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Background: Infection with different species of cutaneous human papillomaviruses (cHPV) of genus alpha (cαHPVs) and associated skin disease are highly prevalent in solid organ transplant recipients (OTR), documenting the importance of the immunological control of HPV infection., Objectives: To investigate the natural course of cαHPV-specific cellular and humoral immune responses during systemic long-term immunosuppression., Methods: Integrating bead-based multiplex serology and flow cytometry we analyzed natural cαHPV-specific antibodies and T(H) cell responses against the major capsid protein L1 of HPV types 2, 27, 57 (species 4) and 3, 10 and 77 (species 2) in sera and blood of OTR before and after initiation of iatrogenic immunosuppression and in comparison to immunocompetent individuals (IC)., Results: Among OTR we observed an overall 42% decrease in humoral L1-specific immune responses during the course of iatrogenic immunosuppression, comparing median values 30 d before and 30 d after initiation of immunosuppressive therapy (p < 0.05). This difference disappeared after long-term (>1 year) immunosuppression. The predominant cellular L1-specific immune response was of type T(H)1 (CD4(+)CD40L(+)IL-2(+)IFN-γ(+)). Consistent with the detected L1-specific antibody titers, L1-specific T(H)1 responses were unchanged in long-term immunosuppressed OTR compared to IC. Notably, cαHPV-L1-specific IL-2(+)/CD40L(+)CD4(+) or IFN-γ(+)/CD40L(+) CD4(+) T(H) cell responses against any of the cαHPV-L1 types were significantly higher in OTR with clinically apparent common warts., Conclusion: The systemic humoral immune response against cαHPV may reflect the individual degree of iatrogenic immunosuppression indicating a higher susceptibility for cαHPV infection among OTR during the early phase after organ transplantation. Humoral cαHPV-specific immune responses may show a reconstitution to pre-transplantation levels despite continuous potent immunosuppression., (Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Natural killer (NK) cells are central effector cells during innate immune responses against cancer. Natural cytotoxicity receptors expressed by NK cells such as NKp30 are involved in the recognition of transformed cells. Recently, the novel B7 family member B7-H6, which is expressed on the cell surface of various tumor cells including hematological malignancies, was identified as an activating ligand for NKp30. To investigate expression and regulation of B7-H6, we generated monoclonal antibodies. Our study reveals that B7-H6 surface protein and messenger RNA (mRNA) expression in various tumor cell lines was downregulated upon treatment with pan- or class I histone deacetylase inhibitors (HDACi) as well as after small interfering RNA-mediated knockdown of the class I histone deacetylases (HDAC) 2 or 3. B7-H6 downregulation was associated with decreased B7-H6 reporter activity and reduced histone acetylation at the B7-H6 promoter. In certain primary lymphoma and hepatocellular carcinoma samples, B7-H6 mRNA levels were elevated and correlated with HDAC3 expression. Finally, downregulation of B7-H6 on tumor cells by HDACi reduced NKp30-dependent effector functions of NK cells. Thus, we identified a novel mechanism that governs B7-H6 expression in tumor cells that has implications for potential cancer treatments combining immunotherapy with HDACi.

In light of continued uncertainty regarding postkidney donation medical, psychosocial and socioeconomic outcomes for traditional living donors and especially for donors meeting more relaxed acceptance criteria, a meeting was held in September 2010 to (1) review limitations of existing data on outcomes of living kidney donors; (2) assess and define the need for long-term follow-up of living kidney donors; (3) identify the potential system requirements, infrastructure and costs of long-term follow-up for living kidney donor outcomes in the United States and (4) explore practical options for future development and funding of United States living kidney donor data collection, metrics and endpoints. Conference participants included prior kidney donors, physicians, surgeons, medical ethicists, social scientists, donor coordinators, social workers, independent donor advocates and representatives of payer organizations and the federal government. The findings and recommendations generated at this meeting are presented., (©Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Previous studies suggest that the majority of renal allografts are affected by progressive, severe chronic histologic injury, yet studies using current protocols are lacking. The goal of this study was to examine the prevalence and progression of histologic changes using protocol allograft biopsies at 1 and 5 years after solitary kidney transplantation in patients transplanted between 1998 and 2004. Chronic histologic changes generally were mild at both 1 and 5 years and were similar in deceased and living donor kidneys. The overall prevalence of moderate or severe fibrosis was 13% (60/447) at 1 year and 17% (60/343) at 5 years. In a subgroup of 296 patients who underwent both 1- and 5-year biopsies, mild fibrosis present at 1 year progressed to more severe forms at 5 years in 23% of allografts. The prevalence of moderate or severe arteriolar hyalinosis was similar in tacrolimus and calcineurin inhibitor-free immunosuppression. These results in the recent era of transplantation demonstrate fewer, less severe and less progressive chronic histologic changes in the first 5 years after transplantation than previously reported., (©2010 CSIRO©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Nephrogenic systemic fibrosis (NSF) is a debilitating disease in patients with severely diminished kidney function. Currently, no standard treatment exists but improvement has been reported after restoration of kidney function. We retrospectively studied 17 NSF patients with and without successful kidney transplantation (KTx) to evaluate the effects of KTx on NSF. Nine of the 11 KTx developed NSF pretransplant whereas two developed NSF immediately after KTx with delayed graft function. Two of the six dialysis patients had previous failed kidney transplants. Age and sex were well matched. All but one patient was dialysis dependent at the time of NSF. Median follow-up was 35 months for KTx patients and 9 months for dialysis patients. Kidney transplants achieved adequate renal function with median serum creatinine of 1.4 (0.9-2.8) mg/dL and a glomerular filtration rate of 42 (19-60) mL/min/1.73 m(2). NSF improved in 54.6% of the transplanted patients and 50% of the nontransplanted patients (p = 0.86). Two KTx patients had complete resolution of their symptoms whereas four had partial improvement. Improvement in the dialysis patients was all partial. Successful KTx did not insure improvement in NSF and in fact appeared to have no significant benefit over dialysis.

The link between obesity and renal disease is unclear, and there is no consensus as to whether obese individuals are at increased risk for kidney disease after living kidney donation if they otherwise meet acceptance criteria. We retrospectively studied time-zero (implantation) biopsies in 49 obese (body mass index (BMI) > or = 30 kg/m2) and 41 non-obese (BMI < 30 kg/m2) renal donors that met acceptance criteria. We found that our obese donor population had higher systolic blood pressure (P < 0.001 vs non-obese) and higher absolute iothalamate clearance (P = 0.001 vs non-obese) before donation. The obese donors had larger glomerular planar surface area compared to non-obese controls (P = 0.017), and this parameter correlated with patient weight and urinary microalbumin excretion. Detailed examination of the biopsies revealed that although most histologic findings were similar between groups, the obese donors had more tubular dilation (P = 0.01), but less tubular vacuolization (P = 0.02) than the non-obese controls. There was also a trend toward more arterial hyalinosis in the obese patients than controls (P = 0.08). From these data, our studies detected subtle differences in donor organs obtained from obese compared to non-obese individuals. Further studies should be carried out to quantify the long-term impact of these findings.

Polyomavirus-associated nephropathy (PVAN) is managed by reduced immunosuppression with or without antiviral therapy. Data from 55 patients with biopsy-proven PVAN were analyzed for adverse outcomes and influence of baseline variables and interventions. During 20+/-11 months follow-up, the frequencies of graft loss, major and any functional decline were 15%, 24% and 38%, respectively. Repeat biopsies were performed in 45 patients with persistent PVAN in 47%. Low-dose cidofovir, IVIG and cyclosporine conversion were used in 55%, 20% and 55% of patients. No single intervention was associated with improved outcome. Of the variables examined, only degree of interstitial fibrosis at diagnosis was associated with kidney function decline. In contrast, donor source, interstitial fibrosis, proportion of BKV positive tubules and plasma viral load at diagnosis were all associated with failure of histological viral clearance. This retrospective, nonrandomized analysis suggests that: (i) Graft loss within 2 years of PVAN diagnosis is now uncommon, but ongoing functional decline and persistent infection occur frequently. (ii) Low-dose cidofovir, IVIG and conversion to cyclosporine do not abrogate adverse outcomes following diagnosis. (iii) Fibrosis at the time of diagnosis predicts subsequent functional decline. Further elucidation of the natural history of PVAN and its response to individual interventions will require prospective clinical trials.

Calcineurin inhibitors have decreased acute rejection and improved early renal allograft survival, but their use has been implicated in the development of chronic nephrotoxicity. We performed a prospective, randomized trial in kidney transplantation comparing sirolimus-MMF-prednisone to tacrolimus-MMF-prednisone. Eighty-one patients in the sirolimus group and 84 patients in the tacrolimus group were enrolled (mean follow-up = 33 months; range 13-47 months). At 1 year, patient survival was similar in the groups (98% with sirolimus, 96% with tacrolimus; p = 0.42) as was graft survival (94% sirolimus vs. 92% tacrolimus, p = 0.95). The incidence of clinical acute rejection was 10% in the tacrolimus group and 13% in the sirolimus group (p = 0.58). There was no difference in mean GFR measured by iothalamate clearance between the tacrolimus and sirolimus groups at 1 year (61 +/- 19 mL/min vs. 63 +/- 18 mL/min, p = 0.57) or 2 years (61 +/- 17 mL/min vs. 61 +/- 19 mL/min, p = 0.84). At 1 year, chronicity using the Banff schema showed no difference in interstitial, tubular or glomerular changes, but fewer chronic vascular changes in the sirolimus group. This study shows that a CNI-free regimen using sirolimus-MMF-prednisone produces similar acute rejection rates, graft survival and renal function 1-2 years after transplantation compared to tacrolimus-MMF-prednisone.

Glucosinolates are a group of sulfur-rich thioglucoside natural products common in the Brassicaceae and related plant families. The first phase in the formation of many glucosinolates involves the chain extension of the amino acid methionine. Additional methylene groups are inserted into the side chain of methionine by a three-step elongation cycle involving 2-oxo acid intermediates. This investigation demonstrated the first step of this chain elongation cycle in a partially-purified preparation from arugula (Eruca sativa). The 2-oxo acid derived from methionine, 4-methylthio-2-oxobutanoic acid, was shown to condense with acetyl-CoA to form 2-(2'-methylthioethyl)malate. The catalyst, designated as a 2-(omega-methylthioalkyl)malate synthase, belongs to a family of enzymes that mediate the condensation of acyl-CoAs with 2-oxo acids, including citrate synthase of the citric acid cycle, and 2-isopropylmalate synthase of leucine biosynthesis. The 2-(omega-methylthioalkyl)malate synthase studied here shares properties with other enzymes of this class, but appears chromatographically distinct and is found only in extracts of plant species producing glucosinolates from chain-elongated methionine derivatives. Although the principal glucosinolates of arugula are formed from methionine that has undergone two rounds of chain elongation to form dihomomethionine, studies with substrates and substrate analogs of different chain lengths showed that the isolated enzyme is responsible only for the condensation step of the first round of elongation.

The effect of renal artery stenosis on intrarenal perfusion and volume in renovascular hypertensive patients is unclear. Alterations in these attributes may ultimately be involved in deterioration of renal function. We measured whole kidney, cortical, and medullary perfusion and volume with electron beam computed tomography (EBCT) in 33 hypertensive patients, with well-preserved renal function, scheduled for renal angiography. EBCT-derived whole kidney perfusion was lower in patients with atherosclerotic renal artery stenosis (RAS; N = 20) than in fibromuscular dysplasia (FMD; N = 10) or essential hypertension (N = 28; P < 0.05), as was cortical perfusion (2.44 +/- 0.16 vs. 3.26 +/- 0.17 and 3.07 +/- 0.09 ml/min/cc tissue, respectively, P < 0.005), but medullary perfusion was similar. Whole kidney, cortical, and medullary perfusion correlated inversely with degree of stenosis in FMD, but not in atherosclerotic RAS. Renal volumes were similar. These results demonstrate that, in contrast to patients with FMD, in patients with atherosclerotic RAS the decrease in cortical perfusion is not directly related to the degree of stenosis in the main renal artery. Factors other than the stenosis itself may play a role in the pathophysiology of atherosclerotic RAS and associated renal failure.

Transplant immunosuppression using either cyclosporine (CsA) or FK506 leads to renal vasoconstriction. To examine the role of endothelin (ET) in this process, we measured plasma and urinary ET before and at intervals for two years after liver transplantation. Urinary prostacyclin (as 6-keto-PG-F1 alpha), thromboxane, glomerular filtration rate and renal plasma flow were also measured. Forty-four patients were treated with CsA-based regimens and 31 patients with FK506-based regimens. Prednisone doses after one year were lower with FK506 (5.5 +/- 0.5 vs. 10.5 +/- 0.5 mg/day) by study design. Circulating plasma ET remained above normal, but not different from pre-transplant levels. Urinary ET was elevated before transplant (24.6 +/- 3.4 ng/day vs. normal 16 +/- 1.5 ng/day, P < 0.05) and rose further after transplantation (48.5 +/- 13 ng/day, P < 0.05), remaining elevated for two years. 6-keto-PG-F1 alpha fell from 2567 +/- 338 ng/day to subnormal levels and remained suppressed (1158 +/- 128 ng/day, P < 0.01). Over the same period GFR fell (84 +/- 3 ml/min to 60 +/- 3 ml/min, P < 0.01) and renal vascular resistance index rose (11,119 +/- 561 to 23,279 +/- 1692 d.s.cm-5.m-2, P < 0.01). Similar changes were observed both with CsA and FK506-based immunosuppression. No changes in ET were attributable to dihydropyridine calcium channel blockers. These results demonstrate that urinary ET changes independently from plasma ET after transplantation. Elevated ET and suppression of endothelium-derived prostacyclin persist with intense renal vasoconstriction for at least two years after transplant.

Purpose: The primary aims of this study were to delineate trends in medical comorbidity and surgical approach in patients with renal atherosclerosis and azotemia., Methods: We reviewed 1643 patients undergoing renovascular surgery between 1970 and 1993. We focused on those with the most advanced kidney disease (serum creatinine > 2 mg/dl) (n = 402). Attention was focused specifically on trends in sex, age, medical risk factors, surgical technique (bypass vs endarterectomy), and outcome including eventual need for long-term dialysis., Results: From 1970 to 1980, 652 patients underwent renovascular surgery, with 98 (15%) having a serum creatinine > 2 mg/dl. From 1980 to 1993, the percentage of patients with renal insufficiency increased to 31% (304 of 991) (p < 0.001). Gender distribution did not change, but median age rose from 63.5 years in the first decade to 68.0 in the past 13 years. A remarkable increase in all serious medical risk factors also occurred (first vs second decade). Another significant trend was a shift toward bilateral simultaneous transaortic endarterectomy (18% from 1980 to 1985 vs 53% from 1986 to 1993; p < 0.01), which simplified and achieved complete renal revascularization, especially in patients having multiple renal artery stenoses and those needing aortic grafting for occlusive or aneurysmal disease (56% from 1970 to 1980 vs 75% from 1980 to 1993). Patients at low risk (0 to 1 comorbid medical conditions) had a 30-day mortality rate of 5.6% compared with patients at high risk (2 to 3 comorbid conditions) (15.5%) (p = 0.016). The eventual need for long-term dialysis remained low (9%) for patients with a preoperative serum creatinine of 2 to 2.9 mg/dl compared with those with a serum creatinine greater than 3 mg/dl (35%, p < 0.01)., Conclusions: In the past 20 years, there has been a remarkable increase in the medical comorbidity and extent of aortic disease in patients undergoing surgical revascularization for advanced renovascular hypertension and renal insufficiency. However, the surgical approach can be simplified and expedited by bilateral transaortic endarterectomy, and the risk of late dialysis can be reduced significantly by operating before the serum creatinine exceeds 3 mg/dl.

Renal artery stenosis, particularly related to advancing atherosclerotic disease, is a common concern to internists seeing patients with worsening hypertension and deteriorating renal function. Understanding the hormonal and hemodynamic consequences of critical vascular lesions allows better selection of antihypertensive therapy. With the application of potent antihypertensive agents--especially those that block the renin-angiotensin system, such as ACE inhibitors or the soon-to-be-released angiotensin receptor antagonists--blood pressure control often is not the primary reason to consider renal revascularization. Instead, protection of renal function beyond a critical level of arterial stenosis is becoming the main indication for both percutaneous angioplasty and surgical revascularization. Both procedures pose hazards, so optimal management of the patient with renovascular hypertension depends on achieving a balance between the risks and benefits to the individual patient. It remains incumbent upon the internist to weigh the cardiovascular and cerebrovascular risks against both the gains in blood pressure control and the likely progression of renal compromise during the patient's lifetime. Improved understanding of the outcomes of medical therapy versus revascularization depends on future prospective studies.

Sudden death after subcutaneous injection of silicone has been described. However, there are no cases in the literature of clinically diagnosed noncardiogenic pulmonary edema. In the patient reported here, progressive hypoxemia and diffuse pulmonary infiltrates occurred following intramammary injection of a material presumed to be silicone. The presence of birefringent particles in the alveolar macrophages implies entrance of this material into the vascular compartment, its embolization to the lung and migration across the damaged alveolar-capillary membrane. Large volume subcutaneous injections of silicone should be added to the differential diagnosis of the etiology of the adult respiratory distress syndrome.