Long-term use of burosumab for the treatment of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumoral overproduction of FGF-23. Due to local recurrence, we describe the long-term efficacy and safety profile of burosumab, an anti-FGF-23 monoclonal antibody, in a TIO patient after three unsuccessfully surgical attempts. INTRODUCTION: TIO is a rare paraneoplastic syndrome caused by tumoral overproduction of fibroblast growth factor 23 (FGF23), resulting in hyperphospaturia, hypophosphatemia, and osteomalacia. Surgery is the only definitive treatment, but tumor can locally recur, even after years from primary surgery. Furthermore, some tumors cannot be removed by surgery due to their location. METHODS: We describe the case of a 54-year-old woman affected by recurrent TIO who, after three unsuccessful surgical attempts of tumor removal, was treated with burosumab, an anti-FGF-23 monoclonal antibody. RESULTS: The patient was referred to our Bone Unit after experiencing several fractures in different sites, both traumatic and non-traumatic. At the time of first evaluation, at the age of 46, serum-phosphate (SP) was 1.2 mg/dL (reference range (RR) 2.5-4.5), 24-h urinary phosphate was 842 mg (RR 400-1000), and intact-FGF-23 was 117 pg/mL (RR 25-45). Imaging showed a metabolic pre-sacral lesion that firstly underwent to exploratory laparotomy. Then, patient underwent to surgical excision of tumor. After 18 months of well-being, tumor relapsed and even the subsequent surgery was not able to completely remove it. Since 2015, patient was maintained in phosphorus supplements and 1,25(OH)2vitamin D3, but SP levels never normalized. In September 2019, she was started on burosumab, initially at the dose of 0.3 mg/kg/month, progressively increased to the current 0.8 mg/kg/month, with great improvement of pain, physical performance, and normalization of SP levels. Burosumab was temporary and cautionary discontinued for COVID-19 pneumonia, with a worsening of SP. After restart of burosumab, biochemistry returned to normal. CONCLUSIONS: To our knowledge, this is the first European patient affected by TIO treated with burosumab for more than 2 years. Burosumab is a promising therapy in the medical treatment of TIO refractory or not eligible for definitive surgery, with good efficacy and safety profile.

Outcome of COVID-19 Infections After Vaccination in Kidney Transplant Patients

Background: Kidney transplant recipients (KT) are a vulnerable population with a risk of death after COVID-19 infection (COV-I) four times higher than in the general population. mRNA COVID-19 vaccines changed the prognosis. Although KT have an impaired immunological response to mRNA vaccines, in March 2021 we started a vaccination campaign. Method(s): Among 1611 KT, 72 (4.2%) had COV-I (positive molecular nasopharyngeal swab) between 31 October 2021 and 15 January 2022 (3rd outbreak). Fourty-one (57%) were male and 58 (80.5%) had a deceased donor transplant, median age was 52 (43-60) years, median transplant vintage 57 (27-159) months, median serum creatinine 1.37 (1.0-1.7) mg/dL. KT were on calcineurin inhibitors, prednisone, mycophenolate (MMF) and mTOR inhibitors in 93-87-79% and 5.6% respectively. At COV-I 43 KT had received 3 doses of Comirnaty (BNT162b2), 21 two and 4 one, 4 were not vaccinated. DELTA variant was present in 36. Treatment included: increase of the daily steroid dosage (69%), MMF withdrawal (70%) or halving (5%) and monoclonal antibodies: Ronapreve or Xevudy (32%). Nine delta positive KT were hospitalized for severe respiratory distress: 2 died (6.6%). Result(s): The variables associated with an increased risk for hospitalization were older age and dyspnea (p=0.023, p<0.0001 respectively). At multivariate analysis, dyspnea (p <0.0001) and MMF (p=0.003) were independently associated with the risk for hospitalization. Combination of the two variables increased the significance (p<0.0001). Comparing this series to the 82/1503 (5.4%) KT infected during the previous waves, hospitalization, mortality and cumulative mortality rates dropped from 45%, 29.3% and 13.4% to 30%, 6.6% and 2.7% respectively, main difference being the absence of vaccination in the first group. Conclusion(s): Vaccinations did not reduce the incidence of COV-I among KT but provided certain protection associated with a significantly better outcome.

Vitamin D Status and SARS-CoV-2 Infection in a Cohort of Renal Transplanted Patients

Purpose: Immunomodulatory and anti-inflammatory properties have been hypothesized for native vitamin D (nVD). Very little is reported about nVD and risk of Sars- CoV-2 infection (COV) in renal transplant (RTx). In a cohort of renal transplanted patients (RTxp) we retrospectively evaluated: a) nVD status in patients with (COV+) and without (COV-) COV infection;b) the impact of nVD status on severity of COV. Method(s): The study includes 61 COV+ in whom nVD status was available in the year before the infection, and 122 COV- matched 1:2 for age (53[45-64]years), gender (M=60.7%), RTx vintage (7[2-15]years), presence of diabetes (18%), arterial hypertension (85%) and cardiac symptomatic disease (3%). Renal function, 24-h proteinuria, mineral metabolism (MM) parameters were evaluated at 1, 6 and 12 months before COV whereas nVD status was considered as the mean 25-OH-VD levels at the same timepoints. Severity of COV was based on the need for hospitalization (HOSP+: 27/61, 44.3%) and death (D+: 6/61, 9.8%). Result(s): a) nVD levels were significantly lower in COV+ than in COV- (19[12-26] ng/mL and 23[16-30] ng/mL, respectively, p=0.01). No differences in the other biochemical parameters were found. The COV discriminative power of nVD status was evaluated by ROC curve (AUC 0.61, 95% CI 0.54-0.68, p=0.01), with a value of 25-OHVD 23.9 ng/mL showing the best discriminative power (sensibility 72%, specificity 47%).b) nVD levels showed a trend towards lower values in HOSP+COV+ than HOSP-COV+ (17[8-25] ng/mL vs 20[14-26] ng/mL) and in D+COV+ than D-COV+ (13[6-23] ng/mL vs 20[13-26] ng/mL), although these differences did not reach the statistical significance (p=0.1 and p=0.2, respectively). Conclusion(s): With the limitations of the retrospective nature of the study and the small sample size, our data report that:COV+ showed lower nVD levels in the year preceding the infection compared to controls with similar main demographic features and comorbid conditionsNo differences were found in renal function, proteinuria, and other MM parameters between the two groupsNo association was found between nVD levels in the year preceding the infection and COV severity.

VITAMIN D STATUS AND SARS-COV-2 INFECTION IN A COHORT OF RENAL TRANSPLANTED PATIENTS

BACKGROUND AND AIMS: Immunomodulatory and anti-inflammatory properties have been hypothesized for native vitamin D (nVD). Very little is reported about nVD and risk of Sars-CoV-2 infection (COV) in renal transplant (RTx). In a cohort of renal transplanted patients (RTxp) we retrospectively evaluated: (i) nVD status in patients with (COV+) and without (COV-) COV infection;(ii) the impact of nVD status on severity of COV. METHOD: The study includes 61 COV + in whom nVD status was available in the year before the infection, and 122 COV- matched 1:2 for age (53[45-64]years), gender (M = 60.7%), RTx vintage (7[2-15] years), presence of diabetes (18%), arterial hypertension (85%) and cardiac symptomatic disease (3%). Renal function, 24-h proteinuria and mineral metabolism (MM) parameters were evaluated at 1, 6 and 12 months before COV whereas nVD status was considered as the mean 25- OH-VD levels at the same timepoints. Severity of COV was based on the need for hospitalization (HOSP+: 27/61, 44.3%) and death (D+: 6/61, 9.8%). RESULTS: (i) nVD levels were significantly lower in COV + than in COV- (19[12- 26] ng/mL and 23[16-30] ng/mL, respectively, P = 0.01). No differences in the other biochemical parameters were found. The COV discriminative power of nVD status was evaluated by ROC curve (AUC 0.61, 95% CI: 0.54-0.68, P = 0.01), with a value of 25-OHVD 23.9 ng/mL showing the best discriminative power (sensibility 72%, specificity 47%). (ii) nVD levels showed a trend towards lower values in HOSP + COV + than HOSP-COV+ (17[8-25] ng/mL versus 20[14-26] ng/mL) and in D + COV + than D-COV+ (13[6-23] ng/mL versus 20[13-26] ng/mL), although these differences did not reach the statistical significance (P = 0.1 and P = 0.2, respectively). CONCLUSION: With the limitations of the retrospective nature of the study and the small sample size, our data report that: (i) COV + showed lower nVD levels in the year preceding the infection compared with controls with similar main demographic features and comorbid conditions (ii) No differences were found in renal function, proteinuria and other MM parameters between the two groups. No association was found between nVD levels in the year preceding the infection and COV severity.

COVID-19 VACCINE IN KIDNEY TRANSPLANTED PATIENTS. IS THERE A CLINICAL RELEVANCE? AN ITALIAN SINGLE CENTER EXPERIENCE

BACKGROUND AND AIMS: COVID-19 is a life-threatening infection among elderly, comorbid patients or transplanted patients. In our recently published paper (Campise, M.;Alfieri, C.M.;et al. Pathogens 2021, 10, 964), we described our single Centre experience with 82 adult kidney-transplant patients (KTxp) with COVID-19 infection during the previous two pandemic outbreaks: 27 KTxp (first outbreak) and 65 (second). We observed a relatively low and possibly underestimated incidence of infection (5.1%) with a incidence of death almost four times higher than in general population (13%). The availability of COVID-19 vaccines has undoubtedly changed the outcome of the infection in both immunocompetent and immunosuppressed patients. Aim of this second ongoing observational and descriptive study, is to evaluate if the vaccination performed extensively among our KTxp, has modified the incidence and gravity of COVID-19 infection. METHOD: Data on KTxp with COVID-19 infection (COV+) from the 29 October 2021 to 31 December 2021 were collected. Particularly, we focused our anthropometric, clinical and therapeutic aspects. In the statistical analyses, continuous variables were expressed as median and interquartile range (25%-75%), and nominal variables were reported as percentage of cases. RESULTS: From the 29 October 2021 to the 31 December 2021, 33 KTxp developed COVID-19 infection, 60% were male. Median age was 50[29-58] years. Transplant vintage was 57[27-163] months. Median serum creatinine was 1.30[1.0-1.9] mg/dL and body mass index was 23[21-28] kg/m2. Immunosuppressive schedule included: CNI inhibitors, steroids and mycophenolate (MMF) in 97-90 and 70% of COV + respectively. In 50% of cases native vitamin D supplementation was present, whereas only 30% of cases were treated with renin-angiotensin inhibitors. Only one had insulin dependent diabetes. At the moment of nasopharyngeal swab positivity 64% of COV + had already received three doses of vaccine (Comirnaty (BNT162b2)®) and 30% 2 doses. Only 3% of pts had received a single dose. One patient had refused vaccination for personal reasons. Antigenic nasopharyngeal swab was performed in 70% of COV + and molecular swab in 60%. Thirty-five % of COV + were tested with both methods. The most frequent symptoms were: fever (70%), cough (75%) and headache (40%). In the previous outbreaks dyspnea was present in 33% of cases dropping to 13% in this cohort. Smell and taste alteration were present in 25% and 28% respectively. We did not perform the COVID-19 sequence. But, on the base of the symptoms referred, we are confident that 17 patients had delta variant and remaining had omicron. The first therapeutic approaches were the increase of the daily steroid dosage up to 25 mg (60% of cases) together with MMF temporarily withdrawing in 70% of cases and halving in 10%. Forty % of pts were also treated with monoclonal antibodies (Ronapreve®) upon infectious disease specialist evaluation. During the first two outbreaks, hospitalization was necessary in 45% of cases, and 13% of pts died. In the present cohort only 10% of patients required oxygen support and hospitalization. Nobody died. CONCLUSION: Although very preliminary, our results indicate that the vaccination campaign has noticeably ameliorated the incidence, the clinical presentation and the outcome of COVID-19 in KTxp. This comforting data should further sensitize the medical community on vaccination counseling in KTxp as soon as possible. Study with higher number of patients are needed to further clarify the individual response on antibody production and sensitivity to this still life-threatening infection.

Outcomes of kidney transplantation at the epicenter of the covid-19 pandemic: The experience of the ospedale maggiore policlinico

Purpose: To evaluate patient-and allograft-related outcomes following living and deceased donor kidney transplantation (KTx) in a unit operating at the epicentrum of the COVID-19 pandemic. Methods: Single-centre observational study comparing results of patients transplanted during the COVID-19 pandemic (SARS2-Tx group;71#) with those remaining on the transplant waiting list (TWL) during the same period (SARS2-TWL group;142#) or receiving a kidney in 2019 (CONTROL group;75#) at the Ospedale Maggiore Policlinico, Milan, Italy. Data refer to latest follow-up available. Donor and recipient screening included: real-time reverse transcriptase polymerase chain reaction based molecular assay on nasal swab and BAL (at induction of anesthesia), serologic test, CRP, and chest high-resolution CT scan. Results: Demographic and clinical characteristics of the three groups were similar with an equivalent proportion of high immunological and surgical risk subjects. Patient survival was 98.6% in SARS2-Tx, 96% in CONTROL, and 97.2% in SARS2-TWL (P=ns) whereas death-censored transplant survival was 97% in SARS2-Tx and 96% in CONTROL (P=ns). There were 3 episodes of COVID-19 infection in SARS2-Tx (4.2%;2 asymptomatic and 1 with moderate respiratory symptoms), 6 in CONTROL (8%;5 asymptomatic and 1 fatal), and 3 in SARS2-TWL (97.9%;all fatal). The vast majority of COVID-19 infections were acquired during transplantrelated hospital stay or dialysis sessions. Rejection rates before and during the pandemic were comparable (6% vs 4.2%;P=ns) reflecting the fact that we did not change our immunosuppression strategy. In fact, median tacrolimus C0 as well as MMF and steroid daily doses in SARS2-Tx and CONTROL were not significantly different at any time point of the study. Conclusions: Overall, our data seem to reassure centres worldwide willing to effectively continue their KTx program despite the COVID-19 crisis as no clinically relevant differences were observed among patients transplanted before and during the pandemic. The perceived increased risk of SARS-CoV-2 infection and virusrelated death among patients remaining on dialysis further supports this point of view as long as strict and rigorous infection control strategies are embraced. A national multicentre study with larger population and longer follow-up is warranted to confirm these findings and help clinicians offer their patients adequate counselling.

Vitamin d status and sars-cov-2 infection in a cohort of renal transplanted patients

Background: Immunomodulatory and anti-inflammatory properties have been hypothesized for native vitamin D (nVD). Very little is reported about nVD and risk of Sars-CoV-2 infection (COV) in renal transplant (RTx). In a cohort of renal transplanted patients (RTxp) we retrospectively evaluated: a) nVD status in patients with (COV+) and without (COV-) COV infection;b) the impact of nVD status on severity of COV. Methods: The study includes 61 COV+ in whom nVD status was available in the year before the infection, and 122 COV-matched 1:2 for age (53[45-64]years), gender (M=60.7%), RTx vintage (7[2-15]years), presence of diabetes (18%), arterial hypertension (85%) and cardiac symptomatic disease (3%). Renal function, 24-h proteinuria, mineral metabolism (MM) parameters were evaluated at 1, 6 and 12 months before COV whereas nVD status was considered as the mean 25-OH-VD levels at the same timepoints. Severity of COV was based on the need for hospitalization (HOSP+: 27/61, 44.3%) and death (D+: 6/61, 9.8%). Results: a) nVD levels were significantly lower in COV+ than in COV-(19 [12-26] ng/mL and 23[16-30] ng/mL, respectively, p=0.01). No differences in the other biochemical parameters were found. The COV discriminative power of nVD status was evaluated by ROC curve (AUC 0.61, 95% CI 0.54-0.68, p=0.01), with a value of 25-OHVD 23.9 ng/mL showing the best discriminative power (sensibility 72%, specificity 47%). b) nVD levels showed a trend towards lower values in HOSP+COV+ than HOSPCOV+ (17[8-25] ng/mL vs 20[14-26] ng/mL) and in D+COV+ than D-COV+ (13 [6-23] ng/mL vs 20[13-26] ng/mL), although these differences did not reach the statistical significance (p=0.1 and p=0.2, respectively). Conclusions: With the limitations of the retrospective nature of the study and the small sample size, our data report that: a) COV+ showed lower nVD levels in the year preceding the infection compared to controls with similar main demographic features and comorbid conditions;b) No differences were found in renal function, proteinuria, and other MM parameters between the two groups;c) No association was found between nVD levels in the year preceding the infection and COV severity.