for comparison with mice given CsA (5 mg/kg/d), SRL (0.1 or 0.5 mg/kg/d), or CsA (5 mg/kg/d) plus SRL (0.1 mg/kg/d). Transplant arteries were examined 28 days later by histology and immunohistochemistry; circulating human interferon-gamma was evaluated by ELISA, and intragraft interferon-gamma mRNA by qRT-PCR. RESULTS: The characteristic TA was modestly reduced by CsA or low-dose SRL, but eliminated by combination CsA plus SRL or higher dose SRL alone. Circulating interferon-gamma was reduced by CsA, but inhibition was dramatic with SRL alone or combined with CsA. Intragraft interferon-gamma and HLA-DR expression were moderately reduced by CsA or SRL, and eliminated with combined CsA plus SRL. CONCLUSIONS: SRL plus CsA prevented allograft arteriopathy, correlating with suppression of intragraft interferon-gamma, suggesting that SRL effects may result from anti-inflammatory consequences from inhibiting interferon-gamma.     

Early loss of peritubular capillaries after kidney transplantation

Inflammation, interstitial fibrosis (IF), and tubular atrophy (TA) precede chronic transplant dysfunction, which is a major cause of renal allograft loss. There is an association between IF/TA and loss of peritubular capillaries (PTCs) in advanced renal disease, but whether PTC loss occurs in an early stage of chronic transplant dysfunction is unknown. Here, we studied PTC number, IF/TA, inflammation, and renal function in 48 patients who underwent protocol biopsies. Compared with before transplantation, there was a statistically significant loss of PTCs by 3 months after transplantation. Fewer PTCs in the 3-month biopsy correlated with high IF/TA and inflammation scores and predicted lower renal function at 1 year. Predictors of PTC loss during the first 3 months after transplantation included donor type, rejection, donor age, and the number of PTCs at the time of implantation. In conclusion, PTC loss occurs during the first 3 months after renal transplantation, associates with increased IF and TA, and predicts reduced renal function.     

Functional and morphologic evaluation of kidney proximal tubuli and correlation with renal allograft prognosis

Renal transplant patients with stable graft function and proximal tubular dysfunction (PTD) have an increased risk for chronic allograft nephropathy (CAN). In this study, we investigated the histologic pattern associated with PTD and its correlation with graft outcome. Forty‐nine transplant patients with stable graft function were submitted to a biopsy. Simultaneously, urinary retinol‐binding protein (uRBP) was measured and creatinine clearance was also determined. Banff’s score and semi‐quantitative histologic analyses were performed to assess tubulointerstitial alterations. Patients were followed for 24.0 ± 7.8 months. At biopsy time, mean serum creatinine was 1.43 ± 0.33 mg/dl. Twelve patients (24.5%) had uRBP ≥1 mg/l, indicating PTD and 67% of biopsies had some degree of tubulointerstitial injury. At the end of the study period, 18 (36.7%) patients had lost renal function. uRBP levels were not associated with morphologic findings of interstitial fibrosis and tubular atrophy (IF/TA), interstitial fibrosis measured by Sirius red or tubulointerstitial damage. However, in multivariate analysis, the only variable associated with the loss of renal function was uRBP level ≥1 mg/l, determining a risk of 5.290 of loss of renal function (P = 0.003). Renal transplant patients who present PTD have functional alteration, which is not associated with morphologic alteration. This functional alteration is associated to progressive decrease in renal function.