Publications by authors named "Giulia Frontini"

9 Publications

  • Page 1 of 1

When and How Is it Possible to Stop Therapy in Patients with Lupus Nephritis?

Clin J Am Soc Nephrol 2021 Jun 23. Epub 2021 Jun 23.

C Ponticelli, Nephrology, IRCCS Ospedale Maggiore Policlinico, Milano, Italy.

Glucocorticoids and other immunosuppressants still represent the cornerstone drugs for the management of SLE (Systemic Lupus Erythematosus) and lupus nephritis. The refined use of these drugs over the years has allowed to obtain stable disease remission and improvement of the long-term kidney and patient survival. Nevertheless, a prolonged use of immunosuppressive agents may be accompanied by severe and even life-threatening side effects. Theoretically, a transient or even definitive withdrawal of immunosuppression could be useful to prevent iatrogenic morbidities. For many years, however, the risk of SLE reactivation has held clinicians back from trying to interrupt therapy. In this review we report the results of the attempts to interrupt glucocorticoids and other immunosuppressive agents in lupus nephritis and in SLE. The available data suggest that the therapy withdrawal is feasible at least in patients enjoying a complete clinical remission after a prolonged therapy. A slow and gradual reduction of treatment under medical surveillance is needed to prevent flares of activity. After therapy withdrawal around one quarter of patients may have kidney or systemic flares. However, most flares may respond to therapy if rapidly diagnosed. The other patients can enter stable remission even for 20 years or more. The use of antimalarials can help in maintaining the remission after the withdrawal of the immunosuppressive therapy. A repeated kidney biopsy could be of help in deciding to stop therapy, but given the few available data, it cannot be considered essential.
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http://dx.doi.org/10.2215/CJN.04830421DOI Listing
June 2021

Acute kidney injury and chronic kidney disease after liver transplant: A retrospective observational study.

Nefrologia 2021 Jun 7. Epub 2021 Jun 7.

Division of Nephrology, Dialysis and Renal Transplantation, Maggiore Policlinico Hospital and Cà Granda IRCCS Foundation, Milano, Italy; University School of Medicine, Milano, Italy.

Background And Rationale: Chronic kidney disease remains an important risk factor for morbidity and mortality among LT recipients, but its exact incidence and risk factors are still unclear.

Material And Methods: We carried out a retrospective cohort study of consecutive adults who underwent liver transplant (January 2009-December 2018) and were followed (at least 6 months) at our institution. CKD was defined following the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines. Long-term kidney function was classified into 4 groups: no CKD (eGFR, ≥60mL/min/1.73m), mild CKD (eGFR, 30-59mL/min/1.73m), severe CKD (eGFR, 15-29mL/min/1.73m), and end-stage renal disease (ESRD).

Results: We enrolled 410 patients followed for 53.2±32.6 months. 39 had CKD at baseline, and 95 developed de novo CKD over the observation period. There were 184 (44.9%) anti-HCV positive, 47 (11.5%) HBsAg positive, and 33 (8.1%) HBV/HDV positive recipients. Recipient risk factors for baseline CKD were advanced age (P=0.044), raised levels of serum uric acid (P<0.0001), and insulin dependent DM (P=0.0034). Early post-transplant AKI was common (n=95); logistic regression analysis found that baseline serum creatinine was an independent predictor of early post-LT AKI (P=0.0154). According to our Cox proportional hazards model, recipient risk factors for de novo CKD included aging (P<0.0001), early post-transplant AKI (P=0.007), and baseline serum creatinine (P=0.0002). At the end of follow-up, there were 116 LT recipients with CKD - 109 (93.9%) and 7 (6.1%) had stage 3 and advanced CKD, respectively. Only two of them are undergoing long-term dialysis.

Conclusion: The incidence of CKD was high in our cohort of LT recipients, but only a slight decline in kidney function over time was recorded. Prevention of post-transplant AKI will improve kidney function in the long run. We need more studies to analyze the function of kidneys among LT recipients over extended follow-ups and their impact on mortality.
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http://dx.doi.org/10.1016/j.nefro.2021.01.009DOI Listing
June 2021

Lack of EULAR/ERA-EDTA response at 1 year predicts poor long-term renal outcome in patients with lupus nephritis.

Ann Rheum Dis 2020 08 5;79(8):1077-1083. Epub 2020 Jun 5.

Division of Rheumatology, Department of Medicine, DIMED, University of Padova, Padova, Italy.

Objectives: Short-term predictive endpoints of chronic kidney disease (CKD) are needed in lupus nephritis (LN). We tested response to therapy at 1 year.

Methods: We considered patients with LN who underwent renal biopsy followed by induction therapy between January 1970 and December 2016. LN was assessed using the International Society of Nephrology/Renal Pathology Society (2003) criteria and the National Institute of Health (NIH) activity and chronicity index. The renal outcome was CKD. Response was defined according to EULAR/European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations: proteinuria <0.5 g/24 hours, (near) normal estimated glomerular filtration rate (eGFR); ≥50% proteinuria reduction to subnephrotic levels, (near) normal eGFR; and all the other cases. Logistic regression analysis was employed for 12-month response and Cox regression for CKD prediction.

Results: We studied 381 patients (90.5% Caucasians). After 12-month therapy, 58%, 26% and 16% of patients achieved complete, partial and no response, respectively, according to EULAR/ERA-EDTA. During a median follow-up of 10.7 (IQR: 4.97-18.80) years, 53 patients developed CKD. At 15 years, CKD-free survival rate was 95.2%, 87.6% and 55.4% in patients with complete, partial and no response at 12 months, respectively (p<0.0001). CKD-free survival rates did not differ between complete and partial responders (p=0.067). Serum creatinine (HR: 1.485, 95% CI 1.276 to 1.625), eGFR (HR 0.967, 95% CI 0.957 to 0.977) and proteinuria at 12 months (HR 1.234, 95% CI 1.111 to 1.379) were associated with CKD, yet no reliable cut-offs were identified on the receiver operating characteristic curve. In multivariable analysis, no EULAR/ERA-EDTA response at 12 months (HR 5.165, 95% CI 2.770 to 7.628), low C4 (HR 1.053, 95% CI 1.019 to 1.089) and persistent arterial hypertension (HR 3.154, 95% CI 1.500 to 4.547) independently predicted CKD.

Conclusions: Lack of EULAR/ERA-EDTA response at 12 months predicts CKD.
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http://dx.doi.org/10.1136/annrheumdis-2020-216965DOI Listing
August 2020

Multicentric study comparing cyclosporine, mycophenolate mofetil and azathioprine in the maintenance therapy of lupus nephritis: 8 years follow up.

J Nephrol 2021 04 27;34(2):389-398. Epub 2020 May 27.

Divisione di Nefrologia e Dialisi-Padiglione Croff, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Milano, Via della Commenda 15, 20122, Milano, Italy.

Background: The ideal long-term maintenance therapy of Lupus Nephritis (LN) is still a matter of debate. The present study was aimed at comparing the efficacy/safety profile of cyclosporine (CsA), mycophenolate mofetil (MMF) and azathioprine (AZA) in long-term maintenance therapy of LN.

Methods: We performed a retrospective study of patients with biopsy-proven active LN. After induction therapy, all patients received maintenance therapy with CsA, MMF or AZA based on medical decision. Primary endpoint was complete renal remission (CRR) after 8 years (defined as proteinuria < 0.5 g/24 h, eGFR > 60 ml/min/1.73 mq); secondary endpoints were: CRR after 1 year, renal and extrarenal flares, progression of chronic kidney disease (CKD stage 3 or above) and side-effects.

Results: Out of 106 patients, 34 received CsA, 36 MMF and 36 AZA. Clinical and histological characteristics at start of induction therapy were comparable among groups. At start of maintenance therapy, CsA patients had significantly higher proteinuria (P = 0.004) or nephrotic syndrome (P = 0.024) and significantly lower CRR (23.5% vs 55.5% on MMF and 41.7% on AZA, P = 0.024). At one year, CRR was similar in the three groups (79.4% on CsA, 63.8% on MMF, 58.3% on AZA, P = 0.2). At 8 years, the primary endpoint was achieved by 79.4% of CsA vs 83.3% of MMF and 77.8% of AZA patients (P = 0.83); 24 h proteinuria, serum creatinine, eGFR were similar. CKD stage 3 or above developed in 8.8% of CsA, in 8.3% of MMF and in 8.3% of AZA patients (P = 0.92). Flares-free survival curves and incidence of side-effects were not different.

Conclusions: This is the first study comparing CsA, MMF and AZA on long-term LN maintenance therapy. All treatments had similar efficacy in achieving and maintaining CRR, despite more severe baseline clinical features in patients treated with CsA.
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http://dx.doi.org/10.1007/s40620-020-00753-wDOI Listing
April 2021

Remission in systemic lupus erythematosus: testing different definitions in a large multicentre cohort.

Ann Rheum Dis 2020 07 22;79(7):943-950. Epub 2020 Apr 22.

Department of Medicine, Division of Rheumatology, University of Padua, Padova, Italy

Objectives: Remission in systemic lupus erythematosus (SLE) is defined through a combination of 'clinical SLE Disease Activity Index (cSLEDAI)=0', 'physician's global assessment (PGA) <0.5' and 'prednisone (PDN) ≤5 mg/day'. We investigated the performance of these items, alone or in combination, in defining remission and in predicting SLICC/ACR Damage Index.

Methods: We tested seven potential definitions of remission in SLE patients followed-up for ≥5 years: PDN ≤5 mg/day; PGA <0.5; cSLEDAI=0; PGA <0.5 plus PDN ≤5 mg/day; cSLEDAI=0 plus PGA <0.5; cSLEDAI=0 plus PDN ≤5 mg/day; cSLEDAI=0 plus PDN ≤5 mg/day plus PGA <0.5. The effect of these definitions on damage was evaluated by Poisson regression analysis; the best performance was identified as the lowest Akaike and Bayesian information criterion (AIC and BIC). Positive and negative predictive values in identifying no damage increase were calculated.

Results: We included 646 patients (mean±SD disease duration 9.2±6.9 years). At multivariate analysis, ≥2 consecutive year remission according to all definitions protected against damage (OR, 95% CI: PGA <0.5 0.631, 0.444 to 0.896; cSLEDAI=0 0.531, 0.371 to 0.759; PGA <0.5 plus PDN ≤5 mg/day 0.554, 0.381 to 0.805; cSLEDAI=0 plus PGA <0.5 0.574, 0.400 to 0.826; cSLEDAI=0 plus PDN ≤5 mg/day 0.543, 0.376 to 0.785; cSLEDAI=0 plus PDN ≤5 mg/day plus PGA <0.5 0.532, 0.363 to 0.781, p<0.01 for all), except PDN ≤5 mg/day, which required four consecutive years (OR 0.534, 95% CI 0.325 to 0.877, p=0.013). Positive and negative predictive values were similar; however, cSLEDAI=0 showed the best performance (AIC 1082.90, BIC 1109.72, p<0.0001). Adding PGA <0.5 and/or PDN ≤5 mg/day to cSLEDAI=0 decreased remission duration (-1.8 and -1.5 year/patient, respectively) without increasing cSLEDAI=0 performance in predicting damage accrual.

Conclusions: cSLEDAI=0 is the most attainable definition of remission, while displaying the best performance in predicting damage progression in the short-to-mid-term follow-up.
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http://dx.doi.org/10.1136/annrheumdis-2020-217070DOI Listing
July 2020

Adjuvanted recombinant HBV vaccine (HBV-AS04) is effective over extended follow-up in dialysis population. An open-label non randomized trial.

Clin Res Hepatol Gastroenterol 2020 11 3;44(6):905-912. Epub 2020 Mar 3.

Division of Nephrology, Maggiore Hospital and IRCCS Foundation, Pad. Croff, Via Commenda 15, 20122 Milano, Italy; University School of Medicine, Milan, Italy.

Background: Patients on regular dialysis show a poor response to hepatitis B vaccine due to uremia. A recombinant HB vaccine (containing an improved adjuvant system AS04, HBV-AS04) has been licensed but the evidence on its efficacy and safety in dialysis population over the long term is extremely limited.

Aim: We have measured antibody (anti-HBs) persistence for up to 72 months in a large cohort of patients on long-term dialysis (with susceptibility to HBV infection) who underwent vaccination with HBV-AS04 vaccine.

Methods: Patients were prospectively recruited to receive four 20-mcg doses of HBV-AS04 by intramuscular route (deltoid muscle). Two vaccine schedules were adopted: 0,1,2, and 3 month (n=217 patients) and 0,1,2, and 6 month (n=31 patients). Anti-HBs antibody concentrations were tested at 1,2,3, 4, 7 and 12 months and then every year up to 72 months. Multivariate analysis was made to find the baseline parameters that were associated with the immune response to HBV-AS04 vaccine.

Results: Two hundred and seventy-two patients were included and 248 completed the study. At completion of vaccine schedule, the frequency of responders (anti-HBs titers≥10mIU/mL) was 81.5% (202/248) (mean anti-HBs antibody titers, 384.9±391.9mIU/mL), according to per-protocol analysis. On the grounds of univariate analysis, age was lower in responder than non- responder patients to HBV AS04 even if no statistical significance was achieved (P=0.09). The sero-protection rate at month 72 was 77% (7/9) (anti-HBs antibody titers, 184.9±360.1mIU/mL, P=0.001). Multivariate analysis found a relationship between sero-response rate and age (P=0.04). No major side effects and no de novo HBV episodes were observed.

Conclusions: Our open-label nonrandomized trial performed in a 'real-world' practice showed the persistence of anti-HBs antibody among responder patients over a very long follow-up. Studies with longer observation periods are under way.
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http://dx.doi.org/10.1016/j.clinre.2020.01.010DOI Listing
November 2020

Belimumab may decrease flare rate and allow glucocorticoid withdrawal in lupus nephritis (including dialysis and transplanted patient).

J Nephrol 2020 Oct 30;33(5):1019-1025. Epub 2020 Jan 30.

Divisione Di Nefrologia E Dialisi-Padiglione Croff, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Di Milano, via della Commenda 15, 20122, Milan, Italy.

Background: Belimumab (Benlysta) is currently approved for the treatment of active Lupus despite standard therapy. Few data are available on the efficacy of this drug in lupus nephritis (LN).

Methods: 17 LN female followed in two Nephrology Italian Unit received belimumab for a median period of 36 months (range 6-42 months). The indications were: arthralgia in 3 patients, cutaneous manifestations in 2, residual proteinuria in 8, and the need to reduce steroids for severe side effects in 4. Of interest, 1 patient started therapy during Peritoneal Dialysis and continued after kidney transplantation due to non-responsive arthralgias.

Results: Arthralgia and skin manifestations resolved in all patients. Proteinuria normalized in three patients and stabilized in all but one of the others. Steroids were indefinitely stopped in six patients (35%) and reduced to around 40% of the basal dosage in the other patients. During belimumab therapy, three extrarenal and one renal SLE flares were diagnosed accounting for a rate of renal flares of 0.02/patient/year. No major adverse events leading to therapy withdrawal occurred.

Clinical Case: Arthralgia resolved, immunological parameters improved and prednisone could be reduced within few months in the patient who started belimumab during peritoneal dialysis. After kidney transplantation belimumab was stopped but due to arthralgias unresponsive to standard immunosuppressive therapy it was restarted with success.

Conclusions: Belimumab allows the achievement of complete response together with the withdrawal or the reduction of corticosteroids in almost all our patients. Of interest its satisfactory use in a patient in peritoneal dialysis and after kidney transplantation.
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http://dx.doi.org/10.1007/s40620-020-00706-3DOI Listing
October 2020

Immunoglobulin A Nephropathy. Recurrence After Renal Transplantation.

Front Immunol 2019 19;10:1332. Epub 2019 Jun 19.

Dialysis, and Renal Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. The disease generally runs an indolent course but may lead to ESRD in 20-30% of patients in 20 years or more after diagnosis. Patients with IgA nephropathy are ideal candidates for renal transplant because they are generally relatively young and with few comorbidities. Their graft survival is better or comparable to that of controls at 10 years, though few data are available after 10 years of follow-up. Recurrence of the original disease in the graft is a well-known complication of transplant in IgAN and is a significant cause of deterioration of graft function. Recurrent IgAN rarely manifests clinically before 3 years post transplantation. Recurrence rate is estimated to be around 30% with considerable differences among different series. Despite these factors there is no certain recurrence predictor, young age at renal transplant, rapid progression of the original disease and higher levels of circulating galactose-deficient IgA1 and IgA-IgG immune complexes are all associated with a higher rate of recurrence. Which pathogenetic mechanisms are responsible for the progression of the recurrence to graft function deterioration, and what therapy can prevent or slow down the progression of the disease in the graft, are open questions. The aim of this review is to describe the clinical outcome of renal transplantation in IgA patients with attention to the rate and the predictors of recurrence and to discuss the available therapeutic options for the management of recurrence.
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http://dx.doi.org/10.3389/fimmu.2019.01332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593081PMC
October 2020

Does pregnancy have any impact on long term damage accrual and on the outcome of lupus nephritis?

J Autoimmun 2017 Nov 21;84:46-54. Epub 2017 Jun 21.

Nephrology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via della Commenda 15, 20122, Milan, Italy. Electronic address:

No data are available about the impact of pregnancy on the long-term outcome of lupus nephritis. Thirty-two women with lupus nephritis with a 10-year follow-up after their first pregnancy ("women who gave birth") and 64 matched controls with the same follow-up and who never had pregnancies ("controls") were compared for the occurrence of SLE flares, chronic kidney disease (CKD), and SLICC/ACR Damage Index (SDI) in the post pregnancy period. The same evaluations were done before and after pregnancy in women who gave birth. The predictors of CKD and damage accrual in the whole population were studied. All patients were Caucasians and had biopsy proven LN. At conception and after 10 years, in both groups, less than 10% of patients had active renal disease (p = ns). Controls had more frequent arterial hypertension (p = 0.025). Between the two groups there was no difference in SLE flares and in CKD free survival curves (p = 0.6 and p = 0.37) during the 10-year follow-up. In both groups, the temporal trend, based on annual evaluation, of glomerular filtration rate and serum creatinine shows a significant decrease and increase respectively. However, the women who gave birth persistently maintained better values of renal function than controls during the whole follow-up (P = 0.00001). There was no difference in the CKD-free survival curves. SDI did not increase significantly in women who gave birth in comparison to controls. All the above mentioned clinical parameters were comparable before and after pregnancy in the women who gave birth. Among the basal clinical characteristics, high serum creatinine and occurrence of SLE flares predicted CKD, whereas low levels of C3, pre-existing damage score, and occurrence of SLE flares predicted SDI increase. Pregnancy was not a predictor of CKD or SDI increase. Carrying a pregnancy during inactive lupus nephritis does not seem to increase the rate of SLE flares, worsen renal prognosis or increase SDI significantly in the very long-term.
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http://dx.doi.org/10.1016/j.jaut.2017.06.003DOI Listing
November 2017
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