Idiopathic IgA mesangial nephropathy. Clinical and histological study of 374 patients.

Histological features and data on the natural history after 1 to 45 years (mean 6.56 +/- 8.55) of total apparent duration and 1 to 13 years (mean 3.48 +/- 5.04) of post-biopsy follow-up, are reported in 374 patients (mean age, 33.9 +/- 11.9 yrs) with idiopathic mesangial IgA nephropathy, who presented with a history of macroscopic hematuria (56%), recurrent in two-thirds of the patients, or with persistent microscopic hematuria and no previous episodes of gross hematuria (44%). Mesangial cell proliferation ranged from minimal to diffuse. Associated varying degrees of extracapillary proliferation, segmental and global glomerular sclerosis, tubulo-interstitial damage and arteriolar hyalinosis usually correlated with each other and with the extent of mesangial proliferation (P less than 0.05). The actuarial curve of progression to renal death showed a 75% survival after 20 years from apparent onset. Progression to renal failure was more rapid in patients with: an older age at onset (P = 0.0582); male sex (P = 0.0730); no history of recurrent gross hematuria (P = 0.0406); high blood pressure (P = 0.0011); more marked global (P = 0.0007) and segmental (P = 0.0026) glomerular sclerosis; more severe interstitial sclerosis (P = 0.0147); more diffuse and global mesangial proliferation (P = 0.0820); mesangio-parietal pattern at immunofluorescence (P = 0.0778). However, all these parameters showed a poor predictive value if applied to any single patient.

Prevention of calcium nephrolithiasis with low-dose thiazide, amiloride and allopurinol.

We report 5 years' experience with low-dose hydrochlorothiazide, 50 mg/day and amiloride, 5 mg/day, in 519 patients with recurrent calcium nephrolithiasis. Additional treatment with allopurinol, 100 mg/day was prescribed for approximately 50 percent of the patients. All patients had active stone formation, having 3,464 stones in 3,126 patient-years (6.67 stones per patient, 1.10 stones per year). Hypercalciuria was present in 65 percent of the patients and hyperuricosuria in 24 percent. The administration of low-dose hydrochlorothiazide was effective in reducing urinary calcium excretion in most patients. It is possible that the hypocalciuric effect of hydrochlorothiazide were enhanced by amiloride, an agent which has been shown to cause hypocalciuria when given alone. Significant side effects requiring discontinuation of the drug were observed in only 5 percent of the patients. During 872.8 patient-years of treatment, only 53 new stones were formed (0.10 stones per patient, 0.06 stones per year) in contrast with the 916 predicted ones. The difference (chi-square) is statistically significant (p less than 0.001). These results show that the administration of low-dose hydrochlorothiazide and amiloride, either alone or in association with allopurinol, is clinically effective in reducing the rate of recurrence of calcium nephrolithiasis.

The Milan clinical trial with cyclosporine in cadaveric renal transplantation. A three-year follow-up.

Between February and November 1983, 108 recipients of cadaveric renal transplants entered a randomized multicenter trial and were treated either with cyclosporine (CsA) and prednisone (n = 55) or with conventional treatment based on azathioprine (Aza) and glucocorticoids (n = 53). The graft survival probability at 3 years was 76% for CsA patients and 48% for Aza patients (P less than 0.001). The cumulative number of acute rejections was significantly lower in the CsA group (32 vs. 104, P less than 0.001). Incidence of early posttransplant anuria was similar in both groups and did not affect renal function after three years. Nephrotoxicity in CsA patients, when present, was handled by reducing the dose of CsA, but in 12/55 patients a change to conventional therapy was thought to be necessary. However, in this group of 12, one patient lost the allograft because of irreversible rejection and one patient died 14 months later because of an infection. Mean creatinine clearance after three years was significantly lower in the CsA patients (54.7 +/- 2.6 ml/min) than in Aza patients, (67.2 +/- 4.9 ml/min, P less than 0.05). Considering only patients with grafts functioning after three years and still on the original randomized therapy, the mean creatinine clearance was similarly and significantly decreased from 1 to 3 years in both groups. There were no significant differences in occurrence of severe infections. Side effects such as hypertension, hypertrichosis, tremor and gum hyperplasia were more frequent in CsA patients.

Effect of acetate, bicarbonate dialysis, and acetate-free biofiltration on nitric oxide synthesis: implications for dialysis hypotension.

The effect of acetate dialysis (AD), bicarbonate dialysis (BD), and acetate-free biofiltration (AFB) on nitric oxide (NO) synthesis and the implications for dialysis hypotension was studied. The finding that uremic plasma is a potent inducer of NO synthesis by endothelial cells in vitro suggested that the cardiovascular instability of dialysis patients might result from excessive NO formation. Cardiovascular instability is more frequent in patients undergoing AD than BD. To see whether these differences were attributable to NO, we studied the NO synthetic pathway ex vivo in patients undergoing different dialysis procedures. Five patients were treated, in a random order, with AD, BD, and AFB, a technique using a buffer-free dialysate and postdilution of a sterile bicarbonate solution. Each type of dialysis was used for 1 week, comprising three dialysis sessions. A polyacrylonitrile dialyzer was used for all three methods. Before and after the third dialysis, plasma was collected, added to [3H]L-arginine, and incubated with human umbilical vein endothelial cells (HUVECs) for 24 hours. NO synthesis was evaluated as [3H]L-citrulline formation. Plasma concentrations of interleukin-1beta (IL-1beta), a potent inducer of inducible NO synthase (iNOS) in endothelial cells, were also measured. Plasma collected from patients after AD stimulated endothelial NO synthesis more than plasma from the same patients before the dialysis session (pre-AD, 0.173+/-0.028 nmol/10(5) cells v post-AD, 0.280+/-0.093 nmol/10(5) cells; P < 0.05). A slight, although not significant, increase was also observed when HUVECs were incubated with plasma drawn after BD (pre-BD, 0.151+/-0.014 nmol/10(5) cells; post-BD, 0.230+/-0.055 nmol/10(5) cells). AFB did not aggravate the stimulatory effect of uremic plasma on endothelial NO synthesis (pre-AFB, 0.184+/-0.038 nmol/10(5) cells; post-AFB, 0.189+/-0.040 nmol/10(5) cells). Plasma IL-1beta was greater (P < 0.01) after AD than after BD and AFB (post-AD, 0.234+/-0.028 pg/mL; post-BD, 0.124+/-0.019 pg/mL; post-AFB, 0.120+/-0.013 pg/mL). With AD, there was a greater intradialytic decrease in systolic blood pressure than with BD or AFB. Weight and blood volume loss and sodium balance were similar in AD, BD, and AFB. These data were consistent with the possibility that NO and cytokines, released in excessive amounts during AD, may contribute to hemodynamic instability.

Evidence for multiple sites of interaction between IL-12 and its receptor.

We have previously described the identification of a protein, now designated IL-12R beta 1, that binds 125I-huIL-12 with a Kd of about 10 nM, corresponding to the low affinity 125I-huIL-12 binding sites seen on PHA-activated human lymphoblasts. Using expression cloning techniques, we have recently identified an additional IL-12-binding protein subunit, IL-12R beta 2, which binds 125I-huIL-12 with a Kd of about 5 nM when expressed alone in COS-7 cells. Coexpression of IL-12R beta 1 and IL-12R beta 2 in COS-7 cells results in formation of two classes of 125 I-huIL-12-binding sites with Kds of about 50 pM and 5 nM. Mouse IL-12 p40 subunit homodimer (mo(p40)2) blocked 125I-huIL-12 binding to human IL-12R beta 1, but did not inhibit binding to human IL-12R beta 2. In contrast, anti-huIL-12 monoclonal antibody 20C2, which does not block 125I-huIL-12 binding to human IL-12R beta 1, completely blocked binding to human IL-12R beta 2. These results demonstrate that two classes of IL-12 inhibitors, one that primarily blocks IL-12/IL-12R beta 1 interaction (e.g., mo(p40)2), and one that primarily blocks IL-12/IL-12R beta 2 interaction (e.g., 20C2), can be identified.

Alterations in the HDL system after rapid plasma cholesterol reduction by LDL-apheresis.

Changes in high density lipoprotein (HDL) subfraction structure and composition were analyzed during and after extracorporeal removal of apo B containing lipoproteins in seven familial hypercholesterolemic (FH) patients. After the apheretic procedure, carried out with dextran-sulfate-cellulose columns, the plasma levels of very low density lipoproteins (VLDL), low density lipoproteins (LDL), and HDL decreased by 72%, 50%, and 19%, respectively. The free cholesterol to esterified cholesterol ratio in plasma increased, with a 26% drop in the lecithin:cholesterol acyl transferase (LCAT) activity. In the ensuing 24 hours, VLDL, HDL, and LCAT activity approached the pretreatment levels. During this phase, possibly as a consequence of increased cholesterol esterification and exchange of cholesteryl esters for triglycerides between HDL and VLDL, HDL2a particles were detected in plasma. However, these metabolic changes did not result in clearcut modifications in the HDL2-HDL3 subfraction distribution. These findings clearly demonstrate that rapid changes in the plasma VLDL-LDL levels affect several processes involved in the HDL metabolism, but confirm that the HDL system, in spite of a considerable plasticity, displays a marked stability of the HDL2-HDL3 subfraction distribution.

Immune response to hepatitis B vaccine in staff and patients in renal dialysis units.

Anti-HBs response was detected in 96 per cent of staff members in three haemodialysis units after three 20 microgram doses of hepatitis B vaccine and in 82 per cent of adult patients treated with three 40 microgram doses. The percentage of responders and levels of antibody remained unchanged at 12 months from the beginning of the trial. Three out of six children injected with three 20 microgram doses in a paediatric haemodialysis unit remained free from markers of HBV infection and had high levels of anti-HBs after the second dose of vaccine. The other three children who developed serological markers of HBV infection seroconverted to anti-HBc within six months from the first dose and, in one of them, antigenaemia at three and four months was detected.

Immunophenotyping of mononuclear cell infiltrates associated with renal disease.

Twenty-eight frozen renal biopsy specimens with a marked mononuclear cell interstitial infiltrate (MCI) were analyzed with monoclonal antibodies and a biotin-avidin peroxidase technique to define the surface phenotype distribution of the infiltrating cells. Twelve cases were diagnosed as tubulointerstitial nephritis of acute and chronic presentation, of unknown cause in 5 cases or secondary to multiple myeloma or drug reactions. Sixteen cases occurred in primary and secondary glomerulonephritis, 3 cases being associated with lymphoproliferative disorders. The results showed a remarkable heterogeneity of the MCI composition, even in cases with similar clinical and pathological findings. Namely, the T cells accounted for the majority of the infiltrating cells in most cases but a variable predominance of the T cell subsets Leu3 and Leu2 was observed. B cells and monocytes were also prominent in some cases. Such differences in the MCI composition may indicate the activation of different mechanisms of tissue damage, or a different phase of the renal disease. In the three cases of glomerulonephritis associated with lymphoproliferative disorders, the malignant origin of the MCI was demonstrated in one case, while in the remaining cases it was excluded.

Fluorocytometric analysis of anti-HLA class 2 autoantibodies in patients with lupus nephritis.

Systemic lupus erythematosus (SLE) patients are known to produce a variety of autoantibodies (AAb), some of which may be directed against immunocompetent cells. Anti-B cell autoimmunity may encompass reactivity against HLA-class 2 molecules, which are also expressed on kidney tissue. We studied 15 patients with moderate to severe renal involvement and 5 lupus patients with no clinical renal disease, in order to detect the presence of anti-HLA class 2 AAb. Flow cytometry was employed in an inhibitory assay using patient sera, autologous cells and two anti-class 2 monoclonals, to establish the specificity of anti-B cell AAb. Seven out of 15 nephritis patients had detectable anti-class 2 AAb with an epitopic heterogeneity, as demonstrated by different degrees of inhibition on the binding of non-overlapping monoclonals. The specificity of the reaction was confirmed by the lack of inhibition of non-class 2 antibody binding. The presence of such AAb was not correlated with disease activity but with the presence of a diffuse proliferative glomerulonephritis on renal biopsy. Anti-class 2 AAb may be a marker of SLE diffuse proliferative nephritis.

Clinical evaluation of a peritoneal dialysis solution with 33 mmol/L bicarbonate.

OBJECTIVE: To evaluate the efficacy and safety of a new peritoneal dialysis solution with 33 mmol/L bicarbonate. DESIGN: In an acute, prospective, randomized cross-over study, 8 patients were randomized in two groups of 4. On the first study day, the first group performed two consecutive 4-hour exchanges with a dialysis solution containing 35 mmol/L lactate: the first exchange with 13.6 g/L and the second with 38.6 g/L dextrose. On the second study day, the same type of exchanges were performed with bicarbonate. The second group underwent the same treatment, but used bicarbonate solutions on the first day and control solutions on the second study day. Thirty-three patients participated in a 2-month prospective and randomized study. After a 4-week baseline period using solutions containing 40 mmol/L lactate, the patients were dialyzed with either 33 mmol/L bicarbonate solutions or 40 mmol/L lactate solutions. SETTING: Peritoneal dialysis units at the University Hospital of Brescia and the Niguarda Hospital of Milan, Italy. RESULTS: Acute study: Control and bicarbonate solutions had similar effects on blood chemistries and peritoneal transport. Chronic study: Mean venous bicarbonate concentrations remained unchanged in the control group (26.6-27.2 mmol/L), but decreased significantly in the bicarbonate group from 28.8 mmol/L at the start of the study to 23.0 mmol/L after 2 months of bicarbonate administration. Other biochemical parameters remained unchanged. CONCLUSION: A peritoneal dialysis solution with a bicarbonate level of 33 mmol/L does not adequately correct uremic acidosis.

Impaired efficacy of selective LDL-apheresis in primary biliary cirrhosis.

Low-density lipoprotein apheresis (LDL-apheresis) was done with either cascade filtration (DF) or dextran sulfate cellulose adsorption (DSC) in a patient with primary biliary cirrhosis who developed severe dyslipidemia associated with cholestasis and accumulation of lipoprotein-X (LP-X). The extracorporeal treatment was initially performed weekly, and resulted in a sharp drop in total cholesterol from 1038 to 430 mg/dl. During the next four months the patient was treated every 10-15 days, and pre-apheresis cholesterol levels were maintained between 438 and 505 mg/dl, until an orthotopic liver transplantation was successfully performed. With semi-selective DF a mean 47.1% of total cholesterol was removed per procedure compared to 30.0% with DSC, although the volume of treated plasma was 38.0 vs 49.9 ml/kg body weight. The changes in plasma cholesterol levels during DSC and DF showed that the kinetics of cholesterol removal were similar with both techniques, but the efficacy differed; DF removed both LDL and LP-X from plasma, whereas DSC selectively lowered the LDL content. Cascade filtration may therefore be considered as a first-choice treatment for patients with LP-X accumulation due to cholestasis.

Performance evaluation of cascade filtration with high flow rate recirculating plasma on the secondary filter.

Cascade filtration (CF) has been performed in 67 on-line procedures in 9 normolipidemic patients with paraproteinemic disorders. A modified dead-end technique has been employed, with high flow rate recirculating plasma on the plasma fractionation filter (QD recycled CF), and an albumin-rich, globulin-poor filtrate was reinfused into the patient. Postprocedure recoveries were 81 +/- 15% for albumin, 55 +/- 23% for IgM and 48% for cryocrit, with an increase in A/G ratio from 1.8 to 2.1. An improvement was observed also in antiatherogenic/atherogenic lipoproteins ratio, suggesting a possible use of this technique in the treatment of familial hypercholesterolemia. Plasma primary separation was obtained by centrifugation or by filtration, and no significant differences were observed on subsequent protein fractionation process. An albumin priming of the plasmafractionation circuit accounted for an additional 13% saving in postprocedure level. Different surface area secondary filters have been employed: with larger surfaces, larger volumes were processed without any increase in the waste volume and with reduced need for washouts, but with an additional loss of small molecules possibly due to entrapping onto the membrane.

Efficacy of a combined treatment with plasma exchange and cytostatics in macroglobulinemia.

Monthly plasma exchange (PE) sessions have been carried out in 3 patients with advanced Waldenström macroglobulinemia, in order to reduce electrophoretic M band under 2g/100 ml. When PE was combined to low doses of cytostatics (n = 18), 3 procedures per session were required to obtain a mean 57.4 +/- 12.3% IgM reduction, from 4.2 +/- 1.2 to 1.7 +/- 0.5 g/100 ml. A mean 61.5 +/- 13.1% IgM reduction, from 5.5 +/- 1.3 to 2.1 +/- 1 g/100 ml, was obtained in 64 procedures carried out as the only therapy in 12 sessions, with 5.3 procedures requirement per monthly session. IgM percent reduction 24 hours after PE was greater with combined treatment (45 +/- 9.7 vs. 28.9 +/- 15.4%; p = 0.001). The advantage of a combined treatment is therefore either a lowered PE requirement or a tapered maintenance cytostatic dosage.

Different cascade filtration operating modalities in clinical use.

Cascade filtration (CF) can be performed in either the single-pass or dead-end configuration. The distinction, as predicted by experimental models, is that solute removal is lower but constant in the former, and higher but variable with the quantity of filtrate in the latter. Moreover, unpredictable plugging reduces permeability during operation. It is therefore unclear which configuration is preferable in clinical use. In four cryo- and three macroglobulinemic patients, the data of 10 dead-end CF (QP) and 11 modified single-pass CF with high flow rate recycling plasma (QD) were compared. Both groups had similar starting values. Centrifugal primary plasma separation was performed. No exogenous reinfusions were used. Either 0.8 and 1.2 sq.m. surface secondary filters were employed. The ratio of plasma processed to patients' plasma volume was 1.1 +/- 0.3 in QP, and 0.94 +/- 0.09 in QD. The mean percentage removals of albumin, IgG and IgM respectively were 25.8 +/- 9, 32 +/- 17 and 47.5 +/- 26% in QP, 30.5 +/- 12, 40.5 +/- 19 and 48 +/- 17.5% in QD: albumin vs IgM p less than 0.025 in QP and p less than 0.02 in QD. A/G ratio increased from 1.6 +/- 0.5 to 2.06 +/- 0.6 in QP, and from 1.5 +/- 0.3 to 1.7 +/- 0.3 in QD. Plugging occurred in both groups, requiring 2.3 +/- 1.8 washouts/run in QP vs 1.5 +/- 1.2 in QD. IgM removal was comparable. Removal of albumin and IgG was slightly higher in QD. Similar performances can be obtained with either technique in clinical use, provided an adequate fractionation surface is available.

Renal abnormalities reverted by plasma exchange in thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is usually accompanied by renal disfunction presumable due to diffuse thrombotic occlusions in the microcirculation. Two patients with TTP and slight renal failure with proteinuria and microscopic hematuria, were treated by repeated plasma exchanges with fresh frozen plasma, associated with prednisone and cyclophosphamide in one case, and prednisone alone in the other one. Platelet count, hematocrit and lactic dehydrogenase reverted to normal values within the fourth exchange; circulating immune complexes were never detected. Plasma factor stimulating prostacyclin activity lacked in only one patient and returned to normal levels after plasma exchange without being affected during a hematologic relapse. Renal function and urinary abnormalities reverted to normal by the end of plasma exchange and nine and six months renal and hematologic follow-up is still negative. Renal abnormalities in TTP seem to take advantage of early treatment by plasma exchange, which further to replacement of missing plasma factors, can account for the removal of toxic substances to be further investigated on.

Hemofiltration in diabetic uremic patients.

The increasing number of Diabetic Uremic Patients (DUP) starting the substitutive treatment (ST) constitutes a difficult and often disappointing problem in terms of efforts, clinical results and side-effects. While treatment of these patients by C.A.P.D. is well documented, the adoption of Hemofiltration (HF), has been, up to now scarcely considered. In order to define the potentialities of a HF policy in the treatment of these patients, data from 6 DUP treated with postdilutional HF for a 10.6 months/patient period were collected on a multi-center basis and retrospectively examined. Good results were achieved in terms of vascular stability, control of arterial hypertension and of retinopathy, clinical complications and hospitalization rate. Although C.A.P.D. may represent a first choice treatment for DUP with residual function, satisfactory glicemic control, difficult blood access and a motivation to full autonomization, HF may constitute a logical alternative when C.A.P.D. should be unmanageable (visus impairment, history of repeated peritonitis and dismetabolism, considerable weight gain): an integration of HF and C.A.P.D. can assure PDU with a continuative treatment.

Plasma exchange in acute renal failure by cortinarius speciosissimus.

Mushroom poisoning by Cortinarius speciosissimus (C. spec.) leading to irreversible renal failure has been described; in a recent report, an expected bad prognosis has probably been overcome as a result of the very early use of hemoperfusion. In Sep. '81, a healthy couple of wife and husband, both aged 38, had gastrointestinal symptoms 2 days after ingestion of C. spec. On day 8 an acute renal failure developed and the same day, before dialysis, plasma exchange (PE) was undertaken. Renal biopsies disclosed a common pattern of tubular necrosis, scattered infiltrates and interstitial edema. Diuresis and partial recovery started in the man on day 10, while failure persisted over six months in the woman. Further to individual sensitivity to C. spec. toxins, renal damage, once established, may be irreversible, irrespectively of early treatment. Limited usefulness of PE in C. spec. poisoning is probably related to the long latency between ingestion and occurrence of the first renal symptoms.