Frank Darras

Effect of ritonavir and atazanavir on human subcutaneous preadipocyte proliferation and differentiation.

Protease inhibitors (PIs) have been implicated in the development of HIV-associated lipodystrophy through a reduction in the differentiation of preadipocytes. While atazanavir (ATV) is associated with fewer clinical metabolic abnormalities in the short-term, the effects of long-term exposure are not known. ATV effects on preadipocyte replication or differentiation would indicate the potential for long-term problems. This study compared ritonavir (RTV) and ATV effects on preadipocyte replication and differentiation in human primary cultures. Preadipocytes from subcutaneous fat were studied in the presence of therapeutic concentrations of RTV and ATV for replication, differentiation, and adipokine secretion. The effects of the drugs on the expression of PPARgamma and related genes during differentiation were also assessed by real-time quantitative PCR. RTV induced a significant inhibition of preadipocyte proliferation, differentiation and adiponectin secretion. ATV at concentrations within the range of therapeutic levels did not affect differentiation or adiponectin secretion, but did have inhibitory effects on preadipocyte proliferation. Inhibition of differentiation by PIs was associated with decreased expression of PPARgamma, C/EBPalpha, and aP2 genes. In summary, although ATV at therapeutic levels has a smaller impact on adipogenesis, alterations in preadipocyte proliferation suggest the potential for adverse effects with long-term use.

Invasive Aspergillosis in a Renal Transplant Recipient Successfully Treated with Interferon-Gamma

Invasive aspergillosis is a serious complication of solid organ transplantation. An early diagnosis is hampered by the lack of reliable serum markers and, even if appropriately diagnosed and treated with current antifungal agents, has a high mortality rate. We report a case of invasive pulmonary and cerebral aspergillosis in a renal transplant patient treated with IFN-γ in conjunction with combination anti-fungal therapy for six weeks in whom complete resolution of the fungal infection was achieved. Renal function remained intact throughout the treatment period. Surveillance CT scans of the chest and head showed resolution of prior disease but revealed a new left upper lobe mass four months after completion of treatment with IFN-γ. Biopsy of the lesion was positive for primary lung adenocarcinoma, for which she underwent left upper lobe resection. The pathology report confirmed clear surgical margins and lymph nodes and no evidence of fungal hyphae. IFN-γ should be considered early in the management of invasive aspergillosis in renal transplant patients. To date, allograft rejection has not been encountered.

Highly active antiretroviral therapy dysregulates proliferation and differentiation of human pre-adipocytes

AIM To investigate the mechanism(s) by which potential effects of multi-drug highly-active antiretroviral therapy contributes to lipodystrophy syndrome. METHODS Preadipocytes from healthy donors were assessed for proliferation and differentiation in the presence of nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) individually and in combination. Effects on proliferation were assessed with a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and effects on differentiation were assessed from glycerol-3-phosphate dehydrogenase (GP DH) activity and quantitation of Oil Red O staining for intracellular lipid. Data were analyzed with a randomized block ANOVA with post-hoc Fisher’s Least Significant Difference test. RESULTS Preadipocyte proliferation was inhibited by a combination of NNRTI + NRTI (14% at 48 h, P < 0.001) and PI + NRTI (19% at 48 h, P < 0.001) with additional suppression when ritonavir (RTV) was added (26% at 48 h). The drug combination of atazanavir (ATV) + RTV + emtricitabine (FTC) + tenofovir (TDF) had the greatest inhibitory effect on proliferation at 48 h. Preadipocyte differentiation was most significantly reduced by the efavirenz + FTC + TDF assessed either by GPDH activity (64%) or lipid accumulation (39%), P < 0.001. Combining NRTIs with a PI (ATV + FTC + TDF) significantly suppressed differentiation (GPDH activity reduced 29%, lipid accumulation reduced by 19%, P < 0.01). This effect was slightly greater when a boosting amount of RTV was added (ATV + FTC + TDF + RTV, P < 0.001). CONCLUSION Although combination antiretroviral therapy is clinically more efficacious than single drug regimens, it also has a much greater inhibitory effect on preadipocyte proliferation and differentiation.

5 Years Experience With Drug Eluting and Bare Metal Stents as Primary Intervention in Transplant Renal Artery Stenosis

Background Transplant renal artery stenosis (TRAS) is a common vascular complication after kidney transplantation and is associated with refractory hypertension, volume overload, and graft injury or loss. This article describes 5-year outcomes of endovascular intervention for TRAS with bare metal and drug eluting stents (DES). Methods We investigated, as a prospective cohort study, patient and graft outcomes after the targeted use of DES for vessel diameter less than 5 mm and bare metal stents (BMS) for vessel diameter greater than 5 mm as the primary management for TRAS. Results From March 2008 to November 2014, 57 patients were stented for hemodynamically significant TRAS; 29 received DES, 26 received BMS, and 2 patients received both stent types. They were followed up for a mean of 35.1 ± 22.8 months; a subset of these patients who all received DES were followed up for 61.7 ± 17.5 months. Mean serum creatinine declined from 2.87 ± 1.5 mg/dL at the time of intervention to 1.98 ± 0.76 mg/dL (P < 0.001) at one month follow-up and was 1.96 ±0.92 mg/dL (P < 0.001) at 35.1 ± 22.8 months. Mean systolic blood pressure declined from 159.05 ± 19.68 mm Hg at time of intervention to 135.65 ± 15.10 mm Hg (P < 0.001) at most recent visit. Clinically driven restenosis requiring repeat revascularization occurred in 15.7% of patients. Conclusions Primary stenting with DES and BMS is both successful in the initial treatment of TRAS and also produced an immediate and long-term reduction in serum creatinine and systolic blood pressure.

Different Management Options for Transplant Ureteral Obstructions within an Inguinal Hernia.

Ureteral obstruction secondary to an inguinal hernia with transplant ureteral component is an extremely rare entity with only several case reports found in literature. In all previously reported cases, management of the obstruction involved temporary drainage with ureteral stenting or nephrostomy tube placements followed by delayed definitive repair. We present two case reports, here one being the first one managed by immediate definitive repair via ureteral reimplant and herniorrhaphy and a second case by delayed definitive repair after percutaneous nephrostomy tube placement. Both patients continued to do well postoperatively with normalization of renal function on follow-up.

Partial nephrectomy for a large renal lymphatic malformation in a child presenting with hypertension

A 9-year-old girl had hypertension (systolic blood pressure of 125 mm Hg) noted at an annual well child visit. An ultrasound study demonstrated a large right renal cystic mass. A partial nephrectomy was performed. The surgical specimen was 9.7 × 9.4 × 6.4 cm and weighed 413.2 g. The tumor stained diffusely positive for smooth muscle actin and focally positive for factor VIII. Final histologic diagnosis was primary intrarenal lymphatic malformation. The case is unusual because of the presentation, size of the mass, as well as the therapeutic approach of partial nephrectomy.

Renal Artery Pseudoaneurysm in Kawasaki Disease.

Whereas coronary aneurysms are commonly associated with Kawasaki disease, involvement of the renal vasculature is exceedingly rare. Genitourinary involvement in patients with Kawasaki disease is typically limited to sterile pyuria and proteinuria. In this case, a 13-year-old girl who presented with right flank pain and microhematuria was found to have an intraparenchymal hemorrhagic mass on computerized tomography scan. Renal arteriography confirmed the diagnosis of pseudoaneurysm in a lower pole segmental artery branch and complete occlusion was achieved with endovascular embolization.

1814: Prednisone-Free Renal Transplant Outcomes with Campath Induction in African-American Recipients

1836 Poster Board #-Session: P163-II PREDNISONE-FREE RENAL TRANSPLANT OUTCOMES WITH CAMPATH INDUCTION IN AFRICAN-AMERICAN RECIPIENTS. Vance J Moss, Ron Chay, Ijaz Ali, Gampala Reddy, Heesuck Suh, Edward P Nord, Wayne C Waltzer, Frank S Darras. Transplant Services, SUNY at Stony Brook University, Stony Brook, NY. Introduction:Multi-center data has shown that renal transplants in AfricanAmericans have higher rejection rates and lower graft survival compared to caucasians and others. Almost all of this data is with prednisone-based immunosuppression. With 2 1/2 years experience using a prednisone-free immunosuppression regimen with Campath induction, we compare the success of our African-American patients to other renal recipients at our center. Methods:Between 7/30/03 and 12/31/05, we performed 144 adult renal transplants, 76(53%) from living donors. All received a single intraoperative 30mg dose of Campath plus 3 doses IV Solumedrol. Of these 144 recipients, 27(19%) were African-American recipients. All 27 received tacrolimus plus mycophenolate mofetil as maintenance immunosuppression. Mean African-American recipient age was 48 years(range 22-71), 16(59%) were male, and only 4(15%) were from living donors. Results:Of the 27 African-Americans, there was 1 early post operative death, and 1 with primary non-function and graft failure without rejection.Two of 27 recipients (8%) had acute cellular and humoral rejection that led to eventual graft failure, 1 of whom was grossly noncompliant and lost his live donor kidney after only 6 months. In the remaining 23 recipients with functioning kidneys, Scr is 1.7 +/0.5mg/dl with mean follow up 14 months(range 2-28). This compares favorably with a mean Scr of 1.4 +/0.4mg/dl at 14 months, and acute rejection rate of 5% in the rest of our recipient population.One African-American recipient treated for rejection required treatment for CMV gastritis. No malignancies or episodes of Polyoma BK virus or PTLD have been noted. No cases of post-transplant diabetes mellitus have been seen in this group, and hypertension and hyperlipidemia are comparable to other patient groups. Conclusions:Prednisone-free immunosuppression with single dose Campath induction provides excellent and safe immunosuppression in African-American renal transplant recipients with tacrolimus and mycophenolate mofetil maintenance therapy. These results compare favorably with our other renal transplant recipients after Campath induction with low rates of acute rejection and complications. Our African-American renal recipients do well in comparison to historical data with patients in prednisone based regimens with excellent graft function and survival without the steroid related side effects. Abstract# 1837 Poster Board #-Session: P164-II IMMEDIATE GRAFT FUNCTION POSITIVELY AFFECTS LONGTERM OUTCOME OF RENAL ALLOGRAFTS FROM OLDER BUT NOT FROM YOUNGER DONORS. Piergiorgio Messa, Brigida Brezzi, Luisa Berardinelli, Francesca Poli, Giovanni Tripepi, Mario Scalamogna, Claudio Ponticelli. Medicine and Medical Specialties, Ospedale MaggiorePoliclinico, Milan, Italy; Transplant Surgery, Ospedale MaggiorePoliclinico, Milan, Italy; Immunology, Ospedale Maggiore-Policlinico, Milan, Italy; CNR Ibim, Epidemiology and Clinical Pathophysiology, Ospedali Riuniti, Reggio Calabria, Italy; Medicine, Ospedale Auxologico,