Relevance of chronic kidney disease classification (K/DOQI) in renal transplant patients.

The National Kidney Foundation has developed guidelines for diagnosis and classification of chronic kidney disease (CKD) but it is not known whether they are applicable to renal transplant patients. This study analyzed the prevalence, the complications, and the influence of the CKD stage on the presence of complications in 506 stable transplant recipients. The mean age of the patients was 52.9 +/- 12 years, 34% were men, and the mean time after transplantation was 9.56 +/- 6.18 years. CKD was present in 90.3% with 9.9% were in CKD stages 4 or 5 with glomerular filtration rates lower than 30 mL/min per 1.73 m(2). The prevalence of anemia, phospho-calcium metabolism disorders, hypertriglyceridemia, and hypertension increased with the stage of CKD. We concluded that CKD and the complications of CKD were highly prevalent in renal transplant recipients. The classification of renal transplant patients by CKD stage may help clinicians to identify patients at increased risk and to target appropriate therapy to improve outcomes.

Conversion to everolimus in kidney transplant recipients: a safe and simple procedure.

To date there is a substantial experience with rapamycin conversion in stable renal transplant recipients with respect to the procedure of conversion, initial doses, and target blood levels as well as adverse events, but in the case of Everolimus there is almost no experience with conversion and calcineurin inhibitor (CNI) withdrawal. We describe an initial experience among 32 renal transplant recipients who were converted to Everolimus with complete suspension of CNI in two Spanish transplant centers. Our results emphasised the procedure for conversion, the target levels, the adverse events, and the initial efficacy, over the first month after conversion. Our conclusions were that conversion from CNI to Everolimus was a simple, safe procedure with a predictable profile of adverse events, which were, in general, of mild intensity. There was a good correlation between initial dose and blood level. Initial doses of about 3 mg/d combined with rapid reduction in CNI exposure seemed to be adequate. The target range levels between 5 and 10 ng/mL seemed to be sufficient for complete CNI elimination, especially in patients also receiving antiproliferative drugs (such as mycophenolate mofetil or azathioprine) in whom levels near the lower end of the range might be adequate.

Prevalence of anemia in renal transplant patients: results from MOST, an observational trial.

INTRODUCTION: Anemia is one of the most common complications of chronic renal disease. However, the incidence or prevalence of anemia in kidney transplant recipients has not been well studied. The aim of this study was to assess the prevalence of anemia in renal transplant in early and late posttransplant period and the influence of drugs (immunosuppressive and antihypertensive). METHODS: MOST is an observational, prospective trial of renal transplant receiving cyclosporine-based immunosuppressive regimen under condition of normal practice in de novo or maintenance recipients. We analyzed the Spanish data from 397 de novo recipients and 2102 maintenance recipients. RESULTS: In maintenance recipients mean hemoglobin levels were 12.8 +/- 1.6 g/dL (13.2 +/- 1.7 in men and 12 +/- 1.4 in women); 22.73% of men and 20.19% of women were found to be anemic. There was a significant correlation between hemoglobin and graft function (r = .14, P < .0001). The percentage of patients with anemia increased with the severity of chronic renal disease according to the KDOQI classification. Therapy with mycophenolate mofetil was also associated with a higher likehood of anemia as compared with other immunosuppressive therapies (azathioprine or sirolimus). There were no differences with angiotensin-converting enzyme inhibitors or ARB II. In de novo patients postransplant anemia was a frequent complication during the first 3 to 6 months. In patients with delayed graft function the recovery of anemia was slower. CONCLUSION: The prevalence of anemia in transplant recipients was remarkably high, especially in the early postransplant period, and appeared associated with impaired renal function and with immunosuppressive treatment.

Markers of fibrosis in early biopsies of renal transplants.

Many factors are involved in the development of chronic allograft nephropathy (CAN). Extracellular matrix turnover depends on the balance between fibrogenic and antifibrogenic cytokines. The aim of our study was to analyze the presence of transforming growth factor beta-1 (TGF-beta1), matrix metalloproteinase-2 (MMP-2), and mast cells in 53 early transplant biopsies using immunochemistry with specific monoclonal antibodies. We divided the patients into two groups depending on graft evolution (lost due to CAN versus functioning), renal function, presence of proteinuria, and graft survival. There were no differences in the demographic or immunological data. Renal function was worse and proteinuria greater among the group with CAN. The presence of mast cells was similar in both groups, but TGF-beta1 was expressed more and MMP-2 less in the CAN group. We observed a negative correlation between donor age and mast cells, and a positive correlation between TGF-beta1 and MMP-2. Grafts from younger donors showed better renal function, less proteinuria, greater graft survival, and less frequent development of CAN. According to our experience, cytokines involved in matrix turnover are expressed in early stages, correlating with donor age. The expressions of TGF-beta1 and MMP-2 seem to be important for the development of fibrosis in CAN.

Impact of HLA antibodies on transplant glomerulopathy.

The influence of humoral rejection on the development of chronic allograft nephropathy (CAN) is controversial, especially in relation to transplant glomerulopathy. The aim of our study was to analyse the influence of anti-HLA antibodies on the development of transplant glomerulopathy (cg0, cg1, cg2, and cg3; Banff'97). We selected all renal transplants patients from 1975 to 2003 who had a functioning graft for at least 6 months and a clinically indicated graft biopsy with CAN and chronic glomerular changes (case group). We studied the presence of anti-HLA antibodies (Ab) in the last serum taken while the graft was functioning and divided them into three groups according to the severity of glomerular lesions. We also selected 52 contemporary and comparable cases without transplant glomerulopathy (control group). A total of 77 case had transplant glomerulopathy: 39 cg1, 29 cg2, and 9 cg3. Pretransplant Ab titers and number of previous blood transfusions were higher among the subgroup with the most severe glomerulopathy. Patients who developed posttransplant anti-HLA Ab more frequently showed transplant glomerulopathy. Serum creatinine and proteinuria were higher among cases with chronic glomerulopathy, and more grafts were lost in that group. Thus, the presence of HLA-Ab is a key factor in the development of transplant glomerulopathy and chronic allograft rejection.

Higher initial tacrolimus blood levels and concentration-dose ratios in kidney transplant recipients who develop diabetes mellitus.

Posttransplantation diabetes mellitus (PTDM) is a common complication of kidney transplantation, associated with poorer graft and patient outcomes. Tacrolimus is a strong immunosuppressive drug associated with low acute rejection rates, but a higher risk for PTDM. High trough levels of tacrolimus during the first month after transplantation have been found to be a significant risk factor for the development of PTDM. The aim of this single-center study was to identify the risk factors for the development of PTDM among kidney transplant recipients under tacrolimus therapy. We examined 73 cadaveric kidney transplant recipients receiving tacrolimus between 1994 and 2003. Age, donor and recipient gender, dialysis method, body mass index (BMI), first year weight gain, mismatches, incidence of acute rejection and delayed graft function, hepatitis C serology, first year cumulative steroid dose, first tacrolimus blood level, first tacrolimus blood level <15 ng/mL, and corresponding tacrolimus daily doses and concentration/dose ratios (CDR) were also collected. PTDM was defined as at least 2 fasting blood glucose values > or =126 mg/dL, according to the World Health Organization criteria. Incidence of first year PTDM was 27.4%. Patients with PTDM showed significantly higher age, BMI, first tacrolimus blood level, first tacrolimus CDR, and CDR with tacrolimus blood level <15 ng/mL as well as less 1-year weight gain. After logistic regression, age (relative risk [RR] 1.060, confidence interval [CI] 95%, 1.001-1.122; P = .043) and first tacrolimus blood level (RR 1.154; CI 95%, 1.038-1.283; P = .008) remain significant risk factors for developing PTDM. Older age and initial tacrolimus blood levels were the main risk factors for PTDM among our group of patients. Kidney transplant recipients who develop PTDM maintain a high CDR of tacrolimus.

High initial blood levels of tacrolimus in overweight renal transplant recipients.

For the purpose of both efficacy and safety, exposure to tacrolimus and other immunosuppressive drugs must be monitored, since initial levels influence the development of acute rejection episodes, nephrotoxicity, and posttransplantation diabetes mellitus. The aim of this study was to identify risk factors for developing high initial tacrolimus blood levels. We analyzed clinical and biochemical parameters of 85 renal transplant recipients receiving tacrolimus-based immunosuppressive therapy by stratifying into subgroups of patients who displayed first tacrolimus concentrations higher and lower than 15 ng/mL. Patients with a first level of tacrolimus higher than 15 ng/mL were older (52 +/- 13 vs 40 +/- 12 years, P < .05) and had a larger body mass index (27 +/- 4 vs 23 +/- 3 kg/m2, P < .05) than patients with lower levels, despite receiving a lower weight-adjusted cumulative steroid dose (8.2 +/- 2.2 vs 9.3 +/- 2.5 mg/kg, P < .05). Upon logistic regression, age (RR 1.047, 95% CI 1.007 to 1.08, P = .021) and body mass index (RR 1.176, 95% CI 1.009 to 1.371, P = .036) remained significant risk factors for high initial blood levels of tacrolimus. As these subgroups of patients are most prone to develop posttransplantation glycemic disorders, attention must be paid to avoid high tacrolimus blood levels by diminishing initial tacrolimus doses or estimating them from ideal body weight.

Differences in anti-CREG antibody formation between transplanted and nontransplanted renal patients.

BACKGROUND: The aim of this study was investigation of the HLA-I cross-reactive group (CREG)-specific antibodies (Abs) in sera from patients with a failed renal transplant and from nontransplanted patients. METHODS: A total of 5292 sera from 570 patients awaiting kidney transplantation were screened for the presence of HLA-I CREG-specific Abs. Patients who had never received a transplant (group A), and those with a previous transplant and Abs either not related (group B) or related to donor specificities (group C) were studied. A further division was made for Abs directed against specificities either included in (intra-CREG) or not included in patients' HLA-CREG (extra-CREG). RESULTS: Twelve of 24 (50%) Abs produced in response to mismatched donor HLA specificities after a failed graft were intra-CREG Abs, compared to 7 of 39 (18%) Abs that were not transplant-related. CONCLUSIONS: Renal grafts showed a stronger immunogenicity than other sources of allosensitization. Our data also suggest that CREG matching may not be useful for renal allocation.

Circulating adhesion molecules during kidney allograft rejection.

Adhesion molecules appear on leukocytes and endothelial cells mediating the localization and migration of leukocytes to sites of inflammation. Rejecting kidney grafts have shown an increased expression of these molecules. Recent reports have detected in serum soluble forms of adhesion molecules that could play a role in regulating inflammation. We have measured by ELISA the circulating serum levels of ICAM-1, VCAM-1 and E-selectin in: 23 controls, 33 chronic renal failure patients (CRF), 20 hemodialysis patients (HD), 17 samples from 6 patients with stable kidney graft function (STx), 25 samples from 8 patients with steroid-responsive rejection proven by biopsy, and 28 samples from 9 patients with steroid-resistant rejection and good response to OKT3. There was not a rise in cICAM-1 or cE-selectin levels during rejection compared with the steady phase before and after rejection. In the case of cVCAM-1, only the OKT3 group showed increased rejection levels (P < 0.05) that were maintained after rejection. For ICAM-1, CRF and HD groups had higher levels than the remaining groups. cVCAM-1 levels were elevated in all groups when compared with control, furthermore, OKT3 and HD groups had higher levels than the STx, CRF, or steroid-responsive groups. For cE-selectin, we only found differences between the CRF and both rejection groups. Serum creatinine correlated significantly with c-ICAM-1 and cVCAM-1 R = 0.30 and R = 0.22), but not with cE-selectin. We conclude that soluble adhesion molecules levels are not valuable markers for rejection. Patients with chronic renal failure have increased levels of adhesion molecules, which could reflect an impaired elimination.

Glioblastoma multiforme of donor origin after renal transplantation: report of a case.

A case of transmission of a glioblastoma multiforme from the donor to a kidney transplant recipient in the absence of previous ventriculosystemic shunt is described. The recipient was a 48-year-old woman who developed a fever with no other associated symptoms 17 months posttransplant. Physical examination revealed a large nonpulsatile mass on the upper graft pole. Histopathologic examination showed a highly cellular neoplasm with fusiform and globoid cells, a high grade of nuclear pleomorphism and mitosis, necrosis with pseudopalisading, and vascular proliferation. Immunohistochemistry of the cells showed them to contain glial fibrillary acidic and S-100 proteins, consistent with a glioblastoma multiforme. We conclude that the risk of tumor transmission from donors with primary central nervous system tumors to kidney transplant recipients, is real and should be considered when evaluating a graft mass in such patients.

Pulsatile-secretion of parathyroid hormone in patients with chronic renal failure.

Peripheral blood concentration of intact PTH is a simple assay very useful in the diagnosis and evolutive control of secondary hyperparathyroidism in patients with chronic renal failure. Episodic secretion of PTH in CRF patients would affect interpretation of single random determinations. To evaluate the secretory pattern of intact PTH we sampled peripheral blood at 6-min intervals for 60 to 90 min from seven normal subjects (group I) and seven patients with chronic renal failure (group II: 4 with normal parathyroid function and 3 with hyperparathyroidism). The resultant time series of serum intact PTH and ionized calcium were assessed by computerized cluster data analysis program. Evaluation of episodic intact PTH pulsatile nature revealed that in group I, 3 out of 7 normal subjects presented 1 maximum and 6 subjects presented at least one minimum. In group II, 3 out of 4 CRF patients with normal parathyroid function presented at least 1 maximum and all four patients at least one minimum. One out of 3 CRF patients with hyperparathyroidism presented 2 maximum and all three at least one minimum. Despite pulsatile character intact PTH levels were maintained all the time within the normal range in control group and in CRF patients with normal parathyroid function. In CRF patients with hyperparathyroidism intact PTH changes were restricted within a level of hyperparathyroidism. Ionized calcium levels in control group remained virtually constant along the period and in CRF group fluctuated widely. Parathyroid hormone is secreted in a pulsatile fashion in normal subjects and in patients with chronic renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

The macrophage infiltration index and matrix metalloproteinase-II expression as a predictor of chronic allograft rejection.

The presence of macrophages on renal biopsy specimens is considered an important cofactor in the development of chronic allograft nephropathy (CAN). Macrophages can activate the expression of matrix metalloproteinases (MMP), which induce glomerulosclerosis, arteriosclerosis, and interstitial fibrosis. The aim of our study was to demonstrate if they were related to the development of CAN. We analyzed matrix metalloproteinase (MMP) expression with specific monoclonal antibodies on 53 kidney biopsies performed due to the suspicion of a first acute rejection (AR) episode: 24 of the grafts have been lost due to CAN and the rest are still functioning. The group with CAN showed worse graft function and greater proteinuria from the beginning. The macrophage infiltration index (MI) expression was significantly higher in that group also (18.8 +/- 12 vs 12.5 +/- 9.15; P < .05), with a more important presence of macrophages in the interstitium and tubules. We observed a positive correlation between MI and tubular infiltration (r(2) = 0.52; P < .001) and between MMP-II and MI in the interstitium (r(2) = 0.3; P < .05) and with the global MI (r(2) = 0.3; P < 0.05). The last correlation was more powerful in the group with CAN (r(2) = 0.4; P < .05). According to our experience, global MI and tubular infiltration during an AR episode are good markers of long-term graft survival. The correlation between MI and MMP-II supports the role of macrophages in the development of CAN, although further studies are needed to clarify the nature of this relationship.

Effect of early graft function on patient survival in renal transplantation.

The influence of early graft function on long-term graft survival has been widely reported but its association with patient survival has received less attention. We investigated the effect of early renal function on patient survival and on cardiovascular disease after renal transplantation among 532 transplant patients who had grafts functioning for >1 year. Patients were classified into two groups, depending on the early creatinine clearance (< or >60 mL/min). We analyzed graft and patient survival, posttransplant cardiovascular disease, and the principal causes of death. Five- and 10-year graft and patient survival were lower among the group with worse early renal function. The main cause of death was vascular disease. Poorer early renal function increased the risk (RR) of patient death by 2.2-fold, and also the presence of posttransplant cardiovascular disease. In conclusion, patients with poor levels of early graft function are at an increased risk of death. These high-risk groups should be targeted for interventional studies to improve patient survival.

Assessment of glomerular filtration rate in transplant recipients with severe renal insufficiency by Nankivell, Modification of Diet in Renal Disease (MDRD), and Cockroft-Gault equations.

Measurement of glomerular filtration rate (GFR) is time consuming and cumbersome. Several formulas have been developed to predict creatinine clearance (CrCl) or GFR using serum creatinine (Cr) concentrations and demographic characteristics. However, few studies have been performed to discern the best formula to estimate GFR in kidney transplantation. In this study, Cockroft-Gault (CG), Nankivell, and Levey (MDRD) formulas were tested to predict GFR in 125 cadaveric renal transplant patients with severe renal insufficiency (GFR less than 30 mL/min per 1.73 m2). The GFR was estimated as the average Cr and urea clearances. The mean GFR estimated by averaged Cr and urea clearances (22.18+/-5.23 mL/min per 1.73 m2) was significantly different from the mean values yielded by the MDRD formula (20.42+/-6.65 mL/min per 1.73 m2, P=.000), the Nankivell formula (30.14+/-11.98 mL/min per 1.73 m2, P=.000), and the CG formula (29.42+/-8.64 mL/min per 1.73 m2, P=.000). The MDRD formula showed a better correlation (R=0.741, P=.000) than the CG (R=0.698, P=.000) and the Nankivell formulas (R=0.685, P=.000). Analysis of differences using the Bland-Altmann method demonstrated that MDRD gave the lowest bias (MDRD: -1.65+/-4.4 mL/min per 1.73 m2; CG: 7.33+/-6.24 mL/min per 1.73 m2; Nankivell: 8.05+/-9.23 mL/min per 1.73 m2) and narrower limits of agreement (Nankivell: -10.41-26.51 mL/min per 1.73 m2; CG: -5.15-19.81 mL/min per 1.73 m2; MDRD: -10.61-7.31 mL/min per 1.73 m2). In transplant patients with severe renal insufficiency, the MDRD equation seems better than the other formulas to estimate GFR.

Pulse pressure is an independent risk factor of cardiovascular disease in renal transplant patients.

Elevated pulse pressure in the general population has been shown to be associated with cardiovascular disease, which is the main cause of death in renal transplant patients. We investigated the effects that a wide pulse pressure has on cardiovascular disease after renal transplantation in a cohort of 532 transplant patients with functioning grafts for more than one year. Patients were classified into two groups depending on whether the one-year pulse pressure was less than or greater than 65 mm Hg. We analyzed patient survival, posttransplant cardiovascular disease and principle causes of death. Five- and ten-year patient survival were lower among the group with higher pulse pressures. The main cause of death was vascular disease in both groups. The presence of posttransplant cardiovascular disease was higher among the group with higher pulse pressures (RR=1.73). In addition, the incidence of an elevated pulse pressure was directly associated with recipient age and posttransplant diabetes mellitus. In conclusion, pulse pressure represents an independent risk factor for increased cardiovascular morbidity and mortality in renal transplant patients.

Minoxidil in severe and moderately severe hypertension, in association with methyldopa and chlortalidone.

Minoxidil is a potent antihypertensive drug widely used in severe arterial hypertension and in that refractory to treatment. Its effectiveness in less severe forms of hypertension was evaluated in 15 patients who had either a severe to moderate arterial hypertension not previously treated, or who did not tolerate the side effects of other antihypertensive drugs. The usefulness of methyldopa and chlortalidone to prevent a potential minoxidil-induced tachycardia and fluid retention, respectively, was also tested. The patients were initially treated with chlortalidone 100 mg/day, and methyldopa 500 mg/day. Minoxidil was then given in increasing doses until the diastolic blood pressure was equal to or inferior to 90 mmHg. This occurred consistently at doses which ranged from 5 to 50 mg/day (average, 29 mg). Treatment with minoxidil was continued for four months; tolerance to the drugs was not observed. Low doses of methyldopa and chlortalidone were effective in controlling the tachycardia and the retention of sodium and water induced by minoxidil. The three associated drugs were well tolerated and the life quality improved in most patients. Hypertrichosis was the most consistent side effect. Two patients were withdrawn from the study after the blood pressure was controlled by minoxidil, because of the appearance of angor in one, and edema and heart failure in the other.

Influence of dialysis membranes on the convective transport of middle molecules.

Ultrafiltrates from 10 patients in chronic maintenance hemodialysis (7 males and 3 females) were obtained simultaneously using three different membranes: cuprophan, polyacrilonitrile and polysulfone. Middle molecules (MM) chromatographic profiles and total MM amount were determined by gel chromatography and high performance liquid chromatography. The convective transport of MM was similar and not membrane related. Hemofiltration, a predominantly convective solute transfer procedure using high flux membranes such as polyacrilonitrile and polysulfone, in which large amounts of fluids have to be ultrafiltered, is an effective form of MM removal.

[Effect of recipient age on the clinical course of renal transplantation]. / Influencia de la edad de receptor en la evolución del trasplante renal.

Since the immune response in older recipients has been described as weaker they may have a lower risk of rejection of a transplanted organ. Therefore a less aggressive immunosuppressive regimen should be the best option. The aim of our study was to evaluate the incidence and severity of acute rejection (AR) episodes on graft survival of older patients (> or = 60 years) and to compare them with the younger ones (< 60 years). A total of 439 kidney transplants were performed between 1/94 and 12/99 at our Transplant Unit. Clinical and immunological data, incidence and severity of AR and cause of graft loss were recorded. Patients were divided into two groups, according to age at transplantation [A (< 60, n = 342/77.9%) and B (> or = 60, n = 97/22.1%)]. The percentage of aging recipients and mean age of both donors and recipients increased through the period of study. Although the incidence of acute tubular necrosis was higher in the older group (31% vs 22.8%, pNS), the incidence of AR was also similar (31.6% vs 29.8%, pNS). The number of AR episodes per patient was 0.44 and 0.41 respectively. The incidence of AR was higher in those patients who had ATN (50% vs 19.6%), p < 0.01). The severity of AR was: Banff grade I: A (40.3%)/B (45.7%) pNS; grade II: A (44.1%)/B (48.5%) pNS; grade III: A (15.6%)/B (5.8%) pNS. One-year patient survival was 96%/91% (p < 0.001) and graft survival was 81%/78% (pNS) respectively. The age of recipient does not seem to have a significant influence on the incidence and severity of AR or on graft survival. So immunosuppression should be individualized for each patient.