BACKGROUND AND AIMS Haemolytic uremic syndrome (HUS) is a rare disease characterized by macroangiopathic haemolytic anaemia, thrombocytopaenia and severe AKI, belonging to the thrombotic microangiopathies (TMAs). It is divided into typical and atypical HUS: the first one occurs most frequently in children within the first 5 years of life and it is associated with Shiga-like toxin producing Escherichiacoli infection; the second one (aHUS) is less common (10%) and it is due to complement abnormalities with coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs or pregnancy. There is an increasing interest in SARS-CoV-2 infection as new trigger for complement activation. Nine cases of aHUS were recently associated with COVID-19, most of them occurring within 1 month from the infection. Available data suggest that SARS-CoV-2 is a potential trigger for aHUS: it can induce an over inflammatory state and to activate coagulation and complement pathway. Likewise, mRNA-based vaccines against COVID-19 inducing the expression of SARS-CoV-2 spike protein to stimulate immune recognition and antibody response could be a suitable trigger for HUS. METHOD We report the case of a 17-year-old woman, who presented at our emergency department with fever, dyspnoea, acute kidney injury AKI III with anuria, hypertension, severe anaemia, no diarrhoea, severe thrombocytopaenia and myocarditis, about 2 weeks after the first administration of SARS-CoV-2 vaccine (Comirnaty) and recent exposition to SARS-CoV-2 positive individual. SARS-CoV-2 nasal PCR swab was negative (as well as successive ones) and she was immediately admitted to paediatric intensive care unit and treated with transfusions and haemodialysis. Laboratory exams suggested a thrombotic microangiopathy with normal ADAMTS-13 activity and no E. coli infection. She underwent a renal biopsy that confirmed our hypothesis of aHUS: wrinkled capillaries, subendothelial expansion, mesangiolysis and rare thrombi in capillaries lumen. Arterioles had intimal proliferation with mucoid oedema who gave rise to onionskin like lesion that obliterates lumens. One glomerulus showed extracapillary proliferation (crescent), and there was interstitial lymphomonocytic inflammatory infiltration in the nearby. Also signs of acute tubular injury and atrophy were reported. Positive stain to fibrinogen in the arterioles at immunohistology was noted. She immediately performed genetic exams for aHUS-related complement mutations and she started immunosuppression with corticosteroids and eculizumab infusions. After 2 months of eculizumab, she was still oliguric, requiring renal replacement therapy. Genetic analysis showed no mutations. Therefore, she was examined for other genetic causes of thrombotic microangiopathies. RESULTS Finally, came to light that she had high levels of homocysteine, and she was diagnosed with secondary HUS associated with cobalamin C deficiency, which manifests with methylmalonic aciduria and homocystinuria due to a recessive mutation in the MMACHC gene, causing a cobalamin C type deficiency, which is the common functional variant of vitamin B12. After metabolic therapy with hydroxocobalamin, she gradually recovered diuresis and partially renal function without need for replacement therapy. CONCLUSION Reports from immunization programs show as myocarditis and thrombotic thrombocytopaenia are considered among main serious complications caused by COVID-19 vaccines, representing 12.6 cases per million doses and 0.73 cases per 100 000, respectively. This interesting case probably supports data about the role of mRNA-based anti-SARS-CoV-2 vaccines like a precipitant factor for TMAs. Moreover, our patient turned out to be an extremely rare case of HUS secondary to cobalamin C deficiency, that is generally diagnosed in early infancy and show typically neurological symptoms (absent in our case). Probably, the mRNA-based vaccine acted like ‘a second hit’, but existing predisposition should always be investigated including also the less frequent forms.

BACKGROUND AND AIMS Cystinuria is a rare genetic disease characterized by impaired tubular transport of cystine and other dibasic amino acids that leads to cystine renal calculi. Although being a rare condition, cystinuria is the most frequent monogenic cause of nephrolithiasis accounting for 1% of kidney stones in adults and 8% in children with an average prevalence of 1 in 7000 births. Up to date, clinical features of cystinuria are believed to be attributable only to nephrolithiasis although cystinuric patients may present other comorbidities (chronic kidney disease, progression toward end-stage kidney disease and hypertension). All these features may be partially explained by recurrent nephrolithiasis. There are currently no data on bone features of patients with cystinuria. Data on a murine model demonstrated the presence of reduced bone mineral density irrespective of the presence or absence of uremia, suggesting bone metabolic abnormalities in cystinuria even in the absence of reduced glomerular filtration rate (GFR). Our aim is to characterize bone mineral density (BMD) in patients affected by cystinuria. METHOD The present study included 13 patients affected by cystinuria followed at the Rare Kidney Diseases outpatient clinic of our Institution. All eligible patients were more than 18 years of age with an estimated GFR ≥15 mL/min/1.73 m2 and provided written informed consent. Patients who did not sign informed consent, pregnant women, patients undergoing chronic hemodialysis or with a previous kidney transplant were excluded. History and laboratory data were collected during scheduled outpatient visits from September 2021 to December 2021, and all patients underwent a dual-energy X-ray absorptiometry (DEXA). One sample t-tests were used to assess whether BMD Z-scores were significantly different from 0. RESULTS Patients’ characteristics are summarized in Table 1. Of the enrolled patients, six (46%) were female and four of them (67%) were in menopause, four (31%) had active nephrolithiasis described as at least two episodes in the last 3 months, and two (15%) had a self-reported diagnosis of osteoporosis. Moreover, six patients (46%) had a positive history for bone fractures that were all self-reported as traumatic. Femoral Z-scores were significantly lower than 0 overall (P = 0.015) and across femoral sites, whereas lumbar Z-scores, although low on average, did not meet statistical significance (Figure 1). Interestingly, reduced BMD was very prevalent, with 10 patients (77%) showing osteopenia and 3 (23%) showing osteoporosis. CONCLUSION Our data show a high prevalence of osteopenia and osteoporosis in cystinuric patients, especially when considering that our population was rather young and with a normal or moderately impaired kidney function. Of further interest appears also the differential distribution of decreased BMD that seems to be affecting the femur rather than the lumbar spine. To our knowledge, these are the first data assessing the prevalence and the characteristics of BMD disorder in cystinuric patients.

Background and Aims Pregnancy in women affected by familial hypercholesterolemia is rare. Estrogen and progesterone fluctuations, featuring pregnancy, adversely influence lipid metabolism, causing considerable increase of LDL-C, triglyceride and lipoprotein A levels. These changes in fatty metabolism, essential for embryonic development, might be critical for placental circulation and for mother's health. Indeed, high lipoprotein amount can raise uteroplacental vascular resistance and it is associated with intrauterine growth restriction because of oxidative stress, whereas hypertriglyceridemia and hypercholesterolemia might cause an increased risk of cardiovascular accidents and pancreatitis. Lipid-lowering drugs, such as statins, ezetimibe or PCSK9 inhibitors are discontinued due to possible teratogen effects. Thus, LDL apheresis is the only available therapy for severe hypercholesterolemia during pregnancy. Method A 46 years old woman affected by heterozygous familial hypercholesterolemia in treatment with PCSK9 inhibitors and statins, decided to undergo an heterologous in vitro fertilization with oocyte donation. Hence, pharmacological therapy was stopped to avoid teratogen effects. We started a 10-months apheresis program with double filtration plasmapheresis (DFPP). The treatment was performed by a temporary double lumen central venous catheter. Initially, she underwent apheresis twice a month with an average exchange volume of 1.2, low blood flow (≤ 90 ml/min) and incremental plasma flow (from 5 to 30 ml/min every 10 minutes of treatment), to ensure a physiological procedure. We gradually modulated the exchange volume monitoring blood levels of LDL-C, Lp(a) and triglycerides before and after each procedure. We aimed to keep mean LDL-C level < 200 mg/dl. We did not use anti-coagulation during the procedure, monitoring TMP values and arterial-venous pressure. Results LDL-C levels remained about 227.2 ± SD 91 mg/dl, with a median of 186.8 mg/dl, complying with the target range (Figure 1). Mean triglycerides and Lp(a) values were, respectively, 180.3±94 mg/dl (median 146 mg/dl) and 77.3±36.3 mg/dl (median 55.7 mg/dl) (Figure 1). Our patient did not face any complications related to pregnancy or to the procedure, and gave birth at 38th gestational week to an healthy full-term male baby of 52 centimeters and 3.34 kilograms. Conclusion Although there is a widespread hesitation in performing extracorporeal blood purification treatment in pregnancy, this case underlines the essential role of LDL apheresis in in this setting, giving spark to standardize the procedure and to encourage its use also in pregnancy.