Rituximab Administered for Recurrent Membranous Nephropathy in a Kidney Transplant Recipient Did Not Eliminate Donor-Specific Antibodies.

Chronic active antibody-mediated rejection is the leading cause of kidney transplant failure. Although various immunosuppressive agents have been tested, rituximab included, presently there is no effective treatment. There are reports about the beneficial role of certain immunosuppressive protocols that include rituximab to reduce donor-specific antibodies, the cause of chronic active antibody-mediated rejection. If an immunosuppressive agent reduces donor-specific antibodies, its administration before the occurrence of chronic active antibody-mediated rejection may be beneficial. We describe a case of a renaltransplantrecipient with recurrent membranous nephropathy and recent development of donor-specific antibodies but without histological evidence of active antibody-mediated rejection. The patient received 3 weekly doses of rituximab for recurrent membranous nephropathy, and complete remission was achieved. One year after, he has preserved an excellentrenal function without proteinuria. However, repeated measurements of donor-specific antibodies revealed that rituximab only modestly reduced donor-specific antibodies. Donor-specific antibody levels remained considerably higher than the laboratory reference value. Thus,rituximab alone may not have a role to prevent chronic active antibody- mediated rejection in patients with donor-specific antibodies.

Lymphocutaneous nocardiosis in a kidney transplant patient successfully treated with tigecycline.

Cutaneous nocardiosis is an infrequent infection which has been increasingly reported in immunocompromised patients. Although trimethoprim-sulfamethoxazole is considered to be the agent of choice for treatment of nocardiosis, newer antimicrobials such as tigecycline have been proven to be effective in vitro, as well. We report the first case of primary cutaneous nocardiosis in a renal transplant recipient having corresponded well to treatment with tigecycline.

A case of severe carbamazepine overdose treated successfully with combined hemoperfusion and hemodialysis technique.

Carbamazepine intoxication manifests as altered mental status ranging from drowsiness to a coma and/or cardiac abnormalities such as sinus tachycardia, prolongation of the QRS interval, ventricular tachycardia, and hypotension. The patient may be agitated, but central nervous system (CNS) depression and presentation with coma is more common and could be lethal. Serious CNS toxicity often requires hemoperfusion and/or hemodialysis (HD). Herein, we present a case of a comatose patient, who was treated with a combination of hemoperfusion and HD in series. Our approach to treat the patient with a combination of hemoperfusion and HD was based on evidence from the literature supporting that the hemoperfusion and HD in series might provide the best clearance of carbamazepine.

Melatonin secretion is impaired in women with preeclampsia and an abnormal circadian blood pressure rhythm.

Non-dipping circadian blood pressure (BP) is a common finding in preeclampsia, accompanied by adverse outcomes. Melatonin plays pivotal role in biological circadian rhythms. This study investigated the relationship between melatonin secretion and circadian BP rhythm in preeclampsia. Cases were women with preeclampsia treated between January 2006 and June 2007 in the University Hospital of Larissa. Volunteers with normal pregnancy, matched for chronological and gestational age, served as controls. Twenty-four hour ambulatory BP monitoring was applied. Serum melatonin and urine 6-sulfatoxymelatonin levels were determined in day and night time samples by enzyme-linked immunoassays. Measurements were repeated 2 months after delivery. Thirty-one women with preeclampsia and 20 controls were included. Twenty-one of the 31 women with preeclampsia were non-dippers. Compared to normal pregnancy, in preeclampsia there were significantly lower night time melatonin (48.4 ± 24.7 vs. 85.4 ± 26.9 pg/mL, p<0.001) levels. Adjustment for circadian BP rhythm status ascribed this finding exclusively to non-dippers (p<0.01). Two months after delivery, in 11 of the 21 non-dippers both circadian BP and melatonin secretion rhythm reappeared. In contrast, in cases with retained non-dipping status (n=10) melatonin secretion rhythm remained impaired: daytime versus night time melatonin (33.5 ± 13.0 vs. 28.0 ± 13.8 pg/mL, p=0.386). Urinary 6-sulfatoxymelatonin levels were, overall, similar to serum melatonin. Circadian BP and melatonin secretion rhythm follow parallel course in preeclampsia, both during pregnancy and, at least 2 months after delivery. Our findings may be not sufficient to implicate a putative therapeutic effect of melatonin, however, they clearly emphasize that its involvement in the pathogenesis of a non-dipping BP in preeclampsia needs intensive further investigation.

Spironolactone increases permeability of visceral sheep peritoneum.

Aldosterone is a key component of the renin-angiotensin-aldosterone system, and spironolactone, an aldosterone receptor blocker, shows beneficial effects in patients with end-stage renal disease and heart failure. The aim of the present study was to investigate by means of Ussing chamber technique the effect of spironolactone on the transmesothelial permeability of visceral sheep peritoneum in vitro. Peritoneal samples from the omentum of adult sheep were collected immediately after slaughter in a cooled and oxygenated Krebs-Ringer bicarbonate (KRB) solution. Isolated intact sheets of peritoneum were mounted in an Ussing-type chamber. Spironolactone (10(-5) mol/L) was added apically and basolaterally to the KRB solution. The transmesothelial resistance (R) was measured before and serially for 30 minutes after the addition of the substances. Data present the mean +/- standard error of 6 experiments in each case. The control R was 19.8 +/- 0.36 omega x cm2. The addition of spironolactone resulted in a reduction in the R, which became significant on both sides of the membrane within 10 minutes and remained significantly different thereafter. The maximum reduction of R (deltaR%) reached 24.8% +/- 2.3% (p < 0.01) apically and 26.3% +/- 3.2% (p < 0.01) basolaterally. Our data clearly show that spironolactone increases the permeability of visceral sheep peritoneum in a lasting manner. Increased peritoneal permeability could result in increased sodium removal, which has acknowledged beneficial effects both in patients undergoing peritoneal dialysis and in patients with heart failure. Further clinical studies investigating the effect of spironolactone on sodium removal in peritoneal dialysis are justified.

Effect of cimetidine on the electrophysiologic profile of isolated visceral sheep peritoneum.

The peritoneal mesothelium is a barrier to ion transport in peritoneal dialysis. Cimetidine is an H2 receptor antagonist and a potent inhibitor of Na+/H+ antiporter, which is found in the plasma membranes of various cell types, including mesothelial cells. Recent reports linked Na+/H+ antiporter stimulation with increasing peritoneal fibroblast proliferation. The aim of the present study was to investigate by means of Ussing chamber experiments the effect of cimetidine on the transmesothelial electrical resistance (R) of isolated visceral sheep peritoneum. Peritoneal samples obtained from adult sheep were collected from the slaughterhouse and transferred in oxygenated Krebs-Ringer bicarbonate (KRB) solution to the laboratory within 30 minutes of the animal's death. The peritoneal tissue was transferred in a cooled KRB solution (4 degrees C, pH 7.5) bubbled with 95% O2/5% CO2. A planar sheet of the visceral peritoneum was mounted in an Ussing-type chamber and cimetidine (10(-3) mol/L) was added to the solution on the apical and basolateral sides. The R was measured before and for 15 minutes serially after addition of the cimetidine. Results presented are the means +/- standard error of the mean of 12 experiments. Addition of cimetidine basolaterally induced, within 1 minute, an increase in the deltaR of 35.97% +/- 12.01% (p < 0.05), which returned to baseline after 15 minutes. The action of cimetidine on the apical side of the membrane was similar, with a rapid rise in the deltaR of 47.3% +/- 16.4% (p < 0.05) and a subsequent decline to control values. The R is inversely correlated with membrane permeability. The results of the present study indicate a rapid action of cimetidine on the permeability of visceral sheep peritoneum, probably through inhibition of mesothelial Na+/H+ antiporter. The increase in R observed after addition of the cimetidine clearly indicates the existence of Na+/H+ antiporter on both sides of visceral sheep peritoneum. The clinical implications of our results should be further investigated.

Acute renal failure: a rare presentation of hypothyroidism.

Thyroid hormones affect the function of almost every body organ, and thyroid dysfunction produces a wide range of metabolic disturbances. Severe hypothyroidism is associated with significant effects on the kidney. The pathophysiology is thought to be multifactorial, while the exact mechanism remains unclear. Hypothyroidism as a cause of renal impairment is usually overlooked, leading to unnecessary diagnostic procedures. We describe two patients with acute renal failure due to severe hypothyroidism in whom thyroid hormone substitution therapy led to a significant improvement in renal function.

Rapid effect of dexamethasone on the permeability of visceral sheep peritoneum.

The peritoneal mesothelium is a biologic barrier to water and ion transport. Its functional and structural integrity is crucial for peritoneal dialysis treatment. In vivo studies have shown that corticosteroids increase transcellular water transport and ultrafiltration of the rat peritoneum. In the present study, we used Ussing chamber technique to investigate the effect of dexamethasone on the transmesothelial permeability of the visceral sheep peritoneum in vitro. Peritoneal samples from the omentum of adult sheep were collected in a cooled and oxygenated Krebs-Ringer bicarbonate (KRB) solution immediately after the death of the animals. Isolated intact sheets were mounted in an Ussing-type chamber. Dexamethasone (10(-6) mol/L) and its inhibitor mifepristone (10(-5) mol/L) were added apically and basolaterally, alone and in combination to the KRB solution. The transmesothelial resistance (R) was measured for 1 hour before and serially after the addition of the substances. Data are expressed as mean +/- standard error of 6 experiments in each case. The control R was 21.5 +/- 0.42 omega x cm2. Dexamethasone induced a significant reduction of R within 15 minutes, which continued for the entire experiment. The maximum effect (% deltaR) was observed at 30 - 60 minutes after the addition of dexamethasone apically 46.2% +/- 7.14% (p < 0.01) and basolaterally 35.3% +/- 7.76% (p < 0.01). Mifepristone acted as an agonist on both sides of the membrane and significantly inhibited the dexamethasone effect. Our findings clearly indicate that dexamethasone rapidly increases the transmesothelial permeability of visceral sheep peritoneum. The rapid effect implicates dexamethasone and probably mifepristone as being involved in a common nongenomic pathway. Further investigation is necessary to elucidate the underlying mechanisms and perspectives of these findings.

A case report of osteomyelitis pubis in a hemodialysis patient with diabetes mellitus.

Osteomyelitis pubis is a rare form of osteomyelitis. Known risk factors are urogynecologic surgery, trauma caused by sport activities, pelvic malignancy and intravenous drug use. Immunocompromised patients, including hemodialysis patients, and those with diabetes are also susceptible to infection. Particularly in the hemodialysis population, the use of intravenous catheters frequently results in bacteremia and metastatic infectious complications such as osteomyelitis. We describe the first case of osteomyelitis pubis in a woman on chronic maintenance hemodialysis with diabetes mellitus.

Hepatocyte growth factor exerts its anti-inflammatory action by disrupting nuclear factor-kappaB signaling.

Renal inflammation, characterized by the influx of inflammatory cells, is believed to play a critical role in the initiation and progression of a wide range of chronic kidney diseases. Here, we show that hepatocyte growth factor (HGF) inhibited renal inflammation and proinflammatory chemokine expression by disrupting nuclear factor (NF)-kappaB signaling. In vivo, HGF gene delivery inhibited interstitial infiltration of inflammatory T cells and macrophages, and suppressed expression of both RANTES (regulated on activation, normal T cell expressed and secreted) and monocyte chemoattractant protein-1 in a mouse model of obstructive nephropathy. In vitro, HGF abolished RANTES induction in human kidney epithelial cells, which was dependent on NF-kappaB signaling. HGF did not significantly affect the phosphorylation or degradation of IkappaBalpha; it also did not influence the phosphorylation or nuclear translocation of p65 NF-kappaB. However, HGF prevented p65 NF-kappaB binding to its cognate cis-acting element in the RANTES promoter. HGF action was dependent on the activation of the phosphoinositide 3-kinase/Akt pathway, which led to the phosphorylation and inactivation of glycogen synthase kinase (GSK)-3beta. Suppression of GSK-3beta activity mimicked HGF and abolished RANTES expression, whereas ectopic expression of GSK-3beta restored RANTES induction. HGF also induced renal GSK-3beta phosphorylation and inactivation after obstructive injury in vivo. These observations suggest that HGF is a potent anti-inflammatory cytokine that inhibits renal inflammation by disrupting NF-kappaB signaling and may be a promising therapeutic agent for progressive renal diseases.

Psoas abscess in a dialysis patient with dialysis-related amyloidosis.

Psoas abscess is an infrequent clinical entity which poses diagnostic and therapeutic challenges. Few cases have been reported in chronic hemodialysis patients. We describe a case of psoas abscess in a dialysis patient with dialysis-related amyloidosis, successfully treated with percutaneous drainage and parenteral antibiotics.

Clonal relatedness of methicillin-resistant coagulase-negative staphylococci in the haemodialysis unit of a single university centre in Greece.

BACKGROUND: Coagulase-negative staphylococci (CoNS) are frequently encountered pathogens in hospital environment. Dialysis patients, often carrying central venous catheters, are prone to CoNS infections. Methicillin-resistant (MR) staphylococci in hospitals are resistant to multiple antibiotics and may cause an overall increase in the incidence of staphylococcal infections rather than simply replacing the more susceptible strains. The aim of this study was to evaluate the antimicrobial resistance and the clonal relatedness of all clinically significant CoNS isolates recovered from haemodialysis patient infections treated in a tertiary care centre, the University Hospital of Larissa, in central Greece. In addition, the CoNS isolates from carriers among health-care workers of the local haemodialysis unit were tested. METHODS: All staphylococci recovered from chronic haemodialysis patients who developed CoNS infections according to Herwaldt criteria in the University Hospital of Larissa, from October 2002 to October 2005, were included. In addition, isolates from the palms and the nasal mucosa of the nursing and medical personnel in the haemodialysis unit were also collected. Isolates were identified and tested for antimicrobial resistance by conventional microbiological methods. The clonal relationship of both patients' and carriers' isolates was tested by pulsed-field gel electrophoresis (PFGE) analysis. RESULTS: Forty-two CoNS isolates were recovered from clinical culture specimens of patients hospitalized for various reasons. In 37 out of 42 CoNS isolates, methicillin resistance was determined. The majority of the MR Staphylococcus epidermidis isolates from patients belonged to one main clone (27 out of 32), arbitrarily named clone z. Clone z was also found to colonize 40% of the haemodialysis unit personnel. CONCLUSIONS: The high prevalence of clone z emphasizes the great capacity of CoNS to colonize patients with central venous catheters such as haemodialysis patients and personnel. This emphasizes the need for the establishment of control and prevention measures.

Nocturnal hypertension is associated with an exacerbation of the endothelial damage in preeclampsia.

BACKGROUND: Non-dipping pattern of circadian blood pressure in preeclampsia is associated with an increased risk of cardiovascular disease. The pathogenetic mechanisms of this relationship are still unclear. We investigated whether non-dipping in preeclampsia could relate to endothelial activation or damage. METHODS: Participants, 20 women with normal pregnancy (mean age 29.9 +/- 5.7 years) and 31 women with preeclampsia (mean age 29.1 +/- 5.1 years), underwent 24-hour ambulatory blood pressure monitoring. Plasma levels of von Willebrand factor (vWf), marker of endothelial damage and of soluble adhesion molecules (sVCAM-1, sICAM-1), and markers of endothelial activation were determined using commercially available enzyme-linked immunoassays. RESULTS: Based on whether the nocturnal mean arterial pressure (MAP) relative to the daytime MAP declined by less than 10%, 21 women with preeclampsia were categorized as non-dippers. Compared to healthy pregnant women, patients with preeclampsia showed significantly enhanced levels of vWf (206.9 +/- 40.6 vs. 123 +/- 24 IU/dl;p<0.01) and sVCAM-1 (2,269 +/- 426 vs.1,159.8 +/- 340 ng/ml; p < 0.01). In addition, significantly higher levels of vWf (224.5 +/- 34.9 vs. 170 +/- 23 IU/dl; p < 0.01) and sVCAM-1 (2,405 +/- 421.4 vs. 1,983 +/- 276.7 ng/ml; p = 0.007) were determined, when women with preeclampsia and nocturnal hypertension (non-dippers) were compared to dippers. The results were similar even after adjustment for severity of preeclampsia. In contrast, neither preeclampsia nor dipping status had an effect on sICAM-1 levels. CONCLUSION: Nocturnal hypertension in preeclampsia is associated with elevated levels of molecules related to endothelial damage. Endothelial damage is a recognized pathogenetic factor for atherosclerosis and history of preeclampsia is a risk factor for cardiovascular disease. In this context, possible clinical implications of our findings deserve further investigation.

Effect of endothelin-1 on the transmesothelial resistance of isolated visceral sheep peritoneum.

The mesothelium is part of the peritoneal barrier that manages the water and ion transport essential for peritoneal dialysis (PD) treatment. In addition, it has a central role in the pathogenesis of peritoneal fibrosis and the resulting ultrafiltration failure observed in many PD patients. Endothelin-1 (ET-1) is a potent vasoactive peptide originally described as an endothelial cell-derived factor In addition, ET-1 has been shown to stimulate fibrogenic activity in various organs by regulating the production and turnover of matrix components. The aim of the present study was to investigate, by means of Ussing chamber experiments, the effect of ET-1 on the transmesothelial electrical resistance (RTM) of isolated visceral sheep peritoneum. Intact sheets of visceral sheep peritoneum were obtained from 12 adult sheep. The samples were collected from the slaughterhouse immediately after the deaths of the animals and, within 30 minutes, were transferred in oxygenated Krebs-Ringer bicarbonate (KRB) solution at 4 degrees C to the laboratory to be mounted in an Ussing-type chamber. Endothelin-1 (10(-7) mol/L) was then added to the KRB solution apically or basolaterally, and the RTM was measured before and serially for 10 minutes after the addition of the ET-1. The control RTM (before addition of ET-1) was 22.8 +/- 0.56 Omega x cm2. Addition of ET-1 apically significantly increased the RTM by 63.82% +/- 16.93% (p < 0.05) within 1 minute. After addition of ET-1 basolaterally, the RTM also increased significantly by 90.91% +/- 57.31% within 1 minute (p < 0.05). In both cases, these values persisted throughout the experiment. These results clearly indicate an inhibitory effect of ET-1 on the ionic permeability of visceral sheep peritoneum. The rapid increase in RTM observed after the addition of ET-1 suggests the existence of endothelin receptors (ET-A or ET-B, or both) on visceral sheep peritoneum. Previous studies demonstrated that ET-1, acting on ET-B receptors, potently inhibits epithelial sodium channels in mammalian cell cultures. Nevertheless, the exact pathways that underlie these findings remain unclear; their elucidation requires further investigation.

Distinctive role of Stat3 and Erk-1/2 activation in mediating interferon-gamma inhibition of TGF-beta1 action.

Interferon-gamma (IFN-gamma) is a multifunctional cytokine that elicits antifibrotic activity in a variety of organs. In this study, we investigated the potential role and mechanism of IFN-gamma in modulating the fibrogenic action of transforming growth factor (TGF)-beta(1) in tubular epithelial cells. Incubation of human proximal tubular epithelial (HKC) cells with IFN-gamma inhibited TGF-beta(1)-mediated alpha-smooth muscle actin (alpha-SMA) expression. IFN-gamma also abolished TGF-beta(1)-induced fibronectin and plasminogen activator inhibitor-1 (PAI-1) expression. To explore the mechanisms by which INF-gamma inhibits TGF-beta(1) action, the signaling pathways that are critical for mediating the antifibrotic activity of IFN-gamma were studied. Stimulation of HKC cells with IFN-gamma triggered a sustained activation of Erk-1/2 and signal transducer and activator of transcription-3 (Stat3). Blockade of Erk-1/2 activation with an Mek1 inhibitor abolished the inhibitory effect of IFN-gamma on alpha-SMA expression, whereas inhibition of Stat3 activation had no influence. Constitutive activation of Erk-1/2 by ectopic expression of activated Mek1 mimicked IFN-gamma and suppressed TGF-beta(1)-mediated alpha-SMA expression. Interestingly, inhibition of Stat3 activation abolished the ability of IFN-gamma to attenuate TGF-beta(1)-mediated PAI-1 and fibronectin expression in HKC cells. These findings indicate that IFN-gamma is capable of antagonizing the fibrogenic actions of TGF-beta(1) in renal tubular epithelial cells. The antifibrotic action of IFN-gamma appears to be mediated through a coordinated activation of both Erk-1/2 and Stat3 signal pathways in a mutually independent fashion.

The immunomodulating effect of interferon-gamma intravesical instillations in preventing bladder cancer recurrence.

PURPOSE: The purpose is to investigate the prophylactic effect of intravesically instillated recombinant IFN-gamma against recurrence of superficial transitional cell carcinoma of the bladder and to evaluate its effect in local immune response, presumably mediating its therapeutic efficacy. EXPERIMENTAL DESIGN: We prospectively randomized in two groups 123 patients with initially diagnosed superficial transitional cell carcinoma and stage Ta, T1, grade 2 tumors, who underwent transurethral tumor resection (TUR). In group A, 60 patients received IFN-gamma (1.5 x 10(7) IU/instillation), whereas 63 patients, consisting of the control group B, received mitomycin C (40 mg/instillation). The annual administration schedule consisted of eight weekly followed by four biweekly and then by eight monthly instillations for both regimens. We also analyzed the immunophenotype of the intratumoral and intramural leukocytes by immunohistochemical and flow-cytometric techniques. To this purpose, tumor samples were obtained at TUR and random biopsies at TUR and during cystoscopy at 6 and 12 months, and bladder washings were collected before TUR and at preselected time points. RESULTS: In group A, 44 of 60 (73.4%) patients, and in group B, 36 of 63 (57.2%) patients, were tumor free during the median follow-up period of 26.5 months (range, 3-49 months). IFN-gamma was well tolerated. Six months after starting treatment, follicular cystitis was detected in patients responding to IFN-gamma. After IFN-gamma instillations, statistically significant increases in T cells, T-helper cells, T-cytotoxic cells, natural killer cells, and total leukocytes, as well as in the number of B cells expressing intercellular adhesion molecule-1 and total leukocytes expressing HLA-DR, were observed by flow cytometry in tissue specimens and bladder washings. CONCLUSIONS: Recombinant IFN-gamma appears to be effective against stage Ta, T1, grade 2 bladder tumors' recurrence. Recruitment and activation of intramural leukocytes seem to be involved in the mechanism of IFN-gamma action.

Partial vesiculectomy in an infertile man with seminal vesicle cyst, ipsilateral renal agenesis, and cryptorchidism.

Congenital seminal vesicle cysts associated with renal agenesis are uncommon, but are currently detected more frequently with the use of sectional imaging procedures. Approximately 200 cases have been reported. The unique feature of our case is the combination of this disorder with an ipsilateral undescended testis. Our patient underwent partial vesiculectomy, in which the cyst was removed and the seminal vesicle remnant with its vas deferens was preserved. A review of the infertile cases and the impact of surgical treatment on fertility are discussed. Features that render partial vesiculectomy applicable and the potential effect of this procedure on fertility are highlighted.