The Effect of Decongestion on Intrarenal Venous Flow Patterns in Patients With Acute Heart Failure.

BACKGROUND: Discontinuous intrarenal venous flow patterns, as assessed by renal Doppler ultrasound examination, are associated with changes in hemodynamics such as volume expansion and poorer diuretic response in patients with heart failure (HF). We aimed to study intrarenal venous and arterial flow patterns after decongestive treatment in patients with acute HF. METHODS AND RESULTS: Fifteen patients with acute HF were enrolled. Intrarenal venous and arterial flow patterns were assessed at baseline, 1 hour after administration of loop diuretics, at day 2 and day 3. Among patients hospitalized for acute HF, 13 (87%) had a discontinuous venous flow pattern at admission. After decongestive treatment, a significant improvement of the venous impedance index (P = .021) and venous discontinuity index (P = .004) was observed at day 3 compared with baseline. There was no effect on the intrarenal arterial flow patterns. CONCLUSIONS: In patients who exhibit discontinuous renal venous flow patterns hospitalized for decongestive treatment owing to acute HF led to a normalization of intrarenal venous flow to a continuous pattern.

A noninferiority trial comparing a heparin-grafted membrane plus citrate-containing dialysate versus regional citrate anticoagulation: results of the CiTED study.

Background: Anticoagulation is a prerequisite for successful haemodialysis. Heparin and low-molecular weight heparins are routinely used despite increased bleeding risk. Regional citrate anticoagulation (RCA) is efficacious, but is laborious and may induce metabolic disturbances. Heparin-grafted membranes are less efficacious. It is not known whether combining citrate-containing dialysate and a heparin-grafted membrane is a valid anticoagulation strategy. Methods: We performed a randomized crossover noninferiority trial, with a prespecified noninferiority threshold of 10% in maintenance dialysis patients ( n = 25). We compared the combination of citrate-containing dialysate plus a heparin-grafted membrane [CiTrate and EvoDial (CiTED) protocol] with RCA. The primary endpoint was completion of dialysis without significant clotting. Secondary endpoints included time to clotting, achieved Kt / V urea , loss of total cell volume, venous air chamber clotting score and systemic-ionized calcium concentration. Results: In total, 1284 sessions were performed according to study protocol, 636 in the CiTED arm and 648 in the RCA arm. The primary outcome of preterm interruption due to clotting occurred in 36 (5.7%) of sessions in the CiTED arm, and in 40 (6.2%) sessions in the RCA arm, thereby meeting noninferiority criteria (P < 0.0001). Most of the clotting events occurred in the fourth hour of dialysis. Repetitive clotting occurred in four patients in the CiTED arm and one patient in the RCA arm. Time to preterm interruption due to clotting and achieved Kt / V urea was not significantly different. Systemic-ionized calcium levels during treatment were significantly lower in the RCA arm and clinically relevant hypocalcaemia was noted only in the RCA arm. Conclusion: The combination of citrate-containing dialysate and a heparin-grafted membrane is a valid alternative to RCA.

Tubulointerstitial expression and urinary excretion of connective tissue growth factor 3 months after renal transplantation predict interstitial fibrosis and tubular atrophy at 5 years in a retrospective cohort analysis.

Connective tissue growth factor (CTGF) is an important mediator of renal allograft fibrosis, and urinary CTGF (CTGFu) levels correlate with the development of human allograft interstitial fibrosis. We evaluated the predictive value of CTGF protein expression in 160 kidney transplant recipients with paired protocol biopsies at 3 months and 5 years after transplantation. At month 3 and year 1, CTGFu was measured using ELISA, and biopsies were immunohistochemically stained for CTGF, with semiquantitative scoring of tubulointerstitial CTGF-positive area (CTGFti). Predictors of interstitial fibrosis and tubular atrophy (IF/TA) severity at 5 years were donor age [OR 1.05 (1.02-1.08), P = 0.001], female donor [OR 0.40 (0.18-0.90), P = 0.026], induction therapy [OR 2.76 (1.10-6.89), P = 0.030], and CTGFti >10% at month 3 [OR 2.72 (1.20-6.15), P = 0.016]. In subgroups of patients with little histologic damage at 3 months [either ci score 0 (n = 119), IF/TA score ≤1 (n = 123), or absence of IF/TA, interstitial inflammation, and tubulitis (n = 45)], consistent predictors of progression of chronic histologic damage by 5 years were donor age, induction therapy, CTGFti >10%, and CTGFu. These results suggest that, even in patients with favorable histology at 3 months, significant CTGF expression is often present which may predict accelerated accumulation of histologic damage.

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 .).

Urinary connective tissue growth factor is associated with human renal allograft fibrogenesis.

BACKGROUND: Connective tissue growth factor (CTGF) is a key mediator of tissue fibrogenesis in kidney disease. Its involvement in renal allograft fibrosis was recently demonstrated in a mouse model. METHODS: We prospectively studied the association between urinary CTGF (CTGFu) levels and renal allograft fibrosis during the first 2 years after transplantation. Histologic and biochemical data were collected from 315 kidney transplant recipients enrolled in a protocol biopsy-based clinical program. RESULTS: At 3, 12, and 24 months after transplantation, CTGFu levels were independently associated with the degree of interstitial fibrosis in protocol biopsies, scored according to the revised 1997 Banff criteria. In a subgroup of 164 patients with pristine biopsies at 3 months, higher CTGFu levels at 3 months were associated with moderate and severe interstitial fibrosis developed at 24 months after transplantation. CONCLUSIONS: As it is readily quantifiable in urine, a role for CTGFu as a noninvasive candidate biomarker and predictor of human renal allograft fibrogenesis deserves further study.

Emerging immunosuppressive drugs in kidney transplantation.

Calcineurin inhibitors (CNI), a cornerstone of current immunosuppressive therapy, have important cardiovascular and oncogenic side effects and CNI nephrotoxicity contributes to the multifactorial process called "chronic allograft dysfunction", the leading cause of chronic allograft failure among kidney transplant recipients. New drugs, with a different mechanism of action, are being developed focusing on a better balance between drug efficacy and toxicity. These novel compounds interfere with either T-cell mediated or antibody-mediated rejection. In this review, we report on the mechanism of action, pharmacokinetics and preliminary results of clinical trials of these promising new immunosuppressive drugs.

The P450 oxidoreductase *28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients.

AIM: Recently a SNP of the gene encoding P450 oxidoreductase (POR*28; rs1057868C>T) has been associated with increased in vivo CYP3A activity using midazolam as a drug probe. Because tacrolimus is metabolized by CYP3A isoenzymes, this SNP might affect tacrolimus pharmacokinetics. MATERIALS & METHODS: To test this hypothesis we performed a study in a cohort of 298 de novo renal allograft recipients stratified according to CYP3A5 genotype, which has a known impact on tacrolimus pharmacokinetics. RESULTS: We found that in CYP3A5 expressers (CYP3A5*1 allele carriers) receiving a standard loading dose of 0.2 mg/kg, POR*28T allele carriers had lower tacrolimus C0 levels in the first days post-transplantation and reached target C0 levels significantly later as compared with POR*28CC homozygous patients. The POR*28T allele carriers had significantly higher tacrolimus dose requirements throughout the first year. In CYP3A5 nonexpressers (CYP3A5*3/*3) the POR*28 SNP did not affect tacrolimus pharmacokinetics. CONCLUSION: These data indicate that the POR*28 SNP is associated with additional increases in early tacrolimus dose-requirements in patients carrying a CYP3A5*1 allele.

Expression of CYP3A5 and P-glycoprotein in renal allografts with histological signs of calcineurin inhibitor nephrotoxicity.

BACKGROUND: Susceptibility to calcineurin inhibitor nephrotoxicity (CNIT) after solid organ transplantation could be related to an interindividual variability in renal expression and function of the metabolizing cytochrome P450 3A5 (CYP3A5) isoenzyme and of the multidrug efflux transporter P-glycoprotein (P-gp, ABCB1). METHODS: We compared renal expression of CYP3A5 and P-gp, measured by immunohistochemistry, in 32 renal allograft biopsies with de novo arteriolar hyalinosis as a sign of CNIT with a control group, consisting of normal protocol allograft biopsies (n=50) and protocol biopsies demonstrating alloimmune injury (n=21). In addition, we studied the association between renal expression and donor and recipient single-nucleotide polymorphisms CYP3A5 A6986G (rs776746), ABCB1 C3435T (rs1045642), and G2677T (rs2032582). RESULTS: CYP3A5 positivity at the brushborder of the proximal tubules was present in 47% of CNIT and 14% of control biopsies (P<0.01). In contrast, brushborder staining for CYP3A5 in distal tubules was present in 10% of CNIT and 39% of control biopsies (P<0.01). No significant association between tubular cell P-gp expression and CNIT was detected. The presence of genetic polymorphisms CYP3A5 A6986G and ABCB1 C3435T and G2677T in donors and recipients was not predictive of the renal expression profile of these molecules. CONCLUSIONS: Based on retrospectively collected data of 103 renal transplant recipients receiving tacrolimus in combination with mycophenolate mofetil and corticosteroids, we found that renal expression and localization of CYP3A5 but not P-gp is associated with the occurrence of CNIT. Common genetic polymorphisms in these proteins did not influence their expression profile as measured by immunohistochemistry.

Involuntary weight loss. Does a negative baseline evaluation provide adequate reassurance?

BACKGROUND: Involuntary weight loss frequently poses a diagnostic challenge. Patient and physician alike want to exclude malignant and other major organic illness. The present study aimed to evaluate whether a negative baseline evaluation (consisting of clinical examination, standard laboratory examination, chest X-ray, and abdominal ultrasound) lowers the probability of evolving organic illness in patients with significant unexplained weight loss. METHODS: Prospective observational study of 101 consecutive patients presenting to a general internal medicine department of a university hospital with an unexplained unintentional weight loss of at least 5% within 6-12 months. Laboratory tests of interest included C-reactive protein, albumin, haemoglobin, and liver function tests. RESULTS: Weight loss of the 101 patients [age (mean, interquartile range): 64 (51-71) years, 46% male] averaged 10 (7-15) kg. Organic causes were found in 57 patients (56%), including malignancy in 22 (22%). In 44 patients without obvious organic cause for the weight loss (44%), a psychiatric disorder was implicated in 16 (16%) and no cause was established in 28 (28%), despite vigorous effort and follow-up of at least 6 months. Baseline evaluation was entirely normal in none of the 22 patients (0%) with malignancy, in 2 of the 35 (5.7%) with non-malignant organic disease, and in 23 of the 44 (52%) without physical diagnosis. Additional testing, oftentimes extensive, after a normal baseline evaluation led to one additional physical diagnosis (lactose intolerance). CONCLUSION: In patients presenting with substantial unintentional weight loss, major organic and especially malignant diseases seem highly unlikely when a baseline evaluation is completely normal. In this setting, a watchful waiting approach may be preferable to undirected and invasive testing.