The Phenotypic Variability Associated with Hepatocyte Nuclear Factor 1B Genetic Defects Poses Challenges in Both Diagnosis and Therapy.

The evolving landscape of clinical genetics is becoming increasingly relevant in the field of nephrology. HNF1B-associated renal disease presents with a diverse array of renal and extrarenal manifestations, prominently featuring cystic kidney disease and diabetes mellitus. For the genetic analyses, whole exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were performed. Bioinformatics analysis was performed with Ingenuity Clinical Insights software (Qiagen). The patient's electronic record was utilized after receiving informed consent. In this report, we present seven cases of HNF1B-associated kidney disease, each featuring distinct genetic abnormalities and displaying diverse extrarenal manifestations. Over 12 years, the mean decline in eGFR averaged -2.22 ± 0.7 mL/min/1.73 m2. Diabetes mellitus was present in five patients, kidney dysplastic lesions in six patients, pancreatic dysplasia, hypomagnesemia and abnormal liver function tests in three patients each. This case series emphasizes the phenotypic variability and the fast decline in kidney function associated with HNF-1B-related disease. Additionally, it underscores that complex clinical presentations may have a retrospectively straightforward explanation through the use of diverse genetic analytical tools.

Tubulointerstitial Nephritis and Uveitis Syndrome: A Report of 6 Cases with Renal Biopsy and Electron Microscopy Evaluation.

Tubulointerstitial nephritis with uveitis syndrome is a rare, immune-mediated entity, characterized by oculo-renal inflammation. Diagnosis requires the exclusion of all other causes of tubulointerstitial nephritis (TIN). We present 6 patients with clinical, laboratory, and renal biopsy findings denotative of tubulointerstitial nephritis with uveitis syndrome. All our patients experienced ocular and renal manifestations, defined by bilateral uveitis and photosensitivity, along with a decline of renal function. In some patients, increased serum creatinine was accompanied by non-nephrotic range proteinuria, glucosuria or "full-blown" Fanconi syndrome. The rest of the laboratory evaluation was normal apart from the presence of elevated erythrocyte sedimentation rate and increased urine ß2-microglobulin, as well as normochromic, normocytic anemia in some cases. All patients underwent renal biopsy. Histochemical (PAS, Masson, silver, Congo-red) and immunohistochemical stains for immune cell populations (CD3, CD20, CD4, CD8, PGM1, CD138) and for the assessment of ß2-microglobulin were conducted. Electron microscopy examination of the biopsies was also performed. Follow-up, ranging from 18 months to 10 years, was available for 4 patients. Histological evaluation revealed interstitial inflammatory infiltration consisting mainly of lymphocytes, with a T-cell predominance, along with several macrophages. Inflammation severity varied among different patients, with some showing scarce foci of immune cell clusters, while others demonstrated a dense, diffuse interstitial infiltration. Interestingly, in 2 cases, a granulomatous pattern, characterized by non-necrotic, ill-defined granulomas was detected. Tubulitis was also encountered in some patients. A divergence was noted regarding the chronicity index, with different levels of tubular atrophy, interstitial fibrosis, and global glomerulosclerosis among different cases. ß2-Microglobulin immunohistochemical evaluation revealed a substantial diminishment of cytoplasmic staining in tubular epithelial cells compared to control kidneys. The most notable finding derived from electron microscopy examination was the presence, in 1 patient, of scattered granular electron-dense deposits along some tubular basement membranes. First-line treatment included steroids, supplemented in some cases by additional immunosuppressive agents. Three patients experienced a partial or complete response, while progressive renal damage was observed in a case with severe chronic lesions and persistence of inflammation-triggering factor. Our cases seem to represent progressive stages within the continuum of disease evolution. Patients with more prominent inflammation might represent a more initial state, while those with a more severe chronicity index, probably depict more advanced stages. While the predominance of T-cells predicates a cell-mediated autoimmune mechanism, as the driving force of the disease occurrence, the presence of immune complexes in more advanced stages might indicate the involvement of humoral immunity as a late event during the disease course.

Does the Simultaneous Introduction of Several Pharmaceuticals in the Post-Lenalidomide Era Translate to Better Outcomes in Relapse Refractory Multiple Myeloma? Findings from the Real-World Innovation in Multiple Myeloma (REAL IMM) Study.

Newer methodologies are needed to assess the real-world comparative effectiveness of a "generation" of pharmaceutical innovation versus the prior standard of care. This chart review study aimed to first evaluate the cumulative clinical benefits of pharmaceutical innovation in everyday relapse/refractory multiple myeloma before analyzing findings in the context of respective real-world outcomes from the bortezomib/lenalidomide era. Study endpoints included the 52-week PFS rate in second and third line of therapy (LOT), mPFS-2 across the first and second LOT, the ORR, reasons for discontinuation, and the treatment duration per therapeutic algorithm. Data from 107 patients were collected. The median follow-up was 2.0 years. Of the subjects who met the selection criteria for the second LOT, 72.2% maintained the PFS at 52 weeks. In the third-line setting, the PFS rate at 52 weeks was 63.5%. The mPFS across the first and second, the second, and the third LOTs were 26, 17, and 15 months, respectively. The ORR was 76.1% in the second and 69.7% in the third LOT. After non-response or progression, the main reason for drug discontinuation was treatment intolerability. The second-line ORR and the 52-week PFS rate were similar to previous real-world findings from the bortezomib/lenalidomide era. The cumulative mPFS across the second and third LOTs was higher than the respective mPFS across the first and second LOTs. Despite its limitations, the methodology and findings from this study may be used in future clinical and economic evaluations across all hematological malignancies.

A hackathon as a tool to enhance research and practice on electronic health record systems' interoperability for chronic disease management and prevention.

Objectives: The development of a standardized technical framework for exchanging electronic health records is widely recognized as a challenging endeavor that necessitates appropriate technological, semantic, organizational, and legal interventions to support the continuity of health and care. In this context, this study delineates a pan-European hackathon aimed at evaluating the efforts undertaken by member states of the European Union to develop a European electronic health record exchange format. This format is intended to facilitate secure cross-border healthcare and optimize service delivery to citizens, paving the way toward a unified European health data space. Methods: The hackathon was conducted within the scope of the X-eHealth project. Interested parties were initially presented with a representative clinical scenario and a set of specifications pertaining to the European electronic health record exchange format, encompassing Laboratory Results Reports, Medical Imaging and Reports, and Hospital Discharge Reports. In addition, five onboarding webinars and two professional training events were organized to support the participating entities. To ensure a minimum acceptable quality threshold, a set of inclusion criteria for participants was outlined for the interested teams. Results: Eight teams participated in the hackathon, showcasing state-of-the-art applications. These teams utilized technologies such as Health Level Seven-Fast Healthcare Interoperability Resources (HL7 FHIR) and Clinical Document Architecture (CDA), alongside pertinent IHE integration profiles. They demonstrated a range of complementary uses and practices, contributing substantial inputs toward the development of future-proof electronic health record management systems. Conclusions: The execution of the hackathon demonstrated the efficacy of such approaches in uniting teams from diverse backgrounds to develop state-of-the-art applications. The outcomes produced by the event serve as proof-of-concept demonstrators for managing and preventing chronic diseases, delivering value to citizens, companies, and the research community.

Dialysis Patients Respond Adequately to Influenza Vaccination Irrespective of Dialysis Modality and Chronic Inflammation.

(1) Background: Chronic inflammation and suboptimal immune responses to vaccinations are considered to be aspects of immune dysregulation in patients that are undergoing dialysis. The present study aimed to evaluate immune responses in hemodialysis (HD) and online hemodiafiltration (OL-HDF) patients to a seasonal inactivated quadrivalent influenza vaccine (IQIV). (2) Methods: We enrolled 172 chronic dialysis patients (87 on HD and 85 on OL-HDF) and 18 control subjects without chronic kidney disease in a prospective, cross-sectional cohort study. Participants were vaccinated with a seasonal IQIV, and antibody titers using the hemagglutination inhibition (HI) assay were determined before vaccination (month 0) and 1, 3, and 6 months thereafter. Demographics and inflammatory markers (CRP, IL-6, IL-1ß) were recorded at month 0. The primary endpoints were the rates of seroresponse (SR), defined as a four-fold increase in the HI titer, and seroprotection (SP), defined as HI titer ≥ 1/40 throughout the study period. Statistical analyses were conducted in R (version 3.6.3) statistical software. The differences between groups were analyzed using chi-square and t-test analyses for dichotomous and continuous variables, respectively. To identify independent determinants of SR and SP, generalized linear models were built with response or protection per virus strain as the dependent variable and group, age, sex, time (month 0, 1, 3, 6), diabetes, IL-6, dialysis vintage, HD access, and HDF volume as independent explanatory variables. (3) Results: SR and SP rates were similar between control subjects, and dialysis patients were not affected by dialysis modality. SP rates were high (> 70%) at the beginning of the study and practically reached 100% after vaccination in all study groups. These results applied to all four virus strains that were included in the IQIV. IL-6 levels significantly differed between study groups, with HD patients displaying the highest values, but this did not affect SP rates. (4) Conclusions: Dialysis patients respond to influenza immunization adequately and similarly to the general population. Thus, annual vaccination policies should be encouraged in dialysis units. OL-HDF reduces chronic inflammation; however, this has no impact on SR rates.

Cardiorenal Syndrome: Challenges in Everyday Clinical Practice and Key Points towards a Better Management.

Under the term cardiorenal syndrome (CRS) falls an increasing number of patients who present with combined heart and kidney dysfunction. Despite the increasing knowledge concerning CRS pathophysiology, diagnosis, and treatment, many of the aforementioned aspects remain obscure in everyday clinical practice. Some of the challenges that clinicians face when they treat CRS nowadays is the need for a patient-centered management with early diagnosis, early intervention, the distinction of true kidney injury from permissive renal function deterioration during decongestion therapy, and the development of therapeutic algorithms to guide therapy.

Redefying the therapeutic strategies against cardiorenal morbidity and mortality: Patient phenotypes.

Chronic kidney disease (CKD) patients face an unacceptably high morbidity and mortality, mainly from cardiovascular diseases. Diabetes mellitus, arterial hypertension and dyslipidemia are highly prevalent in CKD patients. Established therapeutic protocols for the treatment of diabetes mellitus, arterial hypertension, and dyslipidemia are not as effective in CKD patients as in the general population. The role of non-traditional risk factors (RF) has gained interest in the last decades. These entail the deranged clinical spectrum of secondary hyperparathyroidism involving vascular and valvular calcification, under the term "CKD-mineral and bone disorder" (CKD-MBD), uremia per se, inflammation and oxidative stress. Each one of these non-traditional RF have been addressed in various study designs, but the results do not exhibit any applied clinical benefit for CKD-patients. The "crusade" against cardiorenal morbidity and mortality in CKD-patients is in some instances, derailed. We propose a therapeutic paradigm advancing from isolated treatment targets, as practiced today, to precision medicine involving patient phenotypes with distinct underlying pathophysiology. In this regard we propose two steps, based on current stratification management of corona virus disease-19 and sepsis. First, select patients who are expected to have a high mortality, i.e., a prognostic enrichment. Second, select patients who are likely to respond to a specific therapy, i.e., a predictive enrichment.

Lower serum magnesium is a predictor of left ventricular hypertrophy in patients on dialysis.

PURPOSE: Left ventricular hypertrophy (LVH) represents one of the main risk factors for cardiovascular mortality in dialysis patients. Low serum magnesium Mg is related with increased mortality in general and dialysis population. Aim of our study was to evaluate the association of Mg with LVH and cardiac geometry in dialysis patients. METHODS: Hemodialysis (HD) and peritoneal dialysis (PD) patients from nine nephrology departments were included. Echocardiographic LVH was defined by LV mass index > 95 g/m2 in women and > 115 g/m2 in men. Four LV geometric patterns were defined: normal, concentric remodeling, eccentric LVH and concentric LVH. Demographic and laboratory data were collected. RESULTS: 133 patients (68 HD, 65 PD) with a median age of 63 years (IQR 52-74) were studied. Mg correlated positively with creatinine, HDL and negatively with CRP levels and BMI. There were no significant differences in Mg between the modality groups. 80 patients presented LVH (43 HD and 37 PD patients). Patients with LVH were older (median age 68 vs 55 years, p < 0.001), with higher BMI (median 26.9 vs 24.7 kg/m2, p = 0.009), had a history of PVD or CAD (55% vs 30.2%, p = 0.003), had higher pulse pressure (median 60 vs 50, p = 0.017), MIS score (median 5 vs 4, p = 0.011), lower albumin (median 3.5 vs 3.8 g/dl, p = 0.011) and Mg levels (median 2.1 vs 2.4 mg/dl, p < 0.001). In univariate analysis age, CVD comorbidities, pulse pressure, CRP, BMI, albumin, Mg, MIS and use of b-blockers or calcium blockers were LVH predictors. In multivariate analysis, Mg was an independent predictor of LVH, adjusted for age, MIS and b-blockers. Considering LV geometry, lower Mg levels were mainly correlated with concentric LVH. CONCLUSION: Low serum magnesium levels seem to be an independent factor for LVH in hemodialysis and peritoneal dialysis patients.

Adherence to the Mediterranean Diet Is Associated with a More Favorable Left Ventricular Geometry in Patients with End-Stage Kidney Disease.

Introduction. The aim of the study was to examine the impact of adherence to a Mediterranean-style diet (MD) on left ventricular hypertrophy (LVH) and cardiac geometry in chronic kidney disease patients on dialysis (CKD-5D), given the high prevalence of cardiovascular morbidity in this population. Methods. n = 127 (77 men and 50 women) CKD-5D patients (69 on hemodialysis and 58 on peritoneal dialysis) with a mean age of 62 ± 15 years were studied. An MD adherence score (MDS) (range 0−55, 55 representing maximal adherence) was estimated with a validated method. Echocardiographic LVH was defined by LV mass index (LVMI) > 95 g/m2 in women and >115 g/m2 in men. Based on LVMI and relative wall thickness (RWT), four LV geometric patterns were defined: normal (normal LVMI and RWT), concentric remodeling (normal LVMI and increased RWT > 0.42), eccentric LVH (increased LVMI and normal RWT), and concentric LVH (increased LVMI and RWT). Results. Patients with LVH (n = 81) as compared to patients with no LVH (n = 46) were older in age (66 ± 13 vs. 55 ± 16 years; p < 0.001) had lower MDS (24 ± 2.7 vs. 25 ± 4.3; p < 0.05) and higher malnutrition-inflammation score (5.0 ± 2.7 vs. 3.9 ± 1.9; p < 0.05), body mass index (27.5 ± 4.9 vs. 24.1 ± 3.5 kg/m2; p < 0.001), prevalence of diabetes (79% vs. 20%; p < 0.05), coronary artery disease (78% vs. 20%; p < 0.05) and peripheral vascular disease (78% vs. 20%; p < 0.01). In a multivariate logistic regression analysis adjusted for all factors mentioned above, each 1-point greater MDS was associated with 18% lower odds of having LVH (OR = 0.82, 95% CI: 0.69−0.98; p < 0.05). MDS was inversely related to LVMI (r = −0.273; p = 0.02), and in a multiple linear regression model (where LVMI was analyzed as a continuous variable), MDS emerged as a significant (Β = −2.217; p < 0.01) independent predictor of LVH. Considering LV geometry, there was a progressive decrease in MDS from the normal group (25.0 ± 3.7) to concentric remodeling (25.8 ± 3.0), eccentric (24.0 ± 2.8), and then concentric (23.6 ± 2.7) group (p < 0.05 for the trend). Conclusions. The greater adherence to an MD is associated with lesser LVH, an important cardiovascular disease risk factor; MD preserves normal cardiac geometry and may confer protection against future cardiac dysfunction in dialysis patients.

Cardiac Imaging and Management of Cardiac Disease in Asymptomatic Renal Transplant Candidates: A Current Update.

Given the high cardiovascular risk accompanying end-stage kidney disease, it would be of paramount importance for the clinical nephrologist to know which screening method(s) identify high-risk patients and whether screening asymptomatic transplant candidates effectively reduces cardiovascular risk in the perioperative setting as well as in the longer term. Within this review, key studies concerning the above questions are reported and critically analyzed. The lack of unified screening criteria and of a prognostically sufficient screening cardiovascular effect for renal transplant candidates sets the foundation for a personalized patient approach in the near future and highlights the need for well-designed studies to produce robust evidence which will address the above questions.

The p.Pro482Ala Variant in the CNNM2 Gene Causes Severe Hypomagnesemia Amenable to Treatment with Spironolactone.

Renal hypomagnesemia syndromes involving CNNM2 protein pathogenic variants are associated with variable degrees of neurocognitive dysfunction and hypomagnesemia. Here, we report a family with a novel CNNM2 p.Pro482Ala variant, presenting with overt hypomagnesemia and mild neurological involvement (autosomal dominant renal hypomagnesemia 6, HOMG6, MIM# 613882). Using a bioinformatics approach, we showed that the p.Pro482Ala amino acid substitution causes a 3D conformational change in CNNM2 structure in the cystathionin beta synthase (CBS) domain and the carboxy-terminal protein segment. A novel finding was that aldosterone inhibition with spironolactone helped to alleviate hypomagnesemia and symptoms in the proband.

Dent-2 disease with a Bartter-like phenotype caused by the Asp631Glu mutation in the OCRL gene.

BACKGROUND: Dent disease is an X-linked disorder characterized by low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and chronic kidney disease (CKD). It is caused by mutations in the chloride voltage-gated channel 5 (CLCN5) gene (Dent disease-1), or in the OCRL gene (Dent disease-2). It is associated with chronic metabolic acidosis; however metabolic alkalosis has rarely been reported. CASE PRESENTATION: We present a family with Dent-2 disease and a Bartter-like phenotype. The main clinical problems observed in the proband included a) primary phosphaturia leading to osteomalacia and stunted growth; b) elevated serum calcitriol levels, leading to hypercalcemia, hypercalciuria, nephrolithiasis and nephrocalcinosis; c) severe salt wasting causing hypotension, hyperaldosteronism, hypokalemia and metabolic alkalosis; d) partial nephrogenic diabetes insipidus attributed to hypercalcemia, hypokalemia and nephrocalcinosis; e) albuminuria, LMWP. Phosphorous repletion resulted in abrupt cessation of hypercalciuria and significant improvement of hypophosphatemia, physical stamina and bone histology. Years later, he presented progressive CKD with nephrotic range proteinuria attributed to focal segmental glomerulosclerosis (FSGS). Targeted genetic analysis for several phosphaturic diseases was unsuccessful. Whole Exome Sequencing (WES) revealed a c.1893C > A variant (Asp631Glu) in the OCRL gene which was co-segregated with the disease in male family members. CONCLUSIONS: We present the clinical characteristics of the Asp631Glu mutation in the OCRL gene, presenting as Dent-2 disease with Bartter-like features. Phosphorous repletion resulted in significant improvement of all clinical features except for progressive CKD. Angiotensin blockade improved proteinuria and stabilized kidney function for several years.

The Pathophysiological Role of Heat Shock Response in Autoimmunity: A Literature Review.

Within the last two decades, there has been increasing evidence that heat-shock proteins can have a differential influence on the immune system. They can either provoke or ameliorate immune responses. This review focuses on outlining the stimulatory as well as the inhibitory effects of heat-shock proteins 27, 40, 70, 65, 60, and 90 in experimental and clinical autoimmune settings.

Intense immunostaining of heat shock protein 70 within renal interstitium associates with long-term renal survival in an ANCA-associated vasculitis cohort.

In anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV) genetic predisposition, ANCA autoantibodies, neutrophil extracellular traps (NETs), complement activation, and toll-like receptor signaling are implicated in AAV pathogenesis. Heat shock proteins (HSPs), a highly conserved group of small-sized molecular chaperones, take part in protein folding during cellular stress. Although HSPs were initially observed intracellularly, it has been shown that they can be secreted in the extracellular space and modulate the immune response in various autoimmune diseases including AAV. The scope of the present study is to investigate the role of heat shock protein 60 (HSP60) and 70 (HSP70) in the long renal effects in an ANCA vasculitis cohort. In this cohort of ANCA-associated vasculitis, 29 patients were followed up over 20 years. At diagnosis, immunohistochemistry was performed for HSP60 and HSP70 within the various nephron compartments. Higher renal HSP60 expression was associated with increased interstitial inflammatory infiltrates at diagnosis, while HSP70 expression was associated with a greater extent of interstitial fibrosis at diagnosis. Notably, intense tissue expression of HSP70 at the time of biopsy was associated with a worsened kidney survival. Renal HSP70 expression was associated with poor renal outcomes during long-term follow-up. This finding may indicate a role of HSPs in renal disease progression in ANCA vasculitis. Further validating studies are needed to verify a causative association between HSP70 expression and renal outcomes in ANCA-associated vasculitis.

Dickkopf 3-a novel biomarker of the 'kidney injury continuum'.

Chronic kidney disease (CKD) is a global public health problem accompanied by substantial comorbidities and reduced life expectancy. In this respect, progressive CKD leading to uraemia can be seen as a systemic disease with a critical impact on virtually all organ systems. Therefore, it is of particular importance to identify patients with ongoing CKD progression, which is challenging, because the individual course of CKD is difficult to predict. Patterns of progression in CKD patients include linear and non-linear trajectories of GFR loss, but kidney function can also remain stable for years. Moreover, a substantial GFR decline may occur in the absence of higher-grade albuminuria (non-proteinuric CKD), rendering the measurement of albuminuria less reliable for progression prediction in such individuals. In the present review, we focus on the recently identified glycoprotein Dickkopf-3 (DKK3) as a stress-induced, renal tubular epithelial cell-derived, pro-fibrotic molecule. In experimental CKD models, DKK3 promoted renal tubulointerstitial fibrosis through modulation of the canonical Wnt/ß-catenin signalling pathway. In clinical studies, increased urinary DKK3 levels identified patients at high risk for short-term CKD progression, regardless of the cause of kidney disease, baseline kidney function and albuminuria. Moreover, increased urinary DKK3 levels are associated with a high risk for acute kidney injury and the subsequent loss of kidney function after cardiac surgery. These findings highlight DKK3 as a mediator of renal tubular cell damage in kidney injury and short-term progression of kidney disease, with potential therapeutic implications.

The Association Between Handgrip Strength and Predialysis Serum Sodium Level in Patients With Chronic Kidney Disease Stage 5D.

Purpose: Handgrip strength (HGS) is a useful tool for the systematic assessment of muscle function related to nutritional status. Reduced HGS has been associated with adverse clinical outcomes in chronic kidney disease (CKD) stage 5D patients. In the same patients, predialysis low serum sodium (sNa) has been associated with malnutrition and mortality. Here, we investigated the role of predialysis sNa on muscle function in CKD-5D patients. Methods: We evaluated 45 patients on hemodialysis (HD) and 28 patients on peritoneal dialysis (PD) with HGS measurement, bioimpedance analysis, anthropometric measures, and malnutrition inflammation score (MIS). According to established diagnostic criteria, reduced HGS was defined as strength below 30 and 20 Kg in men and women, respectively. Predialysis sNa values were defined as the mean of all predialysis measurements during the preceding 6 months. Data analysis was performed separately for each of the HD and PD groups. Results: The proportions of reduced HGS did not differ between the HD (66%) and PD (54%) groups, respectively. Patients in the HD group as compared to those in the PD group had higher serum albumin and potassium and mid-arm muscle circumference and lower residual renal function (RRF) and residual urine volume. Multivariate logistic analysis, after controlling for muscle mass, nutritional biomarkers, MIS, fluid overload and RRF, showed that for every 1 mmol/l increase of sNa the odds of reduced HGS was decreased by 60% (OR = 0.40, 95% CI: 0.16-0.99) and 42% (OR = 0.58, 95% CI: 0.36-0.93) in HD and PD patients, respectively. However, stratified analysis indicated that lower sNa levels predicted reduced HGS in individuals with a background of malnutrition, inflammation, overhydration and less preserved RRF, representing unfavorable conditions strongly related to muscle wasting in the dialysis setting. Conclusions: Predialysis sNa is a strong and independent determinant of HGS, a reliable nutritional marker in CKD-5D stage patients. However, according to our findings, lower sNa levels appear to be a marker of underlying unfavorable conditions that are heavily associated with reduced HGS, rather than a causal determinant of reduced HGS. Whether optimizing sNa levels improves patient muscle performance requires further investigations.

Unraveling innovation potential in the real-world setting: eighteen novel agents with twenty-six approved European indications, in the management of leukemias, lymphomas, and multiple myeloma.

Introduction: Real-world effectiveness of hemato-oncology pharmaceuticals may not necessarily mimic clinical trial efficacy results, mainly due to demographic and clinical practice variability. The aim of this review was to systematically assess the availability of real-world evidence (RWE) and the transferability of clinical trial (CT) efficacy results to real life, for novel agents recently approved to manage lymphomas, leukemias, and multiple myeloma. This is the largest cross-indication review comparing RWE to CT results, aspiring to inform clinical practice and decision-making when funding hemato-oncology pharmaceuticals.Areas covered: The review methodology focused on identifying all novel agents that entered EU landscape between 2012 and 2016 by using European Medicines Agency (EMA) database, while conducting a systematic PubMed literature review of RWE in the specific hematological malignancies, in order to compare RWE versus CT efficacy endpoints.Expert opinion: In total, 18 international nonproprietary names (INNs) that received EMA approval for any indication were included and the registrational efficacy results are presented. Eight (44%) INNs proved to have relevant RWE generated in at least one approved indication. The analysis of findings revealed high variability in terms of RWE availability and transferability of CT results to relevant real-life experience among the disease areas investigated.

Dickkopf-3 (DKK3) in Urine Identifies Patients with Short-Term Risk of eGFR Loss.

BACKGROUND: The individual course of CKD may vary, and improved methods for identifying which patients will experience short-term eGFR loss are needed. Assessing urinary Dickkopf-3 (DKK3), a stress-induced tubular epithelia-derived profibrotic glycoprotein, may provide information about ongoing tubulointerstitial fibrosis and short-term eGFR loss. METHODS: To investigate urinary DKK3's potential as a biomarker of short-term eGFR loss (over 12 months), we prospectively assessed eGFR and urinary DKK3 levels in patients with CKD of various etiologies at baseline and annual follow-ups. We also measured urinary DKK3 in a general population sample and patients with diagnostic kidney biopsies or IgA nephropathy under treatment. RESULTS: Median urinary DKK3-to-creatinine concentration at baseline was significantly higher in patients with CKD than the general population sample (431 versus 33 pg/mg). In the CKD cohort, having a urinary DKK3-to-creatinine level >4000 pg/mg was independently and significantly associated after multiple adjustments with mean annual decline in eGFR of 7.6% over 12 months. Urinary DKK3 significantly improved prediction of kidney function decline compared with eGFR or albuminuria alone. Urinary DKK3-to-creatinine levels were related to the extent of tubulointerstitial fibrosis in kidney biopsies. In patients with IgA nephropathy, a rise in urinary DKK3 was associated with significant eGFR decline within 6 months, whereas stable or decreasing urinary DKK3 indicated a more favorable course. CONCLUSIONS: Urinary DKK3 levels identify patients at high risk for eGFR decline over the next 12 months regardless of the cause of kidney injury and beyond established biomarkers, potentially providing a tool to monitor CKD progression and assess effects of interventions.