The Natural History of Chronic Allograft Nephropathy
Brian J. Nankivell, M.D., Ph.D., Richard J. Borrows, M.B., B.Chir., Caroline L.-S. Fung, M.B., B.S., F.R.C.P.A., Philip J. O'Connell, M.B., B.S., Ph.D., Richard D.M. Allen, F.R.A.C.S., and Jeremy R. Chapman, M.D., Ch.B.
Background With improved immunosuppression and early allograftsurvival, chronic allograft nephropathy has become the dominantcause of kidney-transplant failure.
Methods We evaluated the natural history of chronic allograftnephropathy in a prospective study of 120 recipients with type1 diabetes, all but 1 of whom had received kidney–pancreastransplants. We obtained 961 kidney-transplant–biopsyspecimens taken regularly from the time of transplantation to10 years thereafter.
Conclusions Chronic allograft nephropathy represents cumulativeand incremental damage to nephrons from time-dependent immunologicand nonimmunologic causes.
Chronic allograft nephropathy, characterized by progressiverenal dysfunction accompanied by chronic interstitial fibrosis,tubular atrophy, vascular occlusive changes, and glomerulosclerosis,1,2is the chief cause of kidney-transplant failure despite improvementsin immunosuppression. Although registry data can be used todefine some risk factors, the pathophysiology of chronic allograftnephropathy remains poorly understood. A biopsy of a chronicallyfailing kidney transplant usually shows nonspecific or end-stagechanges, so the relative contributions of preexisting diseasein the allograft and immunologic and nonimmunologic factorsbecome difficult to distinguish. A major impediment has beenthe lack of prospective, longitudinal histologic data from studiesof humans with chronic graft dysfunction.
We determined the natural history of chronic allograft nephropathyin 120 patients by regularly performing kidney-transplant biopsiesfor up to 10 years after transplantation. Sequential biopsyspecimens were used to pinpoint the onset and evolution of histologicfeatures of chronic allograft nephropathy and their relationto potential risk factors.
Methods
Study Population and Design
The study group consisted of 119 consecutive patients with type1 diabetes mellitus who received a kidney–pancreas transplantand 1 such patient who received a kidney transplant alone atWestmead Hospital between 1987 and 2000; three or more sequentialkidney-transplant–biopsy specimens were available fromall these patients. Written informed consent was obtained fromall patients, and the study was approved by the institutionalreview board and ethics committee. Initially, kidney biopsieswere performed according to the protocol at the time of transplantation,at 1 and 2 weeks; at 1, 3, 6, and 12 months; and then yearlyfor 10 years. Beginning in 1997 this schedule was simplified:biopsy was performed at 0, 1, and 3 months and then 1, 3, 5,7, and 10 years after transplantation.
Patients were treated with triple-therapy immunosuppressionthat incorporated cyclosporine (Novartis) in the case of 93patients or, beginning in 1999, tacrolimus (Fujisawa) in thecase of 27. Prednisolone (30 mg per day beginning on the dayof transplantation) was also given with either azathioprine(GlaxoSmithKline; 1.5 mg per kilogram of body weight per day)in the case of 74 patients or mycophenolate mofetil (Roche;3 g per day initially) in the case of 46. Induction antilymphocytetherapy was used in the first 13 patients and in 2 in whom theallograft was initially nonfunctional.
This study formed part of a prospective evaluation of diabeticcomplications after kidney–pancreas transplantation. However,sustained euglycemia3 rendered the original raison d'êtreredundant, and recurrent diabetic nephropathy was not seen.Instead, we observed the evolution of chronic allograft nephropathyover the decade after transplantation, noting that it occurredin kidneys that were essentially normal at implantation.
Per-Protocol Biopsy Study and Definitions
Needle-core biopsies were obtained according to the protocolwith use of a Biopty gun (Bard) with an 18-gauge needle. Renalhistopathological analysis was performed in a blinded fashionby two observers using the Banff working classification,1,2as described previously.4,5 This semiquantitative scoring systemis used for the classification and grading of short- and long-termchanges that occur in the glomeruli, tubules, interstitium,arteries, and arterioles of a renal transplant. Scores rangefrom 0 to 3, with higher scores indicating more severe abnormalities.Chronic allograft nephropathy was defined as chronic interstitialfibrosis and tubular atrophy, with or without fibrointimal vascularthickening, and was graded according to the proportion of corticalarea affected: grade 0, less than 6 percent of the corticalarea affected; grade I, 6 to 25 percent affected; and gradeII, 26 to 50 percent affected; and grade III, more than 50 percentaffected.
Subclinical rejection was defined by histologic findings consistentwith the occurrence of acute rejection1 without immediate functionaldeterioration6 and was classified as acute when histologic evidenceof acute rejection was present (Banff type 1A or higher) orborderline (tubulitis score of 1 and mononuclear-cell–infiltrationscore of 1 or 2, without arteritis).1 True chronic rejectionwas arbitrarily defined as subclinical rejection that occurredbeyond one year, and was present in 50 percent or more of biopsyspecimens from a given patient or in the last two biopsy specimensobtained more than one year after transplantation or evidenceof subclinical rejection for two or more years in sequentialbiopsy specimens. Calcineurin-inhibitor nephrotoxicity was definedby striped cortical fibrosis or new-onset arteriolar hyalinosis(not from renal ischemia or preexisting hyalinosis in the allograft)supported by tubular microcalcification (without preceding acutetubular necrosis).7,8 We excluded alternative explanations forarteriolar hyalinosis, including preexisting disease in theallograft (by comparing the specimens with those obtained attransplantation), hypertension (by means of survival analysis),and dyslipidemia or hyperglycemia (by comparing lipid levelsmeasured after an overnight fast and oral glucose-tolerancedata, respectively).
Statistical Analysis
Cox regression was used for actuarial analysis of survival,and logistic regression was used for dichotomous data, precededby backward elimination. A generalized estimating equation wasused for repeated measurements. Data are expressed as means±SD unless otherwise stated. All P values were two-sided,and a value of less than 0.05 was considered to indicate statisticalsignificance.
Results
Study Group and Clinical Outcomes
Recipients were a mean of 38.2±7.0 years old at the timeof transplantation, 58.3 percent were male, and all but onewere white. The mean number of HLA mismatches was 4.4±1.4,donors were a mean of 25.5±9.8 years old, and hemodialysiswas required after transplantation in three patients. The numbersof episodes of acute cellular and vascular rejection were 1.1±1.1and 0.14±0.4 per patient, respectively, and only 28.6percent of patients had no episodes of rejection. The 1-, 5-,and 10-year survival rates were 96.7, 94.0, and 84.4 percent,respectively. Cardiovascular events caused 64.3 percent of alldeaths.
Diabetes mellitus was present for a mean of 24.9±6.9years before combined transplantation, and after transplantationthe mean glycosylated hemoglobin level was 5.6±1.3 percentand was accompanied by sustained euglycemia.3 The cyclosporinedoses at 1, 5, and 10 years were 5.1±1.5, 4.7±1.5,and 4.1±1.0 mg per kilogram per day, respectively. The1-, 5- and 10-year rates of graft survival with a functioningallograft (data on patients who died were censored)9 were 99.2,98.2, and 95.2 percent, respectively, for kidney allograftsand 87.4, 86.5, and 86.5 percent, respectively, for pancreastransplants. Early thrombosis caused 84.6 percent of the lossesof pancreas transplants. Chronic allograft nephropathy combinedwith cyclosporine nephrotoxicity caused three kidney-transplantfailures over a period of 10 years. The median follow-up was7.0 years (range, 0.21 to 15.7).
Renal-Transplant Biopsies
Of 961 biopsy specimens, 2 were unusable because there was insufficienttissue; thus, 959 biopsy specimens were analyzed; 808 were obtainedaccording to the protocol and 151 were clinically indicatedand were performed at or near the times indicated in the protocol.The mean number of biopsy specimens obtained according to theprotocol was 8.0±4.4 per patient (range, 3 to 18), inaddition to diagnostic biopsies. A total of 67 biopsy specimenswere obtained at or near transplantation, 68 at 1 week, 78 at2 weeks, 118 at 1 month, 138 at 3 months, 87 at 6 months, 101at 1 year, 67 at 2 years, 69 at 3 years, 35 at 4 years, 52 at5 years, 26 at 6 years, 18 at 7 years, 12 at 8 years, 9 at 9years, and 16 at 10 years.
The median histologic follow-up (as measured from the date ofthe last biopsy) was 3.9±3.3 years. Biopsy specimensthat could be assessed histologically were scored by two observers(1 assessed 820 and the other 703), and a mean of 13.8±8.9glomeruli and 2.3±1.2 arteries were present per biopsy.A total of 15.7 percent had fewer than seven glomeruli or noartery. In biopsy specimens obtained at implantation or up toone week after transplantation, 1.7 percent of glomeruli weresclerosed and there was no or minimal preexisting damage (Table 1).
Table 1. Characteristics of the Allograft at and after Transplantation.
The Banff grade of chronic allograft nephropathy inversely correlatedwith the glomerular filtration rate, measured with use of isotopic[Tc99m]diethylenetriamine pentaacetic acid (r = –0.31,P<0.001), but the use of renal-transplant function to determinethe degree of histologic damage resulted in an underestimate.The mean glomerular filtration rate was 66.3±15.8 mlper minute in the absence of chronic allograft nephropathy,59.5±17.9 ml per minute in the presence of grade I nephropathy,and 49.8±21.8 ml per minute in the presence of chronicallograft nephropathy of grade II or higher. The histologicfindings in the limited number of renal-allograft–biopsyspecimens (59) from patients with pancreatic thrombosis duringfollow-up were similar to those in the other biopsy specimens.
Early Tubulointerstitial Damage
The natural history of chronic allograft nephropathy could bedivided into two distinct phases. The first year was characterizedby new-onset tubulointerstitial damage and rapidly increasingBanff scores for interstitial fibrosis and tubular atrophy (Figure 1A).Grade I chronic allograft nephropathy occurred a medianof three months (interquartile range, one to six) after transplantationand was present in 94.2 percent of patients by one year (Figure 1B)as a result of both immunologic and ischemic insults. Acutetubular necrosis was present in 22.7 percent of biopsy specimensat the time of transplantation and was subsequently associatedwith an increased prevalence of chronic allograft nephropathy(55.3 percent among those with acute tubular necrosis, as comparedwith 28.1 percent among those without acute tubular necrosis;P<0.001) and increased fibrointimal vascular thickening (Banffscore, 0.28±0.46, as compared with 0.06±0.22;P<0.001) at one month.
Figure 1. Mean Banff Scores for Chronic Interstitial Fibrosis, Tubular Atrophy, Arteriolar Hyalinosis, Chronic Fibrointimal Thickening, and Chronic Glomerulopathy (Panel A) and Prevalence of Mild (Grade I), Moderate (Grade II), and Severe (Grade III) Chronic Allograft Nephropathy, According to the Banff Criteria (Panel B).
The damage reflected by the Banff scores contributed to chronic allograft nephropathy, whose cumulative actuarial prevalence (1 – the Kaplan–Meier survival estimate) was defined according to the histologic findings on sequential biopsy specimens obtained according to the protocol and classified according to the Banff criteria. The number of biopsy specimens (and patients) at risk are given below the figure.
Severe acute rejection, defined by the need for antilymphocytetherapy, increased the Banff scores for chronic allograft nephropathyat three months (0.91±0.47, as compared with 0.56±0.48in the absence of such therapy; P<0.001). Acute cellularrejection without the need for antilymphocyte therapy had nodirect effect on chronic allograft nephropathy. Cox regressionindicated that prior severe rejection (hazard ratio, 2.03; 95percent confidence interval, 1.36 to 3.04; P<0.001) and evidenceof acute tubular necrosis on biopsy (hazard ratio, 1.80; 95percent confidence interval, 1.04 to 2.99; P<0.05) predictedchronic allograft nephropathy, after adjustment for the upperquartile of donor age of 32.5 years (hazard ratio, 1.52; 95percent confidence interval, 0.97 to 2.38; P=0.06). Chronicglomerulopathy scores, glomerulosclerosis, and fibrointimalvascular thickening were minimal in the first year after transplantation(Figure 1 and Figure 2 and Table 1). Chronic allograft nephropathygradually increased in severity and persisted, once established(Figure 1).
Figure 2. Prevalence of Glomerular Damage and Failure after Transplantation.
The point-prevalence percentages of glomeruli with complete and partial sclerosis and periglomerular sclerosis progressively increased with time.
Clinically significant acute lymphocytic infiltration, tubulitis,and subclinical rejection occurred in 60.8 percent of patientsone month after transplantation, with the prevalence fallingto 45.7 percent at three months, 25.8 percent at one year, andan average of 17.7 percent thereafter (Figure 3A). The three-monthrisk of subclinical rejection was increased by cyclosporinetherapy, as compared with tacrolimus use (hazard ratio, 4.34;95 percent confidence interval, 1.30 to 14.44; P<0.05), anda previous episode of severe rejection (hazard ratio, 2.46;95 percent confidence interval, 1.09 to 5.59; P<0.05). Tacrolimusand mycophenolate mofetil, individually and in combination,reduced the prevalence of subclinical rejection (P<0.05 toP<0.001). Patients who had acute and borderline subclinicalrejection had subsequent biopsy specimens showing higher gradesof chronic allograft nephropathy (2.48±0.66, P<0.001,and 0.75±0.25, P=0.07, respectively), as compared withthose without subclinical rejection (0.32±0.09).
Figure 3. Point Prevalence of Histologically Defined Subclinical Rejection in Sequential Biopsy Specimens (Panel A) and Calcineurin-Induced Nephrotoxic Effects (Panel B).
In Panel A, solid portions of bars represent episodes of clinical acute rejection that occurred at or near the time of biopsy. The prevalence of this complication contrasts with the prevalence of calcineurin-inhibitor nephrotoxicity, which was substantial and increased in concert with the time after transplantation (Panel B).
Among 114 patients who had two biopsies between 1 and 12 monthsafter transplantation, the initial biopsy showing acute subclinicalrejection, borderline subclinical rejection, or no evidenceof subclinical rejection was followed by a second biopsy showingincreased grades of chronic allograft nephropathy (in 44.4,34.1, and 29.6 percent, respectively; P<0.05) or a finalgrade of II or III (in 13.5, 12.7, and 2.2 percent, respectively;P<0.001). By one year, moderate chronic allograft nephropathywas evident in 25.6 percent of biopsy specimens with evidenceof any type of subclinical rejection (as compared with 7.5 percentof those without such evidence, P<0.05). A generalized estimatingequation showed that predictors of the grade of chronic allograftnephropathy 1 to 12 months after transplantation were acutetubular necrosis (P<0.01) and a previous episode of acutesubclinical rejection (P<0.01), with mycophenolate therapyhaving a protective effect (P<0.01). Hence, subclinical rejectionexacerbated chronic allograft nephropathy.
Late Arteriolar Hyalinosis and Glomerulosclerosis
Beyond one year, the patterns of allograft injury changed, reflectingmicrovascular and glomerular damage (Figure 1 and Figure 2).Early arteriolar hyalinosis was common and often transient,resolving in 45.8 percent of serial biopsy specimens by oneyear after transplantation. This abnormality was followed bya pattern of persistent arteriolar hyalinosis accompanied byhigh-grade vascular narrowing, progressive ischemic glomerulosclerosis,additional tubulointerstitial damage, and late renal functionaldecline (Table 1 and Figure 1 and Figure 2). By 10 years aftertransplantation, 37.3 percent of glomeruli were sclerosed andpartial glomerulosclerosis and periglomerular fibrosis wereincreasingly prevalent. Severe chronic allograft nephropathywas present in 58.4 percent of patients by 10 years. Biopsyspecimens with chronic allograft nephropathy were primarily(93.2 percent) Banff type a (reflecting nonspecific tubulointerstitialdamage, 93.2 percent), and a minority (5.4 percent) were Banfftype b (reflecting specific vascular and glomerular alterationssuggestive of the presence of chronic rejection) or had unclassifiablechanges (1.4 percent). Acute inflammatory activity was usuallyminimal or absent (below the Banff cutoff value of 10 percentof cortical area) (Figure 3A) after one year, and vascular fibrointimalthickening and chronic glomerulopathy scores indicated the presenceof only relatively minor abnormalities (Table 1 and Figure 1A).True chronic rejection was found in only seven patients (5.8percent) and significantly increased chronic allograft nephropathyscores (P<0.05). The presence of hypertension or the degreeof HLA mismatching did not appear to have any independent effecton the risk of chronic allograft nephropathy. Calcineurin-inhibitornephrotoxicity became increasingly prevalent (Figure 3B andTable 2), becoming virtually universal by 10 years after transplantationand progressing despite mild-to-moderate reductions in calcineurindoses. Calcineurin-inhibitor nephrotoxicity was the chief causeof late histologic injury and ongoing decline in renal function.
Table 2. Cumulative Kaplan–Meier Estimates of the Prevalence of Histologic Diagnoses, According to the Time after Transplantation.
Discussion
This longitudinal analysis provides new insights into the pathophysiologyand natural history of chronic allograft nephropathy. This typeof nephropathy appears to consist of two distinctive phasesof injury occurring at different times after transplantationwithin different histologic compartments. Early tubulointerstitialdamage correlates with immunologic factors, including severeacute rejection and persistent subclinical rejection with theaddition of ischemia–reperfusion injury. Later damageis characterized by progressive arteriolar hyalinosis, ischemicglomerulosclerosis, and further interstitial fibrosis associatedwith long-term calcineurin-inhibitor nephrotoxicity. Chronicallograft nephropathy thus represents the histologic sequelaeof a series of pathologic insults that result in incrementaland cumulative damage to nephrons within the transplanted kidney.
Our data, derived from diabetic recipients of a kidney–pancreastransplant, demonstrate that chronic allograft nephropathy isa sequential multifactorial process caused by a series of time-dependentinsults. These transplantations were characterized by a youngdonor age, minimal periods of renal ischemia and incidence ofdelayed graft function, high rates of acute rejection, and excellenttreatment compliance among recipients, as compared with a broaderpopulation of kidney-transplant recipients, thus limiting ourability to extrapolate data to transplantations affected byissues such as recurrent glomerulonephritis, marginal donorkidneys, and noncompliance. However, the pristine conditionof the kidneys transplanted allowed us to observe the evolutionof chronic allograft nephropathy without the confounding influencesof preexisting damage in the donor organ.
Immunologic factors including acute rejection have previouslybeen associated with graft loss.10 Acute vascular rejectionresults in immediate and extensive histologic damage,4 initiationof chronic allograft nephropathy,4 and reduced graft survival.11In contrast, acute cellular rejection caused minimal directdamage, unless it was severe (and usually corticosteroid resistant)or heralded persistent subclinical rejection. Subclinical rejectionwas common early after transplantation and was followed by chronicinterstitial fibrosis, tubular atrophy, and nephron loss, contributingto chronic allograft nephropathy especially between 3 and 12months after transplantation. Persistent graft inflammationled to evidence of chronic tubulointerstitial damage on subsequentbiopsy specimens in this and other studies.12,13,14 Becausesubclinical rejection and tubulitis are patchy processes, theuninvolved nephrons can maintain stable serum creatinine levelsby means of compensatory hyperfiltration; consequently, theimmunologic injury is clinically silent. When rejection remainsundetected, as occurs with subclinical rejection or late acuterejection, there may be substantial damage, exacerbating chronicallograft nephropathy.5,15 Hence, the effects of rejection-relatedinjury causing chronic allograft nephropathy are dependent onthe type, persistence, timing, and severity of episodes of rejection.
Progressive functional failure of kidney grafts has been assumedto result from a low-grade process of persistent subclinicalor chronic rejection, a hypothesis never properly validatedby studies in humans. Although early subclinical rejection wascommon in our study, it usually resolved with calcineurin-basedmaintenance immunosuppression. True chronic rejection, definedby sequential histologic abnormalities with implied continuousimmunologic injury, occurred in only 5.8 percent of patientsand thus appears uncommon. The absence of subacute cellularinflammation in most biopsy specimens obtained long after transplantationalters our conception of the pathophysiology of late chronicallograft nephropathy. Although immunologic factors result ina substantial burden of early tubulointerstitial injury, laterdamage appears to be predominantly associated with the histologicpattern of calcineurin-inhibitor nephrotoxicity.
Dr. O'Connell reports having received consulting fees from Wyethand lecture fees from Janssen–Cilag. Dr. Chapman reportshaving received consulting and lecture fees from Novartis, Roche,Fujisawa, and Wyeth; lecture fees from Janssen–Cilag;and a grant from Novartis.
Source Information
From the Departments of Renal Medicine (B.J.N., R.J.B., P.J.O., J.R.C.), Tissue Pathology (C.L.-S.F.), and Transplantation Surgery (R.D.M.A.), University of Sydney, Westmead Hospital, Sydney, Australia.
Address reprint requests to Dr. Nankivell at the Department of Renal Medicine, Westmead Hospital, Westmead, 2145 NSW, Australia, or at brian_nankivell{at}wsahs.nsw.gov.au.
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Chronic Allograft Nephropathy
Ponticelli C., Torras J., Herrero-Fresneda I., Grinyo J. M., Pietrzyk M., Hoffmann U., Krämer B. K., Nankivell B. J., Chapman J. R.
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Elimelakh, M., Dayton, V., Park, K. S., Gruessner, A. C., Sutherland, D., Howe, R. B., Reding, M. T., Eastlund, T., van Burik, J.-A., Singleton, T. P., Gruessner, R. W., Key, N. S.
(2007). Red cell aplasia and autoimmune hemolytic anemia following immunosuppression with alemtuzumab, mycophenolate, and daclizumab in pancreas transplant recipients. haematol
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[Abstract][Full Text]
Djamali, A.
(2007). Oxidative stress as a common pathway to chronic tubulointerstitial injury in kidney allografts. Am. J. Physiol. Renal Physiol.
293: F445-F455
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Joy, M. S., Hogan, S. L., Thompson, B. D., Finn, W. F., Nickeleit, V.
(2007). Cytochrome P450 3A5 expression in the kidneys of patients with calcineurin inhibitor nephrotoxicity. Nephrol Dial Transplant
22: 1963-1968
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Bobadilla, N. A., Gamba, G.
(2007). New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone. Am. J. Physiol. Renal Physiol.
293: F2-F9
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Goes, N. B., Colvin, R. B.
(2007). Case 12-2007 -- A 56-Year-Old Woman with Renal Failure after Heart-Lung Transplantation. NEJM
356: 1657-1665
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Fiorina, P., Perseghin, G., De Cobelli, F., Gremizzi, C., Petrelli, A., Monti, L., Maffi, P., Luzi, L., Secchi, A., Del Maschio, A.
(2007). Altered Kidney Graft High-Energy Phosphate Metabolism in Kidney-Transplanted End-Stage Renal Disease Type 1 Diabetic Patients: A cross-sectional analysis of the effect of kidney alone and kidney-pancreas transplantation. Diabetes Care
30: 597-603
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Djamali, A., Sadowski, E. A., Muehrer, R. J., Reese, S., Smavatkul, C., Vidyasagar, A., Fain, S. B., Lipscomb, R. C., Hullett, D. H., Samaniego-Picota, M., Grist, T. M., Becker, B. N.
(2007). BOLD-MRI assessment of intrarenal oxygenation and oxidative stress in patients with chronic kidney allograft dysfunction. Am. J. Physiol. Renal Physiol.
292: F513-F522
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Tse, K C, Lam, M F, Tang, S C., Tang, C S., Chan, T M
(2007). A pilot study on tacrolimus treatment in membranous or quiescent lupus nephritis with proteinuria resistant to angiotensin inhibition or blockade. Lupus
16: 46-51
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Heine, G. H., Reichart, B., Ulrich, C., Kohler, H., Girndt, M.
(2007). Do ultrasound renal resistance indices reflect systemic rather than renal vascular damage in chronic kidney disease?. Nephrol Dial Transplant
22: 163-170
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Zeyda, M., Geyeregger, R., Poglitsch, M., Weichhart, T., Zlabinger, G. J., Koyasu, S., Horl, W. H., Stulnig, T. M., Watschinger, B., Saemann, M. D.
(2007). Impairment of T cell interactions with antigen-presenting cells by immunosuppressive drugs reveals involvement of calcineurin and NF-{kappa}B in immunological synapse formation. J. Leukoc. Biol.
81: 319-327
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Kambham, N., Nagarajan, S., Shah, S., Li, L., Salvatierra, O., Sarwal, M. M.
(2007). A Novel, Semiquantitative, Clinically Correlated Calcineurin Inhibitor Toxicity Score for Renal Allograft Biopsies. CJASN
2: 135-142
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Perez-Rojas, J., Blanco, J. A., Cruz, C., Trujillo, J., Vaidya, V. S., Uribe, N., Bonventre, J. V., Gamba, G., Bobadilla, N. A.
(2007). Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity. Am. J. Physiol. Renal Physiol.
292: F131-F139
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Tang, S. C.-W., Chan, K. W., Tang, C. S.-O., Lam, M. F., Leung, C. Y., Tse, K. C., Li, C. S., Ho, Y. W., Tong, M. K.-L., Lai, K. N., Chan, T. M., for the Hong Kong Nephrology Study Group,
(2006). Conversion of ciclosporin A to tacrolimus in kidney transplant recipients with chronic allograft nephropathy. Nephrol Dial Transplant
21: 3243-3251
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Ruiz, J. C., Campistol, J. M., Sanchez-Fructuoso, A., Rivera, C., Oliver, J., Ramos, D., Campos, B., Arias, M., Diekmann, F.
(2006). Increase of proteinuria after conversion from calcineurin inhibitor to sirolimus-based treatment in kidney transplant patients with chronic allograft dysfunction. Nephrol Dial Transplant
21: 3252-3257
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Najafian, N., Albin, M. J., Newell, K. A.
(2006). How Can We Measure Immunologic Tolerance in Humans?. J. Am. Soc. Nephrol.
17: 2652-2663
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Beckmann, N., Cannet, C., Zurbruegg, S., Haberthur, R., Li, J., Pally, C., Bruns, C.
(2006). Macrophage Infiltration Detected at MR Imaging in Rat Kidney Allografts: Early Marker of Chronic Rejection?. Radiology
240: 717-724
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Chapman, J. R., Nankivell, B. J.
(2006). Nephrotoxicity of ciclosporin A: short-term gain, long-term pain?. Nephrol Dial Transplant
21: 2060-2063
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Djamali, A., Samaniego, M., Muth, B., Muehrer, R., Hofmann, R. M., Pirsch, J., Howard, A., Mourad, G., Becker, B. N.
(2006). Medical Care of Kidney Transplant Recipients after the First Posttransplant Year. CJASN
1: 623-640
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Harmon, W., Meyers, K., Ingelfinger, J., McDonald, R., McIntosh, M., Ho, M., Spaneas, L., Palmer, J. A., Hawk, M., Geehan, C., Tinckam, K., Hancock, W. W., Sayegh, M. H.
(2006). Safety and Efficacy of a Calcineurin Inhibitor Avoidance Regimen in Pediatric Renal Transplantation. J. Am. Soc. Nephrol.
17: 1735-1745
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Verkoelen, C. F.
(2006). Crystal Retention in Renal Stone Disease: A Crucial Role for the Glycosaminoglycan Hyaluronan?. J. Am. Soc. Nephrol.
17: 1673-1687
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Soulillou, J.-P., Giral, M.
(2006). Influence of graft characteristics on the outcome of kidney transplantation.. NEJM
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Mannon, R. B., Kirk, A. D.
(2006). Beyond Histology: Novel Tools to Diagnose Allograft Dysfunction. CJASN
1: 358-366
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Diekmann, F., Campistol, J. M.
(2006). Conversion from calcineurin inhibitors to sirolimus in chronic allograft nephropathy: benefits and risks. Nephrol Dial Transplant
21: 562-568
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Roos-van Groningen, M. C., Scholten, E. M., Lelieveld, P. M., Rowshani, A. T., Baelde, H. J., Bajema, I. M., Florquin, S., Bemelman, F. J., de Heer, E., de Fijter, J. W., Bruijn, J. A., Eikmans, M.
(2006). Molecular Comparison of Calcineurin Inhibitor-Induced Fibrogenic Responses in Protocol Renal Transplant Biopsies. J. Am. Soc. Nephrol.
17: 881-888
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Saurina, A., Campistol, J. M., Piera, C., Diekmann, F., Campos, B., Campos, N., de las Cuevas, X., Oppenheimer, F.
(2006). Conversion from calcineurin inhibitors to sirolimus in chronic allograft dysfunction: changes in glomerular haemodynamics and proteinuria. Nephrol Dial Transplant
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Rush, D.
(2006). Protocol Transplant Biopsies: An Underutilized Tool in Kidney Transplantation. CJASN
1: 138-143
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Rowshani, A. T., Scholten, E. M., Bemelman, F., Eikmans, M., Idu, M., van Groningen, M. C.R., Surachno, J. S., Mallat, M. J.K., Paul, L. C., de Fijter, J. W., Bajema, I. M., ten Berge, I., Florquin, S.
(2006). No Difference in Degree of Interstitial Sirius Red-Stained Area in Serial Biopsies from Area under Concentration-over-Time Curves-Guided Cyclosporine versus Tacrolimus-Treated Renal Transplant Recipients at One Year. J. Am. Soc. Nephrol.
17: 305-312
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Revelo, M. P., Federspiel, C., Helderman, H., Fogo, A. B.
(2005). Chronic allograft nephropathy: expression and localization of PAI-1 and PPAR-{gamma}. Nephrol Dial Transplant
20: 2812-2819
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Stallone, G., Infante, B., Schena, A., Battaglia, M., Ditonno, P., Loverre, A., Gesualdo, L., Schena, F. P., Grandaliano, G.
(2005). Rapamycin for Treatment of Chronic Allograft Nephropathy in Renal Transplant Patients. J. Am. Soc. Nephrol.
16: 3755-3762
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Bumbea, V., Kamar, N., Ribes, D., Esposito, L., Modesto, A., Guitard, J., Nasou, G., Durand, D., Rostaing, L.
(2005). Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant
20: 2517-2523
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Vallejos, A., Alperovich, G., Moreso, F., Canas, C., de Lama, M. E., Goma, M., Fulladosa, X., Carrera, M., Hueso, M., Grinyo, J. M., Seron, D.
(2005). Resistive index and chronic allograft nephropathy evaluated in protocol biopsies as predictors of graft outcome. Nephrol Dial Transplant
20: 2511-2516
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Perez-Rojas, J. M., Derive, S., Blanco, J. A., Cruz, C., de la Maza, L. M., Gamba, G., Bobadilla, N. A.
(2005). Renocortical mRNA expression of vasoactive factors during spironolactone protective effect in chronic cyclosporine nephrotoxicity. Am. J. Physiol. Renal Physiol.
289: F1020-F1030
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Webster, A. C, Woodroffe, R. C, Taylor, R. S, Chapman, J. R, Craig, J. C
(2005). Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ
331: 810-
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Chapman, J. R., O'Connell, P. J., Nankivell, B. J.
(2005). Chronic Renal Allograft Dysfunction. J. Am. Soc. Nephrol.
16: 3015-3026
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Yuan, R., El-Asady, R., Liu, K., Wang, D., Drachenberg, C. B., Hadley, G. A.
(2005). Critical Role for CD103+CD8+ Effectors in Promoting Tubular Injury following Allogeneic Renal Transplantation. J. Immunol.
175: 2868-2879
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Vincenti, F., Larsen, C., Durrbach, A., Wekerle, T., Nashan, B., Blancho, G., Lang, P., Grinyo, J., Halloran, P. F., Solez, K., Hagerty, D., Levy, E., Zhou, W., Natarajan, K., Charpentier, B., the Belatacept Study Group,
(2005). Costimulation Blockade with Belatacept in Renal Transplantation. NEJM
353: 770-781
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Holzmacher, R., Kendziorski, C., Michael Hofman, R., Jaffery, J., Becker, B., Djamali, A.
(2005). Low serum magnesium is associated with decreased graft survival in patients with chronic cyclosporin nephrotoxicity. Nephrol Dial Transplant
20: 1456-1462
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Avihingsanon, Y., Ma, N., Pavlakis, M., Chon, W. J., Uknis, M. E., Monaco, A. P., Ferran, C., Stillman, I., Schachter, A. D., Mottley, C., Zheng, X. X., Strom, T. B.
(2005). On the Intraoperative Molecular Status of Renal Allografts after Vascular Reperfusion and Clinical Outcomes. J. Am. Soc. Nephrol.
16: 1542-1548
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Hauser, I. A., Schaeffeler, E., Gauer, S., Scheuermann, E. H., Wegner, B., Gossmann, J., Ackermann, H., Seidl, C., Hocher, B., Zanger, U. M., Geiger, H., Eichelbaum, M., Schwab, M.
(2005). ABCB1 Genotype of the Donor but Not of the Recipient Is a Major Risk Factor for Cyclosporine-Related Nephrotoxicity after Renal Transplantation. J. Am. Soc. Nephrol.
16: 1501-1511
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Keith, D. S., deMattos, A., Golconda, M., Prather, J., Cantarovich, M., Paraskevas, S., Tchervenkov, J., Norman, D. J.
(2005). Factors Associated with Improvement in Deceased Donor Renal Allograft Function in the 1990s. J. Am. Soc. Nephrol.
16: 1512-1521
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Ortiz, F., Paavonen, T., Tornroth, T., Koskinen, P., Finne, P., Salmela, K., Kyllonen, L., Gronhagen-Riska, C., Honkanen, E.
(2005). Predictors of Renal Allograft Histologic Damage Progression. J. Am. Soc. Nephrol.
16: 817-824
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Rao, P. S., Schaubel, D. E., Saran, R.
(2005). Impact of graft failure on patient survival on dialysis: a comparison of transplant-naive and post-graft failure mortality rates. Nephrol Dial Transplant
20: 387-391
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Winkelmayer, W. C., Kramar, R., Curhan, G. C., Chandraker, A., Endler, G., Fodinger, M., Horl, W. H., Sunder-Plassmann, G.
(2005). Fasting Plasma Total Homocysteine Levels and Mortality and Allograft Loss in Kidney Transplant Recipients: A Prospective Study. J. Am. Soc. Nephrol.
16: 255-260
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Sayegh, M. H., Carpenter, C. B.
(2004). Transplantation 50 Years Later -- Progress, Challenges, and Promises. NEJM
351: 2761-2766
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Hueso, M., Alia, P., Moreso, F., Beltran-Sastre, V., Riera, L., Gonzalez, C., Angel Navarro, M., Grinyo, J. M., Navarro, E., Seron, D.
(2004). Angiotensin Converting Enzyme Genotype and Chronic Allograft Nephropathy in Protocol Biopsies. J. Am. Soc. Nephrol.
15: 2229-2236
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Kunzendorf, U., Ziegler, E., Kabelitz, D.
(2004). FTY720--the first compound of a new promising class of immunosuppressive drugs. Nephrol Dial Transplant
19: 1677-1681
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Poggio, E. D., Clemente, M., Riley, J., Roddy, M., Greenspan, N. S., Dejelo, C., Najafian, N., Sayegh, M. H., Hricik, D. E., Heeger, P. S.
(2004). Alloreactivity in Renal Transplant Recipients with and without Chronic Allograft Nephropathy. J. Am. Soc. Nephrol.
15: 1952-1960
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Ponticelli, C., Torras, J., Herrero-Fresneda, I., Grinyo, J. M., Pietrzyk, M., Hoffmann, U., Kramer, B. K., Nankivell, B. J., Chapman, J. R.
(2004). Chronic Allograft Nephropathy. NEJM
350: 1254-1256
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