Journal of Nephrology最新文献

Background: Chronic kidney disease (CKD)-associated pruritus is a condition that strongly impacts CKD patients and is associated with increased morbidity/mortality, and worse health-related quality of life (HRQoL). Difelikefalin is currently the only drug approved in Europe specifically for treating moderate to severe CKD-associated pruritus in patients undergoing hemodialysis. The KALM-1 and KALM-2 trials showed better efficacy of difelikefalin vs placebo and best supportive care. The aim of this study was to investigate the cost-effectiveness of difelikefalin according to the Italian National Health Service (NHS) perspective.

Methods: A cohort model represented by four health states (No, Mild, Moderate, and Severe pruritus) was adapted to the Italian setting. The model used data from the KALM-1 and -2 trials for efficacy, integrated with other publications for HRQoL estimations. To assess the cost of disease management, a recent Italian publication on CKD-associated pruritus was used and a price of €27 per difelikefalin vial was assumed. The base case analysis over a 15-year time horizon, and an additional 10-year scenario analysis, were established. Additionally, both deterministic univariate analysis and probabilistic multivariate sensitivity analyses were developed. Discount rates of 3% were applied. An acceptability threshold of 40,000 €/quality-adjusted life-year (QALY) was considered.

Results: The results show that difelikefalin plus best supportive care is cost-effective vs best supportive care alone, with an incremental cost-effectiveness ratio, in the base case, of €35,823/QALY. Both the scenario and sensitivity analyses confirmed the strength of the results.

Conclusions: Difelikefalin was found to be a cost-effective treatment for the Italian NHS. These results support its reimbursement and its inclusion in routine clinical practice.

Chronic kidney disease (CKD) is widely recognized as a leading and growing contributor to global morbidity and mortality worldwide. Nutritional therapy is the basic treatment for metabolic control, and may contribute to nephroprotection; however, the absence of solid evidence on slowing CKD progression together with poor adherence to dietary prescription limit de facto its efficacy and prevent its more widespread use. Sodium-glucose transport protein 2 inhibitors (SGLT2is) are now considered the new standard of care in CKD; in addition, novel potassium binders, glucagon-like peptide-1 receptor antagonists (GLP1-RAs) and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) show either direct (SGLT2i, GLP1-RA, nsMRA) or indirect (potassium binders that enable the optimal use of renin-angiotensin-aldosterone system inhibitors) nephroprotective effects. These drugs could potentially lead to a more permissive diet, thereby allowing the patient to reap the benefits of this approach. In particular, SGLT2is, and to a lesser extent also GLP1-RAs and nsMRAs in patients with diabetic kidney disease, can counterbalance hyperfiltration as well as the higher protein intake often recorded in obese patients; on the other hand, potassium binders can facilitate following plant-based diets, which are considered healthy because of the high content of essential micronutrients such as antioxidant vitamins, minerals, alkalies, and fibers. In this review paper, we discuss the current pharmacological paradigm shift that places a new, broader standard of care in light of its interaction with nutritional therapy in order to optimize the global approach to patients with CKD not on dialysis.

Background: Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease in children and young adults. The most severe form of steroid-resistant nephrotic syndrome is congenital nephrotic syndrome Finnish type (CNSF), caused by biallelic loss-of-function variants in NPHS1, encoding nephrin. Since each of the 68 monogenic causes of steroid-resistant nephrotic syndrome represents a rare cause of the disease, tailoring therapeutic interventions to multiple molecular targets remains challenging, suggesting gene replacement therapy (GRT) as a viable alternative. To set the ground for a gene replacement study in vivo, we established rigorous, quantifiable, and reproducible phenotypic assessment of a conditional Nphs1 knockout mouse model.

Methods: By breeding a floxed Nphs1^fl/- mouse (Nphs1^tm1Afrn/J) previously studied for pancreatic β-cell survival with a podocin promoter-driven Cre recombinase mouse model (Tg(NPHS2-Cre)^295Lbh/J), we generated mice with podocyte-specific nephrin deficiency (Nphs1^fl/fl NPHS2-Cre +).

Results: We observed a median survival to postnatal day P5 in nephrin-deficient mice, whereas heterozygous control mice and wild type (WT) control group showed 90% and 100% survival, respectively (at P50 days). Light microscopy analysis showed a significantly higher number of renal-tubular microcysts per kidney section in nephrin-deficient mice compared to the control groups (P < 0.0022). Transmission electron microscopy demonstrated reduced foot process (FP) density in nephrin-deficient mice compared to controls (P < 0.0001). Additionally, proteinuria quantitation using urine albumin-to-creatinine ratio (UACR) was significantly higher in nephrin-deficient mice compared to controls.

Conclusions: This study represents the first comprehensive description of the kidney phenotype in a nephrin-deficient mouse model, laying the foundation for future gene replacement therapy endeavors.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disorder that may progress to kidney failure, accounting for 5-10% of all patients with end-stage kidney disease (ESKD). Clinical data, as well as molecular genetics and advanced imaging techniques have provided surrogate prognostic biomarkers to predict rapid decline in kidney function, nonetheless enhanced tools for assessing prognosis for ADPKD are still needed. The aim of this study was to analyze specific microRNAs involved in the pathogenesis of ADPKD and in the development of renal fibrosis, evaluating their potential role as predictors of renal function loss.

Methods: We evaluated kidney function by estimated glomerular filtration rate (eGFR) in 32 ADPKD patients in different stages of kidney disease at T0 and after a 24-month follow up (T1). Patients were divided into two groups: Rapid disease progression ([RP], n 15) and Non-rapid disease progression ([NRP], n 17), according to the Mayo Clinic classification criteria. At T0, ADPKD patients underwent plasma sampling for quantitative analysis of h-miR-17-5p, h-miR-21-5p and h-miR-199a-5p microRNA expression, using the quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) method and a 3 T magnetic resonance imaging (MRI), using an advanced MRI imaging protocol, for the quantification of total kidney volume (TKV), total perfusion volume (TPV) and total fibrotic volume (TFV).

Results: The expression of h-miR17-5p was higher (p < 0.05) in ADPKD patients with rapid disease progression. h-miR-17-5p, h-miR-21-5p and h-mir-199-5p showed a positive and significant correlation with the eGFR slope (mL/min/1.73 m²/year) (p < 0.05) but not with the eGFR at both T0 and T1. Both total fibrotic volume (cm³) and height-adjusted total fibrotic volume (cm³/m) were positively and significantly correlated to h-miR 21-5p and h-miR 199-5p (p < 0.05), but not to total kidney volume (cm³) and height-adjusted total kidney volume (cm³/m).

Conclusions: The microRNAs we studied were associated with fibrosis and renal damage, suggesting their possible role as biomarkers able to identify ADPKD patients at high risk of disease progression regardless of the degree of kidney function, and therefore suitable for medical therapy, and may help uncovering new molecular mechanisms underlying cystogenesis.

Despite advances in diabetes management, there is an urgent need for novel therapeutic strategies since the current treatments remain insufficient in halting the progression of diabetic nephropathy-diabetic kidney disease (DN-DKD). This review is mainly addressed on the pivotal role of endothelin-1 in the pathophysiology of DN, with a specific focus on its effects on podocytes and the glomerular filtration barrier. Endothelin-1 promotes mesangial cell proliferation, sclerosis, and direct podocyte injury via the activation of endothelin type A and B receptors, that drive the progression of glomerulosclerosis in DN-DKD. Endothelin receptor antagonists, including drugs like atrasentan and sparsentan, have demonstrated nephroprotective effects in experimental models by reducing proteinuria and podocyte injury. The therapeutic potential to slow the progression of DN to end-stage kidney disease (ESKD) of these endothelin receptor antagonists in clinical practice is currently under evaluation. However, fluid retention and increased risk of heart failure associated with endothelin receptor antagonists need careful consideration. This review aims to provide an in-depth analysis of the pathophysiological role of endothelin and the emerging therapeutic implications of targeting this pathway in DN-DKD and discusses efficacy, safety, and the possibility of combining the new generation of endothelin receptor antagonists with the standard treatment of CKD and DN-DKD.

Background: Anti-neutrophil cytoplasmic antibody (ANCA) Renal Risk Score has not been widely validated in Chinese patients with myeloperoxidase -ANCA-associated glomerulonephritis and its predictive ability needs to be improved.

Methods: Three hundred and forty patients with biopsy-proven myeloperoxidase-ANCA-associated glomerulonephritis were included in this study. They were divided into an oliguric group (urine volume < 400 ml/24 h) and a non-oliguric group (urine volume ≥ 400 ml/24 h). The ANCA Renal Risk Score and Berden classes were used to predict the risk of end-stage kidney disease (ESKD), and Cox regression analysis was performed to evaluate the impact of oliguria on ESKD risk.

Results: The predictive performance of ANCA Renal Risk Score was significantly higher than that of Berden classes (AUC: 0.79 vs. 0.709, P = 0.003). Thirty-six (10.6%) patients presented with oliguria. Patients in the oliguric group had significantly lower levels of baseline estimated glomerular filtration rate (eGFR) [6.51(4.55-7.72) vs. 21.22(11.49-36.63) ml/min/1.73 m², P < 0.001], hemoglobin (78.33 ± 16.75 vs. 92.47 ± 18.95 g/L, P < 0.001), serum albumin (32.01 ± 5.92 vs. 36.22 ± 4.84 g/L, P < 0.001), and a lower percentage of normal glomeruli [6.86(0-17.39)% vs. 18.18(9.09-35)%, P < 0.001]. Consistently, the oliguric group had a higher percentage of patients that progressed to ESKD (83.3% vs. 36.2%, P < 0.001). Multivariate Cox regression analysis showed that oliguria was an independent risk factor for ESKD [HR = 2.38(1.39-4.06), P = 0.002]. Oliguria scores (3 points for presence and 0 for absence) were incorporated into the ANCA Renal Risk Score, resulting in ANCA Renal Risk Score-U. The patients were then categorized into four risk groups: low-(0-2 points), moderate-(3-7 points), high-(8-11 points) and very high-(12-14 points). The incidences of ESKD in these groups were 11.1%, 30%, 72.2% and 95.8%, respectively. The predictive efficacy of ANCA Renal Risk Score-U in predicting ESKD risk was significantly higher than that of the ANCA Renal Risk Score (AUC: 0.812 vs. 0.79, P = 0.025).

Conclusions: This study has validated the ANCA Renal Risk Score for predicting kidney outcomes among Chinese patients with myeloperoxidase-ANCA-associated glomerulonephritis. Furthermore, the ANCA Renal Risk Score-U model with oliguria as a variable can further improve the prediction of ESKD risk in patients with myeloperoxidase-ANCA-associated glomerulonephritis.

According to the 10th edition of the IDF Diabetes Atlas, 537 million people suffered from diabetes in 2021, and this number will increase by 47% by 2045. It is estimated that even 30-40% of these individuals may develop diabetic kidney disease (DKD) in the course of diabetes. DKD is one of the most important complications of diabetes, both in terms of impact and magnitude. It leads to high morbidity and mortality, which subsequently impacts on quality of life, and it carries a high financial burden. Diabetic kidney disease is considered a complex and heterogeneous entity involving disturbances in vascular, glomerular, podocyte, and tubular function. It would appear that hypoxia-inducible factors (HIF)-1 and HIF-2 may be important players in the pathogenesis of this disease. However, their exact role is still not fully investigated. In this article, we summarize the current knowledge about HIF signaling and its role in DKD. In addition, we focus on the possible effects of nephroprotective drugs on HIF expression and activity in various tissues.

Background: The Human Protein Atlas, with more than 10 million immunohistochemical images showing tissue- and cell-specific protein expression levels and subcellular localization information, is widely used in kidney research. The Human Protein Atlas contains comprehensive data on multi-tissue transcript and protein abundance, allowing for comparisons across tissues. However, while visual and intuitive to interpret, immunohistochemistry is limited by its semi-quantitative nature. This can lead to mismatches in protein expression measurements across different platforms.

Methods: We performed a comparison of the Human Protein Atlas' kidney-specific RNA sequencing and immunohistochemistry data to determine whether the mRNA and protein abundance levels are concordant.

Results: Our study shows that there is a discordance between mRNA and protein expression in the kidney based on the Human Protein Atlas data. Using an external validation mass spectrometry dataset, we show that more than 500 proteins undetected by immunohistochemistry are robustly measured by mass spectrometry. The Human Protein Atlas transcriptome data, on the other hand, exhibit similar transcript detection levels as other kidney RNA-seq datasets.

Conclusions: Discordance in mRNA-protein expression could be due to both biological and technical reasons, such as transcriptional dynamics, translation rates, protein half-lives, and measurement errors. This is further complicated by the heterogeneity of the kidney tissue itself, which can increase the discordance if the cell populations or tissue compartment samples do not match. As such, shedding light on the mRNA-protein relationship of the kidney-specific Human Protein Atlas data can provide context to our scientific inferences on renal gene and protein quantification.