Unraveling the Link between Interferon-α and Systemic Lupus Erythematosus: From the Molecular Mechanisms to Target Therapies.

Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease with a wide range of clinical expressions. The kidney is often affected, usually within 5 years of the onset of SLE, and lupus nephropathy (LN) carries a high risk for increased morbidity. The clinical heterogeneity of the disease is accompanied by complex disturbances affecting the immune system with inflammation and tissue damage due to loss of tolerance to nuclear antigens and the deposition of immune complexes in tissues. Several studies have reported that in human SLE, there is an important role of the Type-I-interferons (INF) system suggested by the upregulation of INF-inducible genes observed in serial gene expression microarray studies. This review aims to describe the transduction pathways of Type-I-interferons, in particular INFα, and its immune-regulatory function in the pathogenesis of SLE and, in particular, in LN. In addition, recent novelties concerning biologic therapy in LN will be discussed.

History of Preeclampsia in Patients Undergoing a Kidney Biopsy: A Biphasic, Multiple-Hit Pathogenic Hypothesis.

Introduction: It is not fully elucidated whether preeclampsia (PE) is a marker or a cause of chronic kidney disease (CKD). To test the hypothesis of a biphasic relationship between PE and CKD, we assessed PE prevalence in women who underwent a kidney biopsy. Methods: This retrospective, observational study recruited patients who underwent a kidney biopsy after delivery in 2014 to 2019 in 3 Italian Centers (Cagliari, Bari, Messina); low-risk pregnancies observed in Cagliari served as controls. A history of PE was assessed on the clinical charts and by phone interview. Results: In the biopsy cohort (379 pregnancies, 205 patients; 38 PE in 32 patients), kidney biopsy shows clustering in the first 5 years after PE (11 of 32). Pre-existing CKD was detected in 8 of 11 of these cases. Focal-segmental glomerulosclerosis (FSGS) and complex lesions were found in 12 of 32 biopsies. The odds ratio (OR) of having had a PE episode, compared with 561 low-risk pregnancies, was 10.071 (95% CI: 4.859-20.875; P < 0.001); multiparity maintained a protective effect (OR: 0.208). The delivery-to-biopsy time was significantly shorter in women with PE, both considering the first or the last PE versus the first or last delivery in patients with or without PE episodes. The characteristics of PE did not differ as compared with low-risk controls. Conclusion: Within the limitation of the retrospective design, our study, quantifying the association between needing a kidney biopsy and history of PE, suggests a biphasic pattern, with a peak in the first 5 years after delivery (probably due to pre-existing diseases) and a later increase, suggesting that PE may have later played as one hit in a multiple-hit pathogenesis.

Positron Emission Tomography Can Support the Diagnosis of Dialysis-Related Amyloidosis.

BACKGROUND: The improvements in dialysis have not eliminated long-term problems, including dialysis-related amyloidosis (DRA), caused by Beta-2 microglobulin deposition. Several types of scintigraphy have been tested to detect DRA, none entered the clinical practice. Aim of the study was to assess the potential of PET-FDG scan in the diagnosis of DRA. METHODS: Forty-six dialysis patients with at least one PET scan (72 scans) were selected out 162 patients treated in 2016-2018. Subjective global assessment (SGA), malnutrition inflammation score (A), Charlson Comorbidity Index (CCI), were assessed at time of scan; 218 age-matched cases with normal kidney function were selected as controls. PET scans were read in duplicate. Carpal tunnel syndrome was considered a proxy for DRA. A composite "amyloid score" score considered each dialysis year = 1 point; carpal tunnel-DRA = 5 points per site. Logistic regression, ROC curves and a prediction model were built. RESULTS: The prevalence of positive PET was 43.5% in dialysis, 5% in controls (p < 0.0001). PET was positive in 14/15 (93.3%) scans in patients with carpal tunnel. PET sensitivity for detecting DRA was 95% (specificity 64%). Carpal tunnel was related to dialysis vintage and MIS. A positive PET scan was significantly associated with dialysis vintage, MIS and amyloid score. A prediction model to explain PET positivity combined clinical score and MIS, allowing for an AUC of 0.906 (CI: 0.813-0.962; p < 0.001). CONCLUSIONS: PET-FDG may identify DRA, and may be useful in detecting cases in which inflammation favours B2M deposition. This finding, needing large-scale confirmation, could open new perspectives in the study of DRA.

Moderate Protein Restriction in Advanced CKD: A Feasible Option in An Elderly, High-Comorbidity Population. A Stepwise Multiple-Choice System Approach.

BACKGROUND: Protein restriction may retard the need for renal replacement therapy; compliance is considered a barrier, especially in elderly patients. METHODS: A feasibility study was conducted in a newly organized unit for advanced kidney disease; three diet options were offered: normalization of protein intake (0.8 g/kg/day of protein); moderate protein restriction (0.6 g/kg/day of protein) with a "traditional" mixed protein diet or with a "plant-based" diet supplemented with ketoacids. Patients with protein energy wasting (PEW), short life expectancy or who refused were excluded. Compliance was estimated by Maroni-Mitch formula and food diary. RESULTS: In November 2017⁻July 2018, 131 patients started the program: median age 74 years (min⁻max 24-101), Charlson Index (CCI): 8 (min-max: 2⁻14); eGFR 24 mL/min (4⁻68); 50.4% were diabetic, BMI was ≥ 30 kg/m² in 40.4%. Normalization was the first step in 75 patients (57%, age 78 (24⁻101), CCI 8 (2⁻12), eGFR 24 mL/min (8⁻68)); moderately protein-restricted traditional diets were chosen by 24 (18%, age 74 (44⁻91), CCI 8 (4⁻14), eGFR 22 mL/min (5⁻40)), plant-based diets by 22 (17%, age 70 (34⁻89), CCI 6.5 (2⁻12), eGFR 15 mL/min (5⁻46)) (p < 0.001). Protein restriction was not undertaken in 10 patients with short life expectancy. In patients with ≥ 3 months of follow-up, median reduction of protein intake was from 1.2 to 0.8 g/kg/day (p < 0.001); nutritional parameters remained stable; albumin increased from 3.5 to 3.6 g/dL (p = 0.037); good compliance was found in 74%, regardless of diets. Over 1067 patient-months of follow-up, 9 patients died (CCI 10 (6⁻12)), 7 started dialysis (5 incremental). CONCLUSION: Protein restriction is feasible by an individualized, stepwise approach in an overall elderly, high-comorbidity population with a baseline high-protein diet and is compatible with stable nutritional status.

Prescribing Hemodialysis or Hemodiafiltration: When One Size Does Not Fit All the Proposal of a Personalized Approach Based on Comorbidity and Nutritional Status.

There is no simple way to prescribe hemodialysis. Changes in the dialysis population, improvements in dialysis techniques, and different attitudes towards the initiation of dialysis have influenced treatment goals and, consequently, dialysis prescription. However, in clinical practice prescription of dialysis still often follows a "one size fits all" rule, and there is no agreed distinction between treatment goals for the younger, lower-risk population, and for older, high comorbidity patients. In the younger dialysis population, efficiency is our main goal, as assessed by the demonstrated close relationship between depuration (tested by kinetic adequacy) and survival. In the ageing dialysis population, tolerance is probably a better objective: "good dialysis" should allow the patient to attain a stable metabolic balance with minimal dialysis-related morbidity. We would like therefore to open the discussion on a personalized approach to dialysis prescription, focused on efficiency in younger patients and on tolerance in older ones, based on life expectancy, comorbidity, residual kidney function, and nutritional status, with particular attention placed on elderly, high-comorbidity populations, such as the ones presently treated in most European centers. Prescription of dialysis includes reaching decisions on the following elements: dialysis modality (hemodialysis (HD) or hemodiafiltration (HDF)); type of membrane (permeability, surface); and the frequency and duration of sessions. Blood and dialysate flow, anticoagulation, and reinfusion (in HDF) are also briefly discussed. The approach described in this concept paper was developed considering the following items: nutritional markers and integrated scores (albumin, pre-albumin, cholesterol; body size, Body Mass Index (BMI), Malnutrition Inflammation Score (MIS), and Subjective Global Assessment (SGA)); life expectancy (age, comorbidity (Charlson Index), and dialysis vintage); kinetic goals (Kt/V, normalized protein catabolic rate (n-PCR), calcium phosphate, parathyroid hormone (PTH), beta-2 microglobulin); technical aspects including vascular access (fistula versus catheter, degree of functionality); residual kidney function and weight gain; and dialysis tolerance (intradialytic hypotension, post-dialysis fatigue, and subjective evaluation of the effect of dialysis on quality of life). In the era of personalized medicine, we hope the approach described in this concept paper, which requires validation but has the merit of providing innovation, may be a first step towards raising attention on this issue and will be of help in guiding dialysis choices that exploit the extraordinary potential of the present dialysis "menu".

Phosphate binders as a cause of hypothyroidism in dialysis patients: practical indications from a review of the literature.

BACKGROUND: Although fatigue is common in dialysis patients, polypharmacy is seldom listed among its causes. In this report, we describe a dialysis patient who developed severe fatigue due to pharmacological interaction between two commonly prescribed drugs, phosphate binders and levothyroxine. CASE PRESENTATION: A 65-year old woman, on dialysis for 17 years, complained of fatigue (weight 54 Kg, height 1.55 m, BMI: 23 Kg/m2; malnutrition inflammation index: 10; Charlson index 9). She had been treated with lithium for about 20 years. A heavy smoker, she was obese and diabetic when young, but stopped treatment after weight loss. She had undergone thyroidectomy for papillary carcinoma, left hemicolectomy for colon adenocarcinoma, left quadrantectomy followed by radiotherapy for ductal mammary adenocarcinoma, subtotal parathyroidectomy for tertiary hyperparathyroidism. At the time of this report, she was on thrice-weekly hemodiafiltration (Daugirdas 2 Kt/V: 1.6-1.8). Her recent treatment included spironolactone, amlodipine, perindopril, valproate, lamotrigine, levothyroxine, vitamin D, calcium carbonate, sodium polystyrene and sevelamer. After she questioned her doctor about whether her fatigue might be the result of a drug interaction, levothyroxine interference was identified (TSH, previously normal, increased to 13.07 mU/L, after increasing sevelamer dose, and normalized after change of drug schedule). LITERATURE REVIEW: only 5 relevant papers on levothyroxine and phosphate binders on dialysis were found on Pubmed and EMBASE (out of 351 titles retrieved). Information was therefore inferred from studies in normal volunteers or in other diseases. DISCUSSION AND CONCLUSIONS: Our case differs from other reports on lower TSH at diagnosis, underlining the need for awareness of the importance of early diagnosis. Integrating the scant literature on dialysis patients with data available in the general population, some working conclusions can be reached: while all phosphate binders potentially interfere with levothyroxine absorption, interference seems to be highest for sevelamer; interference is limited but not excluded by increasing the intervals between drugs; morning fast is usually indicated but, when clashing with the timing of other drugs, a bedtime dose and liquid preparations may be indicated. In the absence of an agreed control schedule, our case supports close monitoring of TSH (1-3 months if unstable, twice-yearly in stable patients).