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Graphical abstract, Highlights • Radiocontrast medium, sodium diatrizoate, reduces renal cell viability in vitro. • Effect of darbepoetin on diatrizoate-treated cells was studied. • Pre-treatment of renal cells with darbepoetin could reduce diatrizoate toxicity. • Darbepoetin caused changes in the activation state of signaling molecules., The hypersialylated erythropoiesis stimulating agent (ESA) darbepoetin alfa was developed for the treatment of anemia, and has also been reported to have other nonerythropoietic effects. This study outlines one such effect against the toxicity of the radiocontrast medium (RCM) sodium diatrizoate (NaD) in human renal proximal tubular (HK-2) cells in vitro. Using a standard cell viability assay, we observed that pre-incubation of HK-2 cells with darbepoetin (at concentrations of 0.25and 1.0 μg/mL) for 2.5 h prior to addition of NaD (75 mg I/mL, for 2 h) reduced the decrease in cell viability due to the RCM, assayed 22 h after removal of the NaD, whilst maintaining the cells incubated with darbepoetin. Western blot analysis showed that darbepoetin reduced the phosphorylation of c-Jun N-terminal kinases (JNK)1/2 over a period of 1 h incubation with NaD, but did not have an obvious effect on several other targets associated with cell death/survival. However, incubation of HK-2 cells with darbepoetin for a further 22 h after prior exposure to NaD (75 mg I/mL, for 2 h) and subsequent immunoblotting showed that darbepoetin: caused recovery of the activity (phosphorylation) of pro-proliferative/survival signalling molecules, such as Akt (Ser473), STAT (signal transducer and activator of transcription)3(Tyr705); decreased activation of the pro-apoptotic transcription factor FOXO3a by increasing its phosphorylation at Thr32; decreased phosphorylation (activation) of p38 Mitogen activated protein kinase; and reduced poly(ADP-ribose)polymerase (PARP)-1 cleavage. In summary, we present here a beneficial nonerythropoietic effect of darbepoetin alfa against radiocontrast-induced toxicity together with modulation of signalling molecules that play a crucial role in determining cell fate.

CKD is a major public health problem. It is characterized by a multitude of risk factors that, when aggregated, can strongly modify outcome. While major risk factors, namely, albuminuria and low estimated glomerular filtration rate (eGFR) have been well analyzed, a large variability in disease progression still remains. This happens because (1) the weight of each risk factor varies between populations (general population or CKD cohort), countries, and single individuals and (2) response to nephroprotective drugs is so heterogeneous that a non-negligible part of patients maintains a high cardiorenal risk despite optimal treatment. Precision nephrology aims at individualizing cardiorenal prognosis and therapy. The purpose of this review is to focus on the risk stratification in different areas, such as clinical practice, population research, and interventional trials, and to describe the strategies used in observational or experimental studies to afford individual-level evidence. The future of precision nephrology is also addressed. Observational studies can in fact provide more adequate findings by collecting more information on risk factors and building risk prediction models that can be applied to each individual in a reliable fashion. Similarly, new clinical trial designs can reduce the individual variability in response to treatment and improve individual outcomes.

Background and Aims Measurement of urine proteins, mainly through the 24-hour excretion or the albumin-to-creatinine ratio (ACR) has become crucial in current clinical practice in Nephrology. Besides being a biomarker of injury, albuminuria also exerts direct pro-inflammatory and pro-fibrotic effects on renal tubules. Hence, a large number of intervention studies have been aimed at lowering albuminuria levels in patients with Chronic Kidney Disease (CKD). However, albuminuria is a measure characterized by a random variability that has been evaluated in several mechanistic and experimental studies and may be influenced by several factors, such as posture, exercise and dietary factors. The aim of the present study was to evaluate the within-day variability, specifically in a cohort of CKD outpatients who were on Renin-Angiotensin-Aldosterone-System inhibitors (RAASi) therapy. Method We enrolled consecutive CKD patients referred to the Nephrology Unit at Magna Graecia University Hospital of Catanzaro between January 1st and March 30th 2020. Inclusion criteria were: age > 18 years, diagnosis of CKD from any cause, presence of albuminuria in the range 150-3500 mg/g at screening. Patients already treated with RAASi, patients with active malignancy/signs of glomerulonephritis requiring immunosuppressive therapies, were excluded. At screening visit, patients with increased albuminuria were started with an Angiotensin Converting Enzyme inhibitor (ACEi) or an Angiotensin II Receptor Blocker (ARB). A second ambulatory visit was scheduled 1 month after start of RAASi therapy. During this visit, patients were asked to stay in the Renal Unit for 12 hours. They collected urine void for ACR, protein-to-creatinine ratio (PCR) and urine creatinine (Ucreat) assessment at 8am,1pm and 6pm. For each patient, comparisons between ACR, PCR and Ucreat were assessed by Kruskal-Wallis test and Friedman post-hoc, using the Benjamini-Hochberg as adjustment method. Coefficients of variation (CV,standard deviation/mean) were also computed. Results Final analysis included 43 patients (46.5% of males). Mean age was 59.6±16.7 years and median eGFR 41 [21-74] mL/min/1.73m2. A high cardiovascular (CV) risk profile was testified by the prevalence of type 2 diabetes (30.2%) and previous CV disease (34.8%). When patient characteristics were compared across ACR categories (300 mg/g), systolic blood pressure was increased (p=0.020) and mean age decreased from 68.0 to 54.8 years on average (p=0.038). ACR values collected were 189 [38-759], 252 [51-1685] and 229 [56-1185] mg/g at 8am, 1pm and 6pm, respectively, with a CV of 24.6% (95%CI 12.4-39.1). 8am ACR was significantly different from 1pm ACR (p Conclusion The present analysis showed a significant individual within-day variability of albuminuria, measured as both ACR and PCR, suggesting that another parameter, in addition to those already known, may be responsible for the day-by-day albuminuria variation. Moreover, the absence of variability in Ucreat, namely the denominator of the ACR/PCR formula, suggests that the true variation is likely dependent on the urine protein values. Thus, albuminuria reduction in response to RAASi treatment should be carefully evaluated by measuring ACR/PCR preferentially at a similar time of the day for each patient. This would allow to avoid under- or overestimation of the actual treatment effect.

The new respiratory infectious disease coronavirus disease 2019 (COVID-19) that originated in Wuhan, China, in December 2019 and caused by a new strain of zoonotic coronavirus, named severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), to date has killed over 630,000 people and infected over 15,000,000 worldwide. Most of the deceased patients had pre-existing comorbidities; over 20% had chronic kidney disease (CKD). Furthermore, although SARS-CoV-2 infection is characterized mainly by diffuse alveolar damage and acute respiratory failure, acute kidney injury (AKI) has developed in a high percentage of cases. As AKI has been shown to be associated with worse prognosis, we believe that the impact of SARS-CoV-2 on the kidney should be investigated. This review sets out to describe the main renal aspects of SARS-CoV-2 infection and the role of the virus in the development and progression of kidney damage. In this article, attention is focused on the epidemiology, etiology and pathophysiological mechanisms of kidney damage, histopathology, clinical features in nephropathic patients (CKD, hemodialysis, peritoneal dialysis, AKI, transplantation) and prevention and containment strategies. Although there remains much more to be learned with regards to this disease, nonetheless it is our hope that this review will aid in the understanding and management of SARS-CoV-2 infection.

Chronic kidney disease (CKD), defined as the presence of albuminuria and/or reduction in estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, is considered a growing public health problem, with its prevalence and incidence having almost doubled in the past three decades. The implementation of novel biomarkers in clinical practice is crucial, since it could allow earlier diagnosis and lead to an improvement in CKD outcomes. Nevertheless, a clear guidance on how to develop biomarkers in the setting of CKD is not yet available. The aim of this review is to report the framework for implementing biomarkers in observational and intervention studies. Biomarkers are classified as either prognostic or predictive; the first type is used to identify the likelihood of a patient to develop an endpoint regardless of treatment, whereas the second type is used to determine whether the patient is likely to benefit from a specific treatment. Many single assays and complex biomarkers were shown to improve the prediction of cardiovascular and kidney outcomes in CKD patients on top of the traditional risk factors. Biomarkers were also shown to improve clinical trial designs. Understanding the correct ways to validate and implement novel biomarkers in CKD will help to mitigate the global burden of CKD and to improve the individual prognosis of these high-risk patients.

Background and Aims Patients with diabetic kidney disease show a wide variability in their response to established and new treatments. SGLT2 inhibitors have also shown to slow the progression of kidney disease. Some studies have also shown kidney benefits for Mineralocorticoid Receptor Antagonists (MRA). A large outcome trial with the MRA finerenone is currently ongoing to assess effects of this MRA on major kidney outcomes. The individual trials will solve the issue whether a patient may have benefit from an SGLT2 inhibitor or MRA, but they do not address the key question which of the two or their combination is better to reduce albuminuria for each individual patient. Therefore, we designed the ROTATE-3 trial is designed to investigate the individual albuminuria response to MRA (eplerenone), SGLT2 inhibitor (dapagliflozin) or the combination. Method ROTATE-3 is a randomized, prospective, open label, multicentre, crossover trial with a total duration of 28 (to 42) weeks [EudraCT number: 2017-004641-25]. Patients with or without type 2 diabetes, ≥18 years and elevated albuminuria (100-3500 mg/24 hour) already receiving a stable (same dose at least 4 weeks) maximum tolerated dose of an ACE-inhibitor or Angiotensin Receptor Blocker will be enrolled.Patients receive in random order 4 weeks of treatment with the eplerenone 50 mg/day, dapagliflozin 10 mg/day or combination of both drugs with a 4-weeks wash-out period in between. After the last treatment period patients will proceed to a 4-weeks wash-out period. The primary study outcome is the correlation in albuminuria response to eplerenone and dapagliflozin for which 46 patients provides 80% power to detect a Pearson correlation coefficient of 0.4 between the log transformed albuminuria response to eplerenone and dapagliflozin. Blood is collected for clinical chemistry every two weeks during each treatment period. Patients are requested to collect one 24-hour urine sample at start and at end of each treatment period. Home blood pressure is monitored every 2 days. Results As of January 1st 2020 the study has enrolled 13 patients. It is anticipated that recruitment will be completed by December 2020 with study completion in August 2021. Conclusion The results of the ROTATE-3 study will provide more insight in the individual albuminuria lowering response to potentially two new treatment options for patients with CKD and may help to implement personalized medicine in diabetic kidney disease.Study sponsored by University Medical Center Groningen. The Netherlands.

Chronic kidney disease (CKD) is currently defined as the presence of proteinuria and/or aneGFR<60 mL/min/1.73m2on the basis of the renal diagnosis. The global dimension of CKD is relevant, since its prevalence and incidence have doubled in the past three decades worldwide. A major complication that occurs in CKD patients is the development of cardiovascular (CV) disease, being the incidence rate of fatal/nonfatal CV events similar to the rate of ESKD in CKD. Moreover, CKD is a multifactorial disease where multiple mechanisms contribute to the individual prognosis. The correct development of novel biomarkers of CV risk may help clinicians to ameliorate the management of CKD patients. Biomarkers of CV risk in CKD patients are classifiable as prognostic, which help to improve CV risk prediction regardless of treatment, and predictive, which allow the selection of individuals who are likely to respond to a specific treatment. Several prognostic (cystatin C, cardiac troponins, markers of inflammation, and fibrosis) and predictive (genes, metalloproteinases, and complex classifiers) biomarkers have been developed. Despite previous biomarkers providing information on the pathophysiological mechanisms of CV risk in CKD beyond proteinuria and eGFR, only a minority have been adopted in clinical use. This mainly depends on heterogeneous results and lack of validation of biomarkers. The purpose of this review is to present an update on the already assessed biomarkers of CV risk in CKD and examine the strategies for a correct development of biomarkers in clinical practice. Development of both predictive and prognostic biomarkers is an important task for nephrologists. Predictive biomarkers are useful for designing novel clinical trials (enrichment design) and for better understanding of the variability in response to the current available treatments for CV risk. Prognostic biomarkers could help to improve risk stratification and anticipate diagnosis of CV disease, such as heart failure and coronary heart disease.

In Chronic Kidney Disease (CKD) patients, elevated blood pressure (BP) is a frequent finding and is traditionally considered a direct consequence of their sodium sensitivity. Indeed, sodium and fluid retention, causing hypervolemia, leads to the development of hypertension in CKD. On the other hand, in non-dialysis CKD patients, salt restriction reduces BP levels and enhances anti-proteinuric effect of renin–angiotensin–aldosterone system inhibitors in non-dialysis CKD patients. However, studies on the long-term effect of low salt diet (LSD) on cardio-renal prognosis showed controversial findings. The negative results might be the consequence of measurement bias (spot urine and/or single measurement), reverse epidemiology, as well as poor adherence to diet. In end-stage kidney disease (ESKD), dialysis remains the only effective means to remove dietary sodium intake. The mismatch between intake and removal of sodium leads to fluid overload, hypertension and left ventricular hypertrophy, therefore worsening the prognosis of ESKD patients. This imposes the implementation of a LSD in these patients, irrespective of the lack of trials proving the efficacy of this measure in these patients. LSD is, therefore, a rational and basic tool to correct fluid overload and hypertension in all CKD stages. The implementation of LSD should be personalized, similarly to diuretic treatment, keeping into account the volume status and true burden of hypertension evaluated by ambulatory BP monitoring.