Michelle L. Robbin

Renal imaging with ultrasound contrast: current status

The application of UCAs to the kidney is still in its infancy; however, there are several areas of great promise. UCAs may replace CT in complex renal cyst evaluation and follow-up, eliminating the need for costly CT scans with their attendant potential contrast nephrotoxicity. This approach may decrease patient and physician uncertainty and improve diagnostic confidence. The use of UCAs is likely to be clinically useful in the evaluation of the indeterminate small renal mass on CT or MR imaging. Another probable useful application will be in renal artery stenosis. Routine application of UCAs may increase the percentage of diagnostic examinations, increase diagnostic confidence, and decrease examination times. It also will likely become the first line of evaluation in pyelonephritis, and be useful in immediate assessment of residual tumor after radiofrequency ablation. Of course, substantial additional work needs to be performed in large groups of patients to prove this currently optimistic outlook.

Retraction: Peritransplant tolerance induction with anti-CD3-immunotoxin: a matter of proinflammatory cytokine control.

BACKGROUND Tolerance is gaining momentum as an approach to reduce lifelong immunosuppressive therapy while improving transplant longevity. Anti-CD3 immunotoxin (IT), FN18-CRM9, has potential to induce tolerance owing to its exceptional ability to deplete sessile lymph node T cells. However, if initiated at the time of transplantation, alpha-CD3-IT alone elicits a proinflammatory cytokine response, precluding establishment of tolerance. METHODS Four groups of rhesus monkeys received kidney allografts and immunosuppression. Three groups received alpha-CD3-IT alone or alpha-CD3-IT supplemented with 15-deoxyspergualin (DSG) and/or methylprednisolone (MP). One group received alpha-CD3-monoclonal antibody with DSG and MP. Cytokines were measured by enzyme-linked immunosorbent assay. RESULTS Supplementing peritransplant alpha-CD3-IT treatment with a brief course of DSG and MP promoted rejection-free kidney allograft acceptance in 75% of macaques followed for up to 550 days. Among those given alpha-CD3-IT alone or with MP, none were long-term survivors. Tolerance developed after alpha-CD3-IT, DSG, and MP treatment, but not when the unconjugated a-CD3 monoclonal antibody was substituted for IT. Systemic production of proinflammatory cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha induced after peritransplant alpha-CD3-IT was prevented only in animals given DSG. Despite high levels of interleukin (IL)-12 in the first month after transplant, tolerant recipients exhibited IL-12 resistance, as evidenced by baseline plasma levels of IFN-gamma but elevated IL-4. DSG was shown to inhibit IL-12-driven IFN-gamma production by a mechanism associated with inhibition of nuclear factor kappa-B. CONCLUSIONS In this model, peritransplant induction of tolerance is promoted by efficient elimination of sessile lymph node T cells and control of the proinflammatory IFN-gamma response by a mechanism that appears to involve resistance to IL-12.

Comparison of Arteriovenous Grafts in the Thigh and Upper Extremities in Hemodialysis Patients

Placement of a thigh graft is an option in hemodialysis patients who have exhausted all upper extremity sites for permanent vascular access. The outcome of thigh grafts has been reported only in retrospective studies. The outcomes of 409 grafts placed at a single institution during a 3.5-yr period were evaluated prospectively, including 63 thigh grafts (15% of the total). Information was recorded on surgical complications, dates of radiologic and surgical interventions, and date of graft failure. The technical failure rate was approximately twice as high for thigh grafts, as compared with upper extremity grafts (12.7 versus 5.8%; P = 0.046). Intervention-free survival was similar for thigh and upper extremity grafts (median, 3.9 versus 3.5 mo; P = 0.55). Thrombosis-free survival was also comparable for thigh and upper extremity grafts (median, 5.7 versus 5.5 mo; P = 0.94). Cumulative survival (time to permanent failure) was similar for thigh and upper extremity grafts (median, 14.8 versus 20.8 mo; P = 0.62). When technical failures were excluded, the median cumulative survival was 27.6 mo for thigh grafts and 22.5 mo for upper extremity grafts (P = 0.72). The frequency of angioplasty (0.28 versus 0.57 per year), thrombectomy (1.58 versus 0.94 per year), surgical revision (0.28 versus 0.18 per year), and total intervention rate (2.15 versus 1.70 per year) was similar between thigh and upper extremity grafts. Access loss as a result of infection tended to be higher for thigh grafts than for upper extremity grafts (11.1 versus 5.2%; P = 0.07). In conclusion, placement of thigh grafts should be considered a viable option among hemodialysis patients who have exhausted all options for a permanent vascular access in both upper extremities.

Medial Fibrosis, Vascular Calcification, Intimal Hyperplasia, and Arteriovenous Fistula Maturation

BACKGROUND Arteriovenous fistulas (AVFs) for hemodialysis frequently fail to mature because of inadequate dilation or early stenosis. The pathogenesis of AVF nonmaturation may be related to pre-existing vascular pathologic states: medial fibrosis or microcalcification may limit arterial dilation, and intimal hyperplasia may cause stenosis. STUDY DESIGN Observational study. SETTING & PARTICIPANTS Patients with chronic kidney disease (N = 50) undergoing AVF placement. PREDICTORS Medial fibrosis, microcalcification, and intimal hyperplasia in arteries and veins obtained during AVF creation. OUTCOME & MEASUREMENTS AVF nonmaturation. RESULTS AVF nonmaturation occurred in 38% of patients despite attempted salvage procedures. Preoperative arterial diameter was associated with upper-arm AVF maturation (P = 0.007). Medial fibrosis was similar in patients with nonmaturing and mature AVFs (60% ± 14% vs 66% ± 13%; P = 0.2). AVF nonmaturation was not associated with patient age or diabetes, although both variables were associated significantly with severe medial fibrosis. Conversely, AVF nonmaturation was higher in women than men despite similar medial fibrosis in both sexes. Arterial microcalcification (assessed semiquantitatively) tended to be associated with AVF nonmaturation (1.3 ± 0.8 vs 0.9 ± 0.8; P = 0.08). None of the arteries or veins obtained at AVF creation had intimal hyperplasia. However, repeated venous samples obtained in 6 patients during surgical revision of an immature AVF showed venous neointimal hyperplasia. LIMITATIONS Single-center study. CONCLUSION Medial fibrosis and microcalcification are frequent in arteries used to create AVFs, but do not explain AVF nonmaturation. Unlike previous studies, intimal hyperplasia was not present at baseline, but developed de novo in nonmaturing AVFs.

Preoperative Sonographic Radial Artery Evaluation and Correlation With Subsequent Radiocephalic Fistula Outcome

Objective. Primary failure of forearm radiocephalic dialysis fistulas is common even when preoperative vascular mapping is used. Previous studies have suggested that low peak systolic velocity of the radial artery predicts subsequent fistula failure. The study goal was to evaluate whether preoperative spectral Doppler assessment of radial artery inflow can improve forearm fistula outcome prediction. Methods. Forearm fistulas were placed in 112 patients after preoperative sonographic mapping. Preoperative spectral Doppler sonography measured radial artery peak systolic velocity during tight fist clenching for 3 minutes and after fist relaxation. Vessel diameters and peak systolic velocity were assessed for predictive value based on subsequent fistula adequacy. Fistula flow rates were determined 6 to 12 weeks postoperatively in a subset of patients. Results. Failed and successful fistulas were similar in their preoperative arterial and vein diameters, resistive index, and peak systolic velocity during fist clenching and after fist relaxation. Specifically, there was no difference in fistula success with radial artery peak systolic velocity lower than 50 cm/s versus peak systolic velocity of 50 cm/s or higher. The change in peak systolic velocity after fist relaxation was highly predictive of subsequent fistula outcome among female patients in ad hoc analysis. Fistula adequacy for dialysis in women was 11% when the change in peak systolic velocity was lower than 0 cm/s and 50% when the change was 0 cm/sec or higher (P = .02). The postoperative fistula flow rates were lower when the preoperative change in peak systolic velocity was lower than 0 cm/s than when it was 0 cm/s or higher (316 ± 46 versus 781 ± 150 mL/min; P = .003). Conclusions. There was no difference in the preoperative peak systolic velocity or the resistive index of successful and failed fistulas. Measurement of the radial artery peak systolic velocity change after release of fist clenching was not useful in predicting outcomes in male patients but identified a subset of female patients with a very low likelihood of success. This criterion may merit further investigation in future trials.

Hemodialysis vascular access monitoring: Current concepts

Most arteriovenous grafts fail due to irreversible thrombosis, and most clotted grafts have an underlying stenotic lesion. These observations raise the plausible hypothesis that early detection of graft stenosis with preemptive angioplasty will reduce the likelihood of graft thrombosis. A number of noninvasive methods can be used to detect hemodynamically significant graft stenosis with a high positive predictive value. These tests include clinical monitoring, as well as surveillance by static dialysis venous pressures, flow monitoring, or duplex ultrasound. However, these surveillance tests have a much lower positive predictive value for graft thrombosis in the absence of preemptive angioplasty. In other words, none of the currently available surveillance tests can reliably distinguish between stenosed grafts destined to clot, and those that will remain patent without intervention. As a consequence, any program of graft surveillance necessarily results in a substantial proportion of unnecessary angioplasties. Moreover, a substantial proportion of grafts thrombose despite a normal antecedent surveillance test. Numerous observational studies have found an impressive reduction of graft thrombosis after implementation of a stenosis surveillance program. In contrast, 5 of 6 randomized clinical trials failed to show a reduction of graft thrombosis in patients undergoing graft surveillance, as compared with those receiving only clinical monitoring. The lack of benefit of surveillance is largely attributable to the rapid recurrence of stenosis after angioplasty. Thus, routine surveillance for graft stenosis, with preemptive angioplasty, cannot be recommended for reduction of graft thrombosis. Future research should be directed at pharmacologic interventions to prevent graft stenosis.

Resolved: Fistulas Are Preferred to Grafts as Initial Vascular Access for Dialysis

There is growing concern that the Fistula First Initiative, KDOQI guidelines, and subsequent pressure from the Centers for Medicare and Medicaid Services lack reasonableness regarding likely success for fistula maturation in a heterogeneous, new-onset dialysis population. Here the various positions are examined from multiple perspectives.

Posttransplant Lymphoproliferative Disorder Localized Near The Allograft In Renal Transplantation

BACKGROUND Posttransplant lymphoproliferative disorder (PTLD), a complication of immunosuppression, develops in approximately 1% of renal allograft recipients. Typically, PTLD is a proliferation of B-cells associated with Epstein-Barr virus (EBV) infection; it is said to be most often a systemic disease. Involvement occasionally is localized near the allograft. METHODS This is a retrospective analysis of all cases of PTLD in recipients of 1474 renal transplants performed at University of Alabama at Birmingham between 1993 and 1997. RESULTS Of 14 patients developing PTLD, 10 had disease localized near the allograft. The mean interval from transplantation to diagnosis was 221 +/- 70 days. All patients presented with renal dysfunction; an ultrasound examination revealed a hilar mass, with hydronephrosis in five and stenosis of renal vessels in eight. No patient had lymphadenopathy, according to computerized tomographic or magnetic resonance imaging findings. After reduction of immunosuppressive therapy, seven required a nephrectomy because of rejection, progressive dysfunction, or mass enlargement. Tissue recovered in four patients was consistent with PTLD; the tumors in the remaining three patients were unresectable and regressed. One patient died 1 month after a nephrectomy, and another died 4 years after surgery; neither had evidence of PTLD when they died. Three patients retain functional grafts without clinical or radiographical evidence of progression. All patients with disseminated disease died. CONCLUSIONS In a large cohort of renal allograft recipients, PTLD affected 1%. Disease localized near the allograft was the most common variant. For most patients with localized disease, the outcome was graft loss, and the mortality was low. Localized PTLD should be considered in the differential diagnosis of allograft dysfunction in the 1st posttransplant year.

Reversed Diastolic Flow in the Renal Transplant: Perioperative Implications Versus Transplants Older Than 1 Month

OBJECTIVE The purpose of our study was to evaluate the causes, waveform morphology, and clinical outcomes of high-resistance reversed diastolic flow in transplanted kidneys. MATERIALS AND METHODS To identify patients with reversed diastolic flow, we performed a review of 5,089 renal transplant Doppler sonograms obtained over a 10-year period. Waveform morphology was correlated with surgical-histologic findings and clinical outcomes. RESULTS Fifty-nine patients (33 male, 26 female; age range, 14-69 years) with reversed diastolic flow fell into three chronologic groups: acute group (six patients), transplant < 24 hours; perioperative group (34 patients), transplant < or = 30 days; and long-term group (19 patients), transplant > 30 days. Acute reversed diastolic flow was associated with higher likelihood of graft survival (p = 0.001, Fishers exact test) compared with reversed diastolic flow discovered in the perioperative or long-term group. In the acute group, hematoma, acute tubular necrosis, renal vein thrombosis, and vascular kink produced reversed diastolic flow. The causes of reversed diastolic flow for the perioperative group were acute tubular necrosis, rejection, and renal vein thrombosis; for the long-term group, reasons for diastolic reversal were rejection, glomerulosclerosis, low cardiac output, and diabetic nephrosclerosis. The causes of reversed diastolic flow were not differentiated by waveform morphology. CONCLUSION The causes of reversed diastolic flow cannot be distinguished by waveform morphology. Patients with reversed diastolic flow < 24 hours after transplantation warrant emergent exploration because correction of treatable causes may lead to recovered function. Long-standing renal transplants with reversed diastolic flow are not likely salvageable.

Determination of Breast Cancer Response to Bevacizumab Therapy Using Contrast-Enhanced Ultrasound and Artificial Neural Networks

Objective. The purpose of this study was to evaluate contrast‐enhanced ultrasound and neural network data classification for determining the breast cancer response to bevacizumab therapy in a murine model. Methods. An ultrasound scanner operating in the harmonic mode was used to measure ultrasound contrast agent (UCA) time‐intensity curves in vivo. Twenty‐five nude athymic mice with orthotopic breast cancers received a 30‐μL tail vein bolus of a perflutren microsphere UCA, and baseline tumor imaging was performed using microbubble destruction‐replenishment techniques. Subsequently, 15 animals received a 0.2‐mg injection of bevacizumab, whereas 10 control animals received an equivalent dose of saline. Animals were reimaged on days 1, 2, 3, and 6 before euthanasia. Histologic assessment of excised tumor sections was performed. Time‐intensity curve analysis for a given region of interest was conducted using customized software. Tumor perfusion metrics on days 1, 2, 3, and 6 were modeled using neural network data classification schemes (60% learning and 40% testing) to predict the breast cancer response to therapy. Results. The breast cancer response to a single dose of bevacizumab in a murine model was immediate and transient. Permutations of input to the neural network data classification scheme revealed that tumor perfusion data within 3 days of bevacizumab dosing was sufficient to minimize the prediction error to 10%, whereas measurements of physical tumor size alone did not appear adequate to assess the therapeutic response. Conclusions. Contrast‐enhanced ultrasound may be a useful tool for determining the response to bevacizumab therapy and monitoring the subsequent restoration of blood flow to breast cancer.