Effects of anemia and uremia and a combination of both on cardiovascular structures.

BACKGROUND: Cardiovascular complications are a major cause of morbidity and mortality in chronic renal failure (CRF) patients. Chronic anemia is a complication of CRF and a cardiovascular risk factor per se. It was the aim of the present study to clarify whether uremia and anemia are additive or supra-additive with respect to cardiovascular alterations. METHODS: Thirty SD rats were sham operated (sham) or subtotally nephrectomized (SNX). Both groups were subdivided into anemic (target hemoglobin 10 g/dl, by tail artery punctures) and untreated animals. Blood pressure, echocardiographic measurements and morphometric investigations were performed. The study was terminated after 16 weeks. RESULTS: Heart rate and blood pressure were similar in all groups. Anemia was comparable in sham+anemia and SNX+anemia. Left ventricular end-diastolic pressure was significantly higher in untreated SNX and SNX+anemia than in sham. Anemia and SNX caused comparable left ventricular hypertrophy (LVH), which was significantly higher in SNX+anemia. In sham animals, anemia induced thickening of intramyocardial arteries, which was significantly more pronounced in SNX with no additional effect of anemia. CONCLUSIONS: Experimentally, anemia and CRF induced LVH and intramyocardial arteriolar thickening. If both are combined, the increase in LVH is even more marked, whereas there are no additional effects on intramyocardial structural alterations.

[Human papillomavirus-associated warts in organ transplant recipients. Incidence, risk factors, management]. / Humane Papillomvirus-assoziierte Warzen bei organtransplantierten Patienten. Inzidenz, Risikofaktoren, Management.

Human papillomaviruses infect the squamous epithelia of the skin and cause warts, and are occasionally found in squamous cell carcinomas. Since cell-mediated immunity plays a crucial role in the control of HPV-infections, organ transplant recipients, unable to mount an adequate T-helper 1 cell-mediated immune surveillance, frequently develop widespread and resistant induced warts. Skin tumors, especially squamous cell carcinomas, are the most common post-transplantation neoplasm. Warts, actinic keratoses and invasive squamous cell carcinomas are known to develop at the same time in the areas. The role of HPV in the development of invasive squamous cell carcinoma under immunosuppression, remains to be elucidated in respect to common risk factors and increased numbers of warts potentially identifying patients at increased risk for carcinoma. We prospectively studied 1690 organ transplant recipients in the dermatology clinic at the Charité University Hospital in Berlin, to evaluate risk factors being involved in the development of HPV-induced warts and to assess a potential association of with the development of non-melanoma skin cancers in this population. The cumulative incidence of warts steadily increased throughout the post-transplant years. The presence of more than 10 verrucae was associated with the development of actinic keratoses, invasive squamous cell carcinoma and basal cell carcinoma. This study shows clear evidence that certain risk factors of skin carcinogenesis in organ transplant recipient such as increased age at transplantation, a high dose of immunosuppression related to a specific type of graft and use of azathioprine or cyclosporine are strongly associated with an increased incidence of warts. Furthermore, HPV-induced verrucae vulgares could be used as a potential predictor for the development of coincidental non melanoma skin cancer in organ transplant recipients and therefore could serve as an early identification marker of skin cancer high-risk patients. The challenging management of warts in organ transplantation patients is reviewed.

Prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study.

BACKGROUND: Skin cancers represent a major challenge within the ever growing group of long time surviving organ transplant recipients (OTR) world wide. Especially UV-induced non-melanoma skin cancers (NMSC) like invasive squamous cell carcinomas (SCC) and actinic keratoses (AK), and basal cell carcinoma (BCC), outnumber every other form of cancer in organ transplant recipients. Despite encouraging reports of protective effects of broad-spectrum sunscreens in immunocompetent patients, evidence for the prevention of NMSC in immunocompromised patients is still missing. OBJECTIVES: To assess preventive effects of regular sun-screen use on AK, SCC and BCC in chronically immunocompromised organ transplant recipients. METHODS: Hundred and twenty matched (age, sex, skin type, graft, transplant duration, previous post-transplant skin malignancies) organ transplant recipients (40 heart, 40 kidney, 40 liver grafted) were recruited for this prospective, single-center study. Both groups received equally written and oral information on sun protection measures. Sixty patients were provided with a free broad spectrum study-sunscreen (SPF>50, high-UVA absorption) for daily application of 2 mg cm(-2) to the head, neck, forearms, and hands. RESULTS: All 120 patients completed the 24 months study. Within this 24 month study interval 42 of the 120 patients developed 82 new AK (-102 sunscreen group vs. +82 control; P<0.01), 8 new invasive SCC (0 vs. 8; P<0.01) and 11 BCC (2 vs. 9; ns). In spite of equal numbers of AK at baseline, a marked difference in favor of the intent-to-treat sunscreen group was recorded after 24 months (89 vs. 273; P<0.01, mean difference 3.07 [1.76-4.36]) and the lesion count was significantly lower as compared to the initial visit (89 vs. 191; P<0.01, mean difference 1.7 [0.68-2.72]). With an average of 5.6 applications per week throughout the 24 months the study sunscreen was generally well tolerated. Serum 25-hydroxy vitamin D levels as marker for vitamin D status were decreased in all patients without adequate substitution and 25(OH)D was found to be lower in the sunscreen-group as compared to the control group (mean value 53 ng mL(-1) vs. 60 ng mL(-1)). INTERPRETATION: Regular use of sunscreens, as part of a consequent UV-protection strategy, may prevent the development of further AK and invasive SCC and, to a lesser degree, BCC in immune-compromised organ transplant recipients.

Sexual dysfunction after simultaneous pancreas-kidney transplantation.

Simultaneous pancreas-kidney transplantation (SPK) is the treatment of choice for patients with type 1 diabetes mellitus and end-stage renal disease (ESRD) because it improves survival, is cost-effective, and can mitigate secondary complications of diabetes. Patient-reported outcomes such as quality of life (QoL) have recently received increased attention among transplant recipients. However, the impact of erectile dysfunction on patient QoL has not been investigated in this high-risk group with a history of diabetes and uremia. We applied the International Index of Erectile Function (IIEF) to describe the prevalence and severity of self-reported changes in erectile function after transplantation, comparing the quality of well-being (QWB) index of subgroups of 101 consecutive male SPK recipients with varying degrees of erectile function. Only 21% of patients did not suffer from erectile dysfunction; 18% were classified as mild erectile dysfunction, 31% as mild to moderate, 21% as moderate, and 9% as severe according to the IIEF scores. Forty-one percent of patients reported subjective overall improvement in erectile dysfunction compared with their pretransplant status; 7% considered their sexual function to be worse than before, and 51% did not note any change. The QWB index was highest among the group of patients without erectile dysfunction, decreasing gradually but significantly with increasing severity. A direct impact of erectile dysfunction on QoL, as well as a confounding effect of underlying vascular comorbidities, could explain this finding.

The value of risk scores.

Efforts to improve cardiovascular risk scoring should not be limited to broadening the biomarkers but should also include the individual's personal circumstances and socioeconomic status.

Fatal acute diclofenac-induced immune hemolytic anemia.

We report the case of a 72-year-old woman who developed fatal immune hemolytic anemia with multisystem organ failure and shock caused by diclofenac-dependent red blood cell autoantibodies. The patient described dramatically illustrates the potential severity of this adverse reaction and emphasizes the need for increased awareness of this complication of drug therapy.

Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1alpha in clear cell renal carcinomas.

The transcription factor hypoxia-inducible factor (HIF)-1 is an important mediator of hypoxic adaptation of tumor cells and controls several genes that have been implicated in tumor growth. Oxygen-dependent degradation of HIF-1alpha, the regulatory subunit, requires binding to the von Hippel Lindau (VHL) protein. Because functional inactivation of the VHL tumor suppressor gene occurs in up to 70% of clear cell renal carcinomas, we investigated whether this results in overexpression of HIF-1alpha and its target genes. Immunoblotting revealed increased expression of HIF-1alpha in 24 of 32 (75%) clear cell renal carcinomas but only 3 of 8 non-clear cell renal tumors. Somatic mutations of the VHL gene were detected only in clear cell renal carcinomas that overexpressed HIF-1alpha. None of the HIF-1alpha-negative tumors displayed a VHL mutation. The level of HIF-1alpha mRNA was not different between tumors and adjacent kidney tissue. Immunohistochemistry revealed distinct patterns of nuclear staining for HIF-1alpha, depending on histological type and overall abundance of HIF-1alpha. In those clear cell renal carcinomas that showed increased expression on immunoblots, HIF-1alpha was expressed in almost all cells. In the remaining clear cell and in non-clear cell tumors, staining was focal; these different patterns thus were compatible with genetic stabilization in contrast to microenvironmental stimulation of HIF-1alpha as the primary mechanism. The mRNA expression of two known target genes of HIF-1alpha, vascular endothelial growth factor and glucose transporter 1, increased progressively with increasing amounts of HIF-1alpha in tumor extracts. In addition, glucose transporter 1 protein levels correlated with HIF-1alpha abundance. In conclusion, the data provide in vivo evidence for a constitutive up-regulation of HIF-1alpha in the majority of clear cell renal carcinomas, which leads to more widespread accumulation of this transcription factor than hypoxic stimulation. These observations are most likely linked to functional inactivation of the VHL gene product. Increased expression of HIF-1alpha is associated with alterations in gene expression patterns that are likely to contribute to tumor phenotype and progression.

Tie2 receptor expression is stimulated by hypoxia and proinflammatory cytokines in human endothelial cells.

The tyrosine kinase receptor Tie2 (also known as Tek) plays an important role in the development of the embryonic vasculature and persists in adult endothelial cells (ECs). Tie2 was shown to be upregulated in tumors and skin wounds, and its ligands angiopoietin-1 and -2, although they are not directly mitogenic, modulate neovascularization. To gain further insight into the regulation of Tie2, we have studied the effect of hypoxia and inflammatory cytokines, two conditions frequently associated with neoangiogenic processes, on Tie2 expression in human ECs. Exposure to 1% O(2) led to a time-dependent significant rise of Tie2 protein levels in human coronary microvascular endothelial cells (HCMECs) and dermal microvascular ECs (HMEC-1) (3.2- and 2.5-fold within 24 hours), which was reversible after reoxygenation, and induced a less marked increase in human umbilical vein ECs (HUVECs; 1.7-fold). Hypoxia-conditioned medium and D-deoxyglucose did not change Tie2 expression, but desferrioxamine and cobalt, which are known to mimic hypoxia-sensing mechanisms, induced Tie2 at ambient oxygen tensions. Tumor necrosis factor-alpha induced Tie2 in a time- and dose-dependent fashion in all 3 EC types (HUVEC, 2.3-fold; HMEC-1, 2. 8-fold; and HCMEC, 3.0-fold; 10 ng/mL, 24 hours). Enhanced expression was also found after exposure to interleukin-1beta (1 ng/mL). Changes in Tie2 protein levels were paralleled by changes in mRNA expression. In accordance with these in vitro findings, immunohistochemistry revealed focal upregulation of Tie2 in capillaries at the border of infarcted human and rat myocardium. In conclusion, the data show that hypoxia and inflammatory cytokines upregulate Tie2, which may contribute to the angiogenic response in ischemic tissues.