Chronic allograft nephropathy score before sirolimus rescue predicts allograft function in renal transplant patients

Chronic allograft nephropathy (CAN) is a major indication for initiation of sirolimus (SRL) in renal transplantation (TX) to prevent deterioration of renal function. We evaluated whether the CAN score at time of sirolimus rescue (SRL-R) predicts renal allograft function. CAN score is the sum of the following 4 categories: glomerulopathy (cg, 0-3), interstitial fibrosis (ci, 0-3), tubular atrophy (ct, 0-3), and vasculopathy (cv, 0-3). This is a retrospective cohort study of renal transplant recipients from July 2001 to March 2004. Immunosuppression consisted of preconditioning with rabbit anti-thymocyte globulin or alemtuzumab and maintenance with tacrolimus (TAC) monotherapy with spaced weaning, if applicable, SRL-R was achieved by conversion from TAC, or by addition to reduced doses of TAC. Ninety patients received SRL. Thirty-three of these patients met the inclusion criteria of the following: (1) receipt of SRL for >6 months, and (2) follow-up of > or =6 months. There were 16 patients in the low-CAN (0-4) group and 17 patients in the high-CAN (>4) group. Cockcroft-Gault (C-G) glomerular filtration rate (GFR) was calculated at SRL-R and at 1, 3, 6, and 12 months. The DeltaGFR was significantly better in the low-CAN group at 1, 3, and 6 months. A trend toward an improved DeltaGFR was present at 12 months in the low-CAN group (P = .16). CAN scoring at the time of SRL-R predicts recovery of renal allograft function (as measured using DeltaGFR), and should be used in preference to biochemical markers (Cr and C-G GFR), which may not be reliable predictors.     

Pretransplant donor-specific interferon-gamma ELISPOT assay predicts acute rejection episodes in renal transplant recipients

Interferon (IFN)-gamma enzyme-linked immunosorbent spot (ELISPOT) assay is a powerful tool for measuring the frequency of alloantigen-specific T cells, reflecting cellular immunity. We correlated the pretransplant frequencies of donor-specific and third-party-specific IFN-gamma ELISPOT tests, with the posttransplant outcomes of 45 recipients of living donor renal transplantations. The mean frequency of pretransplant donor-specific ELISPOT was significantly greater among patients with acute rejection episodes (ARE) than those without ARE (18.0 [12 to 50] versus 8.8 [5 to 30.4]) spots per 200,000 peripheral blood lymphocytes (PBLs; P=.024). A cutoff level of 12 spots per 200,000 PBLs on the donor-specific ELISPOT identified an ARE-positive patient with a sensitivity of 81.8% and a specificity of 64.7%. The recipients with pretransplant donor-specific ELISPOT+showed higher serum creatinine levels and lower glomerular filtration rate (GFR) at 6 posttransplant months (P<.05). Although the pretransplant third-party-specific ELISPOT results correlated with the donor-specific ELISPOT results (r=.783; P<.001), there was no significant difference in the third-party ELISPOT results between the ARE-positive and ARE-negative recipients. In conclusion, an analysis of pretransplant donor-specific IFN-gamma ELISPOT may identify the posttransplant risk of developing ARE and displaying decreased GFR at 6 months.     

Serum neutrophil gelatinase-associated lipocalin correlates with kidney function in renal allograft recipients

Abstract:  The value of neutrophil gelatinase-associated lipocalin (NGAL) as a novel marker for early detection of acute renal failure has been highlighted recently. The aim of this study was to assess whether serum NGAL correlates with kidney function in kidney allograft recipients. Serum NGAL, creatinine, and estimated glomerular filtration rate (GFR) were evaluated in 100 kidney allograft recipients on triple therapy: calcineurin inhibitor, mycophenolate mofetil or azathioprine, prednisone and healthy volunteers. Kidney transplant recipients had significantly higher NGAL than the control group. Serum NGAL in univariate analysis was strongly correlated with serum creatinine ( r  = 0.78). Estimated GFR ( r  = −0.69), on the other hand, was moderately correlated with white blood cell count ( r  = 0.43) and only weakly with other parameters. In multiple regression analysis, the best predictor of serum NGAL was eGFR (beta −0.69), with other predictors being white blood cell count (beta 0.25) and high sensitivity C-reactive protein (hsCRP) (beta 0.23) explaining 82% of NGAL concentration. Even a successful kidney transplantation is associated with kidney injury as reflected by elevated serum NGAL and lowered eGFR. Therefore, NGAL needs to be investigated as a potential early marker for impaired kidney function/kidney injury, especially in patients with other risk factor for kidney damage, i.e., hypertension or diabetes.     

Kidney injury molecule-1 correlates with kidney function in renal allograft recipients

IntroductionKIM-1 (kidney injury molecule-1) is responsible for the clearance of debris from damaged renal tubules. KIM-1 can be expressed and excreted in urine within 12 hours after the initial ischemic insult and before regeneration of the epithelium, persisting over time thereafter. Urinary KIM-1 has been reported to be a noninvasive, rapid, sensitive, and reproducible biomarker of experimental nephrotoxic and ischemic acute kidney injury. Renal KIM-1 expression is significantly increased in human kidney tissue among patients with a wide range of kidney diseases, including various types of glomerulonephritis, chronic allograft nephropathy, acute rejection, hypertension, and Wegener's granulomatosis. Both renal and urinary KIM-1 correlate with kidney damage and negatively with renal function, but not with proteinuria. The aim of this study was to assess whether urinary KIM-1 correlated with kidney function in kidney allograft recipients.MethodsSerum NGAL, creatinine and estimated glomerular filtration rate (eGFR) were evaluated in 170 kidney allograft recipients on therapy with a calcineurin inhibitor plus mycophenolate mofetil or azathioprine and prednisone as well as in healthy volunteers. KIM-1 was estimated in urine using a commercially available kit.ResultsKidney transplant recipients showed significantly higher KIM-1 values than the control group. Normotensive kidney allograft recipients displayed significantly lower NGAL results than hypertensive subjects. Urinary KIM-1 was significantly higher among diabetic than nondiabetic subjects, whereas creatinine did not differ significantly between them. Upon univariate analysis urinary KIM-1 strongly correlated with serum creatinine (r = .64) and eGFR (r = ?.71), and only weakly with other parameters. Upon multiple regression analysis, the best predictor of urinary KIM-1 was eGFR (beta ?0.61), which explained 61% of KIM-1 concentrations.ConclusionEven a successful kidney transplantation is associated with kidney injury as reflected by elevated urinary KIM-1 and lower eGFR. Therefore, KIM-1 needs to be investigated as a potential early marker for impaired renal function/kidney injury, especially in patients with other risk factors for damage such as hypertension or diabetes.     

Pretransplant serum C-reactive protein and the risk of chronic allograft nephropathy in renal transplant recipients: A pilot case-control study

Multiple factors contribute to the development of chronic allograft nephropathy (CAN) in renal transplant recipients, and atherogenesis is considered to be an important pathologic process contributing to the development of this disease. There is growing acknowledgment of the role of inflammation in the pathogenesis of atherosclerosis, and markers of inflammation, such as C-reactive protein (CRP), have been shown to predict atherosclerotic vascular disease in the general and end-stage renal disease populations. In this pilot study, we hypothesized that elevations in pretransplant concentrations of CRP predict an increased incidence of CAN after renal transplantation. This case-control study compared pretransplant CRP levels in patients with allograft dysfunction and biopsy-proven CAN (n = 15) with a control group of transplant recipients with normal allograft function (n = 43). The median concentration of serum CRP was significantly higher in the CAN versus the control patients (13.1 ± 3.9 mg/L versus 3.5 ± 2.5 mg/L; P = 0.01). This difference was sustained when restricting to patients who did not experience acute rejection. When dividing the patients into tertiles based on CRP concentration, the adjusted risk of CAN increased more than threefold with each increment in CRP by tertile (adjusted odds ratio, 3.16; P = 0.03). The findings of our pilot study show an association between pretransplant elevations of CRP and CAN in end-stage renal disease patients who go on to receive a renal transplant. Cohort studies in larger groups of transplant patients are needed to confirm a causal pathway between pretransplant inflammation, atherogenesis, and CAN. © 2002 by the National Kidney Foundation, Inc.     

Homocysteine in renal transplant recipients: association with transplant duration and renal function

BACKGROUND: Hyperhomocystinemia is an established risk factor for cardiovascular events and has been identified as an important cause of morbidity and mortality in renal transplant recipients. This investigation was aimed to determine the effect of age and transplant duration on serum total homocysteine (tHcy) levels in renal transplant recipients. METHODS: We analyzed serum levels of tHcy, albumin, alkaline phosphatase, alanine transferase, bilirubin, calcium, corrected calcium, cholesterol, creatinine, folate, phosphate, potassium, sodium, triglycerides, urea and vitamin B12 in 88 transplant patients (ages, 14-67 years; transplant duration, 1-252 months) and 60 control subjects. RESULTS: Our results showed significant hyperhomocystinemia in transplant patients (19.92 +/- 0.72) as compared to controls (9.28 +/- 0.25), while male subjects in both groups had significantly higher tHcy than females. There was no correlation between patients' age and serum tHcy, whereas the time after transplantation was significantly correlated with tHcy (r=0.318, P<0.01). A significant correlation was observed between tHcy and serum urea, creatinine, vitamin B12 and potassium in renal transplant patients. CONCLUSION: This study clearly demonstrated significant hyperhomocystinemia and renal impairment in transplant recipients. A time-course increase in serum tHcy during posttransplant duration warrants long-term monitoring of patients for effective clinical management.     

A direct association of polyomavirus BK viruria with deterioration of renal allograft function in renal transplant patients

Abstract: Background:  Polyomavirus BK virus (BKV) causes a BKV-associated nephropathy (BKVAN), frequently causing allograft dysfunction in renal transplant recipients. As BK viruria is a surrogate marker for early detection of BKVAN, the aim of this study was to clarify an association between BK viruria and allograft dysfunction in renal transplant recipients.
Methods:  One hundred and six renal transplant recipients with average 5.9-yr transplant duration received screening for quantification of BK viruria detected by real time polymerase chain reaction and were followed up for 12 months.
Results:  Twenty-six patients (25%) had detectable BK viruria. In comparison of the patients without BK viruria, more patients in the BK viruria group were treated with steroids and had a past history of acute rejection. There was no difference in sex, age, transplant duration, allograft type and previous cytomegalovirus infection. During follow-up, the patients with BK viruria had higher serum creatinine levels at the sixth, ninth and 12th month. Multiple logistic regression analysis revealed that BK viruria was the only risk factor for more than 25% or 50% rise of serum creatinine level above baseline at the end of one yr follow-up.
Conclusions:  BK viruria alone is associated with allograft dysfunction and early intervention is indicated.     

Laboratory assessment of immune function in renal transplant patients.

BACKGROUND: Advances in immunosuppression have made renal transplantation an effective therapy for end stage renal failure; with low rejection rates and long graft survival times. However, the major adverse consequences, infection and malignancy have not diminished. To predict this risk a score of immune competence has been developed from the simultaneous laboratory assessment of multiple parameters of immune function. METHODS: The immune status of 152 transplant recipients (138 renal and 14 pancreas/renal) was assessed by measurement of lymphocyte subsets, mitogen-induced T-cell proliferative responses, neutrophil phagocytic capacity and reactive oxygen species (ROS) generation. A scoring system was devised based on the average number of these parameters below 10th percentile of normal. RESULTS: The most common abnormality was B-cell lymphopenia (85%) followed by reduced neutrophil ROS production (63% of patients), NK cell lymphopenia (50%), lymphocyte mitogen response (49%) and CD4 number (23%). The abnormalities were unrelated to the duration of immunosuppression (up to 15 years), and variable combinations of cyclosporine A, azathioprine, prednisolone and mycophenolate mofetil (MMF) (except for a consistent reduction in lymphocyte mitogen response in MMF treated patients). Retrospective comparison of infective episodes showed a significantly greater index of infections in patients with the worst score compared with a normal score. CONCLUSIONS: The data suggests that this quantification of immune function may allow assessment of the level of host immune defence reflecting the level of drug-induced immunosuppression and thus risks of immunosuppressive complications.     

Minimal sensitization and excellent renal allograft outcome following donor-specific blood transfusion with a short course of cyclosporine

A new protocol of donor-specific blood transfusion under cyclosporine coverage was developed and examined for immunologic consequences and clinical efficacy in recipients of one- or zero-HLA-haplotype-matched renal allografts. Between 1985 and 1989, 75 recipients were transfused with 100 ml of stored whole blood at 1, 8, and 15 days of its storage from either one-HLA-haplotype-matched related donors (n = 65, 33 from their parents, 30 from siblings, and 2 from offspring) or from zero-HLA-haplotype-matched donors (n = 10, 7 from spouses and 3 from siblings). During DST, all recipients received cyclosporine, 6 mg/kg/day, starting a day before and finishing a week after DST (23 days). Recipients were monitored by donor-specific mixed lymphocyte culture responses before and after DST, and serially for antibodies by fluorescence activated cell sorter analysis and by standard complement-dependent lymphocytotoxicity assay. Following DST with CsA, only 3 of 75 patients (4%) were sensitized against the blood donor. This rate is considerably lower, albeit statistically not significantly, compared with the 10% rate found in 30 recipients who had received DST without CsA in our previous study. Repeat MLC studied one to two months after DST (the day before transplant) were significantly increased compared with pre-DST (stimulation index: mean +/- SEM; 10.3 +/- 1.4 to 15.8 +/- 2.8, P = 0.004, and relative response: 40.9 +/- 5.1% to 49.8 +/- 5.5%, P = 0.003). Since the stimulation index with controls did not change after DST (23.4 +/- 2.9 to 26.2 +/- 3.3), enhanced MLC responses appear to be donor-specific. The changes in MLC responses did not correlate with the number of blood transfusion received prior to DST, the number of rejection episodes, or graft outcome. Fifty-seven recipients underwent a kidney transplant from their one-HLA-haplotype-matched blood donors within two to three months after DST. All 10 recipients of zero-haplotype-matched donors were also successfully transplanted from their respective blood donors. The graft survival rates were at least 90% at two years in both groups. In conclusion: (1) 100 ml of stored whole-blood DST, three times at weekly intervals with a short course of CsA is minimally sensitizing but effective in enhancing graft survival; (2) this protocol could be used in donor-recipient pairs who do not share a haplotype; and (3) DST with CsA elicits augmentation of donor-specific MLC responses.     

Post-transplant renal function in the first year predicts long-term kidney transplant survival

BACKGROUND: Improvements in long-term kidney graft survival have been recently noted. However, the reasons for this were unclear. This study examined post-transplant renal function within the first year as an independent variable influencing long-term survival. METHODS: The influence of demographic characteristics (age, sex, race); transplant variables (cadaver versus living donor, cold ischemia time, HLA mismatching, delayed graft function and transplant year), and post-transplant variables (immunosuppressive agents for the prevention of acute rejection, clinical acute rejection and post-transplant renal function in the first year) on graft survival were analyzed for 105,742 adult renal transplants between 1988 and 1998. Renal function in the first year was expressed as serum creatinine at six months and one year and delta creatinine (change in serum creatinine between 6 months and 1 year). Graft half-life was used to measure long-term survival. RESULTS: During this 11-year period, the one-year serum creatinine values for cadaver recipients steadily improved, from 1.82 +/- 0.82 mg/dL in 1988 to 1.67 +/- 0.82 mg/dL in 1998 (P < 0.001), as did the graft half-life. There was a progressive decline in graft half-life for each incremental increase of six month, one year and Delta creatinine for living and cadaver donor transplants as well for cadaver transplants with donor age > and < or =50 years. The Relative Hazard (RH) for graft failure was 1.63 (1.61, 1.65; P < 0.0001) with each increment of 1.0 mg/dL of serum creatinine at one year post-transplant and it increased to 2.26 (2.2, 2.31; P < 0.0001) when the Delta creatinine was 0.5 mg/dL. The RH reduction for graft failure was substantially lower for the years 1993, 1996, 1997 and 1998 when post-transplant renal function was not included in the model (P < 0.05). However, the RH reduction per year was not different when post-transplant creatinine was included in the model, 1.01 (0.94 to 1.05; P = 0.89). CONCLUSION: In conclusion, one-year creatinine and Delta creatinine values predict long-term renal graft survival. Recent improvements in graft half-life are related to conservation of renal function within the first year post-transplantation.     

Correlation between endothelin expression in early post-transplant biopsy specimens and long-term allograft function in living-related renal transplantation

OBJECTIVE: We investigated whether degree of immunohistochemically evident endothelin (ET) expression in early post-transplant biopsy specimens could predict long-term allograft function in living-related renal transplantation. METHODS: Allograft biopsy specimens obtained from 40 patients with living-related transplants were studied. Cases with episodes of acute rejection or calcineurin inhibitor toxicity were excluded. We immunostained graft biopsy specimens obtained at pre-transplantation (PRE) and at 3 months (3M) afterward with anti-ET antibody. The number of stained tubular epithelial cells per 1000 tubular cells was defined as the staining index (SI). In the 21 patients whom we could assess at 3 yr (3Y) after transplantation, the correlation between ET expression and long-term graft function was examined. RESULTS: Anti-ET antibody staining was appreciable in tubular epithelium but not in glomeruli. Tubular SI at PRE and at 3M were 10.6 +/- 15.3 and 32.0 +/- 35.6 (mean +/- SD) respectively (p < 0.01). When patients were classified according to SI (group A, SI < 25; group B, SI > 25), declining ratio in creatinine clearance at 3Y after transplantation for groups A and B with respect was 21.8% +/- 15.4% and 41.9% +/- 21.6% (p < 0.05). CONCLUSION: High ET expression in early post-transplantation, biopsy specimens was related to poor long-term allograft function following living-related renal transplantation.     

Leukocyte phenotype and function predicts infection risk in renal transplant recipients.

BACKGROUND: The degree to which transplant recipients are immunosuppressed influences their risks of rejection, infection and cancer. Current measures of immune suppression are crude (clinical events) or indirect (drug exposure). We assessed a direct measure of immune status, leukocyte phenotype and function (LPF, a composite measure of five aspects of peripheral blood leukocyte phenotype and function), as a predictor of infection. METHODS: A double-blind, prospective, cohort study was conducted, to determine the burden of infection in stable renal transplant recipients with moderate-severe (Group I, n = 34) or minimal (Group II, n = 36) impairment of LPF, a composite score of: (i) CD4 count; (ii) lymphocyte proliferation in response to phytohaemagglutinin A (PHA); (iii) serum Ig concentrations; (iv) neutrophil phagocytic function; and (v) reactive oxygen species generation. Subjects completed a 6 month diary and each recorded infection was scored 1-4: 1, minor undefined infection (e.g. URTI); 2, minor, microbiologically defined infection (e.g. UTI); 3, major defined infection (requiring hospitalization); 4, opportunistic infection (e.g. Herpes zoster). Final infection score was the sum of all infective episodes. Subjects were then followed-up for 5 years for outcome measures. RESULTS: Groups were well matched for age, sex, diabetes, serum creatinine, rejection and trough cyclosporin concentrations. Group I (moderate to severe impairment of LPF) recorded a higher infection score, 2.4+/-2.8 vs 1.2+/-1.2 for Group II, P = 0.02, due to a higher incidence of moderate to severe infection. This relationship was confirmed by multivariate analysis (OR 1.83, CI 1.08, 3.11, P = 0.03 per unit increase in infection score). During the 5 year follow-up period they had significantly more episodes of admission to hospital, and twice as many admissions due to infections, but no difference in malignancy, graft or patient outcome. CONCLUSION: LPF testing prospectively identified a cohort who incurred a higher burden of infection. Further studies are required to determine the predictive value of LPF for acute rejection, infection and cancer, and to determine whether adjustments to therapy on the basis of LPF can lead to improved outcomes.     

Pretransplantation systolic blood pressure and the risk of delayed graft function in young living-related renal allograft recipients

Delayed graft function (DGF) is associated with decreased long-term renal allograft survival, however, the entire mechanism of action of DGF has not yet been established. The goal of this study was to determine possible risk factors for DGF in young living-related renal allograft recipients. We retrospectively analyzed the outcome of 142 renal transplant recipients (115 men and 27 women; mean age, 29.7 +/- 9.43 years; 114 living-related donors and 28 cadaveric donors). Data recorded for each patient and donor included gender, age at transplantation, duration of pretransplantation dialysis (recipients only), body mass index, number of human leucocyte antigen mismatches, panel-reactive antibodies, donor creatinine clearance, body weight, systolic and diastolic blood pressure levels, lipid profile, and biochemical parameters. Having obtained the transplant from a cadaveric donor (P<.000, odds ratio [OR]=17.556, confidence interval [CI]=5.961-51.743) and a pretransplantation systolic blood pressure level in the recipient of <120 mm Hg (P<.021, OR=3.600, CI=1.214-10.672) were possible risk factors for DGF. When only living-related recipients were considered, the systolic blood pressure level was significantly associated with DGF. We concluded that a pretransplantation systolic blood pressure level <120 mm Hg is a risk factor for DGF and that preoperative blood pressure control and intervention may help to decrease the risk of DGF.     

Effect of cyclosporine A on long-term allograft function in pediatric renal transplant recipients

There have been concerns regarding long-term adverse effects of cyclosporine A (CSA) on renal allograft function. In a retrospective study, we compared long-term allograft function up to 70 months after renal transplantation in pediatric recipients treated with and without CSA, using iothalamate clearance to assess glomerular filtration rate. Patients received CSA, prednisone, and azathioprine (CSA group,n=16) or prednisone and azathioprine alone (Pred/AZA,n=11). At 48 months post transplant, the iothalamate clearances (mean±SD) were 57.9±26.8 ml/min per 1.73 m² in the CSA group and 68.5±20.2 in the Pred/AZA group (P>0.05). The mean of the slopes of individual iothalamate clearances versus time during the first 70 months following transplantation were –0.156 in the CSA group and –0.095 in the Pred/AZA group. Neither slope was statistically different from zero. These data suggest that allograft function is not significantly depressed by CSA at 48 months post transplantation and that there is no greater rate of decline in allograft function up to 70 months post transplantation in patients receiving CSA when compared with the AZA/Pred group.     

Impact of donor/recipient body weight mismatch on allograft outcome in renal transplant recipients

BACKGROUND: There have been conflicting reports that kidneys from small donors may be at risk for graft loss if they are transplanted into large recipients. The aim of this work was to examine the impact of donor/recipient body weight ratio (D/RBWR) on allograft outcome. PATIENTS AND METHODS: Two hundred and seventeen kidney transplant recipients from living unrelated donor with 5-year follow-up underwent immunosuppression with cyclosporine, mycophenolate mofetil (or azathioprine), and prednisolone. According to the D/RBWR, the patients were divided into 3 groups: low (less than 0.8; G1), medium (0.81-1.1; G2), and high (more than 1.1; G3). We recorded 1-, 3-, and 5-year graft survivals, episodes of acute rejection, and mean serum creatinine values. RESULTS: Among the patients, 126 (58%) were female and the overall mean age was 41.62 years. There were no significant differences in 1-, 3-, and 5-year allograft survivals between the groups. CONCLUSION: We concluded that low D/RBWR had no effect on short- or long-term renal allograft survival.