Longitudinal relationships between fluid status, inflammation, urine volume and plasma metabolites of icodextrin in patients randomized to glucose or icodextrin for the long exchange.

BACKGROUND: Randomized trials have shown that icodextrin reduces the volume of extra-cellular fluid (ECFv) with variable effects on residual renal function. To explore this fluid shift and its possible mechanisms in more detail, prospectively collected data from one such trial, including measures of inflammation (C-reactive protein, tumour necrosis factor-alpha, albumin and low and high molecular weight hyaluronan) ANP (atrial naturetic peptide), an indirect marker of intra-vascular volume, plasma concentrations of icodextrin metabolites and alpha-amylase activity were analysed. METHODS: 50 patients were randomized to either 2.27% glucose or icodextrin (n = 28) for a long exchange following a month run in. Blood samples were obtained at -1, 0, 3 and 6 months, coincident with measurements of urine volume and fluid status. RESULTS: In both randomized groups, a significant correlation between the fall in ECFv and the decline in urine volume was observed (P = 0.001), although the relative drop in urine volume for patients randomized to icodextrin tended to be less. At baseline, ANP was higher in patients with proportionately more ECFv for a given body water or height. Icodextrin patients had non-significantly higher ANP levels at baseline, whereas by 3 (P = 0.026) and 6 months (P = 0.016) these differed between groups due to divergence. There was a correlation between increasing ANP and reduced ECF at 3 months, r = -0.46, P = 0.007, in patients randomized to icodextrin, but not glucose. There were no relationships between fluid status and any inflammatory markers at any point of the study, with the exception of albumin at baseline, r = -0.39, P = 0.007. Amylase activities at -1 month and baseline were highly correlated, r = 0.89, P < 0.0001. Within patients, concentrations of icodextrin metabolites were highly correlated; the only predictor of between-patient variability on multivariate analysis was body weight. There was no relationship between plasma concentrations of icodextrin metabolites and any of the other clinical parameters, including change in daily ultrafiltration, urine volume, fluid or inflammatory status. CONCLUSIONS: This analysis supports observational data that changes in fluid status are associated with changes in urine volume. Icodextrin was not associated with a greater fall in urine output despite its larger effect on ECFv. Changes in fluid status could not be explained or did not appear to influence systemic inflammation. Nor can they be explained by individual variability in plasma concentrations of icodextrin that are in turn inversely proportional to the volume of distribution.

Light chain multiple myeloma with cutaneous AL amyloidosis.

Cutaneous AL amyloidosis is one complication of multiple myeloma. In our patient, painful sclerotic skin changes on the extremities and macroglossia were the presenting features which led to a more detailed investigation and the diagnosis of multiple myeloma. Histological examination revealed cutaneous deposits of amyloid which were positive with Congo red stain and had an apple green color in polarized light.

Duplex ultrasound and renin ratio predict treatment failure after revascularization for renal artery stenosis.

BACKGROUND: The aim of this study was to find predictors to identify patients with hypertension who will not improve after removal of renal artery stenosis (RAS). METHODS: Prospective study of patients with unilateral stenosis (>60% diameter reduction) and hypertension in 24-h measurements despite antihypertensive drugs, who underwent revascularization (surgery/angioplasty). Examinations were performed before treatment and after 3 and 6 months after exclusion of restenosis. Studies included 24-h blood pressure, creatinine clearance, 99Tc MAG3 scintigraphy, and measurements of renal vein plasma renin activity (PRA). Intrarenal resistance indices (RI) were determined with duplex ultrasound before and 30 min after administration of intravenous enalaprilat. Improvement of hypertension was defined by a score consisting of 24-h mean arterial pressure and the number of antihypertensive drugs. RESULTS: From December 2000 to December 2003, 50 patients completed the study. Improvement of hypertension was observed in 18 patients (36%). Comparison between responders (n = 18) and nonresponders (n = 32) revealed significant differences only for RI and PRA measurements. The largest area under the curve in receiver-operating characteristic (ROC) analysis for prediction of no improvement of hypertension was found for RI (stenosis side), which was nearly identical for measurements before and after administration of angiotensin-converting enzyme (ACE) inhibitor. The highest sensitivities and specificities predicting which patients will not improve were found for RIs > or = 0.55. The highest univariate odds ratio (OR 44, confidence interval [CI] 4.8-404) was found for the parameters of RI > or = 0.55 and a renin ratio of <1:1.5. CONCLUSIONS: Resistance indices of the poststenotic kidney above 0.55 and a negative renin ratio can predict a poor outcome concerning arterial blood pressure response after restoration of renal blood flow for unilateral renal artery stenosis.

Effects of candesartan on glomerular hemodynamics and permselectivity in patients with favorable renal allograft function.

BACKGROUND: Distinct effects of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers on glomerular perfusion and permselectivity are important determinants of the substances nephroprotective quality. In renal allograft recipients, however, specific effects of angiotensin antagonism on glomerular function have not been evaluated so far. METHODS: Twenty patients with favorable allograft function were included into a prospective study within the first year after renal transplantation. Glomerular filtration rate, renal plasma flow, albuminuria, and the fractional clearances of neutral dextrans were determined at baseline and after 3 months of treatment with candesartan. Ten individuals after renal donation served as controls for the baseline evaluation. RESULTS: Compared with the control group, the allograft recipients had a higher renal-vascular resistance and a lower glomerular filtration rate. Albuminuria was significantly higher; however, the difference in the dextran sieving curve was not statistically significant. Apart from mild changes in biochemical parameters, the therapy with candesartan led to a rise in serum creatinine along with a nonsignificant drop in the glomerular filtration rate. There was a highly significant drop in filtration fraction and albuminuria. Glomerular permselectivity clearly improved for a range of dextran molecular diameters from 43 Angstrom up to 73 Angstrom. CONCLUSION: A therapy with candesartan has distinct effects on glomerular function in patients after renal transplantation. A drop in filtration fraction along with an improvement in glomerular permselectivity and albuminuria point to a nephroprotective quality that should lead to a systematic clinical evaluation of candesartan even in patients with favorable renal allograft function.

Cerivastatin inhibits proliferation of interleukin-1 beta-induced rat mesangial cells by enhanced formation of nitric oxide.

The antiproliferative effect of statins on mesangial cells could represent a new therapeutic approach in glomerulonephritis. We studied in rat mesangial cells whether the antiproliferative action of cerivastatin on mesangial cells may be mediated by mesangial nitric oxide (NO) formation due to the inducible NO synthase (iNOS) or by induction of cyclooxygenase-2. Mesangial cells were stimulated with interleukin-1 beta and treated with cerivastatin for 24 h. Cell proliferation was examined by bromodeoxy-uridine (BrdU) incorporation, and nitrite and prostaglandin production was measured in supernatants as a means for iNOS or cyclooxygenase-2 activity. iNOS and cyclooxygenase-2 expression was quantified by Northern and Western blot analyses. Cerivastatin (0.0625 microM) significantly inhibited DNA synthesis in interleukin-1 beta-stimulated mesangial cells without altering cell viability. Interleukin-1 beta-induced nitrite production was twofold increased by 0.05 microM cerivastatin, and this effect could be reversed by addition of 100 microM mevalonate. iNOS mRNA levels increased sixfold (33% of maximum) in cerivastatin-treated mesangial cells as compared with vehicle-treated controls (3.5% of maximum). iNOS and cyclooxygenase-2 protein expression increased threefold (iNOS: 2.77+/-0.53/cyclooxygenase-2: 3.49+/-1.25). The NOS inhibitors N-methyl-L-arginine (L-NMMA) and L-N6-(1-iminoethyl)lysine (L-NIL) reversed the antiproliferative effect of cerivastatin. The cyclooxygenase-2 inhibitor celecoxib did not alter DNA synthesis and iNOS or cyclooxygenase-2 expression, but blocked prostacyclin production in interleukin-1 beta and cerivastatin-treated mesangial cells. In conclusion, cerivastatin increased cytokine-induced iNOS and cyclooxygenase-2 expression, thus constituting NO-regulated growth inhibition of mesangial cells.

Icodextrin improves the fluid status of peritoneal dialysis patients: results of a double-blind randomized controlled trial.

Worsening fluid balance results in reduced technique and patient survival in peritoneal dialysis. Under these conditions, the glucose polymer icodextrin is known to enhance ultrafiltration in the long dwell. A multicenter, randomized, double-blind, controlled trial was undertaken to compare icodextrin versus 2.27% glucose to establish whether icodextrin improves fluid status. Fifty patients with urine output <750 ml/d, high solute transport, and either treated hypertension or untreated BP >140/90 mmHg, or a requirement for the equivalent of all 2.27% glucose exchanges, were randomized 1:1 and evaluated at 1, 3, and 6 mo. Members of the icodextrin group lost weight, whereas the control group gained weight. Similar differences in total body water were observed, largely explained by reduced extracellular fluid volume in those receiving icodextrin, who also achieved better ultrafiltration and total sodium losses at 3 mo (P < 0.05) and had better maintenance of urine volume at 6 mo (P = 0.039). In patients fulfilling the study's inclusion criteria, the use of icodextrin, when compared with 2.27% glucose, in the long exchange improves fluid removal and status in peritoneal dialysis. This effect is apparent within 1 mo of commencement and was sustained for 6 mo without harmful effects on residual renal function.

Iliac artery stenosis proximal to a kidney transplant: clinical findings, duplex-sonographic criteria, treatment, and outcome.

BACKGROUND: Stenosis of the iliac segment proximal to the transplant renal artery (Prox-TRAS) is an uncommon cause of graft dysfunction and hypertension. We assessed the role of duplex sonography (DS) in regard to clinical and angiographic findings and followed the patients after percutaneous transluminal angioplasty (PTA), PTA stenting (PTAS), or surgery. METHODS: From January 1988 to August 2001, 97 of 1,064 kidney recipients underwent angiography for clinical or Doppler-sonographic suspicion of vascular problems. Kidney function, blood pressure, medication, and DS findings after renal transplantation (RTx) at the time of diagnosis of Prox-TRAS and after treatment were evaluated. RESULTS: Prox-TRAS was diagnosed in 16 patients (1.5%) (49.6+/-6.9 years). Four patients demonstrated early presentation of Prox-TRAS 1 to 7 days after RTx (group A), leading to acute renal failure but without hypertension. In all patients, DS revealed pulsus parvus et tardus, low pulsatility index (PI) (<1.0), and a pathologic flow profile in the iliac artery proximal and distal to the graft. After treatment (surgery in two patients, PTA in one patient, PTAS in one patient), all patients developed good renal function (creatinine 1.7+/-0.9 mg/dL). PI increased from 0.9+/-0.1 to 1.2+/-0.1 (P=0.04), and flow profile within the iliac artery distal to the graft normalized. Late presentation (3-209 months after RTx) of Prox-TRAS was observed in 12 patients (group B), causing an increase of creatinine in 11 patients (two patients receiving dialysis treatments), impairment of blood pressure (141+/-15 and 80.7+/-7 to 160+/-18 and 85+/-7 mm Hg, P=0.009), and an increase in antihypertensive drugs (2.1+/-1.1 and 4.3+/-1, P=0.003) in all patients. The PI was decreased when compared with values early after RTx (1.6+/-0.4 to 1.2+/-0.3, P=0.007), and flow profile in the iliac artery was pathologic. All patients except one were managed by surgery (n=6), PTA (n=1), or PTAS (n=4). Creatinine (2.7+/-1.4 to 1.8+/-0.4 mg/dL, P=0.02) and blood pressure (160+/-18/85+/-7 mm Hg to 138+/-7/82+/-9, P=0.018) improved. Antihypertensive drugs were reduced to 2.8+/-0.8 (P=0.01). PI increased from 1.2+/-0.3 to 1.9+/-0.5 (P=0.01). Flow profile within the iliac artery distal to the graft anastomosis normalized. Kidney function, blood pressure, and PI remained unchanged during follow-up (82+/-69.9 months) in both groups. CONCLUSIONS: Prox-TRAS is rare. Because clinical symptoms are similar to those of transplant renal artery stenosis, DS is a valuable tool for diagnosis and follow-up for this type of vascular lesion. Selective treatment with PTA, PTAS, or surgery improves kidney function and hypertension.

Effluent CA 125 concentration in chronic peritoneal dialysis patients: influence of PD duration, peritoneal transport and PD regimen.

In terms of the integrity of the peritoneal membrane in peritoneal dialysis (PD), the peritoneal mesothelial cells play a pivotal role since its monolayer constitutes the first line of the peritoneal membrane. Cancer antigen 125 (CA 125) is released by peritoneal mesothelial cells and correlates with the mesothelial cell mass in PD. Since its effluent concentration is easy to determine in chronic PD patients, CA 125 serves as an in vivo marker of biocompatibility. We performed a cross-sectional study to investigate the relation between PD duration, peritoneal transport and the PD regimen (CAPD/CCPD) on effluent CA 125 concentration in 22 chronic PD patients. We compared long-term (>6 months) with short-term PD treatment, patients with high small solute transport properties (MTAC >11 ml/min, d/p ratio of creatinine >0.72) to patients with low small solute transport and CAPD with APD patients. A peritoneal equilibration test was performed with 1.36% glucose. Dialysate/plasma (D/P) ratio and mass transfer area coefficient (MTAC) of creatinine were calculated and the 4-hour effluent concentration of CA 125 was determined. CA 125 tended to be lower in the long-term PD patients and also in APD patients, but statistical significance was missing. Effluent CA 125 was significantly increased in patients with an MTAC of creatinine >11 ml/min (40.2 +/- 11.2 vs. 20.7 +/- 1.2 U/ml) and in patients with a d/p ratio of creatinine >0.72 (48.2 +/- 11.0 vs. 21.6 +/- 1.6 U/ml). CA 125 and the d/p ratio of creatinine were positively correlated (r = 0.68). The positive correlation of CA 125 with peritoneal small solute transport especially in the early phase of PD treatment indicates an initial correlation of the mesothelial cell mass with the peritoneal surface area. A direct relation between the CA 125 concentration and peritoneal transport is unlikely. In our study the CA 125 effluent concentration tended to be lower in long-term PD patients and also in APD patients, possibly indicating a cell depletory influence of the conventional PD fluid.

Influence of uremia on cell viability and cytokine release of human peritoneal mesothelial cells.

INTRODUCTION: There is still no evidence whether human peritoneal mesothelial cells (HPMC) from patients with end-stage renal failure are altered in cell viability or show a different pattern of the release of proinflammatory cytokines. Also the serum of patients with uremia may contain substances stimulating the cytokine release of HPMC. STUDY DESIGN: The IL-1beta-induced IL-6/IL-8 release of HPMC from healthy donors and from patients with end-stage renal disease (ESRD) were measured before the start of chronic peritoneal dialysis (PD) and during PD therapy. Additionally the influence of uremic and non-uremic serum on IL-6 and IL-8 release of normal HPMC was studied. Cell viability was assessed by MTT assay and by the measurement of intracellular ATP (chemoluminescence assay). HPMC were obtained from the following patient groups: (1) non-uremic control patients (n = 7); (2) patients with ESRD undergoing PD catheter implantation for the first time (n = 7), and (3) patients on PD undergoing catheter exchange for noninfectious reasons (n = 6). Pooled human serum from PD patients and normal controls were used for stimulation experiments. HPMC from different donors were grown to confluence (second passage) and then stimulated with IL-1beta (1,000 pg/ml in M199) for 24 h. IL-6 and IL-8 concentrations were measured in the supernatant by ELISA. Additionally uremic and non-uremic sera were incubated with HPMC from normal donors for 24 h with a subsequent 24-hour IL-1beta stimulation. Mesothelial cell protein mass was determined by the Bradford reagent. RESULTS: Non-uremic patients and ESRD patients did not differ with regard to the global cell viability of HPMC according to MTT assay activity or the intracellular ATP concentration. However, HPMC from uremic patients produced more IL-8 on IL-1beta stimulation than the non-uremic controls (group 2, 53.5 +/- 15.7 pg/microg; group 3, 70.5 +/- 27.3 pg/microg vs. group 1, 24.0 +/- 11.8 pg/microg). HPMC from patients on chronic PD additionally released significantly more IL-6 (30.5 +/- 13.8 pg/microg) on IL-1beta stimulation than uremic patients before the onset of PD (6.2 +/- 2.6 pg/microg; p < 0.01). Incubation of normal HPMC with the serum from uremic donors produced an enhanced stimulated IL-8 release compared to the exposition with normal control serum (50.6 +/- 6.1 vs. 20.8 +/- 2.9 pg/microg; p < 0.01). CONCLUSION: HPMC from uremic patients more readily release IL-8 on stimulation with IL-1beta. On chronic PD treatment IL-6 release was further enhanced. Not further classified serum components in uremia also enhance IL-6 and IL-8 release of HPMC.

Prostacyclin enhances the expression of LPS/INF-gamma-induced nitric oxide synthase in human monocytes.

BACKGROUND: Nitric oxide (NO) is an important mediator of inflammatory processes, including macrophage-mediated cellular host defense, and is found to be increased in peritonitis. The ability of human mononuclear cells to contribute to the NO production by expression of active inducible NO synthase (iNOS) is still discussed controversely. AIMS: This study was designed to investigate the influence of prostacyclin receptor (IP receptor) activation on iNOS expression and NO formation in human peripheral blood monocytes. METHOD AND RESULTS: Using reverse transcriptase-polymerase chain reaction, we demonstrated that human monocytes express high levels of IP receptor mRNA. Stimulation of monocytes with the IP receptor selective agonist cicaprost (100 nM) significantly induced cellular cyclic adenosine monophosphate formation, indicating functional coupling of the receptor to G(s). Treatment of cells with lipopolysaccharide (LPS)/interferon gamma (IFN-gamma) further enhanced the IP receptor mRNA expression 2.7 +/- 0.1-fold above basal levels (n = 6). Analysis of iNOS expression revealed barely detectable mRNA levels in unstimulated monocytes which were increased 3.75 +/- 0.3-fold (n = 5) after costimulation with 1 microg/ml LPS and 250 U/ml INF-gamma for 16 h. Further increases of iNOS mRNA expression (9.4 +/- 0.9-fold above basal, n = 5) were obtained, if the monocytes were costimulated with 1 microg/ml LPS, 250 U/ml INF-gamma, and 100 nM cicaprost for 16 h. Measurement of the NO generation correlated with the polymerase chain reaction data: treatment of cells with 1 microg/ml LPS plus 250 U/ml INF-gamma increased the NO(2) production to 2.6 microM, being above the basal level of 2.0 microM, as determined in the cell culture medium. Additional treatment with 100 nM cicaprost further significantly increased the NO(2) production to 3.43 microM. CONCLUSIONS: An IP receptor mediated increase in cyclic adenosine monophosphate formation plays an important role in enhancing LPS/IFN-gamma-induced iNOS expression in human monocytes/macrophages and may, therefore, contribute to the increased production of NO during peritonitis.

Peritoneal fluid and solute transport: influence of treatment time, peritoneal dialysis modality, and peritonitis incidence.

The integrity of the peritoneal membrane in peritoneal dialysis (PD) is of major importance for adequate dialysis and fluid balance. However, alterations in peritoneal fluid transport, such as ultrafiltration failure, often develop during long-term PD. To investigate peritoneal solute and fluid transport and to analyze the influence of treatment time, peritonitis incidence, and PD modality (continuous ambulatory PD [CAPD] or automated PD [APD]), a cross-sectional study with an extended peritoneal transport test that used dextran 70 in 2 L of glucose was performed in 23 nonselected chronic PD patients. Compared were long-term (>40 mo) with short-term PD patients (<40 mo), CAPD with APD patients, and those with a peritonitis incidence of >0.25/yr to those with an incidence of <0.25/yr. Dialysate/plasma (D/P) ratio and mass transfer area coefficient of creatinine, lymphatic absorption rate (LAR), transcapillary ultrafiltration, and effective ultrafiltration were measured. Long-term PD patients had higher D/P ratio of creatinine (73.5 +/- 2.3% versus 65.9 +/- 2.2%; P < 0.01) and higher LAR (243 +/- 69 ml/4 h versus 96 +/- 31 ml/4 h; P < 0.03), both resulting in lower effective ultrafiltration (242 +/- 35 ml/4 h versus 324 +/- 30 ml/4 h; P < 0.05). D/P ratio (r = 0.66) and LAR (r = 0.67) were positively correlated to PD duration. Patients on APD compared with those on CAPD and patients with a history of peritonitis compared with those without did not differ in terms of D/P ratio, mass transfer area coefficient, LAR, transcapillary ultrafiltration, and effective ultrafiltration. Lower ultrafiltration after long-term PD is both the result of increased small solute transport and increased lymphatic absorption. APD or CAPD modality and peritonitis incidence do not have a significant influence on small solute transport or fluid kinetics.