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Acute kidney injury (AKI) represents a major complication of cardiac surgery. Our aim was to evaluate, in patients undergoing continuous renal replacement therapy (CRRT) for cardiac surgery-associated AKI (CS-AKI), prognostic factors related to in-hospital survival and renal function recovery to independence from RRT. We conducted a retrospective analysis in patients with severe CS-AKI who underwent CRRT for at least 48 h. The sequential organ failure assessment (SOFA) score was calculated on a daily basis to evaluate illness severity throughout the intensive care unit (ICU) stay. In 264 patients (age 66.4 ± 11.7 years, 192 males), 30-day survival was 57.6 % while survival to discharge from the hospital was 40.5 %. Renal function recovery occurred in 96.3 % of survivors and in 13.4 % of non-survivors (p

Aims: To evaluate the efficacy and safety of a commercially available phosphate-containing solution for continuous renal replacement therapy (CRRT) in preventing CRRT-related hypophosphatemia. Methods: In heart surgery patients undergoing continuous veno-venous haemodiafiltration (CVVHDF) with regional citrate anticoagulation (RCA), we combined an 18 mmol/l citrate solution with a phosphate-containing (1.2 mmol/l) dialysate/replacement fluid evaluating the incidence of hypophosphatemia and the need for parenteral phosphorus supplementation. Results: In 75 patients on RCA-CVVHDF, the mean filter life was 53.9 ± 33.6 h. Regardless of baseline levels, phosphoremia was progressively corrected and maintained in a narrow normality range throughout RCA-CRRT days (after 72 h: 1.14 ± 0.25 mmol/l). Considering the whole CRRT period, 45 out of 975 (4.6%) serum phosphorus determinations met the criteria for mild (Conclusions: RCA-CVVHDF with a phosphate-containing solution enabled the maintenance of phosphorus levels within normophosphatemic range in most of the patients, minimizing the occurrence of CRRT-related hypophosphatemia.

Introdução. O objetivo do estudo foi avaliar o equilíbrio através da aplicação da escala de Berg em pacientes com sequela de traumatismos encefálicos que praticam natação associado à realidade virtual atra­vés do Nintendo Wii. Método. Participaram do estudo 3 pacientes, que apresentaram sequela neurológica pós traumatismos encefálicos. Foram submetidos a um programa que constou de realidade virtual com duração de 30 minutos seguida de aula de natação com duração de 50 minutos, ambos com frequência de 2 vezes por semana. Os indivíduos foram avaliados através da Escala de Equilíbrio Funcio­nal de Berg antes de iniciar as aulas de natação e de realidade virtual e foram reavaliados após 6 sessões. Resultados. Todos os pacientes apresentaram melhora do equilíbrio após o programa de natação asso­ciada a realidade virtual. Conclusão. Atualmente essa nova opção de tratamento fisioterapêutico pode contribuir para a melhora do equilí­brio em pacientes neurológicos, uma forma de estimular o indivíduo a adesão ao tratamento.

Regional citrate anticoagulation (RCA) is a valid anticoagulation method in continuous renal replacement therapies (CRRT) and different combination of citrate and CRRT solutions can affect acid-base balance. Regardless of the anticoagulation protocol, hypophosphatemia occurs frequently in CRRT. In this case report, we evaluated safety and effects on acid-base balance of a new RCA- continuous veno-venous hemofiltration (CVVH) protocol using an 18 mmol/L citrate solution combined with a phosphate-containing replacement fluid. In our center, RCA-CVVH is routinely performed with a 12 mmol/L citrate solution and a postdilution replacement fluid with bicarbonate (protocol A). In case of persistent acidosis, not related to citrate accumulation, bicarbonate infusion is scheduled. In order to optimize buffers balance, a new protocol has been designed using recently introduced solutions: 18 mmol/L citrate solution, phosphate-containing postdilution replacement fluid with bicarbonate (protocol B). In a cardiac surgery patient with acute kidney injury, acid-base status and electrolytes have been evaluated comparing protocol A (five circuits, 301 hours) vs. protocol B (two circuits, 97 hours): pH 7.39 ± 0.03 vs. 7.44 ± 0.03 (P < 0.0001), bicarbonate 22.3 ± 1.8 vs. 22.6 ± 1.4 mmol/L (NS), Base excess −2.8 ± 2.1 vs. −1.6 ± 1.2 (P = 0.007), phosphate 0.85 ± 0.2 vs. 1.3 ± 0.5 mmol/L (P = 0.027). Protocol A required bicarbonate and sodium phosphate infusion (8.9 ± 2.8 mmol/h and 5 g/day, respectively) while protocol B allowed to stop both supplementations. In comparison to protocol A, protocol B allowed to adequately control acid-base status without additional bicarbonate infusion and in absence of alkalosis, despite the use of a standard bicarbonate concentration replacement solution. Furthermore, the combination of a phosphate-containing replacement fluid appeared effective to prevent hypophosphatemia.

Background: Contrast-induced acute kidney injury (CI-AKI) represents an important cause of hospital-ac- quired AKI. The aim of this study was to evaluate the incidence of CI-AKI after coronary angiography (CA) or percutaneous coronary intervention (PCI) and the role of patient-/procedure-related risk factors. Methods: For 11 months, patients undergoing CA or PCI were prospectively evaluated for CI-AKI, and factors possibly affecting CI-AKI were analyzed. Statistical anal- ysis was completed using Student's t-test, chi-square or Fisher exact test, and multivariate logistic regression. Results: Among 585 consecutive patients, incidence of CI-AKI was 5.1% (n=30) and renal replacement therapy was required in 10% of those (n=3). Incidence of CI-AKI was higher in patients with anemia or chronic kidney disease (CKD) associated with diabetes. Basal hemo- globin was significantly lower in CI-AKI patients while Mehran score, contrast medium (CM) volume, contrast ratio (CM volume / maximum contrast dose) and ratio glomerular filtration rate (CM volume / GFR) were sig- nificantly higher. Multivariate analysis selected a higher contrast ratio as a factor independently associated with a higher risk of CI-AKI which otherwise appeared to be lower with increasing basal hemoglobin. Conclusions: The incidence of CI-AKI after CA or PCI was higher in patients with CKD associated with diabe- tes. Lower levels of basal hemoglobin appeared to be re- lated to a higher risk of CI-AKI, and contrast media vol- ume, especially if exceeding the dose adjusted for renal function, was a strong modifiable risk factor for CI-AKI.

Background The aim of this study was to evaluate indocyanine green angiographic findings in patients with systemic lupus erythematosus (SLE) with or without lupus nephritis. In particular, the presence of choroidal abnormalities at indocyanine green angiography (ICG-A) that could not be detected by fluorescein angiography (FAG) was investigated. Methods Sixteen patients with SLE underwent simultaneous ICG-A and FAG. Patients were divided into 2 groups based on whether renal disease was present (group A, n=9) or not (group B, n=7). Results Drusen-like deposits were ophthalmoscopically evident in only 1 out of 9 group A patients (11.1%). While FAG disclosed the deposits in 4 out of 9 group A patients (44.4%), drusen-like deposits were otherwise found in all group A patients (100%) by ICG-A. FAG and ICG-A did not show choroidal alterations in group B patients. Conclusions ICG-A can provide information that is not detectable by clinical or FAG examination in patients with lupus nephritis (group A). The findings of choroidopathy by ICG-A represent an indicator of ocular involvement and could be an indirect sign of renal involvement. Given that histological lesions may be present where there are no anomalies in urinary sediment and/or proteinuria, the positivity of ICG-A could help in deciding whether or not to carry out a renal biopsy. Therefore, ICG-A could be useful in the screening of patients with SLE, especially where there are no evident signs of renal involvement.

Low dialysate to blood flow rate ratios are a unique characteristic of continuous arteriovenous hemodiafiltration (CAVHDF) that should allow complete saturation of dialysis fluid with small-molecular-weight blood solutes. The aim of the investigation was to evaluate the performance of different hemofilters in CAVHDF. In 10 critically ill patients with acute renal failure, the efficiency of four hollow-fiber hemofilters, polyamide 0.6 m2, polyacrylonitrile (PAN) 0.3 and 0.6 m2, acrylonitrile sodium methallylsulfonate (AN69HF) 0.6 m2, has been evaluated. For comparison, dialysate flow rates (Qdi) were standardized to 16.6 and 25 ml/min. Samples for urea nitrogen were obtained from the arterial blood line (Cbi) and from the dialysate exit port (Cdo) within 24-hour running time. Outflowing dialysate (Qdo) was also measured at the same time. Blood flow (Qb) was calculated by the bubble transit time technique. Diffusive and total urea clearances were determined. AN69HF and PAN hemofilters provided higher clearances than the polyamide hemofilter. Despite the smaller surface area, PAN 0.3 m2 had a total urea clearance comparable to that of PAN 0.6 m2 and AN69HF at Qdi = 16.6 ml/min. While at Qdi = 16.6 ml/min equilibrium between blood and dialysate (Cdo/Cbi ≅ 1) occurred with the AN69HF and PAN hemofilters, at Qdi = 25 ml/min the equilibrium was obtained only with the AN69HF hemofilter. In conclusion, almost complete urea saturation of dialysis fluid has not been obtained with all hemofilters tested here. In our experience, membrane characteristics play an important role in determining diffusive efficiency in CAVHDF.

Background Recent guidelines suggest the adoption of regional citrate anticoagulation (RCA) as first choice CRRT anticoagulation modality in patients without contraindications for citrate. Regardless of the anticoagulation protocol, hypophosphatemia represents a potential drawback of CRRT which could be prevented by the adoption of phosphate-containing CRRT solutions. The aim was to evaluate the effects on acid–base status and phosphate supplementation needs of a new RCA protocol for Continuous Venovenous Hemodiafiltration (CVVHDF) combining the use of citrate with a phosphate-containing CRRT solution. Methods To refine our routine RCA-CVVH protocol (12 mmol/l citrate, HCO3- 32 mmol/l replacement fluid) (protocol A) and to prevent CRRT-related hypophosphatemia, we introduced a new RCA-CVVHDF protocol (protocol B) combining an 18 mmol/l citrate solution with a phosphate-containing dialysate/replacement fluid (HCO3- 30 mmol/l, Phosphate 1.2). A low citrate dose (2.5–3 mmol/l) and a higher than usual target circuit-Ca2+ (≤0.5 mmol/l) have been adopted. Results Two historical groups of heart surgery patients (n = 40) underwent RCA-CRRT with protocol A (n = 20, 102 circuits, total running time 5283 hours) or protocol B (n = 20, 138 circuits, total running time 7308 hours). Despite higher circuit-Ca2+ in protocol B (0.37 vs 0.42 mmol/l, p

Purpose The need for prolonged anticoagulation and the occurrence of hypophosphatemia are well known drawbacks of continuous renal replacement therapies (CRRT). The aim was to evaluate the effects on acid-base status and serum phosphate of a regional citrate anticoagulation (RCA) protocol for continuous veno-venous hemofiltration (CVVH) combining the use of citrate with a phosphate-containing replacement fluid. Methods In a small cohort of heart surgery patients undergoing CRRT for acute kidney injury, we adopted an RCA-CVVH protocol based on a commercially available citrate solution (18 mmol/l) combined with a recently introduced phosphate-containing replacement fluid (HCO3− 30 mmol/l, phosphate 1.2), aimed at preventing phosphate depletion. Results In 10 high bleeding-risk patients, the RCA-CVVH protocol provided an adequate circuit lifetime (46.8 ± 30.3 h) despite the adoption of a low citrate dose and a higher than usual target circuit Ca2+ (≤0.5 mmol/l). Acid-base status was adequately maintained without the need for additional interventions on RCA-CVVH parameters and without indirect sign of citrate accumulation [(pH 7.43 (7.41-7.47), bicarbonate 24.4 mmol/l (23.2-25.6), BE 0 (-1.5 to 1.1), calcium ratio 1.97 (1.82-2.01); median (IQR)]. Serum phosphate was steadily maintained in a narrow range throughout RCA-CVVH days [1.1 mmol/l (0.9-1.4)]. A low amount of phosphorus supplementation (0.9 ± 2 g/day) was required in only 30% of patients. Conclusions Although needing further evaluation, the proposed RCA-CVVH protocol ensured a safe and effective RCA without electrolyte and/or acid-base derangements. CRRT-induced hypophosphatemia was prevented in most of the patients by the adoption of a phosphate-containing replacement solution, minimizing phosphate supplementation needs.

In the critically ill patient, acute kidney injury (AKI) is frequently associated with infective complications requiring appropriate antimicrobial treatment. AKI and multiple organ dysfunction syndrome can affect the pharmacokinetic parameters of many drugs. Furthermore, the start of renal replacement therapy (RRT) is an additional variable to be taken into consideration to avoid inappropriate antimicrobial therapy. Continuous renal replacement therapies (CRRT) are widely adopted in the intensive care unit (ICU) and antibiotics that are significantly eliminated by the kidney are likely to be removed during RRT. Generally, drug-dosing adjustments are required if the extracorporeal clearance accounts for more than 25-30% of the total body clearance. The molecular weight cutoffs of the more widely used membranes are much higher than the molecular weight of most drugs. Therefore, molecular size will not be a limitation for the removal of the unbound fraction of the antibiotics most commonly used in ICU patients. However, CRRTs are still not standardized and the impact of RRT on plasma drug concentrations can be substantially different depending on the CRRT modality (diffusive, convective or both), membrane characteristics and delivered dialysis dose. In any case, drug-dosing adjustments should be based on the knowledge of the pharmacokinetic and pharmacodynamic properties of the different classes of antimicrobials, taking into account that high extracorporeal clearances could lead to drug underexposure in clinical conditions where appropriate antibiotic treatment is essential.

Introduction Regional citrate anticoagulation (RCA) is a valid option in patients at high risk of bleeding who are undergoing continuous renal replacement therapy (CRRT). The aim of this study was to evaluate, in critically ill patients with severe acute kidney injury following cardiac surgery, the efficacy and safety of RCA-continuous veno-venous hemofiltration (CVVH) using a low concentration citrate solution. Methods In high bleeding-risk cardiac surgery patients, we adopted, as an alternative to heparin or no anticoagulation, RCA-CVVH using a 12 mmol/l citrate solution. For RCA-CVVH settings, we developed a mathematical model to roughly estimate citrate load and calcium loss. In order to minimize calcium chloride supplementation, a calcium-containing solution was used as post-dilution replacement fluid. Statistical analysis was performed using the Student t-test or analysis of variance (ANOVA) with post-hoc tests, Wilcoxon or Kruskal-Wallis tests for non-parametric analysis, and Kaplan-Meier survival analysis with Log Rank test. Results Thirty-three patients (age 70.8 ± 9.5, Sequential Organ Failure Assessment (SOFA) score 13.9 ± 2.5) were switched to RCA-CVVH from no anticoagulation CRRT. Among them, 16 patients had been previously switched from heparin to no anticoagulation because of bleeding or heparin-related complications. RCA-CVVH filter life (49.8 ± 35.4 hours, median 41, 152 circuits) was significantly longer (P < 0.0001) when compared with heparin (30.6 ± 24.3 hours, median 22, 73 circuits) or no anticoagulation (25.7 ± 21.2 hours, median 20, 77 circuits). Target circuit and systemic Ca++ were easily maintained (0.37 ± 0.09 and 1.18 ± 0.13 mmol/l), while the persistence of a mild metabolic acidosis required bicarbonate supplementation (5.8 ± 5.9 mmol/hours) in 27 patients. The probability of circuit running at 24, 48, 72 hours was higher during RCA-CVVH (P < 0.0001), with a lower discrepancy between delivered and prescribed CRRT dose (P < 0.0001). RCA was associated with a lower transfusion rate (P < 0.02). Platelet count (P = 0.012) and antithrombin III activity (P = 0.004) increased throughout RCA-CVVH, reducing the need for supplementation. Conclusions RCA safely prolonged filter life while decreasing CRRT downtime, transfusion rates and supplementation needs for antithrombin III and platelets. In cardiac surgery patients with severe multiple organ dysfunction syndrome, the adoption of a 12 mmol/l citrate solution may provide a suboptimal buffers supply, easily overwhelmed by bicarbonate supplementation.

Continuous renal replacement therapy (CRRT) is the most widely used technique for the treatment of severe acute kidney injury in the critically ill. The need for prolonged anticoagulation is the most important drawback of CRRT and clinically important bleeding significantly increases the risk of death. Therefore, alternative anticoagulation methods should be more widely adopted. Among the potential alternatives to systemic heparin anticoagulation, regional citrate anticoagulation (RCA) is the most promising. By reducing ionized calcium inside the extracorporeal circuit, citrate is able to block the coagulation cascade at different levels. Compared with unfractionated heparin, several studies reported better filter survival times and a marked reduction of transfusion rates with RCA. Despite the positive reports about the efficacy and safety of RCA, the use of this alternative method of anticoagulation appears to be relatively limited. Desirable future improvements in RCA should be focused on simplifying protocols, minimizing the need for calcium and magnesium supplementation, increasing the flexibility of buffer balance, and introducing customized dialysis systems able to deliver automated RCA. In particular, safe protocols with automated delivery of citrate and calcium can allow easy parameter settings that can be adapted to a wide range of clinical situations, facilitating the wider use of RCA in the coming years.

The charge permselectivity of proteins was evaluated in diabetic patients after systemic and renal hemodynamic changes induced by an intravenous injection of an angiotensin-converting enzyme inhibitor (captopril) or of clonidine. Anionic immunoglobulin clearance (IgG4) was compared with that of total immunoglobulins, which have the same size but are mostly cationic, and of albumin. Ten type I hypertensive diabetic patients (group 1), 10 type 2 hypertensive diabetic patients (group 2), 5 type 1 normotensive diabetic patients (group 3), 10 subjects with essential hypertension (group 4), and 7 normal volunteers (group 5) received an intravenous injection of captopril (25 mg/100 ml in 5 min). Twelve of the hypertensive diabetic patients underwent a second provocative test with clonidine (150 micrograms/100 ml) (group 6) or placebo (100 ml saline) (group 7) with the same procedure. None of the patients had clinical nephropathy or other disorders. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured before and during the tests. A significant decrease in diastolic blood pressure was observed in groups 1, 2, 4, and 6, together with an increase in the GFR and RPF values in groups 1, 2, 3, and 4 only, as well as a decrease in renal vascular resistances in groups 1, 2, 3, 4, and 6. Both clearances and fractional clearances of IgG4 and IgG decreased after captopril in groups 1 and 2.2+ The decrease in IgG4 clearance was correlated to that of renal vascular resistances in group 1 patients. A significant decrease in the anionic-cationic immunoglobulin ratio (IgG4/IgG) was observed in groups 1, 2, and 3.(ABSTRACT TRUNCATED AT 250 WORDS)

The time course of blood pressure in clinically healthy (pregnant and nonpregnant) women was followed by automatic ambulatory monitoring. Chronobiologic methods revealed the time course of dynamic rhythm characteristics as a function of gestational age. Differences were found between nonpregnant and pregnant women with an overall lowering during pregnancy of the rhythm-adjusted midline estimating statistic of rhythm (mesor).

Blood pressure (BP) monitoring is a clinical reality because of the availability of non-invasive automated recorders. BP 24-h patterns were explored during physiologic pregnancies in order to obtain time-qualified standards for clinical use. Non-inferential and inferential reference boundaries were computed by using chronobiometric procedures. The computed confidence limits provide a set of reference standards that serves to optimize the diagnosis of pregnancy-induced deviation in BP 24-h patterns.

Mycophenolate mofetil (MMF) has been suggested as a promising therapeutic agent in the treatment of idiopathic nephrotic syndrome. Two patients with persistent nephrotic syndrome, secondary to minimal change disease and idiopathic membranous nephropathy, respectively, who were steroid-, cyclophosphamide- and cyclosporine-resistant, were treated with MMF during a 6-12-month period. In these cases there was no beneficial effect from treatment with MMF. Therapy was stopped after 6 months in case 1 and after 12 months in case 2 due to the persistence of proteinuria.

Cronkhite-Canada Syndrome is a non-inherited, non-congenital disease characterized by juvenile hamartomatous gastrointestinal polyps with a typically late onset. In the case described herein the disease was diagnosed in a 17-year-old male with type I diabetes and thalassaemia minor, in coincidence with severe symptomatic intestinal candidiasis. Following the disappearance of the mycosis and correction of the protein and electrolyte imbalance, the ectodermal abnormalities returned to normal and the patient remained asymptomatic during a 7-year follow-up period, despite proteinuria resulting from membranous glomerulopathy. The concept that Cronkhite-Canada Syndrome is a late-onset disease should probably be reconsidered as it may remain asymptomatic, and thus not diagnosed, for a long a time.

The ongoing necessity for systemic heparinization is a well-known disadvantage of continuous renal replacement therapies (CRRT), and alternative methods of anticoagulation may be required. Our aim was to evaluate, in patients with a high risk of bleeding, the possibility of an acceptable filter life with non-anticoagulation CRRT and, in case of early filter failure, the efficacy and safety of bedside monitored regional anticoagulation with heparin and protamine.Fifty-nine patients underwent CRRT for acute renal failure (ARF) following cardiac surgery. Patients who fulfilled one of the following criteria were selected for non-anticoagulation CRRT: spontaneous bleeding, aPTT45 sec, thrombocytopenia and recent surgery (48 hr). Filter life24 hr without anticoagulation was the cut-off point for starting the regional anticoagulation CRRT. Heparin was infused pre-filter and protamine post-filter at an initial ratio of 1 mg protamine:100 IU heparin. The ratio was adjusted to achieve a patient aPTT45 sec and a circuit55 sec.Twenty-two (37.3%) patients had been selected for non-anticoagulation. Of them, 12 patients continued to receive non-anticoagulation (filter life: 38.3 +/- 30.5 hr) while 10 switched to regional anticoagulation (filter life: 38.6 +/- 25 hr). During regional anticoagulation no statistical difference was found between baseline aPTT (36.7 +/- 6.4 sec) and patient aPTT (41.5 +/- 12.6 sec) while circuit aPTT (77.7 +/- 43.3 sec) was significantly higher than patient aPTT (p0.0001). The probabilities of the circuits remaining free from clotting after 24, 48 and 72 hr were: a) non-anticoagulation: 55.5%, 30.1% and 16.6%, b) regional anticoagulation: 76.2%, 39.6% and 19.8%. There was no rebound anticoagulation observed after regional anticoagulation CRRT ended.Non-anticoagulation CRRT allowed an adequate filter life in most patients with a high risk of bleeding for prolonged aPTT and/or thrombocytopenia. Despite concerns regarding the need for careful monitoring, regional anticoagulation with heparin and protamine can be considered as a safe and valid alternative when non-anticoagulation is unsuitable because of early filter failure.

The finding of increased levels of immunoglobulin A (IgA) against food antigens in patients with IgA nephropathy prompted the hypothesis of an association between IgA nephropathy and celiac disease (CD). Attention was initially directed to antigliadin antibodies, then to IgA antiendomysial antibodies (IgA-EMA). IgG1-EMA have been found in patients with CD with IgA-EMA-negative results. The presence of IgA- and IgG1-EMA was investigated in 36 patients with IgA nephropathy, 15 patients with other primary glomerulonephritis, and 15 patients with lupus nephritis. IgA-EMA and IgG1-EMA were detected by indirect immunofluorescence analysis. At the time of renal biopsy, the following factors were evaluated: history of macroscopic hematuria, serum creatinine level, urinalysis, 24-hour proteinuria, blood pressure, and histological classification of IgA nephropathy. Sixteen of 36 patients with IgA nephropathy (44.4%) showed EMA positivity. Among patients with positive EMA, 12 patients (75%) were IgG1-EMA positive, 2 patients (12.5%) were IgA-EMA positive, and 2 patients (12.5%) were positive for both isotypes. No significant differences were observed between the two groups (EMA positive versus EMA negative) concerning age, serum creatinine level, macroscopic hematuria, blood pressure, 24-hour proteinuria, or degree of renal histological involvement. IgA- and IgG1-EMA were not detected in patients with other primary nephropathies or lupus nephritis. These results, based on the finding of IgG1-EMA, suggest a common pathogenetic pathway for CD and IgA nephropathy. On this basis, the presence of IgG1-EMA and/or IgA-EMA should be investigated in patients with IgA nephropathy. Furthermore, the role of a gluten-free diet in the natural history of IgA nephropathy, at least in EMA-positive patients, needs to be ascertained.

The use of antiplatelet agents in chronic glomerular disease is reviewed, with emphasis on drugs affecting thromboxane A2 synthesis or action. The results of short-term and long-term studies in human as well as animal models suggest a role for enhanced intrarenal synthesis of thromboxane A2, though not clearly defining the potential platelet vs glomerular targets of drug action. The availability of novel inhibitors and antagonists may provide new therapeutic strategies against thromboxane-A2-dependent loss of renal function.

In contrast to a variety of clinical conditions characterized by ineffective circulatory volume, chronic glomerular disease is not usually associated with increased circulating levels of vasoconstrictor hormones. However, a reduction in glomerular prostacyclin production can possibly account for the prostaglandin dependence of renal function in these patients by virtue of the enhanced constrictor effects of angiotensin II on glomerular arterioles and mesangium. The reduction of renal function induced by a nonselective cyclo-oxygenase inhibitor is inversely related to the basal prostacyclin production. Increased renal synthesis of vasoconstrictor thromboxane A2, as noted in patients with systemic lupus erythematosus, might contribute to the cyclo-oxygenase dependence of renal function. Aspirin as well as a variety of structurally unrelated nonsteroidal anti-inflammatory drugs reduce renal function in systemic lupus erythematosus patients. However, the functional consequences of renal cyclo-oxygenase inhibition are partially attenuated in patients with lupus nephritis vis-à-vis other forms of chronic glomerular disease because of concomitant suppression of enhanced glomerular thromboxane A2 production. Animal data consistent with a prevailing functional significance of vasodilator prostaglandins have also been reported. Short-term administration of sulindac at the recommended dosage is relatively safe in patients with chronic glomerular disease because of selective sparing of glomerular cyclo-oxygenase activity. The long-term consequences of selective versus nonselective cyclo-oxygenase inhibition remain to be established in humans. The beneficial effects of a combination of aspirin and dipyridamole in slowing the deterioration of renal function in patients with membranoproliferative glomerulonephritis does provide a rationale for exploring the effects of low-dose aspirin (i.e., 0.5 to 1.0 mg/kg per day), which most effectively suppresses platelet thromboxane A2 production without interfering with renal prostacyclin synthesis.

An analytical method useful for the quantitative determination of some bile acids is proposed. The analysis is carried out in two steps. The first is based on the thin layer chromatographic (TLC) separation of the bile acids on alumina plates. The second is based on the application of differential scanning calorimetry (DSC), which permits the characterization and determination of the amount of compound contained in each spot. The DSC signal is proportional to the amount of sample present in the spot layer, while the various peaks and peak temperatures are used to identify the separated compound.

We investigated whether the glomerular synthesis of prostacyclin modulates the renal blood flow and glomerular filtration rate in chronic glomerular disease. The urinary excretion of 6-keto-prostaglandin F1 alpha, a stable breakdown product of prostacyclin, was significantly (P less than 0.01) reduced in 20 women with chronic glomerular disease, as compared with 19 controls, whereas excretion of urinary prostaglandin E2 was unchanged. In 10 patients randomly assigned to one week of treatment with ibuprofen, excretion of urinary 6-keto-prostaglandin F1 alpha and prostaglandin E2 was reduced by 80 per cent, the level of serum creatinine was increased by 40 per cent, and creatinine and para-aminohippurate clearances were reduced by 28 and 35 per cent, respectively. The reduction of both clearances was inversely related (P less than 0.01) to the basal urinary excretion of 6-keto-prostaglandin F1 alpha but not of prostaglandin E2. No functional changes were detected in five healthy women, despite a similar suppression of renal prostacyclin synthesis by ibuprofen. In contrast, one week of treatment with sulindac did not affect renal prostacyclin synthesis or renal function in the other 10 patients, despite a marked inhibition of extrarenal cyclooxygenase activity. We conclude that in patients with mild impairment of renal function, the renal blood flow and glomerular filtration rate are critically dependent on prostacyclin production. In such patients sulindac may be a safe substitute for other nonsteroidal antiinflammatory drugs.

The effects of Prostacyclin (PGI2) infusion on insulin secretion and glucose tolerance were investigated in 7 healthy subjects. PGI2 infusion caused no statistically significant changes of either glucose or insulin concentration, over the range 2.5-20 ng/Kg/min. A constant PGI2 infusion (10 ng/Kg/min) did not inhibit acute insulin responses to a glucose (20 g i.v.) pulse (response before PGI2 = 612 +/- 307%; during PGI2 = 515 +/- 468%, mean +/- SD, mean change 3-5 min insulin, % basal; P=NS). Glucose disappearance rates were similar after the first and second glucose pulse. Thus, in contrast to PGE2, PGI2 does not affect insulin secretion nor glucose disposal at doses producing platelet and vascular changes. It is hypothesized that an altered PGI2/PGE2 balance in diabetes may represent a link between vascular, platelet and metabolic changes.

Ten hypertensive, non-nephrotic patients with immunoglobulin (IgA) nephropathy treated with conventional therapy (vasodilators, beta-blockers, diuretics) were observed for 21.4 +/- 9 months. Treatment was then changed to an angiotensin converting enzyme (ACE) inhibitor alone for an additional 22.6 +/- 9 months. The ACE inhibitor therapy was associated with a lower diastolic blood pressure and a slowing in the rate of decline in renal function, but no change in proteinuria.

A detailed time course of changes in plasma renin activity (PRA), urinary prostaglandin (PG) E2, PGF2 alpha, thromboxane (TX) B2 and sodium excretion rates following furosemide was obtained in 7 women. PRA increased within the first 15 min and remained elevated all through the experiment. PGE2, PGF2 alpha, TXB2 and sodium increased simultaneously, reached a peak between 15 and 45 min after furosemide and declined thereafter. It is concluded that furosemide induces a generalized activation of the renal PG system temporally related to the increase of renin release and natriuresis.

We have measured the excretion of a major urinary metabolite of thromboxane B2 (TxB2), i.e., 2,3-dinor-TxB2, during the infusion of exogenous TxB2 over a 50-fold dose range to enable estimation of the rate entry of endogenous TxB2 into the bloodstream. Four healthy male volunteers received 6-h i.v. infusions of venhicle alone and TxB2 at 0.1, 1.0, and 5.0 ng/kg X min in random order. They were pretreated with aspirin at a dose of 325 mg/d in order to suppress endogenous TxB2 production. Urinary 2,3-dinor-TxB2 was measured before, during, and up to 24 h after the infusions and in aspirin-free periods, by means of radioimmunoassay. The nature of the extracted immunoreactivity was characterized by thin-layer chromatography and confirmed by negative ion-chemical ionization gas chromatography/mass spectrometry. Aspirin treatment suppressed urinary 2,3-dinor-TxB2 excretion by 80%. The fractional elimination of 2,3-dinor-TxB2 was independent of the rate of TxB2 infusion and averaged 5.3 +/- 0.8%. Interpolation of metabolite values obtained in aspirin-free periods onto the linear relationship between the quantities of infused TxB2 and the amount of metabolite excreted in excess of control values (y = 0.0066x, r = 0.975, P less than 0.001) permitted calculation of the mean rate of entry of endogenous TxB2 into the circulation as 0.11 ng/kg X min. The rate of disappearance of immunoreactive TxB2 from the circulation was monoexponential over the first 10 min with an apparent half-life of 7 min. This corresponded to a maximal estimate of the plasma concentration of endogenous TxB2 of 2.0 pg/ml. These results suggest that ex vivo platelet activation and/or analytical problems confound estimates of endogenous thromboxane release based on plasma TxB2 and provide a rationale for seeking longer-lived enzymatic metabolites of TxB2 in plasma.

The aim of this research was to study exogenous prostacyclin effect on urinary kallikrein excretion (UKK) in man, to define whether prostacyclin-induced renin release and/or endogenously released cyclooxygenase products were responsible for prostacyclin-induced enhancement of UKK, to determine furosemide effect on UKK. Prostacyclin was infused in eight healthy men and repeated after propranolol and indomethacin treatment. Prostacyclin caused a dose-dependent increase of UKK. Pretreatment with propranolol and indomethacin did not affect prostacyclin-induced enhancement of UKK, although it reduced absolute values of plasma renin activity. Furosemide increased UKK and simultaneously urinary 6-keto-prostaglandin F1 alpha. We conclude that prostacyclin induces an increase in UKK in a dose-dependent manner; furosemide-induced renal prostacyclin synthesis is temporally related to enhancement of UKK; partial dissociation of UKK from plasma renin activity under propranolol and indomethacin treatment and in response to furosemide might suggest a direct effect of prostacyclin on UKK.

We measured the renal and extrarenal synthesis of prostacyclin and thromboxane A2, as reflected by the urinary excretion of the stable hydration products 6-keto-prostaglandin F1α and thromboxane B2 and the corresponding 2,3-dinor-derivatives, during chronic administration of sulindac (200, 400, 600, and 800 mg/day, each dose given for 7 days in successive weeks) in seven healthy subjects. Urinary eicosanoids were measured by negative ion, chemical ionization–GC/MS–validated RIA techniques. Both 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1α showed a dose-dependent reduction, ranging between 45% and 85%. In contrast, the urinary excretion of 6-keto-prostaglandin F1α and thromboxane B2 did not change significantly throughout the study. These results extend previous observations of a selective sparing of renal cyclooxygenase activity by sulindac in humans and demonstrate that this selectivity is not related to an overall weaker enzyme inhibition. Clinical Pharmacology and Therapeutics (1987) 41, 380–383; doi:10.1038/clpt.1987.44

We have examined the urinary excretion of stable immunoreactive eicosanoids in 23 female patients with systemic lupus erythematosus (SLE), 16 patients with chronic glomerular disease (CGD), and 20 healthy women. SLE patients had significantly higher urinary thromboxane B2 (TXB2) and prostaglandin (PG) E2 excretion and significantly lower 6-keto-PGF1 alpha than did healthy women. In contrast, CGD patients only differed from controls for having reduced 6-keto-PGF1 alpha excretion. The group of SLE patients with active renal lesions differed significantly from the group with inactive lesions for having a lower creatinine clearance and urinary 6-keto-PGF1 alpha and higher urinary TXB2. Higher urinary TXB2 excretion was associated with comparable platelet TXB2 production in whole blood, undetectable TXB2 in peripheral venous blood, and unchanged urinary excretion of 2,3-dinor-TXB2. A significant inverse correlation was found between urinary TXB2 and creatinine clearance rate (CCr). In contrast, the urinary excretion of 6-keto-PGF1 alpha showed a significant linear correlation with both CCr and para-aminohippurate clearance rate (CPAH). In four SLE and seven CGD patients, inhibition of renal cyclooxygenase activity by ibuprofen was associated with a significant reduction in urinary 6-keto-PGF1 alpha and TXB2 and in both CCr and CPAH. However, the average decrease in both clearances was 50% lower in SLE patients than in CGD patients, when fractionated by the reduction in urinary 6-keto-PGF1 alpha or PGE2 excretion. We conclude that the intrarenal synthesis of PGI2 and TXA2 is specifically altered in SLE. Such biochemical alterations are associated with changes in glomerular hemodynamics and may play a role in the progression of SLE nephropathy.

Prostaglandin (PG) I2 or prostacyclin and thrombaxane (Tx) A2 are labile oxygenated metabolites of arachidonate with contrasting effects on platelet function, vascular tone and glomerular function1,2. In humans the corresponding stable hydration products, 6-keto-PGF1α and TxB2 respectively, are synthesized by renal cortical microsomes3, represent the most abundant cyclooxygenase products of arachidonate in isolated glomeruli4 and can be measured in urine5,6.

A large body of evidence suggests a complex role of renal prostaglandins (PGs) in the control of cortical and medullary functions, i.e., renal blood flow (RBF), glomerular filtration rate (GFR), renin release, urinary concentrating mechanism, and electrolyte and water excretion. Several reviews of renal arachidonic acid metabolism can be recommended (1–4). PGs are considered to be ubiquitous autacoids, that is, substances that act predominantly at their production site. Since different nephron segments have highly specialized structures and functions, the synthesis and functions of the various PGs should be considered separately for each segment, rather than globally for the whole kidney (3). Although no direct evidence exists for a differential origin of any given urinary eicosanoid from a well-defined nephron segment in human kidney, a working hypothesis can be put forward relating cellular sites of biosynthesis and potential actions of eicosanoids to urinary excretion (Table 1). Prostacyclin (PGI2) and prostaglandin (PG)En are powerful vasodilators and appear to serve an important role in maintaining renal vasodilation. However, in the human kidney, PGI2 is primarily involved in the modulation of cortical events, i.e., RBF, GFR and renin release, while PGE2 is largely confined to controlling medullary functions, i.e., medullary blood flow, sodium and chloride reabsorption in the loop of Henle, and collecting-tubule response to vasopressin.

The thermal behaviour of 1,2-dipalmitoyl-L-phosphatidyl choline is examined together with that of a mixture of 1,2-dipalmitoyl-L-phosphatidyl choline and cholesterol to analyse the interactions between these two systems and to obtain useful information at the level of biological membrane bilayers.

To test the hypothesis that the vasoconstrictor thromboxane A2 may affect renal hemodynamics in lupus nephritis, we examined the short-term effects of a selective thromboxane-receptor antagonist, BM 13,177, and of low-dose aspirin. In a randomized, double-blind, crossover study, 10 patients with biopsy-proved lupus nephritis were given a 48-hour continuous infusion of BM 13,177 or placebo. At base line, seven patients had markedly elevated urinary levels of thromboxane B2, the breakdown product of thromboxane A2. During the infusion of BM 13,177, the inulin clearance rate, which was 68 ml per minute per 1.73 m2 of body-surface area at base line, increased by an average of 24 percent (range, 12 to 47 percent; P less than 0.01). Para-aminohippurate clearance was increased to the same extent, with no change in the filtration fraction. The bleeding time doubled, indicating an occupancy of platelet thromboxane receptors of more than 95 percent. The hemodynamic changes were associated with a significant increase in sodium excretion from 76 to 118 mmol per day (P less than 0.01) but with no change in arterial blood pressure. In another study, 10 additional patients with lupus nephritis were randomly assigned to receive either placebo or 20 mg of aspirin twice daily for four weeks. The aspirin regimen produced a selective, cumulative inhibition of platelet cyclooxygenase activity and a doubling of bleeding time. However, there was no change in the inulin clearance rate and no change in urinary levels of thromboxane B2 or 6-keto-prostaglandin F1 alpha, which are indicators of renal synthesis of thromboxane A2 and prostacyclin, respectively. We conclude that in lupus nephritis, impairment of renal function is at least in part mediated hemodynamically and is reversible with a thromboxane antagonist. Platelets, however, are not a major source of thromboxane A2 synthesis and action within the kidney.

Thromboxane (TX) B2, the chemically stable hydration product of pro-aggregatory TXA2, undergoes two major pathways of metabolism in man, resulting in the formation of 2.3-dinor-TXB2 and 11-dehydro-TXB2, respectively. We have measured the excretion of the latter during the infusion of exogenous TXB2 over a 50-fold dose range in order to examine the fractional conversion of TXB2 to urinary 11-dehydro-TXB2 and to re-assess the rate of entry of endogenous TXB2 into the circulation. Four healthy male volunteers received 6-h intravenous infusions of the vehicle alone and TXB2 at 0.1, 1.0 and 5.0 ng.kg-1.min-1 in random order. They were pretreated with aspirin 325 mg/d in order to suppress endogenous TXB2 production. Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were measured before, during and up to 24 h after the infusions and in aspirin-free periods, by means of NICI-GC/MS-validated radioimmunoassays. Aspirin treatment suppressed urinary 11-dehydro-TXB2 by 91%. The fractional elimination of 11-dehydro-TXB2 was independent of the rate of TXB2 infusion and averaged 6.8 +/- 0.7%, as compared to 6.4 +/- 0.9% for 2,3-dinor-TXB2. Interpolation of 11-dehydro-TXB2 values obtained in aspirin-free periods onto the linear relationship between the quantities of infused TXB2 and the amount of metabolite excreted in excess of control values (y = 0.0058x, r = 0.94, P less than 0.001) permitted calculation of the mean rate of entry of endogenous TXB2 into the circulation as 0.12 ng.kg-1.min-1. We conclude that: (a) urinary 11-dehydro-TXB2 is at least as abundant a conversion product of exogenously infused TXB2 as 2,3-dinor-TXB2; (b) its excretion increases linearly as a function of the rate of entry of TXB2 into the circulation up to approx. 40-fold the calculated rate of secretion of endogenous TXB2; (c) the latter is consistent with previous estimates based on monitoring of the beta-oxidation pathway of TXB2 metabolism.

Urinary kallikrein excretion was evaluated in 85 normal subjects and in 149 uncomplicated and recently diagnosed essential hypertensive patients. Moreover, the possible interrelationships between urinary kallikrein excretion and age, sex, electrolyte excretion, and plasma renin activity were examined. In patients with essential hypertension, urinary kallikrein excretion was similar to that of normal subjects. In these patients the enzyme was weakly and positively related to urinary potassium and plasma renin activity; no correlation was found with blood pressure, urinary sodium, age, or sex. In normal subjects and in patients with essential hypertension, the variables studied account for only 25% and 17%, respectively, of the variability of urinary kallikrein excretion. We conclude that the relatively short duration of hypertension in our patients may explain the unaltered values of urinary kallikrein excretion with respect to controls.

Phosphate depletion is a known issue during continuous renal replacement therapies (CRRT) with an incidence of hypophosphatemia up to 80% when standard CRRT solutions are used. The aim was to evaluate the effects on serum phosphate and phosphorus supplementation needs of a regional citrate anticoagulation (RCA) protocol for CRRT combining the use of citrate with a phosphate-containing CRRT solution.