Mario M. Balletta

Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy

We tested the hypothesis that the combination of converting enzyme inhibitor (CEI) with losartan (LOS) produces a more profound antiproteinuric effect than either drug alone in normotensive patients with immunoglobulin A (IgA) nephropathy. Eight normotensive (mean blood pressure, 88.9 +/- 2.1 mm Hg) patients with biopsy-proven IgA nephropathy, nonnephrotic proteinuria (protein, 1 to 3 g/d), and normal or slightly reduced creatinine clearance (range, 69 to 119 mL/min) were studied. Clinical evaluations and laboratory tests were performed (1) before CEI treatment (basal) and after (2) CEI alone (CEI, 12 weeks); (3) the combination of CEI and LOS, the latter at a dosage of 50 mg/d (CEI + LOS, 4 weeks); (4) LOS alone (LOS; 50 mg/d; 12 weeks); (5) the combination of LOS and CEI (LOS + CEI, 4 weeks, at the same dosage as CEI + LOS); and (6) a doubled dose of either CEI alone or LOS alone for 4 weeks. CEI and LOS as monotherapy significantly reduced proteinuria by 38% and 30%, respectively. No further reduction of proteinuria was achieved by doubling the dose of CEI or LOS. Both combinations induced a more remarkable reduction of proteinuria (73%; P < 0.05 v other periods) than either drug administered alone. The antiproteinuric effect of CEI or LOS and the more remarkable effect achieved with both combinations was not dependent on the reduction of blood pressure and/or creatinine clearance. In conclusion, this study provides first-time evidence that the combination of CEI and LOS in normotensive patients with IgA nephropathy produces a more profound decrease in proteinuria than either drug. This additive antiproteinuric effect is not dependent on changes in systemic blood pressure and creatinine clearance. Nevertheless, a larger controlled study is required to confirm this novel observation.

Interleukin-6 release from peripheral mononuclear cells is associated to disease activity and treatment response in patients with lupus nephritis.

Sir, We read with great interest the article by De La Torre, et al. recently published in Lupus. The authors, through clinical and flow cytometric evaluations, demonstrate that there is an increased expression of interleukin-6 (IL-6) agonistic receptor gp130 on peripheral lymphocytes, drawn from patients with systemic lupus erythematosus (SLE). In addition, they interestingly report a significant association between gp130 expression and disease activity score, suggesting that gp130 could provide a useful tool for monitoring patients with SLE. In agreement with these findings, we report the results of a small longitudinal study, which we performed in patients with lupus nephritis, in order to evaluate the relationship among IL-6 release from peripheral blood mononuclear cells (PBMCs), proteinuria and disease activity. In this study, we demonstrate a strong correlation between IL-6 spontaneous release and both systemic and renal disease activity. Moreover, we supply evidence that an effective treatment results in decreasing clinical disease activity and IL-6 production by PBMCs. Fourteen patients (36.5 10.7 year, 12 women) affected by SLE, as defined by American Rheumatism Association criteria, with renal involvement (histological findings:WHO class III for six patients, class IV for five patients and class V for three patients) were enrolled. These patients underwent induction therapy with intravenousmethylprednisolone, followed by oral prednisone, and 6-monthly boluses of intravenous cyclophosphamide. After the induction, patients started the maintenance therapy with oral prednisone combined with either cyclosporine A (eight patients) or mycophenolate mofetil (six patients). A 12-month follow-up was performed. SLE disease activity index 2000 (SLEDAI-2K) was calculated every 3 months, as previously reported. Similarly, urine protein/creatinine (P/C) ratio and creatinine clearance on 24-h urine collection were calculated. IL-6 spontaneous production by PBMCs was evaluated before the initiation of the induction treatment (basal condition) and after 12 months. PBMCs were isolated from blood samples by lymphoprep gradient density centrifugation and were cultured for 24 h. At the end of the incubation period, cell-free supernatants were collected, and IL-6 concentration was evaluated by ELISA, as described elsewhere. IL-6 release by cultured PBMCs was significantly higher in basal condition when compared with posttreatment values (443.0 84.1 vs. 27.4 17.8 pg/mL; P< 0.001) (Figure 1A), whereas there was no significant difference in IL-6 levels between patients treated with mycophenolate or cyclosporine (20.2 10.5 vs. 32.7 20.9 pg/mL, ns). At 12month check-up, patients showed a significant decrease of both proteinuria and SLEDAI-2K, when compared with basal values (P/C ratio 1.76 1.25 vs. 0.69 0.38, P< 0.05, and 8.4 2.2 vs. 4.9 2.4, P< 0.01, respectively). Creatinine clearance did not significantly change (basal value 81.4 18.8 vs. 12-month value 81.3 17.2). IL-6 production resulted significantly associated to both SLEDAI-2K and P/C ratio (rs1⁄4 0.4180, P1⁄4 0.0002 and rs1⁄4 0.2670, P1⁄4 0.0049, respectively) (Figure 1B). However, this association could be due, at least in part, to the fact that an effective treatment may independently decrease both SLEDAI and IL-6 levels, acting as a confounding factor. High serum and urinary IL-6 levels have already been reported in lupus nephritis, but the relationship between IL-6 production and disease activity is still debated. Showing a close correlation between IL-6 spontaneous release and SLE activity, our data, in addition to those reported by De La Torre, could contribute to better define the important role of IL-6 activation in lupus nephritis. Longitudinal and bigger studies are required to confirm these findings and to discriminate the effects of different treatments on inflammatory status in patients with lupus nephritis.

Effects of hypercholesterolemia on renal hemodynamics : Study in patients with nephrotic syndrome

Experimental and clinical studies have demonstrated a positive relationship between hyperlipidemia and rate of progression of renal disease, suggesting that lipids can induce or aggravate glomerular injury mainly by interacting with mesangial cells. Nevertheless, recently has been demonstrated that increased cholesterol levels can also induce endothelial cell dysfunction. Thus, since endothelium is known to play a major role in modulating the vascular tone, we have tested the possibility that hypercholesterolemia impairs the renal hemodynamics in patients with active nephrotic syndrome and elevated serum cholesterol levels. In this single-blind, nonrandom study, 12 patients were treated with pravastatin (group T, treated, n = 12) and 8 with placebo (group C, controls, n = 8). The controls were studied after the pravastatin group had been completed. Before starting the treatment the patients underwent basal determinations including routine laboratory investigations and PAH and inulin clearances. The same determinations were repeated after 48 h, and 6 and 12 weeks from the beginning of the treatment. The study at 48 h was performed to see if pravastatin had a direct, cholesterol-independent effect on renal function. The following basal results were reported (mean +/- SEM; group T vs. group C): serum cholesterol (mmol/l) 9.7 +/- 0.4 vs. 9.1 +/- 0.3 (NS); proteinuria (g/24 h): 6.2 +/- 0.2 vs. 7.0 +/- 0.7 (NS); PAH clearance (ml/min): 353 +/- 21 vs. 385 +/- 31 (NS); inulin clearance (ml/min): 62.5 +/- 7.7 vs. 67 +/- 9.3 (NS). After 48 h, no changes were observed in both groups. Subsequently, in group T, the following percentage changes of basal levels were observed: serum cholesterol -21.4 +/- 3.2% at 6 weeks (p < 0.05) and -34.9 +/- 3.2% at 12 weeks (p < 0.01); inulin clearance +3 +/- 3.7% at 6 weeks (NS) and +9.3 +/- 2.9% at 12 weeks (p < 0.05); PAH clearance +7 +/- 3.1% at 6 weeks (p < 0.05) and +21.2 +/- 5.5% at 12 weeks (p < 0.01). By contrast, no significant changes of these parameters occurred in group C at any time, so that the percent changes of baseline values of CPAH were significantly greater in group T (at 6 weeks: p < 0.05; at 12 weeks p < 0.005). These results indicate that the reduction of cholesterol is associated with a significant increase in renal plasma flow, thus, suggesting that hypercholesterolemia may actually impair the renal hemodynamics. We speculate that this effect may contribute to increase the risk of ischemic acute renal failure in nephrotic patients and, along with changes induced in the mesangium by other mechanisms, to contribute to the progression of renal disease.

Acute Effects of Ciclosporin on Renal Hemodynamics and Urinary Protein Excretion in Patients with the Nephrotic Syndrome

The possibility that the renal hemodynamic abnormalities associated with ciclosporin (CS) administration are enhanced in nephrotic patients (NP), leading to severe impairment of renal function and/or to modifications in proteinuria, has not hitherto been tested. Ten NP and 8 healthy subjects (NC) were examined before and after oral CS administration (10 mg/kg body weight in NP and 12 mg/kg body weight in NC: a lower dosage was adopted in NP because of edema overestimating the actual body weight) under water diuresis by standard renal clearance methods. Basal blood volume was lower in NP. Blood CS levels were not significantly different in the two groups. Basal glomerular filtration rate (GFR) was similar in NP and NC, while renal plasma flow (RPF) was lower in NP. After CS, both GFR and RPF significantly decreased in the two groups, but the percent decrease in inulin clearance was greater in NP. Filtration fraction increased only in NC. Basal renal vascular resistances were greater in NP, and significantly increased after CS in both groups. Basal fractional sodium excretion (FENa) was lower in NP: after CS FENa decreased only in NC. Neither plasma renin activity, nor plasma aldosterone changed after CS. When urinary protein excretion (UP) was corrected by GFR, no change was observed after CS; by contrast, selectivity of proteinuria (as assessed by the CIgG/CTransferrin ratio) markedly increased. Our data indicate that CS induces a greater fall in the GFR in hypovolemic NP than in healthy subjects, probably because in the former GFR becomes extremely plasma flow dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Sublingual administration improves systemic exposure of tacrolimus in kidney transplant recipients: comparison with oral administration

Tacrolimus (TCR) is an immunosuppressive drug used by oral administration. Intravenous (IV) TCR administration is required under conditions of gastrointestinal diseases or abdominal surgery at the onset of paralytic ileus. The infusion formulation needs a large dilution and therefore a careful technical management during continuous infusion by 24 h and may determine anaphylaxis, cardiac arrhythmia, QT prolongation and torsades de pointes. Sublingual (SL) TCR administration was suggested as an alternative route.

Preclinical cardiovascular abnormalities in patients in early stages of renal disease without nephrotic syndrome.

Preclinical cardiovascular abnormalities in patients in early stages of renal disease without nephrotic syndrome

Tubular lesions secondary to conventional urography: a study on renal biopsies by light microscopy.

The contrast media generally used for radiologic examination may cause acute renal failure especially in patients with diabetes mellitus, myeloma and/or dehydration or salt depletion1. Some authors2,3,4 have demonstrated that contrast media often cause tubular changes even when renal function is not impaired.

Eculizumab in pregnancy: a narrative overview

Pregnancy can be a dangerous trigger for patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), or hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome. Due to the possibility of several serious complications, pregnancy is somewhat discouraged in the presence of the above diseases. Eculizumab is a humanized antibody that may dramatically change the clinical course of PNH, aHUS and HELLP syndrome. However, data on the safety of eculizumab in pregnancy are scarce. In this narrative overview, we summarize current evidence on the use of eculizumab during pregnancy in women with PNH, aHUS and HELLP syndrome. Eculizumab is not present in breast milk, and the levels observed in umbilical cord blood samples are not sufficient to affect the concentrations of complement in newborns. Therefore, eculizumab may be regarded as safe in pregnancy. Nonetheless, given that data on eculizumab in pregnancy are limited, it is not possible to completely exclude risks for both mother and fetus in treating PNH, aHUS and HELLP syndrome.

Is Tubulointerstitial Damage a Reliable Index for Predicting Renal Outcome in Primary Membranous Nephropathy

Interstitial changes are often observed in primary glomerular disease. However, the severity of these changes is not always mirrored by the glomerular involvement. Aim of this study is to evaluate if the presence of tubular, interstitial and vascular changes can predict the renal outcome of primary membranous glomerulonephritis (MGN).

Acute Cyclosporine a Nephrotoxicity

Experimental studies in rats have demonstrated that CyA causes tubular necrosis only when given at very high dosage. At a dosage of 20 mg/kg b.w./day proximal tubular changes are subtle and can be detected only by electron microscopy after a week of treatment (1). Some authors have suggested a direct toxic effect of the drug on proximal tubular cells. But the lack of early histopathologic lesions during CyA therapy (2), the increase of fractional proximal tubular reabsorption after acute or short-term administration of the drug (3–6) and the reversibility of renal dysfunction upon discontinuation of CyA (7,8) have supported the hypothesis that acute renal function impairment by CyA is due to reversible changes in renal hemodynamics, a form of “prerenal” failure.