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Background Hereditary transthyretin amyloidosis (ATTRv) is a disabling and life-threatening disease that primarily affects the nervous system and heart. Its kidney involvement has not been systematically studied, particularly in non-V30M mutations, and is not well known to nephrologists. Methods We conducted a retrospective study describing the kidney phenotype of all prevalent patients with ATTR mutations, with neurological or cardiac involvement or presymptomatic carriers, followed up in two university hospitals from the South of France between June 2011 and June 2021. Results A total of 103 patients were included, among whom 79 were symptomatic and 24 were presymptomatic carriers. Patients carried 21 different ATTR mutations and 54% carried the V30M mutation. After a mean follow-up of 7.9 ± 25.7 years, 30.4% of the symptomatic patients had developed chronic kidney disease (CKD) and 20.3% had a urinary protein:creatinine ratio ≥0.5 g/g. None of the presymptomatic carriers had CKD or proteinuria. In a multivariate analysis, late onset of symptoms (after 60 years), the V122I mutation and proteinuria were significantly associated with CKD. The median CKD-free survival in symptomatic patients was estimated at 81.0 years (interquartile range 77.1–84.9). It did not differ between V30M and non-V30M patients, but was lower in patients with the V122I mutation. The average age of the onset of CKD was 69.3 ± 13.0 years. In one 38-year-old V30M female who presented a kidney-predominant phenotype, treatment with patisiran resulted in remission of the nephrotic syndrome. Conclusion CKD affects almost one-third of patients with symptomatic ATTRv. The role of ATTRv per se in the development of CKD in this population remains to be determined, but some patients may benefit from specific therapies.

Background In Fabry nephropathy, podocyturia is an early event that may lead to glomerulosclerosis and chronic kidney disease. The glycocalyx is a potential podocyte damaged compartment in glomerulopathies. We investigated glycocalyx podocalyxin in urinary detached podocytes compared with cytoplasmic synaptopodin. Methods This was a cross-sectional study including 68 individuals: Controls (n = 20) and Fabry patients (n = 48), 15 untreated and 33 treated. Variables included age, gender, urinary protein/creatinine ratio (UPCR), estimated glomerular filtration rate (eGFR), lyso-triasocylsphingosine (lyso-Gb3) levels and enzyme replacement therapy (ERT). Podocyturia was assessed by immunofluorescence and podocyte subpopulations were analyzed. Results Fabry patients displayed higher podocyturia than controls. Fabry treated subjects (n = 33) presented significantly higher UPCR compared with untreated ones (n = 15); podocyturia, eGFR and lyso-Gb3 levels were not different. All control podocytes colocalized synaptopodin and podocalyxin; 13 Fabry patients (27%) colocalized these proteins, while 35 (73%) were only synaptopodin positive. No podocalyxin-positive/synaptopodin-negative cells were encountered. In Fabry patients, podocyturia was significantly higher and proteinuria lower in those that colocalized. Conclusion Fabry patients present higher podocyturia and a presumably more damaged glycocalyx assessed by podocalyxin. Treated patients had significant higher proteinuria suggesting ERT is initiated late, at advanced stages. The degree of podocalyxin-negative podocytes was similar in both groups, but colocalization was associated with lower proteinuria. Podocyturia assessed by podocalyxin alone may be underestimated. The implications of podocyte glycocalyx damage deserve further investigations.

About 85–90% of children with idiopathic nephrotic syndrome responds to steroid therapy while the remaining 10–15% fails to respond and is defined as steroid-resistant nephrotic syndrome (SRNS). The histopathological lesions in SRNS are minimal changes, focal and segmental sclerosis (FSGS) and mesangial proliferation. The response to cyclosporine alone or in combination with prednisolone therapy is variable. Proteinuria in FSGS in some patients is associated with a permeability factor (PF). Galactose has been shown to bind with PF [1] and prevents its interaction with podocyte glycocalyx, and oral administration of galactose may lead to reduction of proteinuria [2]. In view of this, we report an observational case study where two separate courses of oral galactose were given to three children with steroid-resistant idiopathic nephrotic syndrome with FSGS in order to reduce proteinuria and increase serum albumin levels. The patient characteristics are presented in Table ​Table1.1. They had generalized oedema, urinary protein/creatinine ratio of >200 mg/mmol (>2 mg/mg), hypalbuminaemia serum albumin 5.18 mmol/L (>200 mg/dL). The children did not achieve remission with prednisolone (2 mg/kg/day) therapy administered for 4 weeks. Kidney biopsy tissues, examined in light and immunofluorescent microscopy, demonstrated focal and segmental glomerulosclerosis. The patients were tested for C3, C4, ANA, anti-ds DNA, HIV, Hepatitis B surface antigen and tuberculin test. Chest radiographs were normal. NPHS2 gene analysis showed R229Q polymorphism in Case 1. The protocol of the study was approved by the Institute Ethics Committee. Table 1. Patient characteristics The children were treated with cyclosporine (4–5 mg/kg/day in two divided doses), prednisolone (1.5 mg/kg, single dose alternate days with gradual taper to a minimum of 0.5 mg/kg) and ramipril (0.2 mg/kg/day, single dose). Furosemide (1–2 mg/kg/day) was given to reduce oedema. The patients received cyclosporine, prednisolone and ramipril for 11–14 months duration and had stable serum creatinine levels. Doses of cyclosporine and ramipril remained unchanged. Patients did not achieve remission as urine protein/creatinine ratios of >200 mg/mmol (>2 mg/mg) persisted. Thereafter, oral d-galactose (Manufactured by Hi Media Laboratories Pvt. Ltd., Mumbai, India) was added at a dose of 0.2 g/kg/dose, twice daily. The patients were followed regularly at a 30-day interval during the first course of galactose trial given for 90 days. After an interval of 90 days in Case 1, 60 days in Case 2 and 105 days in Case 3, a second course of galactose treatment at the same doses was reinstituted for 30 days. The changes in urinary protein/creatinine ratios and serum albumin levels are shown in Figure 1. In all three patients, urinary protein/creatinine ratios decreased (by 37.9, 50.6 and 77.5%), and serum albumin levels increased (by 56, 72 and 23.3%) at 90 days from their pre-galactose values. After discontinuation of galactose, urine protein/creatinine and serum albumin values showed deterioration at 120 days. After the second course of galactose, there was again a reduction of urinary protein/creatinine ratios by 46.5% in Case 1, 37.5% in Case 2 and 25.7% in Case 3 and an increase in serum albumin levels in comparison to their values 30 days before. However, parameters became again abnormal after discontinuation of galactose. No adverse events were noted following galactose therapy. Fig. 1 Urine protein/creatinine ratios and serum albumin levels during the two periods of galactose therapy and the interval period. It showed gradual reduction in urine protein/creatinine ratios and rise in serum albumin values during, deterioration after discontinuation ... The galactose had a beneficial effect in all three patients. The galactose helps in reduction of proteinuria as it directly binds with PF and prevents interaction of PF to galactose residues of podocyte glycocalyx. Subsequently, the galactose–PF complex is cleared from plasma by hepatocytes or macrophages [2]. De Smet et al. [3] in one adult and Kopac et al. [4] demonstrated the effect of galactose in reduction of proteinuria and its benefit persisted for about 3 months in one case. In our cases, the effect lasted as long as galactose was given; indicating that a continuous treatment is necessary to maintain its positive effect on proteinuria. Our patients had no remission with cyclosporine and prednisolone therapy given for a sufficient period. Galactose had lead to reduction of proteinuria and increase in serum albumin during the treatment period. Recently, Sgambat et al. [5] observed no significant difference between pre- and post-treatment mean urine protein/creatinine ratios after 16 weeks of galactose administration, and the authors concluded that it failed to improve proteinuria. In our study, though no patient achieved complete remission (urine protein/creatinine ratio

Sir, Tacrolimus (Tac) is a T-cell-specific calcineurin inhibitor which prevents activation of helper T cells, thereby inhibiting transcription of the early activation genes of interleukin (IL)-2 and suppressing the production of tumor necrosis factor-α, IL-1β and IL-6 [1]. Thus, Tac is expected to have clinical benefits in patients with rheumatic diseases including systemic lupus erythematosus (SLE). Indeed, to date, several articles have described the efficacy of Tac in patients with difficult SLE [2, 3]. Recently, Tac combined with prednisolone (PDN) has been successfully administered without serious adverse effects, as induction and maintenance treatment for patients with proliferative and membranous lupus nephritis [2–6]. However, to our knowledge, the efficacy of Tac monotherapy in the treatment of patients with lupus nephritis has not been reported. We encountered a Japanese female patient with long-standing SLE, in whom relatively low-dose Tac monotherapy for disease flare was effective and safe. A 38-year-old Japanese female with a 24-year history of long-standing SLE with lupus nephritis suddenly developed significant proteinuria (∼1 g/day), arthralgia, hypocomplementemia and elevation of serum anti-dsDNA antibody titers. When she was 14 years old, active SLE with nephrotic-range proteinuria occurred. Percutaneous renal biopsy revealed Class IVb diffuse proliferative lupus nephritis. She was administered three courses of methyprednisolone pulse therapy followed by oral PDN combined with a 12-week course of cyclophosphamide (CPA) [7]. Thereafter, CPA was replaced by azathioprine, and the concomitantly administered PDN was tapered. The SLE activity, both clinical and serological, was under reasonably good control during maintenance therapy. The second renal biopsy, performed 12 months after the initial biopsy, revealed marked improvement to Class II lupus nephritis. After a 2-year treatment, PDN was successfully discontinued, and she remained free of SLE/lupus nephritis signs for the past 20 years or more. Although her blood pressure and renal function were normal at the time of the flare, significant proteinuria associated with hypocomplementemia and elevation of serum anti-dsDNA antibody titer developed 3 months prior to the time of presentation. However, the patient strongly refused to take PDN, mainly because of the cosmetic adverse effect. In this context, we decided to treat her with Tac monotherapy. After obtaining written informed consent, Tac was administered at a dose of 3 mg/day (0.06 mg/kg) once daily after the evening meal [4–6]. If the Tac-resistant flare persisted, PDN was scheduled to start for treating the flares. Response to the treatment is shown in Table 1. The outcome measures, such as the severity of proteinuria as estimated using the urinary protein/creatinine ratio (U-prot./cr.), the serum C3 level, the serum complement hemolytic activity (CH50), the serum titers of anti-dsDNA antibody (by enzyme-linked immunosorbent assay), the serum creatinine level and the SLE activity as assessed using the European Consensus Lupus Activity Measurement (ECLAM) index [8] were prospectively examined at baseline and after 1, 3, 6 and 12 months of treatment. At 1 month after the start of the protocol, a significant decrease in the ECLAM index was noted. After 3 months of treatment, the improvement in the ECLAM index was associated with a significant decrease in the U-prot./cre. ratio and marked recovery of hypocomplementemia. After 6 months of treatment, a tendency toward a marked decrease in the serum anti-dsDNA antibody titer was observed, with the serum creatinine level remaining unchanged. The blood levels of Tac in the patient were maintained at relatively low levels of