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Recently, anti-C1q autoantibodies have been proposed as a useful marker in systemic lupus erythematosus (SLE) since their occurrence correlates with renal involvement and, possibly, with nephritic activity. We aimed to evaluate the prevalence of anti-C1q antibodies in patients with SLE, with and without renal involvement, and to correlate these markers' presence and levels with the activity of the disease and nephropathy. We studied 61 patients with SLE, 40 of whom had biopsy-proven lupus nephritis; 35 patients with other connective tissue diseases; and 54 healthy controls. In addition, 18 lupus nephritis patients were followed up during the disease time course. Anti-C1q antibodies were measured using "homemade" ELISA with high salt concentration (1 M sodium chloride). High anti-C1q antibody titers (> 55 AU) were present in 27 of 61 (44%) SLE patients and in 4% and 0% of normal blood donors and pathologic controls, respectively. Anti-C1q antibodies were found in 60% of patients with lupus nephritis compared with only 14% of SLE patients without nephropathy (P < 0.05). Moreover, patients who were positive for anti-C1q antibodies had a higher European Consensus Lupus Activity Measurement (ECLAM) score (4.35 vs. 2.2); 89% of patients with active lupus nephritis showed high titers of anti-C1q antibodies compared with 0% of patients with inactive nephritis. Anti-C1q and anti-dsDNA antibodies agreed in 79% of cases. Our results confirm that anti-C1q antibodies are present in a significant percentage of SLE patients, and that their presence and levels correlate with disease activity-in particular, during renal flare-ups. © 2005 New York Academy of Sciences

Aims The aim of the study is to describe the course of the echocardiographically measured pulmonary artery systolic pressure (PAsP) in a series of patients included in the Italian Pulmonary Embolism Registry (IPER). Methods Patients with confirmed PE received an echo-Doppler evaluation within 24 hours from hospital admission and after one year. Pulmonary hypertension (PH) was considered “likely” , “possible” or “unlikely” with a right ventricular-right atrial (RV-RA) pressure gradient > 45 mm Hg, between 32 and 45 mm Hg and ≤ 31 mm Hg and no additional echocardiographic variables suggestive of PH, respectively. Results We studied 286 patients (169 females and 117 males, mean age 67 ± 15; mean follow-up 387 ± 45 days): 240 had a baseline tricuspid regurgitation (TR) and a RV-RA gradient of variable degree. PH was considered likely, unlikely and possible in 97, 93 and 50 patients respectively. At FU echocardiography, 6 patients (2.1%) had a likely PH and all of them were part of the group of 97 patients with a baseline likely PH; 24 patients (8.4%) had a possible PH, and 67% of them had an initial likely PH. No patients with a baseline unlikely PH or without TR developed a follow-up PH (both likely or possible). The probability to show a likely PH at FU echocardiography for patients with a baseline RV-RA gradient > 45 mm Hg was 6.2%, while the probability not to have a likely PH for patients with a baseline RV-RA gradient ≤ 45 mm Hg was 100%. Conclusion In our study population of patients with acute PE, we observed that those presenting with a baseline echocardiographic RV-RA pressure gradient ≤ 45 mm Hg were completely free from a likely PH after 1-year.

Adequacy in hemodialysis: New concepts derived from online urea monitoring. Background The estimation of urea kinetic parameters [urea generation rate (G u ), normalized protein catabolic rate (NPCR), and dialysis dose (Kt/V)] is routinely performed during a single hemodialysis session as a representative sample of a stable series. To ascertain whether the stability assumption is tenable and to estimate the variability of urea kinetic parameters, a number of stable patients on regular dialysis treatment in their usual clinical setting were followed. Methods Thirteen stable patients on regular hemodialysis aged 61 ± 11 were monitored from 5 to 24 weeks (median, 10 weeks) with the urea biosensor system in double-chamber hemodiafiltration. Body weight did not change appreciably. Residual renal function was negligible or absent. Weekly averaged urea concentration (TAC w ), G u , NPCR, and Kt/Veq were calculated, and their serial patterns and interrelationships were evaluated through graphical analysis and linear regression. Results In six patients, the urea pool was substantially unchanged, but variability of G u and Kt/V was comparable to that of the other groups. In three patients, body urea pool increased. G u went from 4.78 ± 0.44 to 5.40 ± 0.65 mg/min, and Kt/V went from 1.25 ± 0.25 to 1.34 ± 0.31. In four patients, body urea pool decreased; G u went from to 6.55 ± 1.91 to 5.85 ± 2.26 mg/min, and Kt/V did not change appreciably. Parameters might change in a nearly linear trend or occasionally as abrupt or oscillating phases. G u was the main factor involved, and the only one affecting four of the seven unstable patients. Kt/V was never solely involved. Conclusions Our data indicate that the estimation of urea kinetic parameters is often affected by a non-negligible degree of variability, which can be ascribed to the variability of the dialytic dose delivered and, above all, to the daily changes of diet protein assumption.

Several mechanisms (trapping of neutrophils, increased extravascular lung water, left ventricular hypertrophy, metastatic lung calcification, and iron deposition) may impair pulmonary function and alter bronchial responsiveness in patients on long-term regular dialysis treatment (RDT), but no studies have been published concerning patients on RDT for a very long time. To assess bronchial reactivity, a methacholine inhalation test was performed 2 to 24 hours after a dialysis session in 19 patients with RDT duration of almost 20 years (221 +/- 26 months) (group 1) and in 14 patients on RDT for a shorter time (24 +/- 22 months) (group 2); all patients had normal standard pulmonary function test results (group 1: forced vital capacity, 95% +/- 13% and forced expiratory volume in one second [FEV1]: 97% +/- 17%; group 2: forced vital capacity, 108% +/- 11% and FEV1, 108% +/- 9% of expected values). The methacholine provocation dose causing a 20% decrease in FEV1 was significantly lower than normal in seven (37%) group 1 patients and only in one (7%) group 2 patient; this difference was statistically significant (P = 0.049). There were no correlations between bronchial hyperresponsiveness and interdialysis weight gain, left ventricular hypertrophy, diastolic dysfunction expressed as the ratio between early diastolic filling and filling during atrial contraction, secondary hyperparathyroidism, and iron overload. Therefore, bronchial hyperresponsiveness is present in a substantial percentage of patients on RDT of very long duration, but the cause is unknown.

To verify whether IgA antineutrophil cytoplasmic antibody (ANCA) represents a serologic marker in Henoch-Schönlein purpura (HPS), we examined sera from 41 patients with the disease. Control sera from 28 patients with primary IgA nephropathy (IgA-N), 26 IgG-ANCA-positive vasculitis, and 28 normal controls were also studied. An increased IgA binding to neutrophil cytoplasmic extracts but not to purified ANCA antigens was found in 12.2-14.6% of HSP patients and in 14.3-21.4% of IgA-N patients versus 3.5% of normal controls. IgA binding to neutrophil cytoplasmic extracts correlated with serum IgA levels, IgA-rheumatoid factor, and IgA-fibronectin binding capacity. Moreover, low amounts of IgG and fibronectin were detected as contaminants in neutrophil cytoplasmic extracts and fibronectin could partly inhibit the binding of IgA to "crude" extracts. We conclude that IgA-ANCA are neither diagnostically nor immunologically specific in HSP and IgA-N. Several factors present in the sera of patients with IgA-related nephropathies seem to contribute to the "false-positive" IgA-ANCA demonstrable in these patients.

Blood lead corrected for hematocrit (PbC) was measured in 115 hemodialysis (HD) patients. Information was collected with a questionnaire about personal and environmental factors thought to influence blood Pb levels. HD patients had significantly higher mean blood Pb than healthy subjects (p < 0.001). A non-negligible percentage of the HD population (13%) had values over 30 micrograms/dl, the threshold for risk in occupational exposure, and 4% over 40 micrograms/dl which reflects Pb intoxication. No association was found between sex, age, duration of HD and PbC. The prevalence of high diastolic blood pressure was associated with PbC over 30 micrograms/dl (p < 0.01). Also, at blood Pb levels generally considered as 'nontoxic' (less than 40 micrograms/dl), we found a low correlation with diastolic blood pressure (r = 0.19, p = 0.049). A correlation was found between PbC and parathyroid hormone (r = 0.22, p = 0.01) and between PbC and mean corpuscular volume (r = -0.21, p = 0.02). The patients with individual risk factors (smoke, alcohol consumption and alkyl Pb from air contamination) had PbC levels higher than patients without (p = 0.001). The patients with environmental risk factors (professional exposure, tap water consumption and older houses) had PbC levels higher than patients without (p = 0.01). Patients with past occupational exposure had the highest mean PbC levels (34.1 micrograms/dl = 1.65 nM/ml).

Iron supplementation in chronic hemodialyzed patients is not yet completely defined concerning the dosing regimen. This study aimed to evaluate the effects of the same iron load administered in different regimens on anemia, iron status and the reticulocyte (Ret) subpopulation patterns in stable patients on chronic hemodialysis (HD).Seventeen patients undergoing thrice-weekly chronic HD and receiving stable alphaerythropoietin therapy with absolute iron deficiency (transferrin saturation (TSAT)20%, ferritin (Frt)100 ng/mL) were randomly divided into two groups: group A (n=9) received 20.8 mg of sodium iron gluconate at the end of each dialysis session; group B (n=8) 62.5 mg only at the end of the 1st dialysis session of the week. The treatment period lasted 3 months (period 1) and was followed by 3 months of observation (period 2).Both treatments increased hemoglobin (Hb) levels by an average of 0.90 g/dL in period 1, with a progressive decline in period 2 (p=ns between groups), peaking at 11.2 g/dL in group A and 10.8 g/dL in group B. The effects on mean red blood cell volume and Hb concentrations were similar. Frt levels more than doubled during period 1 and early in period 2 in both groups (172 microg/L in group A; 149 microg/L in group B, and progressively decreased in period 2 (p=ns between groups). The TSAT index increased progressively peaking to 28.7% in group A and 24.3% in group B. Hypochromic red blood cells (hypocRBC) decreased early from 5.6-2.2% in group A, and from 5.5-2.1% in group B, and persisted in period 2; the between-period differences for the combined groups were statistically significant (p=0.0051). High fluorescence reticulocytes (HFR) increased from period 1 to period 2 only in group B (from 0.8-1.7%, p=0.012).Both regimens replenished iron stores and improved anemia. The HFR increase in group B could be due to soluble transferring receptor (STnfR) gene upregulation; alternatively it could indicate the prevalence of immature Ret release from bone marrow.

Background: Prolonged treatment with steroids and/or cyclophosphamide improves the prognosis of primary focal segmental glomerulosclerosis (FSGS). In nephrotic patients, no clinical or histological feature predicts responsiveness to therapy. Methods: In 50 patients with FSGS, fractional excretion (FE) of immunoglobulin G (IgG), albumin, transferrin, and α 1 -microglobulin (α 1 m) was calculated. The aim of the study is to assess whether FE IgG and FE α 1 m: (1) correlate with histological lesions, (2) predict outcome, and (3) may be useful to guide therapy. Results: The association of FE IgG with percentage of glomeruli with segmental sclerosis was at the limit of significance ( P = 0.01). FE α 1 m was associated with extent of tubulointerstitial damage ( P = 0.008). By multiple regression analysis, FE α 1 m was dependent on FE IgG ( R 2 = 0.76; P = 0.000). The predictive value of proteinuric variables on outcome was evaluated in 29 patients with nephrotic syndrome and baseline normal renal function (serum creatinine level, 1.04 ± 0.22 mg/dL [92 ± 19 μmol/L]; follow-up, 50 ± 33 months); remission rates were 91% and 0% in patients with FE IgG less than versus greater than 0.140 ( P = 0.0009). By multiple logistic regression analysis, only FE IgG was associated with remission ( P = 0.043). Proteinuria less than versus greater than 7.5 g/d of protein predicted end-stage renal failure (0% versus 36%; P = 0.004); the predictive value of FE IgG less than versus greater than 0.140 was higher (0% versus 71%; P = 0.0000). Patients with FE IgG less than 0.025 were responsive to steroids alone (70%) or steroids and cyclophosphamide (20%); patients with FE IgG greater than 0.025 and less than 0.140 were responsive to steroids alone (20%) or steroids and cyclophosphamide (80%); and 100% of patients with FE IgG greater than 0.140 were unresponsive to therapy ( P = 0.000). Conclusion: In FSGS, FE IgG is at the limit of statistically significant association with segmental sclerosis, and FE α 1 m is associated with extent of tubulointerstitial damage. FE IgG shows the best predictive value for remission, progression, and response to therapy and may be useful to guide treatment. Am J Kidney Dis 41:328-335.

Light chain deposition disease (LCDD) is a systemic disorder characterized by deposition of monotypic immunoglobulin light chain (LC) in several organs, and in particular in the kidney1–4. LCDD is part of a large and heterogeneous group of diseases identified as monoclonal Ig-related renal diseases, namely AL amyloidosis, myeloma kidney, LCDD, LHCDD and HCDD5 (heavy chain deposition disease). It has been argued that, if the basic mechanisms responsible for tissue deposition in these forms are different, grouping them together is inappropriate. If, however, the two forms of deposits represent different aspects of the same pathogenetic process resulting from production of the same protein during the course of monoclonal B-cell expansion, such a classification is appropriate. At present the molecular characteristics of LC responsible for different types of tissue deposition have not been clarified, and many authors believe that current data favor a unimodal process with variations due to different physicochemical properties of the individual LC or different local factors6,7.

Background. The urinary excretion of N-acetyl-bglucosamynidase (NAG) is increased in subjects exposed to substances toxic for renal tubular cells. In experimental and human glomerular diseases, its increased excretion is probably due to the dysfunction of tubular epithelial cells induced by increased traffic of proteins in the tubular lumen. The first aim of this study was to evaluate whether NAG excretion is correlated not only with the amount of proteinuria but also with some proteinuric components which reflect both glomerular capillary wall damage (IgG) and an impairment of tubular reabsorption of microproteins (a1 microglobulin). The second aim was to assess whether NAG excretion has a predictive value on functional outcome and response to therapy. Methods. In 136 patients with primary glomerulonephritis [74 with idiopathic membranous nephropathy (IMN), 44 with primary focal segmental glomerulosclerosis (FSGS) and 18 with minimal change disease (MCD)] urinary NAG excretion was measured by a colorimetric method and expressed in units per gram of urinary creatinine. Results. Using univariate linear regression analysis NAG excretion in all 136 patients was significantly dependent on IgG excretion, 24-h proteinuria, fractional excretion of a1 microglobulin (FE a1m) and diagnosis. Using multiple linear regression analysis, NAG excretion was significantly dependent only on IgG excretion and 24-h proteinuria. Limiting the analysis to 67 patients with nephrotic syndrome (NS) and baseline normal renal function, by multiple linear regression, NAG excretion was significantly dependent on IgG excretion (Ps0.0004), 24-h proteinuria (Ps0.0067) and FE a1-m (Ps0.0032) (R 2 s0.63). In 66 patients with NS and normal baseline renal function (MCD 10 patients; FSGS 20 patients; IMN 36 patients), according to values below or above defined cut-offs (IMN, O or )18 Uug urinary Cr; FSGS and MCD, O or )24 Uug urinary Cr), NAG excretion predicted remission in 86 vs 27% of IMN patients (Ps0.0002) and 77 vs 14% of FSGS patients (Ps0.005). Progression to chronic renal failure (CRF) was 0 vs 47% in IMN patients (Ps0.001) and 8 vs 57% in FSGS patients (Ps0.03). Using Cox model, in IMN patients only NAG excretion (Ps0.01, RR 5.8), but not 24-h proteinuria, predicted progression to CRF. All MCD patients had NAG excretion values below the chosen cut-off, and 90% of them developed remission. Response to immunosuppressive therapy was significantly different in patients with NAG excretion values below or above the cut-offs. Conclusion. Urinary NAG excretion can be considered as a reliable marker of the tubulo-toxicity of proteinuria in the early stage of IMN, FSGS and MCD; the excretion values show a significant relationship with 24-h proteinuria, IgG excretion and FE a1m. Its determination may be a non-invasive, useful test for the early identification of patients who will subsequently develop CRF or clinical remission and responsiveness to therapy.

In idiopathic membranous nephropathy (MN), the main predictors for progression to chronic renal failure (CRF) are the amount of proteinuria and extent of tubulointerstitial damage. The aim of this study is to evaluate whether urinary excretion of proteins reflecting the alteration of permselectivity in the glomerular capillary wall, such as immunoglobulin G (IgG), and the reabsorption impairment of low-molecular-weight proteins, such as alpha(1)-microglobulin (alpha(1)m), correlates with the extent of tubulointerstitial damage and have a predictive value for functional outcome and response to therapy better than 24-hour proteinuria. In 78 patients with MN, urinary excretion of albumin, transferrin, IgG, and alpha(1)m was measured by immunonephelometry in second-morning urine samples and expressed in milligrams per gram of urinary creatinine (uCr). In 48 patients with characterization of proteinuria and renal biopsy performed at the same time, excretion of IgG (P = 0.0087) and alpha(1)m (P = 0.0024), but not albumin (P = 0.37), transferrin (P = 0.38), or 24-hour proteinuria (P = 0.32), was associated significantly with the extent of tubulointerstitial damage (score, 0 to 1 versus >/=2). Only alpha(1)m excretion was associated significantly with global glomerular sclerosis (P = 0.0032) and arteriolar hyalinosis (P = 0.0004). Moreover, urinary excretion of alpha(1)m was significantly dependent on IgG excretion (r = 0.67; P = 0.0001), but not on albumin (P = 0.66) or 24-hour proteinuria (P = 0.07). Functional outcome could be evaluated in 38 patients with nephrotic syndrome and baseline normal renal function (serum creatinine, 0.99 +/- 0.20 mg/dL; follow-up, 44 +/- 22 months). Remission was 100% versus 20% in patients with IgG excretion less than 110 mg/g uCr versus 110 mg/g uCr or greater (P = 0.0001) and 77% versus 17% in patients with alpha(1)m excretion less than 33.5 mg/g uCr versus 33.5 mg/g uCr or greater (P = 0.0009), respectively. In patients with IgG and alpha(1)m excretion less than or greater than the cutoff value, progression to CRF was 0% versus 35% (P = 0.0026) and 0% versus 58% (P = 0.0001), respectively. Nineteen patients treated with immunosuppressive therapy were compared with 19 untreated patients. There was no difference in remission or progression between treated and untreated patients when IgG and alpha(1)m excretion were less than the cutoff value. There was a significant difference for progression to CRF between treated and untreated patients when alpha(1)m excretion was greater than the cutoff value (17% versus 100%; P = 0.0076). In conclusion, IgG excretion is associated significantly with the extent of tubulointerstitial damage and alpha(1)m excretion. This observation supports the hypothesis that IgG may be the toxic moiety of proteinuria. Excretion of IgG and alpha(1)m has a significant predictive value for both remission and progression and is useful to identify patients who are at risk for progression and for whom treatment with immunosuppressive therapy is indicated soon after diagnosis.

Idiopathic IgA nephropathy with segmental necrotizing lesions of the capillary wall. Background Segmental glomerular necrosis has been described in the biopsy material in a minority of patients with idiopathic IgA nephropathy in the oldest studies on this disease, but this marker of active capillaritis has received little attention in the subsequent literature, and its significance and relevance for the clinical outcome is still unknown. Methods Thirty-five out of 340 patients (10.3%) biopsied in our division at the San Carlo Hospital since 1974 showed active segmental necrotizing lesions. The morphological features and the natural history of this group of patients were compared with those of a control group of 229 patients who had comparable serum creatinine and extent of glomerular sclerosis, but who lacked active segmental necrosis. Results Patients with the necrotic variant showed a significantly more marked extracapillary proliferation and interstitial accumulation of monocytes and T lymphocytes and, in the segmental areas of necrotizing and extracapillary lesions, infiltration of monocytes, deposition of fibrinogen, and expression of the adhesion molecule vascular cell adhesion molecule-1. No difference was found in the presenting clinical syndrome. The clinical course was frequently characterized by acute flareups, and the progression to end-stage renal failure was more frequent, although actuarial renal survival was not significantly worse ( P = 0.07). The aggressive treatment with steroids and cyclophosphamide, carried out in 20 of the 35 patients, has probably been beneficial, justifying the multicenter controlled trial that recently has been initiated. Conclusions Vasculitic lesions of the glomerular capillaries, with histologic and immunohistological features similar to those of Henoch-Schonlein purpura and antineutrophil cytoplasmic antibody-positive renal vasculitis, were found in 10% of patients with idiopathic IgAN. Clinical features at presentation did not differ from those of the other patients with IgAN, and despite of the more frequent occurrences of recurrent acute flareups, rapid progression to end-stage renal failure was a rare phenomenon, even in untreated patients.

A modern approach to selectivity of proteinuria and tubulointerstitial damage in nephrotic syndrome. Background The selectivity of proteinuria, introduced in clinical nephrology in 1960 and useful in predicting steroid responsiveness in nephrotic syndrome, found little place in clinical practice in subsequent decades, since its assessment did not appear to help predict histologic diagnosis or determine prognosis. The amount of proteinuria and the degree of tubulointerstitial damage appeared to be better predictors of functional outcome. A correlation between them has been found, referred to some toxicity of proteinuria on tubular cells, but so far no single feature or component of proteinuria has been identified as being responsible for this toxicity. Methods We evaluated 89 patients with nephrotic syndrome [9 with minimal change disease (MCD), 29 with primary focal segmental glomerulosclerosis (FSGS), and 51 with idiopathic membranous glomerulonephritis (MGN)] to determine if the selectivity of proteinuria was associated with tubulointerstitial damage. A semiquantitative grading of histologic lesions and qualitative evaluation of the "tubular" component of proteinuria expressed as a pattern of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and as fractional excretion of the low molecular weight (LMW) protein α 1 -microglobulin (FE α 1 m) were used. A second aim of the study was to assess the predictive value on functional outcome [remission or progression to chronic renal failure (CRF)] and response to therapy of the selectivity of proteinuria, considered alone and in combination with FE α 1 m. Results Proteinuria was classified as highly selective [selectivity index (SI) ≤ 0.10, N = 15], moderately selective (SI ≥ 0.11 ≤ 0.20, N = 34), or nonselective (SI ≥ 0.21, N = 40). A significant relationship was found between the SI and the histologic degree of tubulointerstitial damage (score 0 to 1 vs. score ≥2, P = 0.000), severity of the tubular component of proteinuria (mixed SDS-PAGE pattern with LMW proteins not lower than 23 kD vs. mixed pattern with LMW proteins up to 20 to 10 kD, P = 0.000), and FE α 1 m (values below vs. above a defined cut-off, P = 0.000). The functional outcome was evaluated in 60 patients with baseline normal renal function (serum creatinine 0.97 ± 0.19 mg/dL). The patients with high, moderate, or nonselective proteinuria had 100, 50, and 29% of complete or partial remission ( P = 0.0001) and 0, 25, and 35% of progression to CRF, respectively ( P = 0.050). In 45 patients with moderately selective ( N = 28) and nonselective ( N = 17) proteinuria, according to some arbitrary cutoffs for FE α 1 m (MGN, ≤ vs. > 0.240% of creatinine clearance; FSGS and MCD, ≤ vs. > 0.350%), the remission rate was 62 versus 6% in patients with FE α 1 m below or above the cutoffs ( P = 0.0001), and progression to CRF was 7 and 69%, respectively ( P = 0.0001). The response to therapy (complete or partial remission at the last observation), evaluated retrospectively in 40 patients, was 100, 67, and 33% in high, moderate, and nonselective proteinuria ( P = 0.0002); in 30 patients with moderate and nonselective proteinuria, according to an FE α 1 m value that was ≤ or > the cutoffs, the response rate was 75 versus 10% ( P = 0.001). Conclusions There is a significant relationship between selectivity of proteinuria and tubulointerstitial damage. Moreover, the selectivity of proteinuria has a predictive value on functional outcome. When proteinuria is highly selective, the tubulointerstitial damage is rather infrequent, and 100% of patients develop clinical remission. When proteinuria is moderately selective or nonselective, increasing numbers of patients develop tubulointerstitial damage; in these patients, the functional outcome and response to therapy is partly dependent on tubulointerstitial involvement, and the best predictor of functional outcome is the combination of SI and FE α 1 m.

Haemodialysis (HD) is a specific treatment for The aims of the present study were to forecast the uraemia, consisting of multiple doses administered urea concentration profile and TAC urea over time by rhythmically at time intervals not all equally spaced. computer simulation in a single-compartment variable It can be used for only 5‐9% of the lifetime of the volume (SPVV ) model. The eVects on TAC urea and uraemic patients and, therefore, it must be properly Kd*t/V of two HD schedules, the traditional alternate planned to ensure acceptable relief of the uraemic day HD and daily HD, each with three diVerent HD syndrome. However, the design of a good HD schedule durations, were compared at the steady state condition. is empirical, since the concepts of HD dose and The importance of achieving the steady state for adequacy are not completely agreed upon. adequate comparisons is emphasized. The importance of the urea kinetic modelling approach in evaluation of HD was the main conclusion of the National Cooperative Dialysis Study (NCDS) [1], as perhaps should have been expected, considering the fluctuating profiles of urea in the blood of uraemic Subjects and methods patients. The NCDS conclusions emphasized the importance of the time-averaged plasma urea concen- The patient‐haemodialysis system was described as a onetration ( TAC ) as a predictor of a good outcome. TAC compartment variable volume ( V t ) system, in which a diVusive first-order process takes place intermittently for a fixed urea includes removal of urea from the body and its time interval (t d ) and at a fixed frequency. The assumptions production, and thus may be considered a measure of of instantaneous and complete mixing inside the compartthe urea balance, provided that body volumes are not ment are assured by definition. The equations of the model grossly changed. In the following mechanistic analysis are shown in the Appendix. The analytical solutions of the of the NCDS data [2], Kd*t/V was proposed as a model equations are detailed in [3]. The initial compartment quantitative estimation of HD dose, in which Kd is volume ( V 0 ) was set at 38 l. During two consecutive HD, the urea clearance of the haemodialyser, t is the time the V t increased at a constant rate so that the same V 0 was duration of HD, and V is the volume distribution of reached at the end of the interval (t id ). The initial plasma the urea. Kd*t/V is a dimensionless number which urea concentration (C 0 ) was 180 mg/dl. A urea generation arises from analytical solution of ordinary diVerential rate (G u ) of 8.0 mg/min was assumed to follow zero-order kinetics. The HD filter was modelled as a subsystem with equations of the single-pool urea model and has clinical concentrated parameters, characterized by a clearance ( Kd ) meaning on its own. Neither TAC urea nor Kd*t/V of 160 ml/min and an ultrafiltration rate ( UFR) of 10 ml/min enable us to separate production of urea (represented during HD. Two HD regimens were planned, as follows: one by the protein catabolic rate in patients on nitrogen daily regimen with t

In 142 patients with primary glomerulonephritis (GN), there were polymers of albumin (PAs) in the urine samples of 87% of 15 minimal-change disease (MCD) patients, 52% of 27 focal segmental glomerulosclerosis (FSGS) patients, 51% of 47 membranous glomerulonephritis (MGN) patients, 55% of 20 membranoproliferative glomerulonephritis (MPGN) patients, and 9% of 33 immunoglobulin A nephropathy (IgAN) patients (P = 0.000). In IgAN, only three patients with nephrotic syndrome were PA positive. The PAs were significantly correlated with nephrotic syndrome (NS) (P = 0.000) and with the degree of proteinuria, ranging from 8% in patients with proteinuria less than 0.5 g/d to 58% in patients with proteinuria > or = 15.0 g/d (P = 0.001), but 40% of the nephrotic syndrome patients were PA-negative despite values of proteinuria comparable to those of PA-positive patients, suggesting that the presence of PAs is not simply related to protein loss, but probably to some other unidentified factor or lesion. For 72 patients (43 with NS) (22 FSGS, 36 MGN, and 14 MPGN patients) with normal renal function at entry (serum creatinine, 1.02 +/- 0.23 mg/dL) and a mean follow-up duration of 52 +/- 27 months, for whom PAs were determined and urinary protein characterized by sodium-dodecyl-sulphate polyacrylamide gel electrophoresis (SDS-PAGE) at the beginning of the follow-up period, the functional outcome was correlated with the patterns of proteinuria. Chronic renal failure (CRF) developed in 24% of all 72 patients, in 36% of the PA-positive patients, in 9% of the PA-negative patients (P = 0.007), in 44% of the SDS-PAGE 10-kd mixed glomerulotubular pattern patients, and in 17% of the SDS-PAGE 23-kd mixed-pattern patients (P = 0.001). The association of PAs with the 10-kd pattern enhanced the predictive value for CRF outcome: CRF developed in 62% of the PA-positive patients with the 10-kd pattern compared with 11% of the PA-negative patients with the 23-kd pattern (P = 0.0001). CRF developed in 32% of 43 patients with the nephrotic syndrome, in 48% of the PA-positive patients, and in 11% of the PA-negative patients (P = 0.037); in 50% of the 10-kd patients and in 24% of the 23-kd patients (P = 0.007); and in 70% of the PA-positive patients with the 10-kd pattern and 14% of the PA-negative patients with the 23-kd pattern (P = 0.001). In a retrospective study of 21 treated patients (11 FSGS, nine MGN, and one MPGN patient), a response to therapy with complete or partial remission was observed in 57% of all 21 patients; in 58% of patients with the nephrotic syndrome; in 88% of the PA-negative patients versus 38% of the PA-positive patients (P = 0.027); in 90% of the 23-kd patients versus 27% of the 10-kd patients (P = 0.004); and in 100% of the PA-negative patients with the 23-kd pattern versus 12% of the PA-positive patients with the 10-kd pattern (P = 0.001). In conclusion, urinary PAs are associated with GN characterized by lesions mainly localized in the glomerular capillary wall, with the presence of the nephrotic syndrome, and with the degree of proteinuria. In patients with FSGS, MGN, MPGN, and normal renal function at entry, the presence of polymers has a predictive value for CRF outcome; this value is enhanced by the contemporaneous presence of an SDS-PAGE proteinuric pattern with low molecular weight proteins up to 10-kd, which is known to be associated with diffuse tubulointerstitial lesions. Therefore, the best predictive value for either CRF outcome or for response to therapy was provided by a combination between a marker associated with the degree of proteinuria and the types of GN characterized by lesions mainly localized in the glomerular capillary wall and a marker associated with tubulointerstitial damage (SDS-PAGE mixed glomerulotubular pattern with low molecular weight proteins between 20 and 10 kd).

In 145 patients with focal segmental glomerulosclerosis (43), membranous glomerulonephritis (72), and membranoproliferative glomerulonephritis (30), 71% with normal renal function (NRF) and 63% with nephrotic syndrome (NS), the proteinuria was evaluated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and classified into four main patterns: physiological (termed 70 kd), pure glomerular (150 kd), mixed with low molecular weight (LMW) proteins as low as 23 kd (23 kd), and mixed with very LMW proteins (20 to 10 kd; termed 10 kd). The relative frequencies were 70 kd, 0.7%; 150 kd, 1.4%; 23 kd, 61%; and 10 kd, 37%. Therefore, only the two patterns characterized by LMW ("tubular") proteins were compared to determine whether they have different clinical and prognostic significance. The serum creatinine (sCr) values (P < 0.0001), the degrees of proteinuria (P = 0.007), and the tubulointerstitial damage (P = 0.015) were significantly different in the two subgroups of patients with 23-kd and 10-kd LMW proteinuria; the difference for tubulointerstitial damage was at the limit of statistical significance after Bonferroni correction. In 82 patients with NRF at entry (sCr, 1.00 +/- 0.22 mg/dL; range, 0.6 to 1.4 mg/dL) and a follow-up of 46 +/- 22 months (range, 12 to 84 months), the predictive value of the 23-kd and 10-kd SDS-PAGE patterns on functional outcome (chronic renal failure [CRF] or clinical remission) was evaluated. A total of 12.5% of 64 patients with mixed 23-kd proteinuria and 50% of 18 patients with mixed 10-kd proteinuria developed CRF. At this time, the difference between the survival curves was highly significant (P = 0.0001), as it also was after correction for NS (P = 0.0002). When the statistical analysis was limited to 69 patients with sCr < or = 1.2 mg/dL, the difference was still highly significant (P = 0.0016), as after correction for NS (P = 0.0064). Clinical remission developed in 30% of 64 patients with 23-kd proteinuria and in 33% of 18 patients with 10-kd proteinuria; this difference was not significant. In a retrospective analysis of 20 patients (13 focal segmental glomerulosclerosis and seven membranous glomerulonephritis; 10 with the 23-kd pattern and 10 with the 10-kd pattern) treated with steroids alone or with steroids and cyclophosphamide, 80% of the patients with the 23-kd pattern and 30% of the patients with the 10-kd pattern were responsive to treatment (P = 0.025). The SDS-PAGE patterns of 54 patients with NRF at entry were again evaluated after 48 +/- 22 months: 11 patients who developed clinical remission had changed from a prevalent (91%) 23-kd pattern to a prevalent physiological (55%) or glomerular (36%) pattern; eight patients who had developed CRF showed an increase from 37% to 100% of the 10-kd pattern. In 35 patients with normal and stable renal function (sCr from 1.08 +/- 0.20 mg/dL to 1.06 +/- 0.19 mg/dL) who had persistent proteinuria (20 patients) or NS (15 patients), the rate of the 10-kd pattern increased from 6% to 46% (72% in persistent NS), suggesting an impairment of tubular protein reabsorptive function even without a concomitant impairment of glomerular filtration rate, a phenomenon that can be hypothetically attributed to tubular toxicity of persistent proteinuria. The characterization of proteinuria by SDS-PAGE in primary progressive glomerulonephritis is a useful clinical tool: it can be used to identify the main pathophysiologic determinants of excretion of LMW proteins and it has a predictive value on CRF outcome in patients with NRF, reducing the unpredictability of clinical evolution. In focal segmental glomerulosclerosis and membranous glomerulonephritis, it seems to be of predictive value on responsiveness to therapy; monitoring the SDS-PAGE patterns over time may give some insights into the relationship between the persistent protein loss and the progression of the disease.

Background. Hearing loss has been described in patients with chronic renal failure on regular dialysis treatment (RDT) with very different frequency, ranging from 20 to 75% ; RDT does not seem to worsen hearing function for at least the first 5 years of treatment ; no studies are available on patients on RDT for more than 10 years. Methods. We performed an audiometric evaluation in 91 patients on RDT for various periods : group I (34 patients), 10 years ; patients with histories of chronic otitis, ototoxic drug treatment, and chronic auditory trauma were excluded ; the possible correlations with some biochemical parameters (urea, creatinine, PTH) were also looked for. Results. Hearing loss was present in 77% of patients and 69.2% of ears ; the percentage of patients with hypoacusia was higher in group III (84%) than in group I (76.3%) and II (71.7%), but the differences were not statistically significant. Hypoacusia was cochlear neurosensory in 61.5%, conductive in 6.5%, and mixed in 9.0% of patients ; the percentage of patients with cochlear neurosensory hypoacousia was similar in the three groups (I, 61.7% ; II, 59.3% ; III, 64%). Hearing loss was of slight to moderate degree and not different in the three groups (I, 22.7±15 dB ; II, 26.9±6.0 dB ; III, 29.1±8.9 dB). There were no correlations between hearing loss and plasma creatinine and PTH values ; patients with plasma urea >200 mg/dl had higher percentage of hypoacousia (86%) than patients with plasma urea

To evaluate the presence and the severity of uraemic encephalopathy (UE) in regular dialysis treatment patients in relation to dialytic age, pattern reversal visual evoked potentials (PRVEPs) and brainstem auditory evoked potentials (BAEPs) were respectively performed in 86 and 98 patients on haemodialysis for 1-194 months, divided into three subgroups according to dialytic age (group 1, 10 years). VEPs in the whole group of 86 patients and in each subgroup with different dialytic age differed significantly from controls for both eyes, 41.7% of whom had pathological P100; no differences were observed between the three subgroups. BAEPs were pathological in 9.7% of the ears and 18.4% of patients. On the right ear the three subgroups were significantly different from controls in the latencies of peaks III and V; subgroup 2 and 3 differed from controls in the I-V interpeak, while the interpeak I-III was different from controls only in subgroup 3. On the left ear the three subgroups differed significantly from controls in the latencies of peak V; subgroup 2 and 3 were significantly different from controls in the latency of peak I; subgroup 3 was different in the peak III latency; subgroup 1 and 3 were different from controls in the interpeak I-V; no differences were observed in BAEPs between the three subgroups with increasing dialytic age. No significant correlations were found between the neurophysiological parameters and some biochemical parameters (urea, creatinine, PTH).(ABSTRACT TRUNCATED AT 250 WORDS)

In an uncontrolled trial, patients with IgA nephropathy (IgAN) were treated with drugs that can alter the intestinal mucosal permeability to food antigens. These drugs are known to ameliorate urinary abnormalities and histological lesions of IgAN associated with ulcerative colitis or Crohn's disease [5-aminosalicylic acid (5-ASA)] or to prevent, in mice, the induction of IgAN-like disease by oral immunization [disodium cromoglycate (SCG)]. Nine patients [serum creatinine (s-Cr) less than 2 mg/dl; 24-hour proteinuria higher than 1.5 g, but not nephrotic) were treated with 5-ASA (2.4 g/day for 6 months); 9 similar patients were treated with SCG (400 mg/day for 6 months); the follow-up extended to 6 months after stopping therapy. The 5-ASA group showed a slight but not significant decrease in s-Cr, 24-hour/proteinuria, IgA circulating immune complexes (IgA-CIC) and IgA rheumatoid factor (IgA-RF); serum beta 2-microglobulin and serum IgA were unchanged; 2 of 9 treated patients showed, after 6 months of therapy, a reduction in proteinuria of more than 50% that lasted for the subsequent 18 months. The SCG-treated group showed a slight but not significant increase in 24-hour proteinuria and a significant decrease in serum IgA; unchanged were s-Cr, IgA-CIC, IgA-RF, serum beta 2-microglobulin; no patient treated with SCG showed a reduction in proteinuria of more than 50%. At the dosages and for the periods used, 5-ASA and SCG did not show a significant influence on clinical and laboratory parameters of disease in IgAN; other trials with increased dosages are warranted to definitely ascertain the possible therapeutic role of these drugs in IgAN.

Nephrotoxicity of intravenous contrast media is more frequent and striking in patients with risk factors, the major one being preexisting chronic renal insufficiency. New nonionic low-osmolal contrast media allegedly have less nephrotoxicity than the traditional ionic high-osmolal ones. This was tested for two contrast media in a group of 18 patients with stable chronic renal insufficiency. The urinary excretion of two brush-border enzymes (alanine aminopeptidase, AAP, and gamma-glutamyl transpeptidase, gamma-GT) and of a lysosomal enzyme (N-acetyl-beta glucosaminidase, NAG), functional markers of tubular injury, were measured before and after intravenous urography with an ionic high-osmolal radiocontrast medium, meglumine sodium diatrizoate, or with a non ionic low-osmolal one, iopamidol. Urinary NAG excretion did not change significantly after administration of either contrast media. Urinary AAP and gamma-GT excretion increased significantly (p less than 0.01) after diatrizoate. After iopamidol, only gamma-GT excretion increased significantly (p less than 0.05). Our data suggest that the nonionic low-osmolal radiocontrast medium iopamidol is less toxic to tubules than the ionic high-osmolal medium diatrizoate and that the brush-border enzymes AAP and gamma-GT are sensitive markers for this toxicity.