Cristiana Rollino

Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin–angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.

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

Toll‐like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy

We investigated Toll‐like receptors (TLR‐3, ‐4 and ‐7) expression in circulating mononuclear cells of patients with immunoglobulin A nephropathy (IgAN), a disease with debated relationships with mucosal immunity. TLR‐4 expression (detected by fluorescence activated cell sorter) and mRNA transcriptional levels (Taqman) were significantly higher in patients with IgAN than in healthy controls (P = 0·00200 and P = 0·0200). TLR‐3 and TLR‐7 were not modified significantly. In IgAN patients proteinuria was correlated significantly with TLR‐4 expression (P = 0·0312). In a group of nephrotic syndromes, TLR‐3, ‐4 and ‐7 expression was similar to healthy controls. A significant difference in TLR‐4 expression and mRNA levels was found between very active IgAN patients (proteinuria > 1 g/1·73 m2/day in association with severe microscopic haematuria) and inactive patients (proteinuria < 0·5 g/1·73 m2/day, with absent or minimal haematuria). No correlation with levels of aberrantly glycosylated IgA1, age, renal biopsy features or therapy was found. This study shows for the first time an up‐regulation of TLR‐4 in circulating mononuclear cells of patients with IgAN, particularly in association with proteinuria and heavy microscopic haematuria.

Glomerulonephritis with organized deposits: A mesangiopathic, not immune complex-mediated disease? A pathologic study of two cases in the same family

Similar glomerular changes (marked widening of the mesangial stalk, irregular basement membrane thickening, and presence of mesangial and subendothelial deposits) were observed by light microscopy in renal biopsy specimens from two patients (mother and daughter) affected by nephrotic syndrome. Electron microscopy disclosed huge glomerular electron-dense deposits containing 12-nm fibrils in both patients. Immunohistochemical investigations performed with antisera anti-immunoglobulin (Ig) and anti-complement fractions, anti-laminin, anti-collagen IV, and anti-fibronectin (FN) showed scant and focal Ig and complement deposits and strong deposits of FN in the mesangium and along glomerular basement membranes. Most glomerular FN was plasma-derived, as shown by immunohistochemical tests with monoclonal antibodies specific for both plasma and cell-derived FN (IST-4) and for cell-derived FN (IST-9). Electron-dense deposits with fibrillar component could hardly correspond to the Ig and complement deposits, whereas they could be related to FN deposits. Since it is known that in glomeruli FN binds to Ig and immune complexes, and the latter seem to be too scant to justify light and electron microscopic lesions and clinical findings, the hypothesis of a primary mesangiopathic glomerulonephritis in some way connected with abnormal plasma FN deposition within the glomeruli and subsequent non-specific immune reactant entrapment could be considered. We could be dealing with a peculiar form of fibrillary glomerulonephritis with rather indolent evolution, as shown by a slow decrease of glomerular function and the scarcely modified glomerular changes found in the second biopsy performed in the mother 8 years after the first investigation.

The verapamil versus amlodipine in nondiabetic nephropathies treated with trandolapril (VVANNTT) study

BACKGROUND We tested whether the combination of verapamil (V) or amlodipine (A) with trandolapril (T) affected proteinuria differently from T alone in patients with nondiabetic nephropathies. METHODS After T, 2 mg, in open conditions for 1 month, 69 patients were randomly assigned to be administered T, 2 mg, combined with V, 180 mg, plus a placebo or T, 2 mg, plus A, 5 mg, once a day in a double-blind fashion. Patients were followed up for 8 months. RESULTS Proteinuria diminished significantly after T treatment from mean protein excretion of 3,078 +/- 244 (SEM) to 2,537 +/- 204 mg/24 h (P = 0.018). In the randomized phase, there was a slight reduction in proteinuria in both groups without significant differences within and between treatments (T + V, protein from 2,335 +/- 233 to 2,124 +/- 247 mg/24 h; T + A, protein from 2,715 +/- 325 to 2,671 +/- 469 mg/24 h). The selectivity index (SI; calculated as the ratio of immunoglobulin G to albumin clearance) was slightly and not significantly reduced in patients treated with T plus V from a median of 0.20 (interquartile range, 0.13) to 0.16 (interquartile range, 0.15; P = not significant), whereas it significantly increased from 0.20 (interquartile range, 0.14) to 0.30 (interquartile range, 0.14; P = 0.0001) in patients treated with T plus A. Modifications in SI and serum creatinine levels at the end of the study from randomization were significantly directly correlated (r = 0.45; P = 0.001). The number of patients reporting adverse effects was significantly higher in the T plus A than T plus V group (63.8% versus 33.3%; P = 0.016). CONCLUSION In patients with nondiabetic proteinuric nephropathies treated with T, the combination of V or A does not significantly increase its antiproteinuric effect.

Glomerulonephritis with Organized Deposits: A New Clinicopathological Entity? Light-, Electron-Microscopic and Immunofluorescence Study of 12 Cases

Twelve cases of glomerulonephritis in patients without systemic diseases, displaying organized glomerular deposits, were reported. Microfibrils (11-30 nm diameter) were found in 9 patients and microtubules (20-35 nm diameter) in the other 3. Histochemical stainings for amyloid were always negative. By light microscopy, mesangial proliferative, membranous and membranoproliferative patterns were seen in 5, 3 and 4 patients, respectively. By immunofluorescence, granular deposits, mainly of IgG and C3, were found in all cases, either in the mesangium or in the mesangium and in the capillary walls. A second biopsy was performed in 2 patients. The number of hyaline glomeruli was increased, but the general pattern of glomerular changes remained unchanged. The commonest clinical findings were hypertension, microhematuria and proteinuria, often of nephrotic range. At variance to what is reported in the literature, 2 pediatric cases were found as well, and the overall prognosis (mean follow-up 54.3 months) was mostly favorable. The diagnostic relevance of these findings is pointed out, but further investigations are needed, before suggesting a new clinicopathological entity.

IL-10 stimulates production of platelet-activating factor by monocytes of patients with active systemic lupus erythematosus (SLE)

IL‐10 displays modulatory properties on the synthesis of platelet‐activating factor (PAF), a potent inflammatory mediator of vascular injury. Despite the fact that IL‐10 is considered to be an anti‐inflammatory cytokine, IL‐10 levels correlate with disease activity in SLE. Moreover, in SLE IL‐10 is unable to exert its immunosuppressive and anti‐inflammatory effects. We have investigated the ability of IL‐10 to stimulate PAF production from monocytes of SLE patients. Spontaneous and IL‐10‐stimulated PAF production by peripheral blood monocytes was measured in active (n = 13) and inactive (n = 14) SLE patients and in 15 normal control subjects. We observed that monocytes derived from patients with active SLE, but not from controls or inactive SLE, spontaneously produced significant amounts of PAF. Moreover, IL‐10 enhanced the synthesis of PAF from monocytes of active SLE patients only. IL‐10‐induced PAF production correlated with the severity of the disease and with the extent of proteinuria. These results indicate that IL‐10 only stimulates the synthesis of PAF from monocytes of SLE patients when immunologically active, suggesting that IL‐10 may possess a paradoxical proinflammatory effect in SLE by promoting the production of PAF, a secondary mediator of inflammation.

Acute pyelonephritis in adults: a case series of 223 patients

BACKGROUND Acute pyelonephritis (APN) is a common disease which rarely evolves into abscesses. METHODS We prospectively collected clinical, biochemical and radiological data of patients hospitalized with a diagnosis of APN from 2000 to 2008. RESULTS Urinary culture was positive in 64/208 patients (30.7%) and blood cultures in 39/182 cases (21.4%). Two hundred and thirteen patients were submitted to computed tomography (CT) or nuclear magnetic resonance (NMR): confirmation of APN was obtained in 196 patients (92%). Among these, 46 (23.5%) had positive urine culture, 31 (15.8%) had positive blood culture and 15 (7.6%) had positive cultures of both urine and blood. In 98 patients, either urine or blood cultures were negative, but CT/NMR were positive for APN. Fifty of the 213 patients submitted to CT/NMR (23.5%) had intrarenal abscesses: only 2 were evidenced by ultrasound examination. No differences were found between patients with positive or negative CT with regards to fever, leucocytosis, C-reactive protein, pyuria, urine cultures and duration of symptoms before hospitalization. No differences were found between patients with or without abscesses with regards to these parameters and risk factors. Patients with abscesses had a longer duration of treatment and hospitalization. CONCLUSIONS Our data suggest that in APN it is not always possible to routinely document urinary infection in a clinical setting. This finding could be explained by previous antibiotic treatment, low bacterial growth or atypical pathogens. Systematic CT or NMR is necessary to exclude evolution into abscesses, which cannot be suspected on clinical grounds or by ultrasound examination and may also develop in the absence of risk factors.

Monoclonal Gammopathy and Glomerulonephritis With Organized Microtubular Deposits

We report a case with IgG-kappa monoclonal gammopathy of unidentified significance (MGUS) and glomerulonephritis (GN) with organized microtubular deposits on electron microscopy (EM). Light microscopy (LM) examination showed exudative features and moderate extracapillary proliferation. An acute nephritic syndrome with a rapidly progressive renal failure was clinically manifest at the onset and during each relapse. The patient was treated with methylprednisolone pulses followed by oral prednisone, cyclophosphamide, plasmapheresis, and maintenance courses of chemotherapy. The response to treatment was good, with a temporary improvement of renal function and control of the downhill course over a 3-year follow-up.

Tonsillectomy in a European Cohort of 1,147 Patients with IgA Nephropathy

Background: Tonsillectomy has been considered a treatment for IgA nephropathy (IgAN). It is aimed at removing a source of pathogens, reducing mucosa-associated lymphoid tissue and decreasing polymeric IgA synthesis. However, its beneficial effect is still controversial. In Asia, favorable outcomes have been claimed mostly in association with corticosteroids. In Europe, small, single-center uncontrolled studies have failed to show benefits. Methods: The European validation study of the Oxford classification of IgAN (VALIGA) collected data from 1,147 patients with IgAN over a follow-up of 4.7 years. We investigated the outcome of progression to end-stage renal disease (ESRD) and/or 50% loss of estimated glomerular filtration rate (eGFR) and the annual loss of eGFR in 61 patients who had had tonsillectomy. Results: Using the propensity score, which is a logistic regression model, we paired 41 patients with tonsillectomy and 41 without tonsillectomy with similar risk of progression (gender, age, race, mean blood pressure, proteinuria, eGFR at renal biopsy, previous treatments and Oxford MEST scores). No significant difference was found in the outcome. Moreover, we performed an additional propensity score pairing 17 patients who underwent tonsillectomy after the diagnosis of IgAN and 51 without tonsillectomy with similar risk of progression at renal biopsy and subsequent treatments. No significant difference was found in changes in proteinuria, or in the renal end point of 50% reduction in GFR and/or ESRD, or in the annual loss of eGFR. Conclusion: In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline.