Adina Voiculescu

Prospective Age‐Matching in Elderly Kidney Transplant Recipients—A 5‐Year Analysis of the Eurotransplant Senior Program

Renal transplantation faces challenges: the organ shortage resulting in extended waiting times and an aging population resulting in death with a functioning graft. The Eurotransplant Senior Program (ESP) allocates kidneys within a narrow geographic area from donors aged ≥65 years to recipients ≥65 years regardless of HLA. This analysis investigates the impact of the ESP on waiting time, graft and patient survival. The ESP group (n = 1406, old to old) was compared to two groups allocated via the Eurotransplant Kidney Allocation System (ETKAS) with either similar donor age (old to any [O/A], donor age ≥65, n = 446) or recipient age (any to old, [A/O], recipient age 60–64, n = 1687). All patients were transplanted between 1999 and 2004. Since initiation of the ESP (1999), availability of elderly donors doubled and waiting time for ESP patients decreased. Local allocation led to shorter cold ischemia time (11.9 vs. >17.0 h, p < 0.001) and less delayed graft function (DGF, ESP 29.7% vs. O/A 36.2%, p = 0.047) but 5–10% higher rejection rates. Graft and patient survival were not negatively affected by the ESP allocation when compared to the standard allocation. The ESP age matching of elderly donors and recipients is an effective allocation system for organs from elderly donors.

Mycophenolate mofetil versus cyclosporin A in high risk keratoplasty patients: a prospectively randomised clinical trial

BACKGROUND/AIMS The requirement for an effective, minimally toxic immunosuppressive agent remains a major obstacle to performing high risk corneal transplantation. Although therapy with cyclosporin A (CSA) allows superior graft survival, its use is limited because of a wide range of side effects. Mycophenolate mofetil (MMF) has been shown to be a safe and effective immunosuppressive agent following renal transplantation. This prospective, randomised clinical trial was carried out to investigate the efficacy and safety of MMF in preventing corneal allograft rejection. METHODS Recipients of corneal transplants who were at high risk for graft failure were randomly assigned to either CSA or MMF immunosuppressive therapy. CSA was given in doses to achieve whole blood trough levels of 120–150 ng/ml. MMF was given in a daily dose of 2 g. Both therapy groups additionally received oral corticosteroids (fluocortolone 1 mg/kg) which were tapered and discontinued within the first 3 postoperative weeks. Patients were monitored closely for evidence of corneal graft rejection and adverse side effects. Drug efficacy was measured, primarily, by the number of patients who experienced at least one episode of clinical graft rejection. Safety analysis focused on reported adverse side effects and laboratory measurements. RESULTS 41 patients were enrolled in the study. There was no statistically significant difference between the two groups. 20 patients received CSA and 21 patients received MMF. Two patients in each group showed evidence of acute graft rejection which could be treated effectively by corticosteroids. All corneal grafts remained clear throughout the follow up. CONCLUSIONS In this study it was shown that MMF is just as effective as CSA in preventing acute rejection following high risk corneal transplantation. Mycophenolate mofetil represents a promising alternative therapeutic option in patients who are at high risk for corneal graft failure.

Management of arterial stenosis affecting kidney graft perfusion: a single-centre study in 53 patients.

We assessed clinical and duplex sonographic (CDS) findings, and outcome in patients with stenosis of the transplant renal artery (TRAS) or the aorto‐iliac segment proximal to the graft (Prox‐TRAS) treated with dilatation (PTA), stenting (PTAS) and surgery. From 1988 to 2002, of 1189 patients with renal transplantations, 117 underwent angiography. Fifty‐three patients with TRAS (n = 37)/Prox‐TRAS (n = 16) were found (4.4%).

ECG-gated Nonenhanced 3D Steady-State Free Precession MR Angiography in Assessment of Transplant Renal Arteries: Comparison with DSA

PURPOSE To evaluate noncontrast material-enhanced steady-state free precession (SSFP) magnetic resonance (MR) angiography in the assessment of transplant renal arteries (RAs) by using digital subtraction angiography (DSA) as the reference standard. MATERIALS AND METHODS This prospective study was approved by the institutional review board; written informed consent was obtained from all participants. In 20 renal allograft recipients scheduled for DSA, the transplant RAs were assessed with electrocardiographically gated nonenhanced SSFP MR angiography performed at 1.5 T; the degree of stenosis was compared with that of DSA. Subjective image quality for SSFP MR angiography was assessed independently by two radiologists on a four-point scale (from 1, nondiagnostic to 4, excellent) in four predefined segments (I, the iliac artery; II, the main transplant artery; III, segmental branches; and IV, parenchymal branches). Sensitivity, specificity, and accuracy of SSFP MR angiography for the detection of relevant (> or =50%) transplant RA stenosis (TRAS) were calculated on a per-artery basis. RESULTS One patient was excluded because SSFP MR angiography failed to adequately visualize the allograft vasculature owing to low cardiac output. The mean image quality assessed by both readers was 3.98 +/- 0.16 (standard deviation), 3.5 +/- 0.68, 2.71 +/- 1.12 and 2.03 +/- 1.09 for segments I, II, III, and IV, respectively (kappa = 0.80). DSA helped identify eight relevant (> or =50%) stenoses in six transplant RAs. Kinking of the transplant artery without relevant stenosis was found in seven patients. The degree of stenosis was overestimated in three patients by using SSFP MR angiography. As compared with DSA, the sensitivity, specificity, and accuracy of SSFP MR angiography to help detect relevant TRAS were 100% (six of six), 88% (14 of 16), and 91% (20 of 22), respectively. CONCLUSION Nonenhanced SSFP MR angiography is a reliable alternative imaging technique for the assessment of transplant RAs in patients for whom contrast-enhanced MR angiography is contraindicated.

Prospective randomized trial of operative vs interventional treatment for renal artery ostial occlusive disease (RAOOD)

INTRODUCTION AND OBJECTIVES Patients with either renovascular hypertension (RVH) and/or renal insufficiency (RI) due to renal artery ostial occlusive disease (RAOOD) can successfully undergo an open surgical reconstruction procedure (OSRP), but since the publication of Blum et al(1) percutaneous balloon stent angioplasty (PTRA + stent) leaving a small part of the stent within the aorta has become very popular. However, balloon dilatation and stenting does not remove the atherosclerotic plaque, which is often heavily calcified but leads to disruption of the plaque causing myointimal hyperplasia and recurrent stenosis. Therefore, a comparison of the two treatment modalities concerning complications and durability in a prospective randomized design was felt to bring more insight to the discussion. METHODS From 1998 to 2004, we performed OSRP in 330 patients with RVH and/or RI for various locations of RAOOD. During this time period, 50 patients (female 18, male 32, mean age 64.4 years) with RAOOD of at least 70% stenosis (DSA and duplex criteria) in one or both renal arteries, who did not require other aorto/mesenteric/iliac reconstructive procedures agreed and were randomized to either OSRP (n = 25 patients, 49 arteries) or PTRA + stent (n = 25 patients, 28 arteries). Two patients crossed over to surgical treatment. Patients were followed on a regular basis for 4 years and longer. Endpoints were re-occurrence of RAOOD and impairment of either kidney function or RVH. RESULTS We approached 77 arteries. There was no early mortality in either group, but directly procedure-related morbidity was 13% in the interventional group and 4% in the surgical group. Four-year follow-up mortality was 18% in the interventional group and 25% in the surgical group. Both groups showed significant improvement of RVH (P < .001 in each group) as well as improvement or stabilization in patients with insufficient renal function. Freedom from recurrent RAOOD (>70%) was achieved in 90.1% of the surgical group and 79.9% of the interventional group. CONCLUSION Both treatment modalities showed good early results concerning RVH, kidney function, and renal perfusion. Despite a higher number of bilateral renal artery reconstructions in patients undergoing OSRP, which was probably due to the preferred technique of transaortic endarterectomy eliminating the plaque originating in the aorta and usually extending into both renal arteries, mortality was not higher and procedure-related morbidity was even lower compared to PTRA + stent. These findings and also longer durability of OSRP imply that surgical reconstruction remains the gold standard for patients with RAOOD before PTRA + stent may be considered.

Noninvasive investigation for renal artery stenosis : Contrast-enhanced magnetic resonance angiography and color Doppler sonography as compared to digital subtraction angiography

Introduction: The question about the most appropriate non-invasive method for detecting a renal artery stenosis (RAS) when comparing contrast enhanced magnetic resonance angiography (MRA) and color Doppler sonography (CDS) is still under discussion. Therefore we conducted a prospective study in order to evaluate both methods as compared to digital subtraction angiography (DSA). Patients/Methods: Thirtysix consecutive patients (53,9±13,7 years) with suspected RAS were investigated. MRA was performed using gadolinium for contrast enhancement. CDS was performed using a 2.5 and 3,5 MHz transducer. A peak systolic velocity (Vmax) >200 cm/sec within renal arteries and/or a side to side difference of the resistive index (RI) of >0,05 were used to discriminate stenosis. A diameter reduction of ≥60% by DSA was considered a stenosis relevant to the patient. Results: Sixtyeight main renal arteries and 9 accessory vessels were detected by DSA. Twenty main and 3 accessory arteries were found to be stenosed ≥60%, while 4 main and 1 accessory artery presented with occlusion. MRA detected 70 renal vessels (65 main and 5 accessory arteries). Twentyone stenosed arteries and 4 occluded vessels were correctly diagnosed by MRA. With CDS 68 renal vessels (62 main and 6 accessory arteries) could be visualized out of which 21 stenoses were diagnosed because of increased Vmax and 6 stenoses were detected because of a side to side difference of RI. For main renal arteries sensitivities and specificities were 96% and 86% for MRA and 96% and 89% for CDS. Conclusions: MRA and CDS are both comparable methods for detection of a renal artery stenosis ≥60%. Despite several limitations, CDS can at the moment still be favored as a screening method.

Iliac artery stenosis proximal to a kidney transplant: Clinical findings, duplex-sonographic criteria, treatment, and outcome

Background. Stenosis of the iliac segment proximal to the transplant renal artery (Prox-TRAS) is an uncommon cause of graft dysfunction and hypertension. We assessed the role of duplex sonography (DS) in regard to clinical and angiographic findings and followed the patients after percutaneous transluminal angioplasty (PTA), PTA stenting (PTAS), or surgery. Methods. From January 1988 to August 2001, 97 of 1,064 kidney recipients underwent angiography for clinical or Doppler-sonographic suspicion of vascular problems. Kidney function, blood pressure, medication, and DS findings after renal transplantation (RTx) at the time of diagnosis of Prox-TRAS and after treatment were evaluated. Results. Prox-TRAS was diagnosed in 16 patients (1.5%) (49.6±6.9 years). Four patients demonstrated early presentation of Prox-TRAS 1 to 7 days after RTx (group A), leading to acute renal failure but without hypertension. In all patients, DS revealed pulsus parvus et tardus, low pulsatility index (PI) (<1.0), and a pathologic flow profile in the iliac artery proximal and distal to the graft. After treatment (surgery in two patients, PTA in one patient, PTAS in one patient), all patients developed good renal function (creatinine 1.7±0.9 mg/dL). PI increased from 0.9±0.1 to 1.2±0.1 (P =0.04), and flow profile within the iliac artery distal to the graft normalized. Late presentation (3–209 months after RTx) of Prox-TRAS was observed in 12 patients (group B), causing an increase of creatinine in 11 patients (two patients receiving dialysis treatments), impairment of blood pressure (141±15 and 80.7±7 to 160±18 and 85±7 mm Hg, P =0.009), and an increase in antihypertensive drugs (2.1±1.1 and 4.3±1, P =0.003) in all patients. The PI was decreased when compared with values early after RTx (1.6±0.4 to 1.2±0.3, P =0.007), and flow profile in the iliac artery was pathologic. All patients except one were managed by surgery (n=6), PTA (n=1), or PTAS (n=4). Creatinine (2.7±1.4 to 1.8±0.4 mg/dL, P =0.02) and blood pressure (160±18/85±7 mm Hg to 138±7/82±9, P =0.018) improved. Antihypertensive drugs were reduced to 2.8±0.8 (P =0.01). PI increased from 1.2±0.3 to 1.9±0.5 (P =0.01). Flow profile within the iliac artery distal to the graft anastomosis normalized. Kidney function, blood pressure, and PI remained unchanged during follow-up (82±69.9 months) in both groups. Conclusions. Prox-TRAS is rare. Because clinical symptoms are similar to those of transplant renal artery stenosis, DS is a valuable tool for diagnosis and follow-up for this type of vascular lesion. Selective treatment with PTA, PTAS, or surgery improves kidney function and hypertension.

Kidney transplantation in the elderly: age-matching as compared to HLA-matching: a single center experience.

Background. We report the short-term outcome of our patients participating within the Eurotransplant age-matching program, where kidneys from donors >65 years are transplanted to recipients >65 years regardless of human leukocyte antigen (HLA) compatibility but with short cold ischemia times, in comparison with patients >60 years transplanted with HLA-matching. Methods. Twenty-five patients (66.7±2.6 years) (donors 69±4.3 years) participated in this program (group A). The control group consisted of 21 patients (63±2.6 years) (group B) (donors 47.6±17.3 years). Results. Despite significant differences in donor age, cold ischemia time (12.3±4.6 hr in A, 22.8±4.8 hr in B, P <0.001) and a mean of 4.4±1.4 vs. 2.3±1.6 HLA-mismatches (P <0.001), there was no difference regarding the incidence of delayed graft function (64 vs. 57%), rejections (52 vs. 66.7%), infections (56 vs. 52.4%), and other complications (80 vs. 71.4%). Mean serum creatinine after 6 months was 1.94±0.49 and 1.83±0.67 mg/dl (NS). Conclusion. The short-term results of the age-matching program are promising and comparable with results from patients of similar age with HLA-matching.

Renal Outcome in Patients with Lupus Nephritis Using a Steroid-free Regimen of Monthly Intravenous Cyclophosphamide: A Prospective Observational Study

Objective. Intravenous cyclophosphamide (IV CYC) in combination with high doses of corticosteroids is considered the “gold standard” of therapy for lupus nephritis (LN). However, the optimal dose of corticosteroids needed has not been defined. We evaluated the efficacy of a monotherapy with IV CYC in patients with a first episode of LN (duration ≤ 6 months). Methods. Forty patients with LN received IV CYC (12 pulses). Prednisone alone was administered and dose-adjusted to control extrarenal manifestations. Response after 24 months was defined as normalization of creatinine level, inactive urinary sediment, and proteinuria ≤ 0.2 g/day [complete response (CR)] or ≤ 0.5 g/day [partial response (PR)]. Results. CR was achieved in 25 (62.5%) and PR in 8 (20%) patients. Mean starting dose of prednisone was 23.9 ± 23.8 mg/day. In a posthoc analysis, we separately analyzed patients initially treated with prednisone doses ≥ 20 mg/day (Group A, n = 19) or < 20 mg/day (Group B, n = 21). CR was achieved in 52.6% (Group A) versus 71.4% (Group B; p = 0.37); and PR in 26.3% versus 14.3%, respectively (p = 0.58). During longterm followup (10.4 ± 3.1 yrs), 37.8% experienced a renal flare. Thirty patients (81%) still have normal renal function. Renal outcome was irrespective of initial prednisone doses (p = 0.46, Pearson chi-square test of independence). Conclusion. Our rates of CR and PR and longterm outcomes were comparable with rates after treatment with a combination of IV CYC with high doses of corticosteroids. These data warrant randomized controlled trials evaluating different doses of corticosteroids in LN.

Systemic mycophenolate mofetil avoids immune reactions in penetrating high-risk keratoplasty: preliminary results of an ongoing prospectively randomized multicentre study*

Recently, in a monocentre study mycophenolate mofetil (MMF) was demonstrated to be efficacious and safe in penetrating high‐risk keratoplasty. Here, preliminary results of a randomized multicentre trial are presented. To date, 86 of 140 scheduled patients undergoing high‐risk penetrating keratoplasty have already been randomized into the two study groups: 48 into the MMF group and 38 into the control group. All 86 patients received fluocortolon 1 mg/kg body weight/day, tapered within 3 weeks, and topical prednisolone acetate 1% tapered within 5 months. MMF was administered at a daily oral dose of 2 × 1000 mg for the first 6 postoperative months. Thereafter, MMF was tapered within 2 weeks. The proportion of grafts with immune reactions and side‐effects were the main outcome measures. Within an average follow up of 9.2 ± 6.6 months two patients developed reversible endothelial immune reactions in the MMF group after cessation of MMF application. In the control group, five reversible and three irreversible immune reactions were observed within an average follow up of 10.1 ± 7.6 months. According to Kaplan and Meier analysis, the ratio of grafts without immune reactions was estimated 89% 1 year postoperatively in the MMF group, in contrast to only 67% in the control group (P = 0.03; log‐rank test). Fifteen patients experienced side‐effects, especially gastroenterotoxicity, tachycardia, arthralgia or systemic infections. All attributable side‐effects were reversible. Systemic MMF may be an effective and safe immune modulating drug in the prophylaxis of immune reactions after penetrating high‐risk keratoplasty.