Giuseppe Piccoli

Hepatitis C virus infection and membranous glomerulonephritis.

Cristiana Rollino, MD, Divisione di Nefrologia e Dialisi, Ospedale Giovanni Bosco, Piazza del Donatore di Sangue 3, I-10154 Torino (Italy) Dear Sir, Chronic hepatitis B virus (HBV) infection is known to be associated with membranous glomerulonephritis (MGN), where it represents one of the etiologic factors identified up to now [1]. The frequency of association varies according to different authors and is particularly high in childhood [2]. HBs, HBe and HBc antigens have been identified in subepithelial deposits [3–5]. Whether other forms of hepatitis can also be associated with this nephropathy is still unknown. As new tests for the detection of anti-hepatitis C virus antibodies (HCV-Abs) have become available recently, we looked for a possible association between HCV and MGN. We tested sera of 27 adult patients (16 males, 11 females; mean age 49.8 ± 12.2 years) with biopsy-proven MGN. None of them exhibited systemic lupus erythe-matosus, diabetes mellitus, syphilis, malignancy or exposure to heavy metals or drugs known to induce MGN. HBV antigen and antibody were negative in all the patients. The presence of HCV-Abs was evaluated by the enzyme-linked immunosorbent assay ‘Abbott HCV EIA’, which employs a recombinant antigen of HCV. The neutralizing confirmatory Abbott test was used to bear out the positive results. Only 1 of 27 patients showed the presence of HCV-Abs in several sera; this result was corroborated by the confirmatory test. The onset of MGN in this patient occurred in July 1989. At the time of the admittance to our nephrology department (April 1990), laboratory investigations showed slight elevation of serum transaminases; alkaline phosphatase and prothrombin time were within the normal range, proteinuria was 4,400 mg/24 h, and renal function was normal. The patient was given a treatment with 3 × 1 g methylprednisolone pulses followed by oral prednisone 25 mg daily for 1 month and by chlorambucil 10 mg daily for the next month. The treatment was repeated 3 times and lasted on the whole 6 months [6]. At the end of the therapy, complete remission of the nephropathy (proteinuria 0.2 g/day) was achieved and transaminases were within the normal range. The relationship between hepatitis and occurrence of the nephrotic syndrome is not simply defined. At the time of the admittance to our department, we probably might have observed a late

Angiotensin II Local Hyperreactivity in the Progression of IgA Nephropathy

Immunologic and hemodynamic factors are likely to work in synergism in the progression of immunoglobulin A nephropathy (IgAN) toward sclerosis. The local activation of the renin-angiotensin system may be one the most relevant mechanisms. We investigated the hemodynamic effects of the acute administration of angiotensin-converting enzyme inhibitor (ACEI) (captopril 50 mg). The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) were measured by 51Cr-EDTA and 125I hippurate clearances. The correspondent filtration fractions (FFs) in basal conditions and after administration of ACEI were calculated, then the changes in FF (delta FF and % delta FF) were determined. We studied 27 IgAN patients. Eighteen patients had normal renal function (GFR, 112 +/- 19 mL/min/1.73 m2) and nine had moderate renal impairment (GFR, 54 +/- 13 mL/min/1.73 m2). Sixteen patients had proteinuria > or = 0.5 g/d. In addition, 12 glomerulonephritis control cases and eight healthy subjects were investigated. After the administration of ACEI in healthy subjects we observed slight modifications in the GFR, a significant increase in the ERPF (P < 0.005), and a significant decrease in FF (P < 0.04). Similarly, in IgAN patients with normal renal function the GFR increased slightly, the ERPF increased significantly (P < 0.01), and there was a decrease in FF (P < 0.01). The delta FF and % delta FF values were not significantly different from those found in the controls. In patients with initial renal failure GFR remained unchanged, ERPF increased significantly (P < 0.005), and FF significantly decreased (P < 0.004). However, the changes in delta FF and % delta FF were significantly greater than those found in healthy controls (P < 0.01) and in IgAN patients with normal renal function (P < 0.001). IgAN patients with proteinuria levels > or = 0.5 g/d showed greater changes in delta FF and % delta FF after the administration of ACEI than patients with proteinuria levels lower than 0.5 g/d (P < 0.003 and P < 0.04, respectively) or proteinuric control cases (P < 0.05 and P < 0.01, respectively). This different response in proteinuric and nonproteinuric patients was evident even when the analysis was limited to the subgroup of IgAN patients with normal renal function. The decrease in FF consequent to an increase in the ERPF after the administration of ACEI suggests a local hyperactivity of the renin-angiotensin system in some cases of IgAN.(ABSTRACT TRUNCATED AT 400 WORDS)

The Fate of Aggregated Immunoglobulin A Injected in IgA Nephropathy Patients and Healthy Controls

Organ uptake of IgA-containing immunologically active material was studied in humans by intravenous (IV) injection of 131I-labeled heat-aggregated human secretory IgA (HAS-IgA) in nine patients affected by primary IgA nephropathy and 10 normal volunteers. Aggregated secretory IgA was found to be removed almost exclusively by the liver. The peak activity in liver was reached at 21.1 minutes (range, 18 to 26 minutes) in patients and 19 minutes (range, 14 to 22 minutes) in controls. The rate of increase of liver radioactivity was found to be significantly slower in patients (with a mean slope of 5.0; range, 3.4 to 7.1 v 7.6, 5.6 to 11.4; P less than 0.02). The mean liver to precordium ratio at the peak time was significantly lower in patients (mean value, 2.3; range, 1.9 to 3.1) compared with controls (mean value, 3.3; range, 2.4 to 4.0) (P less than 0.02). These data confirm the pivotal role of the liver in the removal of aggregated IgA in humans and the defective clearance capacity of this test probe in IgA nephropathy patients.

Correlation between Cytomegalovirus Infection and Raynaud’s Phenomenon in Lupus nephritis

Relationships between viruses and autoimmune diseases such as systemic lupus erythematosus (SLE) are still elusive. Recent reports demonstrated the association of some viral infections with peculiar clinical events in the general population, such as cytomegalovirus (CMV) with arterial damage and Parvovirus B19 (PV-B19) with hematologic abnormalities. We planned to look for this kind of viral imprinting in SLE, hypothesizing that traces of specific features of some viral infections might be found in some subsets of seropositive SLE patients. In 60 SLE patients recruited at our nephrologic center, serology for CMV, PV-B19, Epstein-Barr virus viral capsid antigen (EBV-VCA), Epstein-Barr nuclear antigen (EBNA) and Epstein-Barr virus early antigen (EBV-EA) was performed. χ2 and ANOVA were employed to compare the frequency and titers of antiviral antibodies in SLE patients with groups of transplant, hemodialysis and blood donor subjects. χ2, Fisher’s test, Bonferroni and Scheffe’s test were employed to compare the different biochemical/clinical features between seropositive and seronegative SLE patients. Univariate and multivariate analysis (logistic regression models) were employed to evaluate the odds ratio (OR) of different risk factors for vascular events (including Raynaud’s phenomenon, deep venous thrombosis) and hematologic abnormalities (including severe anemia, leukopenia and thrombocytopenia). Anti-CMV (82%), anti-PV-B19 (60%), anti-EBV-VCA (92%) and EBV-EA (45%) IgG antibodies were frequent in SLE, with higher prevalence in comparison with the blood donor group and higher titers in comparison with transplant and hemodialysis groups. CMV seropositivity was a highly significant risk factor for Raynaud’s phenomenon (OR +α in univariate and multivariate analysis = 13.51 using a correction of 0.5 in case of a zero event), but not for venous vascular events (OR = 1.31). An increased though not significant risk factor was found for antiphospholipid antibodies (OR = 2.71, p = 0.19), while the presence of nephrotic syndrome during the follow-up was a significant protective factor (OR = 0.15, p = 0.035). There was no significantly increased OR for PV-B19 seropositivity in cases with severe anemia (OR = 2.09, p = 0.29). No significant associations were found with the status of EBV reactivation. In conclusion, our results support the hypothesis that viral infection may imprint the course of SLE leading to specific clinical subsets (i.e. CMV and ‘vascular’ SLE, with more frequent Raynaud’s phenomenon and a less frequent typical histological renal picture responsible for nephrotic syndrome). Further prospective studies are justified to validate these correlations, mainly dealing with associations between acute viral infections and vascular events, thus eventually leading to a better understanding of mutual relationships between viruses and SLE.

Kidney biopsy in pregnancy: evidence for counselling? A systematic narrative review

Kidney diseases, which have a prevalence of 3% in women of childbearing age, are increasingly encountered in pregnancy. Glomerulonephritis may develop or flare up in pregnancy, and a differential diagnosis with pre‐eclampsia may be impossible on clinical grounds. Use of kidney biopsy is controversial, but a systematic review has not been carried out to date.

Modulatory effect of interleukin‐10 on the production of platelet‐activating factor and superoxide anions by human leucocytes

We observed that human monocytes (MO) and polymorphonuclear neutrophils (PMN) stimulated by lipopolysaccharide (LPS) produce platelet‐activating factor (PAF) in a pattern characterized by an early and a delayed peak of synthesis. The early peak of PAF synthesis was due to a direct stimulation of these cells through mCD14 receptor as it was inhibited by anti‐CD14 monoclonal antibody. The delayed and sustained peak of PAF synthesis was dependent on protein synthesis and cytokine production as shown by the inhibitory effect of cycloheximide on both MO and PMN, and of anti‐tumour necrosis factor‐α (anti‐TNF‐α) and of anti‐interleukin‐8 (anti‐IL‐8) neutralizing antibodies on MO and PMN respectively. IL‐10 completely prevented this second, cytokine‐dependent peak of PAF synthesis. In contrast, IL‐10 markedly enhanced the first peak of PAF synthesis both in MO and PMN. Moreover, IL‐10 was shown to modulate the production of superoxide anions (O‐2) on both MO and PMN. As suggested by previous studies, IL‐10 inhibited the delayed production of O‐2. In the present study, we observed that IL‐10 directly stimulated an early production of O‐2. In addition, IL‐10 enhanced the synthesis of O‐2 by MO and PMN challenged with LPS. The IL‐10‐induced O‐2 production was dependent, at least in part, from its effect on PAF synthesis, as it was inhibited by the PAF receptor antagonist WEB 2170. These results suggest that IL‐10 may upregulate the early synthesis of PAF and O‐2 triggered by direct LPS stimulation, whereas it may downregulate the delayed production of these mediators.

Vegan–vegetarian diets in pregnancy: danger or panacea? A systematic narrative review

Although vegan–vegetarian diets are increasingly popular, no recent systematic reviews on vegan–vegetarian diets in pregnancy exist.

Plasmapheresis in a Patient with Rapidly Progressive Idiopathic IgA Nephropathy: Removal of IgA-Containing Circulating Immune Complexes and Clinical Recovery

Primary IgA nephropathy is generally considered a benign disease, but progression to renal failure is not uncommon and a rapidly progressive course is observed in some cases, especially when extensive epithelial crescents are present. Circulating IgA-containing immune complexes (IgAIC) seem to play the most important pathogenetical role, hence the authors adopted plasmapheretic treatment in association with immunosuppressive drugs for 1 patient affected by primary IgA nephritis, with florid crescents and progressive renal failure. IgAIC decreased significantly after each plasma exchange and finally returned to normal values; over the same period urinary protein loss and heavy microscopic hematuria gradually disappeared and renal function was completely recovered.

Presence and origin of IgA1- and IgA2-containing circulating immune complexes in chronic alcoholic liver diseases with and without glomerulonephritis

Levels of IgA-containing circulating immune complexes (IgAIC) and their content of IgA1 and IgA2 subclasses were determined in chronic alcoholics with various degrees of liver damage and with or without associated glomerulonephritis. In patients with chronic alcoholic liver diseases, significantly increased IgAIC mean values were found independent of the presence of renal involvement, while in chronic alcoholics without biochemical evidence of liver damage IgAIC levels were normal. Both IgA subclasses were evidenced in IgAIC with an IgA pattern similar to that found in secretions, in agreement with the impaired liver clearance of IgAIC derived from intestinal mucosa. Nevertheless, no significant correlation between IgAIC and markers of hepatocytolysis or of cholestasis was found. One cannot therefore rule out the hypothesis of increased IgA synthesis in alcoholic liver disease due to abnormal alimentary antigen challenge and pathologic lymphocytic responsiveness. Finally, high IgAIC levels were found not only in patients with IgA glomerular deposits, but also in patients without clinical evidence of renal involvement.

Angiotensin I-converting enzyme genotype significantly affects progression of IgA glomerulonephritis in an italian population.

To evaluate the role of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in the progression of immunoglobulin A glomerulonephritis (IgA-GN), genotype distribution in 81 biopsy-proven cases of IgA-GN was studied. A logistic regression model showed that the risk for homozygous DD was not significantly elevated in patients with IgA-GN compared with healthy subjects (odds ratio = 1.16; confidence interval [CI], 0.4 to 3.3). However, the 5-year (78% v 90%) and 10-year (52% v 82%) renal survival rates for 47 patients with serum creatine (Cr) levels of 1.5 mg/dL or less at biopsy was significantly less in DD patients (n = 18; chi2 = 5.41; P = 0.02). The hazard ratio (HR) for DD (multivariate analysis from Cox proportional model after adjustment for known factors of progression, such as hypertension [HPT] and proteinuria [PTO]) was 3.07 (CI, 1.1 to 9.4). The HR for heavy PTO was 6.1 (CI, 1.9 to 19). The association of DD genotype with progression was even more striking when patients with other risk factors (heavy proteinuria) were excluded, as shown by DD-related risk in the absence (HR = 3.6; CI, 1.1 to 12) and presence (HR = 2; CI, 0.4 to 10) of PTO. The risk ratio was further increased by the coexistence of DD + PTO (HR = 9.16; CI, 1.8 to 15.7). Furthermore, in a cross-sectional study among patients with IgA-GN, a logistic regression model showed that the risk for homozygous DD was greater, although not at a statistically significant level in the end-stage renal failure subgroup compared with the normal renal function subgroup (odds ratio = 3.16; CI, 0.7 to 13.7) after adjustment by sex, age at biopsy, HPT, PTO, and therapy. Last, DD was significantly more frequent in those patients who started hemodialysis at an earlier age (chi2 for trend = 6.81; P = 0.009). Our study further supports that ACE genotype is a risk factor not for the development, but for the worsening of IgA-GN clinical course. However, on the basis of current knowledge, we cannot exclude that I/D polymorphism may simply serve as a prognostic marker, eventually linked with other discrete loci involved in the progression of renal damage.