The steroid-sparing effects of a mycophenolate mofetil-based regimen in the management of immunoglobulin A nephropathy in patients with histologically active lesions: A comparison with a control cohort receiving conventional therapy.

INTRODUCTION: While the use of different immunosuppressants has been investigated in immunoglobulin A nephropathy, further investigation is needed to assess the effect of a regimen of mycophenolate mofetil combined with a short course of glucocorticosteroids in the subset of patients with histologically active features. We compared the efficacy and safety of a combined regimen of mycophenolate mofetil and glucocorticosteroids to a conventional regimen of glucocorticosteroids alone in patients with immunoglobulin A nephropathy who have active lesions and major urinary abnormalities. METHODS: This retrospective study involved 30 immunoglobulin A nephropathy patients with active histological lesions, 15 of whom were treated with both mycophenolate mofetil 2 g/day for 6 months and 3 pulses of 15 mg/kg methylprednisolone, followed by a short tapering schedule of oral prednisone. The control group was made up of the remaining 15 clinically- and histologically-matched patients treated with glucocorticosteroids alone according to a validated schedule, i.e., 1 g of methylprednisolone given intravenously for 3 consecutive days, followed by oral prednisone 0.5 mg/kg every other day for 6 months. At diagnosis, all patients had urinary protein excretion > 1 g/24 h and microscopic hematuria. RESULTS: At the end of the first year of follow-up (30 patients) and after 5 years (17 patients), there were no differences between the two groups in terms of urinary abnormalities and functional parameters. Both regimens achieved a statistically significant decrease in 24-h urinary protein excretion (p < 0.001) and a reduction of microscopic hematuria. However, the mycophenolate mofetil-based regimen allowed a cumulative sparing dose of 6 g of glucocorticosteroids. CONCLUSION: In this single center study on immunoglobulin A nephropathy patients with active lesions and major urinary abnormalities and at increased risk of glucocorticosteroid-related complications, a mycophenolate mofetil-based regimen demonstrated similar outcomes in terms of complete response and relapse (at 1 and 5 years) compared to a conventional glucocorticosteroid-based protocol, while achieving a consistent reduction of glucocorticosteroid cumulative dose.

Treating Patients With ANCA-Associated Vasculitis and Very Severe Renal Injury With an Intensified B Cell Depletion Therapy: Comparison With a Control Cohort Receiving a Conventional Therapy.

Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown to be an effective induction treatment for small-vessel vasculitides associated with antineutrophil cytoplasm antibodies (AAV) in both newly diagnosed and relapsing patients. However, the role of RTX in the management of the most severe cases of AAV remains to be fully elucidated. The aim of this study was to assess both safety and efficacy of an intensified B-cell depletion therapy (IBCDT) protocol, including RTX, cyclophosphamide (CYC), and methylprednisolone pulses without additional maintenance immunosuppressive therapy in a cohort of 15 AAV patients with the most severe features of AVV renal involvement (as <15 ml/min GFR and histological findings of paucimmune necrotizing glomerulonephritis with more than 50% crescents of non-sclerotic glomeruli at the renal biopsy). Results of the IBCDT regimen have been compared to those obtained in a control cohort of 10 patients with AAV treated with a conventional therapy regimen based on oral CYC and steroids followed by a prolonged maintenance therapy with azathioprine (AZA). Plasma exchange was equally employed in the study and the control group. Complete clinical remission (BVAS 0) was observed at 6 months in 14 of 15 patients treated with IBCDT (93%). All cases who achieved a complete clinical remission experienced a depletion of peripheral blood B cells at the end of therapy. Of the 10 dialysis dependent patients at onset, 6 subjects (60%) experienced a functional recovery allowing the suspension of dialysis treatment. When compared to the control group, no statistically significant difference was observed in patients treated with IBCDT in terms of overall survival, 6-month therapeutic response rate, and 6-, and 12-month functional renal recovery. The cumulative total dose of CYC in the case group was on average 1 g/patient while in the control group on average 8.5 g/patient (p = 0.00008). Despite the retrospective design and relative limited sample size, IBCDT appeared to be safe and had the same efficacy profile when compared to the conventional therapy with CYC plus AZA in the management of the most severe patients with AAV. Additionally, this avoided the need of prolonged maintenance therapy for long, and limited the exposure to CYC with consequent reduced toxicity and drug-related side effect rates.

Management of acute kidney injury in frail patients with biopsy-proven cast nephropathy: a combined approach with chemotherapy plus Supra-hemodiafiltration with post-adsorption endogenous reinfusion.

BACKGROUND: Patients with multiple myeloma often have kidney involvement with acute kidney injury which is frequently due to cast nephropathy. Hemodiafiltration with endogenous reinfusion (HFR) allows removal from the circulation of significant amounts of free light chains (FLCs) responsible for tubular damage. METHODS: Between 2014 and 2018, 13 patients affected by multiple myeloma (64% λ chain and 36% k), including 10 cases with biopsy-proven cast nephropathy, were treated with this technique. Each patient had high free light chains levels at diagnosis: median 8586 mg/l for λ and 4200 mg/l for k, and stage III acute kidney injury (median serum creatinine 7.5 mg/dl). We initially performed daily HFR-Supra sessions and then modulated them based on renal response (mean 10 sessions/patient). At the same time, the patients also received various chemotherapy regimens, depending on their hematological criteria. RESULTS: Forty-six percent of patients showed at least partial renal function recovery within the third month, thus allowing dialysis discontinuation; 38% remained on dialysis. Two patients died. The mean reduction rate of free light chains at the end of the HFR-Supra cycle was 85% (k) and 40% (λ), respectively. Serum albumin remained stable during the whole treatment. DISCUSSION: In our experience, the synergistic effect of chemotherapy and HFR-Supra led to a recovery of renal function in 6 out of 13 patients presenting with severe dialysis-requiring acute kidney injury. HFR-Supra allowed stable albumin levels, with high free light chains removal rate, at a relatively low costs.

Renal involvement in sarcoidosis: histological patterns and prognosis, an Italian survey.

BACKGROUND: Granulomatous interstitial nephritis in sarcoidosis (sGIN) is generally clinically silent, but in <1% causes acute kidney injury (AKI). METHODS: This Italian multicentric retrospective study included 39 sarcoidosis-patients with renal involvement at renal biopsy: 31 sGIN-AKI, 5 with other patterns (No-sGIN-AKI), 3 with nephrotic proteinuria. We investigate the predictive value of clinical features, laboratory, radiological parameters and histological patterns regarding steroid response. Primary endpoint: incident chronic kidney disease (CKD) beyond the 1°follow-up (FU) year; secondary endpoint: response at 1°line steroid therapy; combined endpoint: the association of initial steroid response and outcome at the end of FU. RESULTS: Complete recovery in all 5 No-sGIN-AKI-patients, only in 45% (13/29) sGIN-AKI-patients (p=0.046) (one lost in follow-up, for another not available renal function after steroids). Nobody had not response. Primary endpoint of 22 sGIN-AKI subjects: 65% (13/20) starting with normal renal function developed CKD (2/22 had basal CKD; median FU 77 months, 15-300). Combined endpoint: 29% (6/21) had complete recovery and final normal renal function (one with renal relapse), 48% (10/21) had partial recovery and final CKD (3 with renal relapse, of whom one with basal CKD) (p=0.024). Acute onset and hypercalcaemia were associated to milder AKI and better recovery than subacute onset and patients without hypercalcaemia, women had better endpoints than men. Giant cells, severe interstitial infiltrate and interstitial fibrosis seemed negative predictors in terms of endpoints. CONCLUSIONS: sGIN-AKI-patients with no complete recovery at 1°line steroid should be treated with other immunosuppressive to avoid CKD, in particular if males with subacute onset and III stage-not hypercalcaemic AKI.

A Prospective Study on Long-Term Clinical Outcomes of Patients With Lupus Nephritis Treated With an Intensified B-Cell Depletion Protocol Without Maintenance Therapy.

BACKGROUND: We aimed to investigate the safety and efficacy of an intensified B-cell depletion induction therapy (IBCDT) without immunosuppressive maintenance regimen compared with standard of care in biopsy-proven lupus nephritis (LN). METHODS: Thirty patients were administered an IBCDT (4 weekly rituximab [RTX] 375 mg/m2 and 2 more doses after 1 and 2 months; 2 infusions of 10 mg/kg cyclophosphamide [CYC], 3 methylprednisolone pulses), followed by oral prednisone (tapered to 5 mg/d by the third month). No immunosuppressive maintenance therapy was given. Thirty patients matched for LN class and age were selected as controls: 20 received 3 methylprednisolone pulses days followed by oral prednisone and mycophenolate mofetil (MMF) 2 to 3 g/d, whereas 10 were given the Euro Lupus CYC. MMF (1-2 g/daily) or azathioprine (AZA, 1-2 mg/kg/day) were given for > 3 years as a maintenance therapy. RESULTS: At 12 months, complete renal remission was observed in 93% of patients on IBCDT, in 62.7% on MMF, and in 75% on CYC (P = 0.03); the dose of oral prednisone was lower in the IBCDT group (mean ± SD 2.9 ± 5.0 mg/dl) than MMF (10.5 ± 8.0 mg/d, P < 0.01) or CYC group (7.5 ± 9.0 mg/d, P < 0.01). Mean follow-up after treatment was 44.5 months (interquartile range [IQR] 36-120 months), 48.6 months (IQR 36-120 months), and 45.3 (IQR 36-120 months) for IBCDT, MMF, and CYC, respectively. At their last follow-up visit, we observed no significant differences in proteinuria and serum creatinine, nor in the frequency of new flares among the 3 groups. CONCLUSION: In biopsy-proven LN, the IBCDT without further immunosuppressive maintenance therapy was shown to be as effective as conventional regimen of MMF or CYC followed by >3-year maintenance either MMF or AZA regimen. Moreover, the use of IBCDT was associated with a marked reduction of glucocorticoid cumulative dose.

Efficacy of low or standard rituximab-based protocols and comparison to Ponticelli's regimen in membranous nephropathy.

BACKGROUND: Patients (pts) with primary Membranous nephropathy (MN) have an autoimmune disease caused by autoantibodies against podocyte antigens and 60-80% of them have antibodies directed against the M-type phospholipase A2 receptor (PLA2R). Immunosuppressive treatment is recommended in high-medium risk pts. Recently the use of rituximab (RTX), has emerged as an important therapeutic option in pts with primary MN. The appropriate cumulative dose of RTX in PMN pts is still uncertain, and favorable outcomes even with low-dose of RTX has been described. We compared efficacy and safety of 3 different treatment regimens: low-dose RTX (Protocol 1, one dose of RTX 375 mg/m2), standard RTX protocol (Protocol 2, four weekly doses of rituximab 375 mg/m2) and Ponticelli's regimen. METHODS: 42 pts with primary MN and nephrotic syndrome were assigned to Protocol 1 (14 pts) or Protocol 2 (14 pts). All patients were followed for 24 months after RTX. Fourteen pts, matched for age and baseline serum creatinine (sCr) and proteinuria, treated with Ponticelli's regimen were examined as controls. RESULTS: At 24 months, a significant improvement in proteinuria levels was observed in pts treated with Protocol 1 (7.5 ± 4.8 at T0; 0.21 ± 0.15 at T24, p < 0.01), Protocol 2 (5.1 ± 1.41 g/24 at T0; 0.35 ± 0.39 at T24 p < 0.01) and controls (8.27 ± 4.78 T0; 2.2 ± 1.9 g/24 h at T24, p < 0.01). No differences in clinical response (p = 0.53) was observed comparing the 3 groups. CONCLUSIONS: Our data suggest that the RTX is a promising alternative to Ponticelli's regimen even at low-doses. This makes RTX a cost-effective treatment of primary MN in the short and medium terms.

Outcome of patients with severe AL amyloidosis and biopsy-proven renal involvement ineligible for bone marrow transplantation.

INTRODUCTION: AL amyloidosis is caused by a clone of plasma cell. Due to the impact of the disease on patient survival, careful evaluation of organ involvement is essential and treatment should be tailored to single patient's risk. AIM: We analyzed the clinical, laboratory and histological characteristics of 21 elderly patients (pts) (mean age 74.7 ± 7.97 years, range 55-81) with AL amyloidosis, including 17 patients (81%) with biopsy-proven renal involvement, who were ineligible for bone marrow transplantation, and evaluated the impact of renal impairment on survival. RESULTS: Cardiac and renal involvement was found in 14 (67%) cases. Among the 17 patients with renal involvement, 12 had renal failure with proteinuria, and one showed isolated renal failure and vascular amyloid deposition. Hematological response occurred in 57.1% after first line therapy (75% after three cycles). In six of the patients with renal involvement, proteinuria decreased from 4.2 to 1.1 g/24 h (range 0.2-3 g/24 h), serum Creatinina (sCr) levels declined or stabilized. Severe renal failure at diagnosis was found to directly influence patient survival, while the Staging System for Renal Outcome in AL Amyloidosis did not associate with outcomes. CONCLUSIONS: To the best of our knowledge this is the first case series in which the whole cohort of patients with urinary or functional abnormalities underwent a histological evaluation. None of the patients were eligible for bone marrow transplantation. Hematologic response was 57.1%, while renal response was much lower (35%). Of note, the Staging System did not completely apply to this peculiar setting of patients in whom renal involvement was not presumptive but biopsy-proven. More aggressive approaches may be needed in these patients to avoid the inexorable progression of the disease.

The Challenging Management of Cancer: An Immunonephrologist's Perspective.

INTRODUCTION: Onconephrology is an emerging medical subspecialization that focuses on the numberless interrelations between cancer and kidney diseases. Tumor cells evade immune surveillance through activation of immune checkpoint pathways that suppress antitumor immune responses. By blocking checkpoints, new anticancer agents disrupt immune homeostasis but potentially induce immune-mediated diseases. Nephrologists and nephroimmunologists should be able to treat the nephrotoxic sequelae of cancer therapy and ensure continuation of the life-saving treatment. METHODS: Thirty-seven renal biopsies have been carried out over 42 months in oncologic patients, that is, 5.2% of the total native renal biopsies were carried out in the same period. The commonest diagnoses (>6 cases) were interstitial tubular nephritis, membranous glomerulopathy, IgA nephropathy, vasculitis, and focal and segmental glomerulosclerosis. CASE PRESENTATION: Three example cases, including focusing on key questions which could involve the nephrologists are reported in detail. They include a cancer-related Goodpasture Syndrome, the peculiar toxic effects of pemetrexed on tubular cells, and the intriguing relationship between bevacizumab and cryoglobulinemic glomerulonephritis. CONCLUSION: As shown by these 3 example cases, nephrologists need to be open-minded with regard to kidney biopsy in order to get a timely diagnosis. Nephrologists also need to improve their knowledge of cancer biology and therapy in order to prevent kidney problems, manage therapy-related immune-mediated disorders, and improve patient life expectancy.

Cryoglobulinemic glomerulonephritis: clinical presentation and histological features, diagnostic pitfalls and controversies in the management. State of the art and the experience on a large monocentric cohort treated with B cell depletion therapy.

Cryoglobulinemia is defined by the presence of immunoglobulins having the following characteristics: forming a gel when temperature is <37 °C, precipitate in a reversible manner in the serum, and redissolve after rewarming. The presence of both polyclonal IgG and monoclonal IgM (type II), or of polyclonal IgG and polyclonal IgM (type III) identifies the mixed cryoglobulinemia (MC). The identification of the Hepatitis C virus (HCV) infection in most of the cases previously defined as "essential" represented a cornerstone in the understanding the pathogenesis of this condition. The picture of MC comprehends heterogeneous clinical presentations: from arthralgias, mild palpable purpura, fatigue to severe vasculitis features with skin necrotic pattern, peripheral neuropathy and, less commonly, lungs, central nervous system, gastrointestinal tract, and heart involvement. The kidney represents the most common organ presentation, and the presence of glomerulonephritis is a key element when considering prognosis. We discuss the clinical presentation and histological features, diagnostic pitfalls, and controversies in the management of patients with cryoglobulinemic glomerulonephritis, with a special focus on reporting our experience in treating patients with B cell depletion therapy.

Long-term effects of intensive B cell depletion therapy in severe cases of IgG4-related disease with renal involvement.

IgG4-related disease (IgG4-RD) is an immune-mediated disorder often showing elevated serum IgG4 concentrations, dense T and B lymphocyte infiltration, and IgG4-positive plasma cells and storiform fibrosis. We prospectively evaluated for 4 years 5 patients with histologically proven IgG4-RD of whom 3 had tubulointerstitial nephritis (TIN) and 2 had retroperitoneal fibrosis (RPF). They received an intensive B depletion therapy with rituximab. The estimated glomerular filtration rate of TIN patients after 1 year increased from 9 to 24 ml/min per 1.73 m2. IgG/IgG4 dropped from 3236/665 to 706/51 mg/dl, C3/C4 went up from 49/6 to 99/27 mg/dl, and the IgG4-RD responder index fell from 10 to 1. CD20+ B cells decreased from 8.7 to 0.5%. A striking drop in interstitial plasma cell infiltrate as well as normalization of IgG4/IgG-positive plasma cells was observed at repeat biopsy. Both clinical and immunological improvement persisted over a 4-year follow-up. Treating these patients who were affected by aggressive IgG4-RD with renal involvement in an effort to induce a prolonged B cells depletion with IgG4 and cytokine production decrease resulted in a considerable rise in eGFR, with IgG4-RD RI normalization and a noteworthy improvement in clinical and histological features. Furthermore, the TIN subgroup was shown not to need for any maintenance therapy.

Daratumumab Monotherapy in Severe Patients with AL Amyloidosis and Biopsy-Proven Renal Involvement: A Real Life Experience.

OBJECTIVES: This paper aims to describe the clinical experience with Daratumumab (DARA), a first-in-class anti-CD38 human monoclonal IgG1κ antibody monotherapy, in severe patients with AL and biopsy-proven renal involvement. Immunoglobulin light chain (AL) amyloidosis with multi-organ involvement is characterized by short survival. Novel powerful drugs are expanding the therapeutic options. Current treatment of AL amyloidosis, which has been adopted from multiple myeloma (MM), is based on chemotherapy targeting the underlying plasma cell clone. DARA is effective in treating MM. The clinical activity and toxicity profile of DARA as a single agent in the treatment of AL amyloidosis is currently under evaluation. PATIENTS AND METHODS: DARA was administered in a series of patients with severe AL amyloidosis and biopsy-proven renal involvement. Five patients(mean age 64.2 years) were treated. One patient was refractory and one intolerant to conventional bortezomib-based therapy, two were treated with DARA for relapsing disease, and one was treated front-line. RESULTS: Data showed that DARA monotherapy resulted in good clinical results, with the disappearance of M-proteins in four out of five patients and with serum free light chains (sFLC) ratio normalization in three out of four and a remarkable amelioration in the remaining patient. The four patients with still preserved renal function at baseline also showed serum creatinine stabilization or improvement and a decrease in proteinuria. These data were paralleled by the reduction of the N-terminal prohormone of brain natriuretic peptide (NT pro-BNP)values. CONCLUSIONS: Our data show that monotherapy with DARA had significant clinical efficacy in pretreated/naïve patients with severe AL amyloidosis and biopsy-proven renal involvement.

Towards a novel target therapy for renal diseases related to plasma cell dyscrasias: The example of AL amyloidosis.

Immunoglobulin light chain amyloidosis is a rare systemic disease caused by monoclonal light chains (LCs) depositing in tissue as insoluble fibrils resulting in irreversible damage of vital organs. The mechanisms involved in aggregation and deposition of LCs are not fully understood, but CD138/38 plasma cells are undoubtedly involved in monoclonal LC production. We are reporting favorable effects on AL amyloidosis patients with renal involvement using the anti-CD38 monoclonal antibody Daratumumab. We speculate that research for the near future should be devoted to design similar therapeutic approaches for other diseases attributable to a plasma cell dyscrasia.

CD38 and Anti-CD38 Monoclonal Antibodies in AL Amyloidosis: Targeting Plasma Cells and beyond.

Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare systemic disease characterized by monoclonal light chains (LCs) depositing in tissue as insoluble fibrils, causing irreversible tissue damage. The mechanisms involved in aggregation and deposition of LCs are not fully understood, but CD138/38 plasma cells (PCs) are undoubtedly involved in monoclonal LC production.CD38 is a pleiotropic molecule detectable on the surface of PCs and maintained during the neoplastic transformation in multiple myeloma (MM). CD38 is expressed on T, B and NK cell populations as well, though at a lower cell surface density. CD38 is an ideal target in the management of PC dyscrasia, including AL amyloidosis, and indeed anti-CD38 monoclonal antibodies (MoAbs) have promising therapeutic potential. Anti-CD38 MoAbs act both as PC-depleting agents and as modulators of the balance of the immune cells. These aspects, together with their interaction with Fc receptors (FcRs) and neonatal FcRs, are specifically addressed in this paper. Moreover, the initiallyavailable experiences with the anti-CD38 MoAb DARA in AL amyloidosis are reviewed.

Rituximab in severe immunoglobulin-A vasculitis (Henoch-Schönlein) with aggressive nephritis.

OBJECTIVES: Immunoglobulin-A vasculitis (IgAV) is a systemic small-vessel vasculitis in which renal involvement indicates severity of illness, and chronic kidney disease represents the most serious long-term complication. No treatment at present is specifically recommended for IgAV. Recently, rituximab (RTX) has been shown to be effective in case series of adults with IgAV. However, long term results are lacking. Aim of the study is to evaluate the effectiveness of RTX as induction therapy and maintenance of remission in adults with severe IgAV and aggressive glomerulonephritis. METHODS: This study included 12 adult-onset patients, 8 males and 4 females, mean age 45.1 years (range 19-75) with a mean follow-up duration of 33.7 months (range 6-144). All patients had a severe IgAV with biopsy proven crescentic nephritis. RTX was given for the treatment of a refractory disease or because of definite contraindications to standard therapies. RESULTS: Eleven patients (91.7%) achieved a clinical response at 6 months. Ten patients had a complete response (CR) while one had a partial response and was given an additional dose of RTX after 12 months for persistent proteinuria (1gr/24 hrs) despite systemic remission. He achieved a CR 6 months later. One patient was considered unresponsive to RTX and was switched to MMF. Among the 10 patients with CR, 1 needed maintenance doses of RTX every 6 months for iterative relapsing of severe purpura, 1 relapsed after 15 months and received a new induction course showing a CR again. A significant decrease in BVAS (p=0.031) and 24-hour-proteinuria (p=0.043) from RTX initiation through the last follow-up has been detected. One patient, who had a CR with RTX alone died after 6 months for therapy-unrelated cardiovascular cause. CONCLUSIONS: RTX proved to be effective and safe for induction and maintenance of long-lasting remission in severe IgAV with aggresive renal involvement. Data also suggest that RTX can be indicated not only for refractory cases, but can be also proposed as a first line therapy.

Monoclonal Gammopathy of Renal Significance: Clinical and Histological Efficacy of a Bortezomib-Based Regimen.

Monoclonal Gammopathy of Renal Significance (MGRS) is a group of heterogeneous disorders characterized by renal dysfunction secondary to the production of a monoclonal immunoglobulin by a nonmalignant B cell or plasma cell clone. We report the clinical and histological outcomes of two patients with biopsy-proven MGRS: one patient showed membranoproliferative glomerulonephritis with monoclonal k-light chain and C3 deposits, the second patient showed immunotactoid glomerulopathy. Both patients were treated with a 9-month chemotherapy protocol including bortezomib, cyclophosphamide, and dexamethasone. Renal biospy was repeated after 1 year. The estimated glomerular filtration rate (eGFR) increased from 22.5 (baseline) to 40 ml/min per 1.73 m2 after 12 months, then to 51.5 ml/min per 1.73 m2 after 24 months; proteinuria decreased from 4.85 (baseline) to 0.17 g/day after 12 months, then to 0.14 g/day after 24 months. Repeat renal biopsies showed a dramatic improvement of the glomerular proliferative lesions and near complete disappearance of the immune deposits. A bortezomib-based treatment proved very effective and was well-tolerated in the two patients presenting with clinically and histologically aggressive MGRS.

Reliability of Lupus Anticoagulant and Anti-phosphatidylserine/prothrombin Autoantibodies in Antiphospholipid Syndrome: A Multicenter Study.

Background: Is it well-known that one of the major drawbacks of Lupus Anticoagulant (LA) test is their sensitivity to anticoagulant therapy, due to the coagulation based principle. In this study we aimed to assess the reproducibility of LA testing and to evaluate the performance of solid assay phosphatidylserine/prothrombin (aPS/PT) antibodies. Methods: We included 60 patients that fulfilled the following inclusion criteria: (I) diagnosis of thrombotic antiphospholipid syndrome (APS); (II) patients with thrombosis and (a) inconstant previous LA positivity and/or (b) positivity for antiphospholipid antibodies (aPL) at low-medium titers [defined as levels of anti-ß2Glycoprotein-I or anticardiolipin (IgG/IgM) 10-30 GPL/MPL] with no previous evidence of LA positivity. aPL testing was performed blindly in 4 centers undertaking periodic external quality assessment. Results: The 60 patients enrolled were distributed as follows: 43 (71.7%) with thrombotic APS, 7 (11.7%) with thrombosis and inconstant LA positivity and 10 (16.7%) with low-medium aPL titers. Categorical agreement for LA among the centers ranged from 0.41 to 0.60 (Cohen's kappa coefficient; moderate agreement). The correlation determined at the 4 sites for aPS/PT was strong, both quantitatively (Spearman rho 0.84) and when dichotomized (Cohen's kappa coefficients = 0.81 to 1.0). Discordant (as defined by lack of agreement in ≥3 laboratories) or inconclusive LA results were observed in 27/60 (45%) cases; when limiting the analysis to those receiving vitamin K antagonist (VKA), the level of discordant LA results was as high as 75%(15/20). Conversely, aPS/PT testing showed an overall agreement of 83% (up to 90% in patients receiving VKA), providing an overall increase in test reproducibility of +28% when compared to LA, becoming even more evident (+65%) when analyzing patients on VKA. In patients treated with VKA, we observed a good correlation for aPS/PT IgG testing (Cohen's kappa coefficients = 0.81-1; Spearman rho 0.86). Conclusion: Despite the progress in the standardization of aPL testing, we observed up to 45% of overall discrepant results for LA, even higher in patients on VKA. The introduction of aPS/PT testing might represent a further diagnostic tool, especially when LA testing is not available or the results are uncertain.

Rituximab as a front-line therapy for adult-onset minimal change disease with nephrotic syndrome.

Minimal change disease (MCD) accounts for 15% of adult nephrotic syndrome (NS) cases. Adult-MCD patients may have more severe clinical features than pediatric patients. In children, Rituximab (RTX) has been used since 2006 to treat frequently relapsing NS. In adults, data about the efficacy of RTX for MCD are limited. We report our experience on the use of RTX in adult biopsy-proven MCD. Our series includes 6 adult patients (2 males and 4 females), age 45-73 years, treated with RTX (4 weekly doses of 375 mg/m2). Proteinuria decreased from 11,2 (23-4.8) g/24 hours to 0.6 (0-2) g/24 hours after 6 months, and to 0.4 (0-1, 4) g/24 h in the 4 pts with the longer follow-up. Creatinine decreased from 1.95 (0.5-5) mg/dl to 0.88 (0.6-1.3) mg/l. Five patients achieved a complete renal remission, while in 1 pt proteinuria decreased by 75%. RTX successfully depleted CD19 lymphocytes in 100% of pts for at least 6 months. No clinically relevant adverse events have been observed. This case series shows a remarkable efficacy of RTX in treatment of MCD. RTX can be an attractive alternative both in recurrent forms and in induction-therapy of MCD. RTX may be preferentially used in patients at a high risk of development of the adverse effects of corticosteroids and should be considered as an alternative option in patients with recurrent NS. Additional data are needed to inform clinical practice on how best to use RTX in this patient population, so that definitive randomized trials can be planned.

IgG4-related kidney disease: the effects of a Rituximab-based immunosuppressive therapy.

IgG4-related disease (IgG4-RD) is a recently recognized disorder, characterized by elevated serum IgG4 concentrations, dense tissue infiltration of IgG4-positive plasma cells and storiform fibrosis. Treatment is usually based on steroids, however, relapses and long-term adverse effects are frequent. We prospectively studied 5 consecutive patients with histologically-proven IgG4-RD and renal involvement, treated with an extended Rituximab protocol combined with steroids. Two doses of intravenous cyclophosphamide were added in 4 patients. Five patients with IgG-RD were investigated: three had tubulointerstitial nephritis (TIN), while two had retroperitoneal fibrosis (RPF). In the patients with TIN, renal biospy was repeated after 1 year. In the patients with TIN, estimated glomerular filtration rate (eGFR) at 12 months increased from 9 to 24 ml/min per 1.73 m2; IgG/IgG4 decreased from 3,236/665 to 706/51 mg/dl; C3/C4 increased from 49/6 to 99/27 mg/dl; CD20+ B-cells decreased from 8.7% to 0.5%; Regulatory T-cells decreased from 7.2% to 2.5%. These functional and immunologic changes persisted at 24 months and in two patients at 36 months. A repeat renal biopsy in the patients with TIN showed a dramatic decrease in interstitial plasma cell infiltrate with normalization of IgG4/IgG positive plasma cells. The patients with RPF showed a huge regression of retroperitoneal tissue. In this sample of patients with aggressive IgG4-RD and renal involvement, treatment aimed at depleting B cells and decreasing antibody and cytokine production was associated with a substantial, persistent increase in eGFR, and a definite improvement in immunologic, radiologic and histological parameters.

Acute renal infarction: a single center experience.

BACKGROUND: Acute renal infarction is a rare condition whose diagnosis is often delayed. Major risk factors include atrial fibrillation, valvular or ischemic heart disease, renal artery thrombosis/dissection and coagulopathy. METHODS: We reviewed the medical records of 18 patients admitted to our Nephrology Department between 1999 and 2015 for acute renal infarction diagnosed by computed tomography. Tc-99m dimercaptosuccinic acid (DMSA) scintigraphy was performed in some patients during follow-up to assess parenchymal lesions and estimate differential kidney function. RESULTS: Mean age was 59.8 years. Major associated risk factors included hypertension (44 %), obesity (33 %), atrial fibrillation (28 %), peripheral vascular disease (17 %), smoking (17 %), prior thromboembolic event (11 %), diabetes (11 %), estroprogestinic therapy (11 %). Seventy-two percent of patients presented with flank pain. Mean serum creatinine was 1.2 ± 0.6 mg/dl. Acute kidney injury occurred as the initial manifestation in two patients. Patients were managed conservatively, with low molecular weight heparin (83 %) or aspirin (11 %). At the end of follow-up serum creatinine was 1.1 ± 0.3 mg/dl; one patient remained on chronic hemodialysis. 58 % of patients who underwent renal scintigraphy after a median of 8 months had a reduced contribution of the previously affected kidney to total renal function. CONCLUSION: Risk factors associated with the development of chronic kidney disease following renal infarction are unknown. In our subjects, renal function remained stable in all but one patient who developed end stage renal disease. Further studies should focus on etiology and evolution of kidney function in patients with acute renal infarction.

Rituximab therapy for IgA-vasculitis with nephritis: a case series and review of the literature.

Henoch-Schonlein purpura, also called IgA-vasculitis, is a systemic small vessels vasculitis with immunoglobulin A1-dominant immune deposits. The optimal treatment remains controversial. Because IgA-vasculitis is characterized by leukocyte infiltration of the blood vessel walls along with immunoglobulin A deposition, and because glucocorticosteroids inhibit inflammatory processes, early administration of glucocorticosteroids has been postulated to be effective, but this indication remains controversial. Immunosuppressive agents (azathioprine, cyclophosphamide, cyclosporine, mycophenolate) have been used in combination with glucocorticosteroids without definitive evidence of effectiveness. The efficacy of rituximab in adult IgA-vasculitis has been reported in few cases. We described a monocentric experience on the use of rituximab in adult IgA-vasculitis with biopsy-proven nephritis. The patients achieved a complete remission of nephritis and syndromic manifestations, and no patients experienced adverse reactions. These data have been compared with the limited literature nowadays available.