The heterogeneous and delayed course of blood pressure normalization in hypertensive patients after bilateral nephrectomy with and without subsequent renal transplantation.

BACKGROUND: Controversy exists about the time course of blood pressure normalization following bilateral nephrectomy. We sought to evaluate the time course of blood pressure normalization following bilateral nephrectomy and after subsequent kidney transplantation. METHODS AND RESULTS: Clinical data from 14 hypertensive patients were retrospectively assessed. Baseline blood pressure was 175 +/- 33/109 +/- 9 mmHg. Ten patients firstly underwent unilateral nephrectomy, which resulted in a slight increase of blood pressure (185 +/- 22/110 +/- 5 mmHg). One month following bilateral nephrectomy, blood pressure was 167 +/- 23/104 +/- 17 mmHg, at 3 months 159 +/- 42/104 +/- 25 mmHg, and at 6 months 149 +/- 41/96 +/- 30 mmHg. Antihypertensive medication was necessary in 9/14 patients at a 2 year follow-up. Eight patients remained anephric (group I), 6 patients had subsequent kidney transplantation (group II). In group I, blood pressure was 159 +/- 42/93 +/- 17 mmHg and 129 +/- 34/75 +/- 14 mmHg at 3 and 6 months, respectively (p< 0.05 vs. baseline). In group II, blood pressure decreased from 188 +/- 42/ 128 +/- 46 mmHg to 167 +/- 48/113 +/- 32 mmHg at 3 months, but increased after transplantation to 186 +/- 39/118 +/- 33 mmHg. Antihypertensive medication was still necessary in 5 transplanted patients (83%) and in 3 anephric patients (38%). CONCLUSION: Adaptation of the blood pressure response following bilateral nephrectomy is a time requiring process, and long-term antihypertensive medication may still be necessary.

Glutardialdehyde induced fluorescence technique (GIFT): a new method for the imaging of platelet adhesion on biomaterials.

One of the major limitations of biomaterials used in medicine is the adhesion and subsequent activation of platelets upon contact with blood. The development of new or modified materials necessitates adequate methods for the detection and quantification of platelet/material interactions. These interactions are commonly investigated by means of scanning electron microscopy (SEM), radioisotope and immunological techniques, or by quantification of released platelet contents. Given the lack of a simple, rapid, and inexpensive assay, we developed a novel method for the accurate assessment of platelet adhesion after contact with foreign surfaces, which enables quantitative measurements as well as imaging of the platelet shape change, and which omits conventional or immunological staining and time-consuming preparative steps. The glutardialdehyde induced fluorescence technique (GIFT) uses the epifluorescence of glutardialdehyde-fixed platelets detected by fluorescence microscopy and is suitable for opaque and transparent materials. Combined with computer-aided image analysis, numbers of adherent platelets, platelet-covered surface, and average platelet spread area can be determined as markers of surface thrombogenicity. To validate the technique, four materials of different thrombogenicity [polypropylene (PP), poly(D,L-lactide) (PDLLA), 2-hydroxyethyl-methacrylate-grafted PDLLA (PDLLA-HEMA), and heparin-coupled PDLLA-HEMA] were investigated by GIFT and SEM. We found concordant results with SEM and GIFT with the following ranking of thrombogenicity: PP > PDLLA > PDLLA-HEMA > or = PDLLA-HEMA-heparin. GIFT significantly discriminated between the investigated materials. The surface modifications led to improved thromboresistance with reduced platelet adhesion and shape change. The main advantages of GIFT as compared with SEM are: no vacuum-drying or dehydration, less time-consuming procedure, fixation and fluorescence "staining" in one step, and suitability for computer-aided image analysis allowing quantitative assessment of platelet adhesion as well as imaging of the platelet shape change with high-contrast images. In conclusion, GIFT is a valid, rapid, and simple method for the quantitative determination of platelet/material interactions intended for the evaluation of thrombogenicity of biomaterials surfaces.

Is dialysis membrane type responsible for increased circulating adhesion molecules during chronic hemodialysis?

BACKGROUND: Patients with chronic renal failure under maintenance hemodialysis (HD) present with numerous adverse effects including immunologic alterations. Serious abnormalities of neutrophil function have been reported to be associated with disturbed cell adhesiveness. These adhesion processes are mediated by cytokines and different adhesion molecules. PATIENTS AND METHODS: In this study, serum concentrations of the intercellular adhesion molecule ICAM-1, vascular cell adhesion molecule VCAM-1 and endothelial leukocyte adhesion molecule E-selectin were investigated during employment of different dialysis membranes (cuprophane: n = 23, cellulose: 8, polysulfone: 26, acrylonitrile: 7). These adhesion parameters from 64 patients before and after a hemodialysis session were investigated parallel to the serum levels of circulating cytokines and their inhibitors. RESULTS: Circulating ICAM-1 levels were not elevated in low-flux membranes and most of the high-flux HD membranes, except for one high-flux polysulfone membrane. cVCAM-1 levels were significantly elevated both in low- and high-flux dialysis membranes, whereas cE-selectin was not increased. cICAM-1 levels were not different before and after hemodialysis in the entire study group. In contrast, cVCAM-1 and cE-selectin levels increased significantly during HD in the entire study group (both p < 0.001). Serum levels did not correlate with the duration of end-stage renal failure and hemodialysis. Levels of circulating cytokine antagonists/inhibitors (Il-lra, Il-2R, TNFsRp55/75) were significantly increased in all patients before and after HD, whereas the serum concentrations of the corresponding circulating cytokines (I1-1beta, Il-1, TNF-alpha) were within normal ranges. CONCLUSION: Increased levels of cVCAM-1 which suggest an important role for immunological alterations in HD and cytokine-independent changes during HD sessions in all membranes without alterations of cICAM-1 in most membranes and unchanged cE-selectin indicate that processes such as uremia are responsible for these effects rather than membrane characteristics. The level of circulating adhesion molecules does not serve as an appropriate marker of membrane biocompatibility.

Is cytokine removal by continuous hemofiltration feasible?

Patients who are critically ill with acute renal failure and sepsis have extremely high mortality rates. While it seems reasonable that eliminating the inflammatory mediators (such as cytokines, chemokines, tumor necrosis factor-alpha, etc.) by continuous renal replacement therapy (CRRT) would be effective, studies show that only insubstantial numbers of these mediators are removed in comparison with endogenous clearance. Mass removal seems only to be effective when highly permeable membranes (sieving coefficient of approximately 1.0) are used, there is a filtrate volume greater than 2 liters/hour, and when the half-life of the substance to be eliminated is greater than 60 minutes. Removal of cytokines by membrane adsorption is another possibility. However, because the membrane surfaces are saturated after a few hours, frequent filter changes are necessary for them to generate effective adsorption of these mediators. Despite filter changes, only a brief and transient drop in the TNF plasma level has been observed. Controlled clinical trials are needed to determine whether or not CRRT actually has a beneficial effect on the systemic inflammatory response syndrome (SIRS).

Regulation of beta2-microglobulin expression in different human cell lines by proinflammatory cytokines.

BACKGROUND: Proinflammatory monocytic cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and IL-6 have been incriminated in the pathogenesis of elevated beta2-microglobulin (beta2M) serum concentrations in patients undergoing haemodialysis with so-called bioincompatible dialyser membranes. However, neither the source of the elevated serum beta2M nor the precise role of monocytic cytokines in the expression of the beta2M gene have been elucidated conclusively. The aim of the current study was to evaluate whether monocytic cytokines, and in particular IL-6, are regulators of beta2M gene expression in human hepatoma cells, T-lymphocytes and monocytes. METHODS: HepG2 and HuH7 human hepatoma cells, Jurkat T-cells, monocytic MonoMac6 cells, primary human monocytes and synoviocytes were stimulated with IL-1beta, IL-6, interferon-alpha (IFN-alpha), IFN-gamma or conditioned media from lipopolysaccharide (LPS)-treated monocytes. Expression of beta2M mRNA was analysed by Northern blotting, beta2M protein synthesis was determined by metabolic labelling and immunoprecipitation, and beta2M secretion was measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: In all cell types tested, IFN-gamma and, to a lesser extent, IFN-alpha stimulated gene expression of beta2M resulting in an increased synthesis and secretion of beta2M protein. Neither IL-1beta and IL-6 nor supernatants from LPS-treated monocytes were capable of inducing beta2M gene expression, with the exception of a small increase in HuH7 hepatoma cells upon IL-1beta treatment. CONCLUSIONS: The present study provides evidence that interferons are important regulators of beta2M expression. It also shows that proinflammatory monocytic cytokines do not modulate directly the expression of beta2M in cells of hepatic, monocytic and T-lymphocytic origin. Whether they influence beta2M synthesis and secretion indirectly by modulating interferon synthesis needs to be elucidated.

Successful treatment of pulmonary Mycobacterium xenopi infection in a natural killer cell-deficient patient with clarithromycin, rifabutin, and sparfloxacin.

Isolation of Mycobacterium xenopi from the respiratory tract may indicate pneumonia, often clinically indistinguishable from tuberculosis. Resistance to the classic antituberculous drugs renders the treatment of these infections problematic. We report on a case of cavernous pneumonia caused by M. xenopi in a 36-year-old male with natural killer cell deficiency but without severe immunodeficiency. He was successfully treated with a novel triple-drug combination comprising clarithromycin, sparfloxacin, and rifabutin. An impressive subsequent regression of pathological pulmonary changes was observed, and mycobacteria could no longer be detected. The therapeutic potential of clarithromycin and sparfloxacin in the treatment of M. xenopi infections is discussed.

VCAM-1, ICAM-1, and E-selectin in IgA nephropathy and Schönlein-Henoch syndrome: differences between tissue expression and serum concentration.

The tissue expressions of vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and endothelial leukocyte adhesion molecule 1 (E-selectin-1) were investigated in biopsy specimens from 28 patients with different stages of IgA nephropathy (IgAN) and 20 patients with acute renal failure (ARF) or chronic renal diseases (amyloidosis, Alport's glomerulopathy) by immunohistochemistry. The results were compared with the serum levels of the three adhesion molecules. VCAM-1 expression was significantly increased on parietal/tubular epithelial cells in IgAN and ARF. Significantly elevated circulating VCAM-1 levels were measured in IgAN and amyloidosis, but did not correlate with renal function (creatinine clearance). Significantly increased glomerular endothelial/epithelial ICAM-1 expression was found in IgAN and ARF. Intense mesangial ICAM-1 expression was found in mild stages of IgAN and in Schönlein-Henoch syndrome. Circulating ICAM-1 was not significantly elevated in IgAN and different renal diseases. VCAM-1 and ICAM-1 expressions of interstitial infiltrating cells were significantly higher in severe than in mild IgAN and associated with an increased infiltration of inflammatory leukocytes. Patients with IgAN and different renal diseases had decreased mesangial and almost absent interstitial E-selectin expression as compared with controls. The circulating E-selectin levels were significantly elevated in ARF. In conclusion, the tissue expression of adhesion molecules in IgAN reflects a continuous inflammatory renal activity. However, only increased circulating VCAM-1 serum levels correlated significantly with the histological state of renal inflammation and could be used as a disease marker.

Severe gastrointestinal hemorrhage due to Mycobacterium avium complex in a patient receiving immunosuppressive therapy.

Intense immunosuppressive therapy is used frequently for treatment of systemic vasculitides, collagenoses, rapidly progressive glomerulonephritis, and after organ transplantation. Numerous serious treatment-related side effects include localized or disseminated opportunistic infections, and require careful monitoring of immunosuppressed patients. Gastrointestinal infections with Mycobacterium avium complex (MAC) or other nontuberculous mycobacteria have been previously identified in HIV seropositive patients only. We now report the first case of an HIV seronegative patient who received immunosuppressive therapy for rapidly progressive glomerulonephritis. The patient presented with severe lower gastrointestinal bleeding and was diagnosed to have ulcerative colitis due to infection with MAC. The patient recovered promptly after administration of antimycobacterial therapy. MAC infection should be included in the differential diagnosis of gastrointestinal bleeding in all immunodeficient patients. The significance of repeated colonoscopy to obtain multiple biopsy specimens with histological examination for foam cells and specific staining for acid-fast organisms is emphasized.

Pressure oscillation regulates human mesangial cell growth and collagen synthesis.

Experimental renal disease models establish glomerular hypertension as a crucial determinant in glomerulosclerosis progression and demonstrate that glomerular capillary pressure reduction delays sclerosis development. An oscillating pressure (OP) chamber was constructed as an in vitro model to study human mesangial cells. Cell cultures were grown under atmospheric pressure (AP) and a controlled OP corresponding to intraglomerular capillary pressure. We show that OP significantly decreases mesangial cell proliferation within 24 hours and attenuates DNA synthesis throughout a 7-day period. To explore the effects of OP on cell metabolism, cell-associated and medium-secreted extracellular (CA and EC, respectively) collagen synthesis were measured by [3H]proline incorporation. In subconfluent cultures, total CA and EC collagen synthesis was unaffected by OP, while in confluent cultures total EC collagen [3H]proline incorporation was increased. To determine whether OP influenced mesangial cell growth induction, the effects of increasing glucose in the cell culture media were investigated. Our data show that the high glucose growth stimulatory effect on cell number and DNA synthesis was suppressed by OP. Under high glucose conditions, total CA collagen synthesis was increased in confluent cultures, whereas the EC collagen fraction remained unchanged. In these cultures, OP caused an additional increase in CA collagen synthesis. This study shows that mesangial cell growth and collagen synthesis are influenced by hyperbaric OP, supporting the hypothesis that glomerular capillary pressure plays a role in progressive glomerulosclerosis development.

Smoking as a risk factor for end-stage renal failure in men with primary renal disease.

BACKGROUND: It is not known whether smoking increases the risk of end-stage renal failure (ESRF) in patients with primary renal disease. METHODS: We performed a retrospective multicenter case-control study including 582 patients from nine centers in Germany, Italy and Austria. The diseases investigated were IgA glomerulonephritis (IgA-GN) as a model of inflammatory renal disease and autosomal dominant polycystic kidney disease (ADPKD) as a model of non-inflammatory renal disease. Cases were patients who had progressed to ESRF and controls were patients who were not in ESRF, that is, whose serum-creatinine failed to progress to >3 mg/dl during the observation period and who did not require renal replacement therapy. Matching for renal disease (IgA-GN, ADPKD), gender, age at renal death and region of residence resulted in 102 individually matched pairs (IgA-GN N = 54, ADPKD N = 48). Multiple conditional logistic regression was used to estimate adjusted odds ratios for independent tobacco effects. RESULTS: In men (matched pairs: IgA-GN N = 44, ADPKD N = 28), a significant dose-dependent increase of the risk to progress to ESRF was found (non-adjusted). The baseline risk was defined as <5 pack-years (PY): (i) 5 to 15 PY, odds ratio 3.5 (95% CI 1.3 to 9.6), P = 0.017; (ii) >15 PY = 5.8 (2.0 to 17), P = 0.001. Systolic blood pressure, ACE inhibitor treatment and age at diagnosis emerged as potential confounders. After adjustment, the risk for ESRF in men with >5 PY was highly increased for patients without ACE inhibitor treatment [10.1 (2.3 to 45), P = 0.002] but not with ACE inhibitor treatment [1.4 (0.3 to 7.1), P = 0.65]. CONCLUSION: Smoking increases the risk of ESRF in men with inflammatory and non-inflammatory renal disease.

Renal oncocytoma of the native kidney after renal transplantation.

Patients with acquired cystic kidney disease (ACKD) are at an increased risk of renal neoplasms. Frequent tumors are adenomas and renal cell carcinomas. However, renal oncocytomas may occur in patients with ACKD. Little is known about oncocytomas of the native kidney following renal transplantation. By means of B scan ultrasonography, a solid and echo-inhomogeneous renal mass was incidentically observed in the right native kidney of a 28-year-old female patient with ACKD 4 years following renal transplantation. A nephrectomy was performed. The histological examination revealed a renal oncocytoma. The increased prevalence of neoplasms in the case of ACKD and following renal transplantation requires careful monitoring of the patients concerned. In very rare cases a renal oncocytoma may develop in the native kidney after renal transplantation.

Simulation of a pheochromocytoma--Munchausen syndrome.

A 46-year old female nursing sister was admitted to three different hospitals because of blood pressure crises of 300/150 mmHg which occurred up to six times a day. The rises in blood pressure were accompanied by headache, tachycardia and outbreaks of sweating. Raised catecholamine concentrations were repeatedly measured in the 24-hour urine and in the blood. The diagnosis of pheochromocytoma could therefore be regarded as confirmed. The investigations to establish the localization (including MIBG scintigrams carried out several times) showed negative results. Octreotide scintigraphy finally revealed a raised concentration of nuclides in the right adrenals. Selective venous blood samples showed markedly raised concentrations of adrenaline and noradrenaline in all regions investigated. After removing the right adrenal, which was of normal histological appearance, there was an improvement for six months. Afterwards, up to six blood pressure crises per day were observed once more. Fresh determination of catecholamines at various levels demonstrated the highest concentrations in the left iliac vein. It was then shown that the patient injected catecholamines intravaginally even during the angiographic investigation. A search of the patient s room revealed several ampoules containing noradrenaline and adrenaline as well as syringes and needles. - This case shows that in clinical pictures with typical clinical symptoms and negative results of repeated investigations a factitious disorder must be considered in terms of differential diagnosis especially when female patients with medical knowledge who have ready access to drugs are involved with a history comprising several stays in hospital which have not produced any clarification of their condition.

Renal artery stenosis: evaluation with colour duplex ultrasonography.

BACKGROUND: Detection of renal artery stenoses (RAS) by means of duplex Doppler ultrasound with direct scanning of the main renal arteries is subject to numerous limitations. Using semiquantitative analysis of the Doppler curve, which can be recorded from intrarenal arteries, it is possible to detect RAS unaffected by the problems of direct Doppler scanning of the renal arteries. METHODS: Both angiography of the renal arteries and colour duplex ultrasonography (US) of the intrarenal vessels (interlobar arteries) were performed in 214 patients (53.2 +/- 14.1 years) with severe arterial hypertension. Angiography was used as 'gold standard' in the diagnosis of RAS and the Doppler results were compared with the subsequent findings on angiography. At angiography, the reduction of diameter > 70% was assessed as haemodynamically effective RAS. For the duplex Doppler diagnosis of RAS the following parameters were calculated: (a) resistive index (RI) of each kidney, and (b) side-to-side differences of the resistive indices (delta RI) between the right and left kidney. RESULTS: Angiography demonstrated 59 RAS (> 70%) in 53 patients, including six with bilateral RAS. By means of duplex US we found a significant difference of RI between kidneys with RAS (0.48 +/- 0.11) and without RAS (0.63 +/- 0.08; P < 0.001). In addition, a significant difference of the delta RI was noted in patients with RAS (24.4% +/- 12.5%) and the controls without RAS (3.6% +/- 2.7%). Using a combination of both RI and delta RI, threshold values of RI = 0.45 resp. delta RI = 8% yields a sensitivity of 92.5% and a specificity of 95.7% in the detection of haemodynamically effective RAS. CONCLUSIONS: Colour duplex US with calculation of the RI and delta RI of intrarenal arteries is a valuable non-invasive test assessing the haemodynamic effects of a RAS. Low costs and safety support the use of the Doppler technique in screening for renovascular disease.

Ultrasensitive analysis of the intestinal absorption and compartmentalization of aluminium in uraemic rats: a 26Al tracer study employing accelerator mass spectrometry.

BACKGROUND: Developments in accelerator mass spectrometry (AMS) now permit the determination of femtogram amounts of 26Al in blood and in various tissues with good precision and free of external contamination. METHODS: In the present study we used trace quantities of 26Al to investigate the intestinal absorption and compartmentalization of aluminium in rats with renal failure (Nx, 5/6 nephrectomy) and in pair-fed controls (C). Single oral doses of 20 ng 26Al were administered to six animals in each group and, subsequently, 24-h post-load 26Al was analysed in serum, urine, bone, liver, and spleen by means of AMS. RESULTS: Serum concentrations of 26Al were significantly lower in uraemic rats compared to controls, whereas urinary excretion was comparable (Nx, 7.11 +/- 5.78 pg/day vs C, 9.46 +/- 6.10 pg/day), suggesting a higher fraction of ultrafiltrable serum 26Al in uraemia. The target tissues of cellular transferrin-mediated 26Al uptake, liver and spleen, tended to show a larger degree of aluminium accumulation in controls (0.26 +/- 0.31 pg/g vs Nx, 0.14 +/- 0.10 pg/g and 0.37 +/- 0.27 pg/g vs Nx, 0.25 +/- 0.27 pg/g respectively). In contrast, in bone, a site of extracellular aluminium deposition, 26Al concentrations were more elevated in uraemia (1.22 +/- 0.59 pg/g vs C: 0.68 +/- 0.30 pg/g). Estimated total 26Al accumulation in all measured target tissues was significantly higher in uraemic rats (28.15 +/- 9.90 pg vs C: 17.03 +/- 7.03 pg) and total recovery of 26Al from tissue and urine was 26.58 +/- 6.74 pg in controls and 35.75 +/- 7.03 pg in uraemic animals, suggesting a fractional absorption of 0.133% and 0.175% respectively. CONCLUSIONS: Our data suggest that fractional absorption from a dietary level dose of 26Al is about 0.13%. Compartmentalization occurs in transferrin-dependent target tissues such as liver and spleen; however, in quantitative terms extracellular deposition in bone is more important. Uraemia has a significant effect on the intestinal absorption and compartmentalization of aluminium. It enhances fractional absorption and increases subsequent extracellular deposition of aluminium in bone. However, at the same time uraemia does not increase transferrin-dependent cellular accumulation of aluminium in liver and spleen.