Intrarenal resistive index after renal transplantation.

BACKGROUND: The intrarenal resistive index is routinely measured in many renal-transplantation centers for assessment of renal-allograft status, although the value of the resistive index remains unclear. METHODS: In a single-center, prospective study involving 321 renal-allograft recipients, we measured the resistive index at baseline, at the time of protocol-specified renal-allograft biopsies (3, 12, and 24 months after transplantation), and at the time of biopsies performed because of graft dysfunction. A total of 1124 renal-allograft resistive-index measurements were included in the analysis. All patients were followed for at least 4.5 years after transplantation. RESULTS: Allograft recipients with a resistive index of at least 0.80 had higher mortality than those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 5.20 [95% confidence interval {CI}, 2.14 to 12.64; P<0.001]; 3.46 [95% CI, 1.39 to 8.56; P=0.007]; and 4.12 [95% CI, 1.26 to 13.45; P=0.02], respectively). The need for dialysis did not differ significantly between patients with a resistive index of at least 0.80 and those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 1.95 [95% CI, 0.39 to 9.82; P=0.42]; 0.44 [95% CI, 0.05 to 3.72; P=0.45]; and 1.34 [95% CI, 0.20 to 8.82; P=0.76], respectively). At protocol-specified biopsy time points, the resistive index was not associated with renal-allograft histologic features. Older recipient age was the strongest determinant of a higher resistive index (P<0.001). At the time of biopsies performed because of graft dysfunction, antibody-mediated rejection or acute tubular necrosis, as compared with normal biopsy results, was associated with a higher resistive index (0.87 ± 0.12 vs. 0.78 ± 0.14 [P=0.05], and 0.86 ± 0.09 vs. 0.78 ± 0.14 [P=0.007], respectively). CONCLUSIONS: The resistive index, routinely measured at predefined time points after transplantation, reflects characteristics of the recipient but not those of the graft. (ClinicalTrials.gov number, NCT01879124 .).

[Evaluation of the interdependence between homocystein and folic acid levels in patients after kidney transplantation during a 2 year observation period]. / Ocena zaleznosci homocysteinemii i kwasu foliowego u chorych po przeszczepieniu nerki w róznych okresach od momentu wykonania zabiegu w trakcie dwuletniej obserwacji.

UNLABELLED: Patients on maintenance dialysis have increased heomocystein (Hcy) serum levels. The aim of the study was to evaluate the interdependence between Hcy and folic acid (FA) levels in renal transplant patients (pts) at various time periods during a two year observation period after kidney transplantation (Ktx). PATIENTS AND METHODS: The study included 51 pts (17 F, 34 M) aged 15-62 years (median 38.1) after deceased donors Ktx. Before Ktx, 46 pts were treated with maintenance hemodialysis (HD), while 5 by peritoneal dialysis (PD). The mean observation period equaled 21.2 months (6-24 months); while total observation period was 90 person/years. Hcy level was measured using high performance liquid chromatography (HPLC). FA level was measured using chemiluminesence method (standard methods) using the Immulite 2000 analyzer. Patients blood was drawn before Ktx and 3, 6, 9, 12, 15, 18, 21 and 24 months after procedure. RESULTS: An increased Hcy level (>15 micromol/l) - mean 28.5 +/- 17.8 micromol/l (range from 10.2 micromol/l to 116.8 micromol/I) was noted in the blood of 44 pts before Ktx (86.3% of the examined population). In 31 pts after Ktx (60.8% of the examined population), mean Hcy level remained increased above 15 micromol/I (mean Hcy - 19.2 +/- 5.8 micromol/I). A negative correlation was found between the levels of Hcy and FA directly before Ktx (R= -0.28, p<0.05). A statistically significant drop of FA level of 72.6% (mean 220.5 +/- 395.1 ng/ml to 60.3 +/- 129.8 ng/ mi) was noted 3 months after Ktx in the examined group (p<0.001 in the Wilcoxon test). However, in the following period time after Ktx, FA levels did not differ statistically (ANOVA Friedmana p=NS). Mean concentrations of Hcy after Ktx did not correlate significantly with levels of FA (R = -0.12, p = NS). No significant differences between mean levels of FA after Ktx in pts with normal and increased mean levels of Hcy were found; but one must note that presence of hiperhomocysteinemia (HHcy) was associated with a 42% lower concentration of FA in relation to patients who had Hcy >15 micromol/l (36.4 ng/ml vs. 62.5 ng/ml). CONCLUSIONS: Statistically significant decrease of Hcy concentration was observed after Ktx as compare with values before procedure, however not reached normal values. Significant decrease of FA concentration after Ktx is most likely associated with the discontinuation of FA supplementation, as well as due to the restoration of the erythropoietic line.

Extrarenal factors influencing resistance index in stable kidney transplant recipients.

BACKGROUND: Increased intrarenal resistance index (RI) has been associated with decreased long-term allograft and patient survival in kidney transplant recipients. Taking into account the potential role of endothelial dysfunction, systemic inflammation, arteriosclerotic lesions, and left ventricle remodeling, we performed a cross-sectional study that aimed to evaluate extrarenal factors that may have influence on kidney graft RI in a large cohort of stable kidney transplant recipients. METHODS: One hundred seventy-four kidney transplant recipients were enrolled into the study. Mean time after transplantation was 8.4±1.8 years. Echocardiography, carotid ultrasound (intima-media thickness), pulse wave velocity, and Doppler examination of kidney graft were performed. The inflammatory markers, adhesion molecules, and plasma N-terminal prohormone of brain natriuretic peptide concentrations were also measured. Patients were divided into quartile subgroups based on RI value (Q1: RI≤0.68, Q2: RI=0.69-0.72, Q3: RI=0.73-0.76, and Q4: RI≥0.77). RESULTS: The analyzed subgroups were comparable with respect to demographics (except age) and anthropometric parameters as well as comorbidities. The values of age, serum phosphate, pulse wave velocity, left ventricular mass (LVM), and LVM index (LVMI) increased in subsequent RI quartile subgroups. The strongest correlation was found between RI and age, LVM, LVMI, and plasma parathormone concentration and was negative with estimated glomerular filtration rate. In backward stepwise multivariate regression analysis, the RI variability was explained by age, LVMI, and serum phosphate concentration. CONCLUSION: Arterial stiffness and left ventricular hypertrophy may significantly influence the intrarenal vascular resistance measured using Doppler sonography in stable kidney transplant recipients.

Detection and mechanism of action of ESM-1 in rat kidney transplantation under various immune states.

OBJECTIVE: To investigate whether ESM-1 expression change reflects the impairment of endothelial cells and rejection after kidney transplantation, ESM-1 expression was detected under various immune states in this study. METHODS: Kidney transplantations were performed from BN to LEW rats. Syngenic LEW-LEW grafts were used as controls. The LEW recipient rats were divided into acute rejection (AR) group, ciclosporin A (CsA) group and control group. In each group, 10 rats were sacrificed at 1, 5, and 7d after operation, respectively, and blood and kidney samples were collected. In the rat model of kidney transplantation, ESM-1 mRNA and ESM-1 protein expression were detected in various immune states to verify if ESM-1 can reflect endothelial cell impairment sensitively. RESULTS: ESM-1 mRNA (1d vs. 3d, P<0.01;3d vs. 7d, P=0.018) and ESM-1 protein expression was upregulated significantly in the AR group (P<0.01, 5 and 7d), when compared to CsA group and control group. In CsA group, the cell apoptosis rate decreased when compared to AR group (P<0.01). Pathological impairment was more serious in AR group than in CsA group (P<0.01). CONCLUSIONS: Peripheral blood ESM-1 mRNA and ESM-1 protein expression in kidney grafts can reflect the severity of endothelial cell impairment. Thus, ESM-1 may be used as a new indicator for AR prediction and diagnosis. Nevertheless, further investigation is required to test if it meets the criteria for clinical utility.

Impact of early graft function on 10-year graft survival in recipients of kidneys from standard- or expanded-criteria donors.

BACKGROUND: The use of kidneys from expanded-criteria donors (ECD) is regarded with caution. METHODS: We compared 279 kidney transplant recipients (KTxR) from standard-criteria donors (SCD) and 237 from ECD, transplanted between January 1990 and December 2006. We evaluated the impact of immediate graft function (IGF), slow graft function (SGF), and delayed graft function (DGF) and the drop in estimated glomerular filtration rate (ΔeGFR) ≤ 30% or > 30% during the first year after transplantation on long-term patient and death-censored graft survival (DCGS). RESULTS: Ten-year patient survival was similar in SCD- or ECD-KTxR (P = 0.38). DCGS was better in SCD-KTxR versus ECD-KTxR (77.3% vs. 67.3%; P = 0.01). DCGS did not differ in either group experiencing IGF (P = 0.17) or DGF (P = 0.12). However, DCGS was worse in ECD-KTxR experiencing SGF (84.9% vs. 73.7%; P = 0.04). Predictors of DCGS were 1-year serum creatinine (hazard ratio, 1.03; P < 0.0001) and ΔeGFR > 30% between 1 and 12 months (Δ1-12eGFR) after transplantation (hazard ratio, 2.2; P = 0.02). In ECD-KTxR with IGF and more than 1-year follow-up, 10-year DCGS was better in those with Δ1-12eGFR ≤ 30% versus those with Δ1-12eGFR > 30% (83.8% vs. 53.6%; P = 0.01). CONCLUSION: Recipients of SCD or ECD kidneys with IGF or DGF had similar 10-year patient survival and DCGS. SGF had a worse impact on DCGS in ECD-KTxR. In addition to 1-year serum creatinine, Δ1-12eGFR > 30% is a negative predictor of DCGS. Larger studies should confirm if increasing the use of ECD, avoiding factors that contribute to SGF or DGF, and/or a decline in eGFR during the first year after transplantation may expand the donor pool and result in acceptable long-term outcomes.

Urine but not serum soluble urokinase receptor (suPAR) may identify cases of recurrent FSGS in kidney transplant candidates.

BACKGROUND: Recently, serum soluble urokinase receptor (suPAR) has been proposed as a cause of two thirds of cases of focal segmental glomerulosclerosis (FSGS). It was noted to be uniquely elevated in cases of primary FSGS, with higher levels noted in cases that recurred after transplantation. It is also suggested as a possible target and marker of therapy. METHODS: We studied serum and urine suPAR from pretransplantation banked samples from 86 well-characterized kidney transplant recipients and 10 healthy controls to determine its prognostic utility. Causes of native kidney disease were primary FSGS, diabetic nephropathy, membranous nephropathy, immunoglobulin A nephropathy, and autosomal dominant polycystic kidney disease. suPAR was measured using a commercially available enzyme-linked immunosorbent assay kit. Urinary suPAR was indexed to creatinine. RESULTS: Both serum and urine suPAR correlated with proteinuria and albuminuria. Serum suPAR was found to be elevated in all transplant candidates with advanced renal disease compared with healthy controls and could not differentiate disease diagnosis. Urine suPAR was elevated in cases of recurrent FSGS compared with all other causes of end-stage renal disease. Recurrent FSGS cases had substantially higher proteinuria compared with all other cases. However, elevated urinary suPAR showed a trend in providing additional prognostic information beyond proteinuria in the small cohort of recurrent FSGS cases. CONCLUSION: In advanced renal disease, elevated serum suPAR is not unique to FSGS cases. Urinary suPAR appears to be higher in cases of FSGS destined for recurrence and merits further evaluation.

Noninvasive prognostication of polyomavirus BK virus-associated nephropathy.

BACKGROUND: BK virus-associated nephropathy (BKVN) is associated with an increased risk of graft failure. METHODS: Levels of mRNAs encoding proteins implicated in inflammation and fibrosis were measured in urine collected at the time of biopsy diagnosis of BKVN in 29 kidney graft recipients and analyzed for prognosticating graft failure using logistic regression. RESULTS: Ten of 29 BKVN patients had graft failure within 36 months of BKVN diagnosis and the remaining 19 patients did not. Serum creatinine level, BKVN biopsy stage, and urinary cell levels of mRNA for plasminogen activator inhibitor (PAI)-1, vimentin, tissue inhibitor of metalloproteinase-1, fibronectin, granzyme B, or perforin were associated with graft failure. A combination of PAI-1 mRNA level, BKVN biopsy stage, and creatinine level (P = 0.0015, by logistic regression) and a combination of PAI-1 mRNA and creatinine levels (P = 0.001) were the best-fitting models for prognosticating graft failure, and PAI-1 mRNA level was the only independent predictor (odds ratio, 2.8; 95% confidence interval [CI], 1.1-6.8; P = 0.03) by multivariable analysis. The area under the curve for the combination of PAI-1 mRNA, biopsy, and creatinine was 0.92 (95% CI, 0.80-1.0; P < 0.001) by receiver operating characteristic curve analysis, and the area under the curve was 0.92 (95% CI, 0.80-1.0; P < 0.001) for the combination of PAI-1 mRNA and creatinine. Graft outcome was correctly predicted in 27 of 29 BKVN patients by either model. CONCLUSION: Urinary cell level of PAI-1 mRNA, measured at the time of BKVN diagnosis, is an independent prognosticator of graft failure and a prediction model of serum creatinine and PAI-1 mRNA is as accurate as the model that includes the biopsy result.

Comparison of pharmacokinetics and pathology for low-dose tacrolimus once-daily and twice-daily in living kidney transplantation: prospective trial in once-daily versus twice-daily tacrolimus.

BACKGROUND: A prolonged-release formulation of tacrolimus (Tacrolimus QD) was developed to allow once-daily dosing and to have similar safety and efficacy profiles to twice-daily tacrolimus (Tacrolimus BID). This study compared the pharmacokinetics (PK) and renal pathology by protocol biopsy in de novo living kidney transplant recipients treated with either low-dose Tacrolimus QD or Tacrolimus BID. METHODS: Between November 2009 and January 2011, 102 consecutive adult patients were randomized to receive either low-dose Tacrolimus QD or Tacrolimus BID. All patients underwent PK study and protocol biopsy on postoperative day 14. Additional protocol biopsies were performed between 6 and 12 months after renal transplantation. RESULTS: During the 1-year follow up, the incidence of biopsy-proven acute rejection and toxic tubulopathy was low and similar in both groups. Twenty-four hours area under the curve (AUC0-24) was not different in both groups (285 ± 78.7 and 281 ± 62.4 ng hr/mL in Tacrolimus QD and Tacrolimus BID, respectively). C0 was well correlated with AUC0-24 in both groups and AUC0-24 between 260 and 280 in the Tacrolimus QD group was achieved by 6 to 8 ng/mL of C0. Acute nephrotoxicity was less than 10% in both groups without any clinical manifestation. CONCLUSION: Clinical efficacy, safety, and PK profile of Tacrolimus QD is same as those of Tacrolimus BID.

Effect of ciprofloxacin combined with sulfamethoxazole-trimethoprim prophylaxis on the incidence of urinary tract infections after kidney transplantation.

BACKGROUND: Urinary tract infections (UTIs) are common after kidney transplantation, with limited data to guide antibiotic prophylaxis. METHODS: Retrospective single-center study comparing sulfamethoxazole-trimethoprim 800/160 mg (SMZ/TMP) daily for 30 days followed by Monday, Wednesday, Friday for an additional 5 months (Group 1) versus SMZ/TMP Monday, Wednesday, Friday for 6 months plus ciprofloxacin 250 mg twice daily for 30 days (Group 2) on UTI incidence after kidney transplantation. RESULTS: There were 106 and 130 patients in Groups 1 and 2, respectively. Demographics and transplant characteristics were well matched, except for more patients in Group 2 on corticosteroid maintenance. At 1 year, more patients in Group 1 developed UTIs (23.6% vs. 10.8%; P=0.01) and the mean time to first UTI was shorter (96.6±79.5 vs. 168±89.7 days; P=0.01). UTIs caused by Enterococcus species were higher in Group 2 (28.6% vs. 4%; P=0.047) with enteric gram-negative bacilli accounting for the remaining infections. There was a similar incidence of enteric gram-negative antibiotic resistance to SMZ/TMP (75% vs. 80%; P=1.00) and ciprofloxacin (16.7% vs. 30%; P=0.39) in Groups 1 and 2. For Groups 1 and 2, the proportion of first UTIs requiring hospitalization was 48.9% vs. 40.6%, respectively (P=0.62). Female gender was a UTI risk factor (hazard ratio, 3.5; 95% confidence interval, 1.78-6.8; P=0.0003). CONCLUSIONS: The addition of a 30-day course of ciprofloxacin lowered the incidence of UTI; randomized prospective studies are needed to confirm the safety and efficacy of this approach.

Conversion from twice-daily tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): a phase 2 trial of stable renal transplant recipients.

BACKGROUND: LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Phase 1 studies demonstrated greater bioavailability to twice-daily tacrolimus capsules and no new safety concerns. METHODS: In this phase 2 study, adult stable kidney transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCP-Tacro) once-daily; patients continued on LCP-Tacro once-daily for days 8 to 21; trough levels were to be maintained between 5 and 15 ng/mL; 24-hr pharmacokinetic assessments were done on days 7 (baseline pre-switch), 14, and 21. RESULTS: Forty-seven patients completed LCP-Tacro dosing per protocol. The mean conversion ratio was 0.71. Pharmacokinetic data demonstrated consistent exposure (AUC) at the lower conversion dose. C(max) (P = 0.0001), C(max)/C(min) ratio (P < 0.001), percent fluctuation (P < 0.0001), and swing (P = 0.0004) were significantly lower and T(max) significantly (P < 0.001) longer for LCP-Tacro versus Prograf. AUC24 and C(min) correlation coefficients after 7 and 14 days of therapy were 0.86 or more, demonstrating a robust correlation between LCP-Tacro tacrolimus exposure and trough levels. There were three serious adverse events; none were related to study drug and all were resolved. CONCLUSIONS: Stable kidney transplant patients can be safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allows for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displays flatter kinetics characterized by significantly lower peak-trough fluctuations.