Graft and patient survival in kidney transplant recipients selected for de novo steroid-free maintenance immunosuppression.

Steroid-free regimen is increasingly employed in kidney transplant recipients across transplant centers. However, concern remains because of the unknown impact of such an approach on long-term graft and patient survival. We studied the outcomes of steroid-free immunosuppression in a population-based U.S. cohort of kidney transplant recipients. All adult solitary kidney transplant recipients engrafted between January 1, 2000 and December 31, 2006 were stratified according to whether they were selected for a steroid-free or steroid-containing regimen at discharge. Multivariate Cox regression models were used to estimate graft and patient survival. The impact of the practice pattern on steroid use at individual transplant centers was analyzed. Among 95 755 kidney transplant recipients, 17.2% were steroid-free at discharge (n = 16 491). Selection for a steroid-free regimen was associated with reduced risks for graft failure and death at 1 year (HR 0.78, 95% CI 0.72-0.85, and HR 0.73, 95% CI 0.65-0.82, respectively, p < 0.0001) and 4 years (HR 0.83, 95% CI 0.78-0.87, and HR 0.76, 95% CI 0.71-0.83, respectively, p < 0.0001). This association was mostly observed at individual centers where less than 65% of recipients were discharged on the steroid-containing regimen. De novo steroid-free immunosuppression as currently practiced in the United States appears to carry no increased risk of adverse clinical outcomes in the intermediate term.

Ultrastructural localization of blood-retinal barrier breakdown in diabetic and galactosemic rats.

Breakdown of the blood-retinal barrier (BRB) is an early event in diabetic and galactosemic rats, but the location and nature of the specific defect(s) are controversial. Using an electron microscopic immunocytochemical technique, the retinas of normal, diabetic, and galactosemic rats were immunostained for endogenous albumin. Normal rats showed little evidence of BRB breakdown at either the inner barrier (retinal vasculature) or the outer barrier (retinal pigment epithelium) (RPE). In diabetic and galactosemic rats, as was true in human diabetics, BRB breakdown occurred predominantly at the inner BRB, but in some cases at the outer barrier as well. Treatment with the aldose reductase inhibitor sorbinil largely prevented BRB failure in galactosemic rats. In the inner retina of diabetic and galactosemic rats, albumin was frequently demonstrated on the abluminal side of the retinal capillary endothelium (RCE) in intercellular spaces, basal laminae, pericytes, ganglion cells, astrocytes, and the perinuclear cytoplasm of cells in the inner nuclear layer. Albumin did not appear to cross RCE cell junctions; however, it was occasionally seen in RCE cytoplasm of galactosemic rats. In the outer retina, albumin was frequently detected in the subretinal space, in the intercellular space between photoreceptors, and in the perinuclear cytoplasm of photoreceptor cells, but was only infrequently found in the RPE cells constituting the barrier. Albumin derived from the choroidal vasculature did not appear to cross the tight junctions of the RPE. These findings suggest that specific sites of BRB compromise are infrequent but that once albumin has crossed the RCE or RPE it freely permeates the retinal tissue by filling intercellular spaces and permeating the membranes of cells not implicated in BRB formation. The diffuse cytoplasmic staining of some RCE and RPE cells suggests that the predominant means of BRB breakdown in diabetes and galactosemia involves increased focal permeability of the surface membranes of the RCE and RPE cells rather than defective tight junctions or vesicular transport.

Tsukamurella peritonitis associated with continuous ambulatory peritoneal dialysis.

A case of Tsukamurella peritonitis associated with peritoneal dialysis in a 23-year-old woman is described. The organism was difficult to identify and was mistaken for Corynebacterium and atypical mycobacteria. Despite prolonged, multidrug, antimicrobial therapy with conventional antibiotics including vancomycin, ciprofloxacin, rifampin, gentamicin and ceftazidime, catheter removal was required to successfully treat peritonitis. Human infection due to this organism is rare and has been previously reported in only 13 cases, 1 of which was peritonitis. We describe here the second case of Tsukamurella peritonitis associated with peritoneal dialysis.

Immunohistochemical localization of blood-retinal barrier breakdown in human diabetics.

Localization of the site of blood-retinal barrier breakdown in diabetes has been controversial. It has been particularly difficult to make assessments in clinical material where the use of tracer materials may not be practical. In this study, immunohistochemical staining for albumin was performed on paraffin-embedded eyes from patients with no known ocular disease and those with various stages of diabetic retinopathy. No extravascular albumin was detected in the retina or retinal pigment epithelium (RPE) of normal nondiabetics or diabetics with no ocular findings, but it was detected in 12.5% of mildly affected diabetics, 20% of background diabetic retinopathy cases, and 89% of proliferative diabetic retinopathy cases. The inner retinal vasculature appeared to be the primary site of leakage in diabetics because all cases demonstrating extravascular albumin-positivity expressed it in the inner retina. It usually permeated the vessel walls and spread along the inner surface of the retina. Some of these cases also contained albumin in the outer retina and RPE, suggesting that additional leakage also may occur through the RPE. A case of cytomegalovirus (CMV) retinitis showed albumin staining predominantly in the inner retina, whereas a rhegmatogenous retinal detachment showed only outer retina staining. These data suggest immunohistochemical staining for albumin may be a useful technique for localizing blood-retinal barrier breakdown.

Localization of blood-retinal barrier breakdown in human pathologic specimens by immunohistochemical staining for albumin.

Human pathologic specimens from eyes with several different disease processes were immunohistochemically stained with antisera directed against rat or human serum albumin. In 33 eyes with no known ocular disease and no pathologic abnormalities, positivity was seen in the choroid and within retinal vessels, but not within the retina, except in one case in which focal staining in an area of outer retina was noted. In eyes with a history of ocular disease and/or pathologic findings, extravascular albumin staining was seen in areas of the retina generally corresponding to pathologic abnormalities. Albumin in the inner retina appeared to emanate from retinal vessels, but often collected along the internal limiting membrane. Staining in the outer retina was frequently demonstrated along the external limiting membrane, but in some cases, was also seen between the photoreceptor outer segments and within the retinal pigment epithelium. Eyes with primary retinovascular disease showed staining more commonly in the inner retina (77%) than the outer retina (38%) as would be predicted on theoretical grounds, whereas eyes with other disease processes showed no difference in frequency of staining between inner and outer retina. These data suggest that immunohistochemical staining of extravascular albumin is a useful technique for localizing breakdown of the blood-retinal barrier and is applicable to several disease processes.

Lipids stimulate the production of 6-keto-prostaglandin f(1alpha) in human dorsal hand veins.

Obese hypertensives have increased nonesterified fatty acids (NEFAs) and alpha-adrenergic vascular reactivity. Raising NEFAs locally with intralipid and heparin augments dorsal hand venoconstrictor responses to phenylephrine, an alpha(1)-adrenoceptor agonist. The enhanced venoconstrictor responses were reversed by indomethacin. The findings suggest that raising NEFAs leads to the generation of cyclooxygenase (COX) product(s) that enhance vascular reactivity. To test this notion, 6-keto-PGF(1alpha) and TxB(2), the stable metabolites of prostaglandin H(2) (PGH(2)); prostacyclin (PGI(2)); and thromboxane (TxA(2)), were measured approximately 1.5 to 2 cm downstream of a dorsal hand vein infusion of intralipid and heparin (n=10) or saline and heparin (n=5) for 2 hours each. During the third hour, intralipid and heparin (experimental) and saline and heparin (control) were continued, and either saline (control) or indomethacin (intervention) were infused. Intralipid and heparin raised local 6-keto PGF(1alpha) concentrations by 350% to 500% (P<0.005), but saline and heparin did not (P=NS). TxB(2) levels did not change significantly with any infusion. Infusion of indomethacin during the third hour of intralipid and heparin lowered plasma 6-keto-PGF(1alpha) (P<0.05), whereas infusion of saline with intralipid and heparin did not (P=NS). Oleic and linoleic acids at 100 micromol/L, increased 6-keto-PGF(1alpha) in vascular smooth muscle cells (VSMCs) through a protein kinase C and extracellular, signal-regulated kinase independent pathway. However, oleic and linoleic acids increased intracellular Ca(2+) in VSMCs. The data indicate that NEFAs induce the production of COX products, perhaps via Ca(2+)-dependent activation of phospholipase A(2). The COX product(s) may contribute to increased vascular alpha-adrenergic reactivity among insulin-resistant individuals when NEFAs are elevated.