[Treatment of septic shock with the use of CPFA (associated plasma filtration and adsorption): impact on hemodynamics monitored with PiCCO ]. / Trattamento dello shock settico con l'impiego della CPFA (plasmafiltrazione e adsorbimento associate): impatto sull'emodinamica valutata con sistema PiCCO

BACKGROUND: Septic shock represents an emerging pathology and sepsis and its complications are the main cause of death in medical and surgical intensive care units. Single-target therapeutic trials failed to demonstrate any benefit, suggesting that the unselective removal of different mediators may be a more appropriate approach. METHODS: We evaluated a new technique (CPFA) combining a plasma-adsorption (with plasma filter and sorbent cartridge) with a traditional 'slow' extracorporeal treatment on 10 patients, 7 men and 3 women (mean age 53.8+/-16.3), all on mechanical ventilation, with septic shock and multiorgan failure. To identify easily comparable clinical data, the hemodynamic parameters of the patients were monitored with a recently developed, minimally invasive technology, Pulsion PiCCO . RESULTS: We obtained significant improvement of pre- versus post-treatment mean arterial pressure 77.2+/-12.5 vs. 83.3+/-14.1 mmHg (p<0.0001), cardiac index 4.03+/-0.89 vs. 3.46+/-0.82 L/m2/min (p<0.0001), indexed systemic vascular resistances 1388+/-496 vs. 1753+/-516 dynes x sec/cm5 (p<0.0001), PaO2/FiO2 ratio 204+/-87 vs. 232+/-81 (p<0.0001), and norepinephrine requirements 0.13+/-0.07 vs. 0 y/kg/min after a mean of 5.3+/-2.7 consecutive treatments. The survival at day 28 was 90%. Seven patients were discharged from the intensive care unit after a mean of 37.8+/-24 days (range 10-93). CONCLUSIONS: Our data suggest a promising role for CPFA in improving hemodynamics and correcting vasoparalysis in septic shock. Moreover, the noninvasive monitoring of hemodynamic parameters with PiCCO could become a useful tool for estimating the effect of treatment and gaining easily comparable data in different patients.

[Contrast nephropathy in cardiac procedures: no advantages with prophylactic use of N-acetylcysteine (NAC)]. / Nefropatia da contrasto in cardiologia interventistica: assenza di vantaggi con impiego profilattico di N-Acetilcisteina.

BACKGROUND: Acute renal failure induced by contrast agents represents the third cause of acute nephropathy in hospitalized patients. Some mediators are potentially involved in this process: recent data underscored the role of oxidising agents and prophylactic administration of NAC showed a lower incidence of acute renal damage after using contrast agents. METHODS: We analyzed 100 patients consecutively undergoing coronary angiography and/or transluminal angioplasty: the study group was given NAC orally at a dose of 600 mg twice daily, on the day before and on the day of administration of the contrast agent, together with hydration, while the control group was given only the hydration protocol with hypotonic saline. RESULTS: Twenty patients had baseline serum creatinine concentrations > 1.2 mg/dL (mild renal insufficiency group). The mean dose of contrast agent (Iodixanol; Visipaque 320, Nycomed) was 203 mL/procedure, with no statistical difference between groups. Among the patients with normal renal function, 5.7% in the NAC group and 8.8% in the control group had baseline serum creatinine concentrations above 0.3 mg/dL after 48 hours (p=NS). In patients with mild renal failure, 16.6% in the NAC group and 0% in the control group had serum creatinine concentrations > 0.5 mg/dL at 48 h (p=NS). We found no significant differences in serum creatinine values at 48 hours vs. baseline in anyone (NAC group with normal renal function or mild renal insufficiency, control group with normal renal function or mild renal insufficiency). Similarly, serum creatinine values at either baseline or after 48 hours were not significantly different in patients with normal renal function (NAC vs. control group) and with mild renal failure. CONCLUSIONS: Our study showed no potential advantage in the prevention of acute nephropathy, induced by high volumes of contrast agent, through the administration of NAC in patients with normal renal function and mild renal failure. However, the NAC dose used in our study might not be sufficient in balancing the contrast agent volume employed in these procedures.

[Organohalogen contamination of a dialysis-water treatment plant]. / Contaminazione da organo-alogenati di un impianto di trattamento di acqua per dialisi.

On March 2001 the regular quality control test of the water used for dialysis in an urban centre using a reverse osmosis system revealed a high level of organo-halogenated contamination. The compounds implicated were: trichloroethylene (trielene) [M.Wt. 131 D], tetrachloroethylene, trichloromethane (chloroform) [M.Wt. 121 D], chlorodibromomethane. The dialysis unit was closed. Water samples were analysed in duplicate. The table shows the values (in ppm or microgram/l) obtained for chloroform at the given times: March 8th, altered sample; March 12th, confirmation sample; March 16th, after osmosis membranes change; March 22nd, after carbon filtration replacement; March 26th, after softener resins substitution. The AAMI doesn't recommend any value for organo-halogenated compounds in dialysis water. In the past, the European Pharmacopoeia and the Italian Health Ministry released some reference values for tap water, values which were extended to water used for dialysis. The values are 1 ppm as reference value, 30 ppm as maximum accepted value for the sum of all organo-halogenated compounds, and 10 ppm as the recommended value. In conclusion, the problem was solved by progressive replacement of the components of the water treatment system, even though the real cause remained undetermined. No clinical symptom was recorded and no level of chloroform or trielene was detected in patients' sera despite the low molecular weight and low protein binding of the compounds. A strict control of the water quality and a more comprehensive and updated reference guide are needed for better and safer dialysis delivery.

[Microbiological evaluation of two different disinfection protocols of a new hemodialysis monitor with an ultrafilter]. / Valutazione microbiologica di due diversi protocolli di disinfezione di un nuovo monitor di dialisi dotato di ultrafiltro sul dialisato.

BACKGROUND: Hemodialysis monitors represent a frequent site for bacterial contamination. METHODS: Two different disinfection protocols on a new device (Formula(R), Bellco) have been compared: only chemical or chemical plus heat disinfection by means of CFU, and LAL test. The endotoxin removing capacity of ultrafilter was tested with varying lipopolysaccharide concentrations. RESULTS: Similar results were obtained with heat disinfection compared to chemical disinfection (CFU and LAL test). The LAL test (chromogenic and gel-clot) showed that the ultrafilter performance decreased with use and was significant after 200 operating hours. CONCLUSIONS: Heat disinfection between dialysis shifts and chemical disinfection at the end of the day exclude bacterial contamination of the monitor as well as chemical disinfection; LAL test is a useful and simple tool to assess the ultrafilters performance in each Center.

Dialock(R)subcutaneous port for hemodialysis: A twelve-month experience in a single center.

Background.The arteriovenous fistula (AVF) is still considered the golden standard form of vascular access for hemodialysis. However, the increasing use of central venous catheters mirrors the growing difficulty in planning an AVF. A totally implantable new device, the Dialock(R)system (Biolink Corporation, Norwell, MA), allowed us to conduct the first Italian experience. Methods.From February 1st 2000 to January 31st 2001, we implanted 21 devices in 12 males and 9 females, median age 66+/-12 years, with a dialysis duration ranging from 0 to 22 years. In 6 cases the Dialock (R)was first choice access, in 5 it replaced a malfunctioning tunneled central venous catheter, and in 10 cases it was the rescue access after previous AVF failures. Results.On average, the device was accessed 3.5 days after implantation. Median duration of use was 142 days (range 29-365), for a global observation period of 118.2 pt-months. Nineteen devices are currently working with-out any problem. One port was removed after 60 days due to thrombosis, and another after 9 months of use due to sepsis. Another patient had a systemic infection with cardiac and vertebral involvement with complete remission after 4 months of antibiotic therapy and salvage of the device. The infection rate was 1.3 per 1000 catheter-days. Prescribed blood flow was achieved in 95.7% of the sessions. Conclusion.Our short-term results confirm the efficacy and reliability of the new device. In order to assess the true indication for implanting Dialock(R), a more prolonged observation period is needed.

Steroid and cyclophosphamide in IgA nephropathy.

BACKGROUND: IgA nephropathy is associated with a wide spectrum of possible lesions. Therefore, different responses to anti-inflammatory or immunosuppressive therapies should be expected with acute inflammatory changes, which are predominantly reversible, and with prevalently sclerotic lesions. METHODS: The effects of a combined schedule of prednisone and cyclophosphamide was analysed in the specific subset of IgA nephropathy patients with acute inflammatory histologic changes associated with haematuria and proteinuria. Two groups of patients, with similar histologic lesions and clinical presentation, were considered. The first group (12 patients) was treated within 1 week after renal biopsy; starting with three pulses of methylprednisolone (1 g) followed by oral prednisone (0.8 mg/kg body weight for 2 weeks, 0.6 mg/kg for another 2 weeks, 0.4 mg/kg for an additional 4 weeks, then slowly tapered by 5 mg each month until discontinuation) and 1.5 mg/kg cyclophosphamide for 2 months. A second sample of eight untreated patients served as a control group. Treated and untreated patients had diffuse mesangial proliferation with florid crescents (8-60% in treated and 10-40% in untreated patients) with mild degree of glomerular sclerosis and interstitial changes. Basal creatinine (167 micromol/l, range 79-371 vs 132 micromol/l, range 79-256) and proteinuria (3.0 g/24 h, 1.0-4.9 vs 3.3 g/24 h, 1.0-13.7) were not statistically different between treated and untreated patients respectively. Nine treated and six untreated patients were hypertensive. Blood pressure treatment did not include ACE-inhibitors. RESULTS: Untreated patients' 5-year renal survival, as assessed by the Kaplan-Meier method, was found to be significantly lower than treated patients (37.5 vs 91.6%, log-rank P=0.01 and Breslow test P=0.008; relative risk to reach the endpoint of a 100% increase in serum creatinine=3.58, P=0.03). CONCLUSION: This short course of therapy with prednisone and cyclophosphamide has been effective in a subset of IgA nephropathy patients with florid glomerular changes and major urinary abnormalities, turning off phlogistic activity and preventing subsequent progression toward renal failure.

Effects of angiotensin II blockade on nitric oxide blood levels in IgA nephropathy.

BACKGROUND: The effects of renin-angiotensin system blockade on nitric oxide (NO), especially in pathological conditions, are far from being established. The influence of kinins and angiotensin type 2 receptor are largely speculative and based mainly on animal studies. This study was aimed to address these aspects in humans. METHODS: Eight IgA nephropathy patients with documented clinical and histological indicators of poor prognosis were given 50 mg of losartan, 10 mg of enalapril, and 40 mg of the NO donor isosorbide 5 mononitrate (as a control of NO generation) in randomized order for 7 days each. Treatment periods were separated by washout periods of 7 days each. Laboratory investigations were performed before and after each study period. Seven healthy controls received losartan and enalapril according to the same study design. RESULTS: Glomerular filtration rate remained stable while effective renal plasma flow increased with each treatment (P<0.05). Under losartan and enalapril, filtration fraction fell (P=0.02), plasma renin activity increased (P<0.05) and urinary aldosterone concentration decreased (P=0.02). Angiotensin-converting enzyme activity was reduced to the limit of detection under enalapril (P<0.001). Blood NO, detected as nitrosylhaemoglobin by a recently developed technique of spin-trap electron paramagnetic resonance, increased significantly, as expected, during treatment with isosorbide 5 mononitrate (P=0.01), with enalapril (P<0.05), and also with losartan (P<0.05). Unlike losartan, enalapril significantly reduced albuminuria (P=0.01) in this short-term period. In the seven healthy controls, neither enalapril nor losartan were able to increase blood NO levels significantly. CONCLUSIONS: Blood levels of nitrosylhaemoglobin, a surrogate marker of NO, increased under blockade of the renin-angiotensin system in patients with IgA nephropathy, but not in healthy volunteers. This increase could contribute to changes of effective renal plasma flow in renal disease states.

[Morbidity and mortality in patients undergoing dialysis. Comparison of hemodialysis and peritoneal dialysis. Our experience]. / Morbilità e mortalità in pazienti in dialisi. Confronto fra emodialisi e dialisi peritoneale. Nostra esperienza.

BACKGROUND: We have compared the hemodialysis and peritoneal dialysis populations of our Center for morbidity and mortality, in a retrospective study of six years of activity. METHODS: We enrolled 125 patients (104 patients/year/million inhabitants), who had been in chronic dialysis from 1992 to 1997: 90 (22-90 years old) initiated in hemodialysis and 35 (27-82 years old) in peritoneal dialysis. RESULTS: We have evaluated survival and morbility, as hospitalization/patient/year in both groups. Mortality did not prove significantly different in the two groups. The global average of hospitalization was 8 days/patient/year for hemodialysis and 6 for peritoneal dialysis. CONCLUSIONS: In spite of the short time of observation and the exiguity of numbers, our experience shows that the two methods are equivalent.

[Complex vascular access]. / Gli accessi vascolari complicati.

Availability of a proper vascular access is a basic condition for a proper extracorporeal replacement in end-stage chronic renal failure. However, biological factors, management and other problems, may variously condition their middle-long term survival. Therefore, personal experience of over 25 years has been critically reviewed in order to obtain useful information. In particular "hard" situations necessitating complex procedures have been examined but, if possible, preserving the peripherical vascular features.

Intradialytic cytokine gene expression.

Along with the numerous technological improvements in molecular biology, polymerase chain reaction, which permits analysis of sequences of a very small amount of biological material, enables evaluation of hemodialysis-induced gene transcription of inflammatory cytokines. Blood samples drawn from 22 hemodialysis patients, treated with cellulose-derived or synthetic membranes, were collected at 0 and 15 min of hemodialysis. Total RNA, purified from mononuclear cells, was reverse transcribed and cDNA amplified by polymerase chain reaction primed with specific oligomers in order to determine tumor necrosis factor alpha (TNF alpha), interleukin (IL) 1 beta and IL6 gene expression. Plasma samples were collected at 0 and 180 min for detection of mature cytokines by enzyme immunoassay with plates pre-coated with monoclonal antibodies to TNF alpha, IL1 beta and IL6. A significant increase in TNF alpha mRNA was detected at 15 min of hemodialysis in 12 of 22 patients: 5 of 9 treated with cuprophan; 3 of 3 with cellulose triacetate; 3 of 5 with polysulfone, and only 1 of 5 treated with polymethyl-methacrylate membranes. A parallel increase in IL1 beta or IL6 mRNA was detected, and significant relationships were found between TNF alpha and IL1 beta (p < 0.001), and IL1 beta and IL6 gene expression (p < 0.05). Increased levels of mature TNF alpha and IL1 beta molecules in plasma were detected in the majority of patients showing an increased cytokine gene expression. However, the absolute amount of cytokine mRNA transcription at 15 min did not predict the levels of mature molecules reached in plasma at 180 min. Cytokine mRNA transcription is quite common at the beginning of a dialysis run. Possibly due to intracellular degradation of critical sequences of cytokine mRNA, gene expression does not necessarily imply translation into mature protein. It is suggested that mechanisms related to cell-to-cell interaction, which may possibly involve procytokine biology, are needed to drive phenomena of cytokine activation to clinical effectiveness.

Impaired hepatosplenic elimination of circulating cryoglobulins in patients with essential mixed cryoglobulinaemia and hepatitis C virus (HCV) infection.

The pathogenic mechanisms that lead to renal deposition of the cryoprecipitable IgM rheumatoid factor-IgG complexes in essential mixed cryoglobulinaemia (EMC) are unknown. Defective removal of cryoprecipitable complexes from the circulation has been postulated in EMC-associated nephritis. To test this hypothesis, the kinetics and fate of a trace dose of 123I-radiolabelled autologous cryoglobulins were analysed in 13 patients with EMC grouped according to renal involvement. The time course of radioactivity distribution in the blood and organ uptake were measured by gamma camera scintigraphy. In blood sampled 30-300 s after injection, only a minor fraction (< 15%) of the circulating cryoglobulins bound to the erythrocytes, suggesting the elimination mechanisms are independent of binding to CR1 on erythrocytes. The overall blood disappearance curve showed a fast (< or = 1 min) and slow (> 4 h) biphasic pattern. In patients with quiescent or mild nepthritis, the liver and to a lesser extent the spleen were the major organs that mediated the rapid uptake and processing of the cryoglobulins from the circulation. In contrast, patients with active mesangiocapillary glomerulonephritis showed significantly (P < 0.001) less hepatic uptake, low liver-to-precordium ratio, and slower processing of cryoglobulins, prolonged liver mean transit time, than quiescent patients or mild nephritis patients. To elucidate the role and influence of HCV infection in the pathogenesis of EMC-nephritis, sera and cryoglobulins from all patients were assayed for HCV. None of the control group cases without nephritis showed any evidence of HCV-RNA in serum or cryoglobulin pellet. In contrast, all 10 EMC-nephritis patients' sera, and eight corresponding cryoglobulin pellets contained HCV-RNA. Collectively, these findings suggest an impaired reticuloendothelial system removal of IgM-IgG-HCV complexes may underlie their renal deposition.

[The complement system in kidney diseases]. / Il sistema del complemento in nefropatologia.

The multifaceted relations between complement system and immune-mediated nephropathies are reviewed. Several conditions in which either the complement activation induces renal damage without hypocomplementemia or hypocomplementemia occurs in the absence of circulating IC are reported as well as disorders in which immune complexes promote hypocomplementemia. The complement system is involved in the clearance of immune complexes, both modifying the immune complex size and favouring the physiologic neutralization by the erythrocyte transport system. In certain pathological conditions the immune complex intrinsic characteristic or genetic abnormalities prevent efficient removal from the blood stream. The purpose of the present review is to summarize these conditions, briefly describing their pathological consequences, and indicate a simple scheme to correctly interpret the biochemical abnormalities of the complement system in nephropathology.

Early increase in blood nitric oxide, detected by electron paramagnetic resonance as nitrosylhaemoglobin, in haemodialysis.

The objective of this study was to determine intradialytic blood levels of nitric oxide (NO), in patients undergoing chronic haemodialysis. This was done by detection of nitrosylhaemoglobin by a sensitive technique of spin trap electron paramagnetic resonance at 0, 5, 15, 60, 180 and 240 min of a 4-h standard bicarbonate dialysis, using the same dose (6000 U) of heparin and different dialysis membranes. The study group included 12 patients treated with cellulose-derived dialysis membranes (nine with cuprophan and three with cellulose triacetate) and 10 patients treated with synthetic membranes (five with polysulfone and five with polymethylmethacrylate). Control groups included 11 normal subjects and six patients with end-stage renal failure who were receiving intermittent peritoneal dialysis. Basal blood levels of nitrosylhaemoglobin in haemodialysis patients were significantly higher than normals, but similar to peritoneal dialysis patients. A significant increase (P < 0.01) in nitrosylhaemoglobin level was detected at 15 min of haemodialysis irrespective of the membrane used. A decrease to basal levels at 180 min was observed in all but two cuprophan-treated patients who, in contrast to the others, had a symptomatic hypotension at the end of the session and a further increase in blood nitric oxide. Patients undergoing peritoneal dialysis did not show any change in blood levels of nitrosylhaemoglobin during the first 180 min of the procedure. Thus, a constant increase in nitrosylhaemoglobin levels was observed early in haemodialysis, but not in peritoneal dialysis patients. Very preliminary evidence was obtained for a role of nitric oxide in the vascular instability at the end of haemodialysis in a few patients who had hypotensive episodes.

Adriamycin-induced proteinuria in nude mice: an immune-system-mediated toxic effect.

BACKGROUND: The renal minimal lesion disease induced in rats by adriamycin (ADR) is generally thought to be consequent to a direct cytotoxic effect of this drug on glomerular epithelial cells. Only recently an altered synthesis of mediators, including reactive oxygen species and monocyte-macrophage cytokines, has been hypothesized. METHODS: A mouse strain (nude) bearing a congenital thymic aplasia is a suitable experimental animal to evaluate the role of immune reactions in the development of the ADR nephropathy, provided mouse susceptibility to its toxic effect. Therefore, experimental mice were divided into three groups (G) each receiving adriamycin 7.5 mg/kg b.w.: GA (15 heterozygous nu/O mice with normal immune system); GB (15 homozygous nu/nu athymic mice); GC (15 homozygous nu/nu mice which were also splenectomized, irradiated, and treated with anti-asialo Gm1 antibody to abolish NK and decrease macrophage activity). All animals were maintained under pathogen-free conditions. Urinary proteins, albumin and TNF-alpha excretion were measured. RESULTS: After 14 days the proteinuria was 43.8+/-1.7 microg/min in GA, 30.2+/-2.9 microg/min in GB (P<0.05) and 12.2+/-2.8 microg/min in GC (GA vs GC, P<0.0001; GB vs GC, P<0.05). Albuminuria gave a similar profile. TNG-alpha urinary excretion was significantly higher in GA (17.3+/-3.2 mU/min) than in GB (5+/-0.6 mU/min, P<0.001) and GC (3.2+/-0.9 mU/min, P<0.001). A significant correlation was found in GA between urinary TNF-alpha and protein losses (r2=0.63 P<0.0001). Kidney tissue homogenates failed to show in each experimental group any evidence of mRNA encoding for TNF-alpha, which was detectable in peripheral mononuclear cells from GA and GB, but undetectable in GC mice. Segmental effacements of glomerular epithelial cell foot process were observed by electron-microscopy in GA only, while they were minimal in GB and absent in GC. Iron colloidal staining for anionic sites on frozen sections always showed a normal pattern. CONCLUSIONS: Nude mice bearing cellular immunity deficiency are protected from proteinuria following ADR toxicity. An impaired synthesis and release of lymphomonocyte mediators including TNF-alpha could be envisaged.

Isosorbide 5 mononitrate administration increases nitric oxide blood levels and reduces proteinuria in IgA glomerulonephritis patients with abnormal urinary endothelin/cyclic GMP ratio.

An endothelin urinary hyperexcretion, which is not counterbalanced by an adequate increase in cGMP biosynthesis, was previously detected in some patients with IgA Nephropathy (IgAN). Since this imbalance might potentiate local ET1-mediated hemodynamics effects, 9 IgAN patients with an increased (> or = 0.1) urinary ET1/cGMP ratio (group 1) and 5 IgAN patients with comparable renal function and reduced ET1/cGMP ratio (group 2) were given standard doses of isosorbide 5 mononitrate (as a nitric oxide source). Blood nitric oxide (NO) levels, as detected by electron paramagnetic resonance, significantly increased after isosorbide administration (p < 0.01) and decreased after drug discontinuation in both groups. Nitric oxide levels were significantly related with those of the effective renal plasma flow (p < 0.02), but not with the glomerular filtration rate. Proteinuria levels significantly decreased after drug administration (p < 0.009) in group 1 and returned to baseline levels thereafter, except two cases showing persisting low levels. Values of filtration fraction in the same group decreased after iso5M administration (p < 0.02 compared to basal levels). These results may possibly be related to the counterbalancing effects of nitric oxide on endothelin-mediated mesangial contraction.

Dialysis in the elderly: improvement of survival results in the eighties.

Analysis of long-term dialysis results is the cornerstone of renal replacement therapy evaluation. Elderly patients may be considered a crucial cohort, since subtle differences may be enhanced in a population of lower life expectancy. The aim of the study was an analysis, from the Piedmont Registry of Dialysis and Transplantation, of the results obtained in 1981-1992 (northern Italy, about 4,400,000 inhabitants, 21 dialysis centres, open acceptance since mid-1970s) in patients aged > or = 65 years (475 patients started treatment in 1981-1985, 1026 in 1986-1992). As a first treatment, during the 12 years considered acetate haemodialysis decreased sharply; bicarbonate haemodialysis is currently the standard treatment (68%). Peritoneal dialysis is stable (21%), and haemodiafiltration is increasing (8%). Shifts between treatments are frequent: 15% of elderly patients changed treatment at least once in 1991-1992. Nephroangiosclerosis/ischaemic renal disease, undefined causes and diabetes mellitus are the major causes of end-stage renal disease; 57.3% of patients have high risk conditions in addition to age. In this cohort of patients, mean age of new cases starting dialysis significantly increased in 1986-1992 (72.7 +/- 5.4 years) versus 1981-1985 (71.3 +/- 4.5; P < 0.001). Despite this, survival at 2 years increased significantly from 54.6% in the period 1981-1985 to 59% in the period 1986-1992 (P < 0.05). Even in an ageing dialysis population, therefore, choice of an open dialysis system with easy changes among treatments allowed improvement of survival results; further technical advances may help in maintaining present trends.

Urinary endothelin in glomerulonephritis patients with normal renal function.

The vasoconstrictor peptide endothelin-1 (ET1) has only recently been characterized and its effects are at present largely speculative. It has been hypothesized that ET1 acts on mesangial cells to cause vasoactive changes which might ultimately contribute to the development of glomerulosclerosis. Opposite to ET1, nitric oxide (NO) inhibits mesangial cell contraction and proliferation. NO activates soluble guanylic acid cyclase and the final product, cyclic GMP (cGMP), has been recently used as a marker of NO action. Urinary levels of ET1 and cGMP were detected in 58 patients with biopsy-proven glomerulonephritis (GN), including 36 IgA nephropathy (IgAGN), 30 with normal and 6 with impaired renal function, 10 patients with non-IgA mesangial GN and 12 pts with membranous GN (MGN) with normal renal function. Compared to normal controls (0.019 +/- 0.006 ng/min), urine ET1 levels were significantly higher in patients with normal renal function having IgAGN (0.035 +/- 0.017, p < 0.01), MGN (0.028 +/- 0.013, p < 0.05), non-IgA mesangial GN (0.027 +/- 0.012, p < 0.05) and those with IgAGN and renal failure (0.032 +/- 0.011, p < 0.01). However no difference was found between MGN patients and normals by deleting MGN cases with mild to moderate mesangial proliferation. The mean value of urinary cGMP in IgAGN patients with renal failure (0.186 +/- 0.117 nmol/min) was lower (p < 0.05) than that of each group with normal renal function (IgAGN: 0.378 +/- 0.010 nM/min; MGN: 0.338 +/- 0.064 nmol/min, non-IgAGN: 0.436 +/- 0.168 nmol/min). The same significant differences were obtained by correcting cGMP values for creatinine urinary excretion. Urinary ET/cGMP ratio (assumed as an index of the relative balance between vasoconstrictor and vasorelaxing factors) was found to be higher than normal (0.570 +/- 0.010 ng/nmol) both in IgAGN patients with normal renal function (0.103 +/- 0.064 ng/mol, p < 0.05), and in those with renal failure (0.203 +/- 0.108 ng/nmol, p < 0.02). Urinary cGMP values were not related to plasma levels of atrial natriuretic peptide (ANP). These data show that hyperexcretion of ET1 occurs in a number of patients with mesangial proliferative GN. In some of them, mainly those with established glomerular damage, the local production of ET1 is not counter-balanced by adequate cGMP biosynthesis.