Unveiling the intricacies of chronic kidney disease: From ocular manifestations to therapeutic frontiers.

BACKGROUND: Shared anatomical, histological and physiological pathways between the kidney and the eye are well documented, demonstrating that ocular manifestations serve as valuable prognostic indicators in chronic kidney disease (CKD), providing insights into disease severity and progression. Through non-invasive imaging modalities such as retinal fundus photography, early retinal microvascular alterations indicative of CKD progression can be detected, enabling timely intervention and risk stratification. However, the conclusions drawn from the review primarily demonstrate a strong or independent association between glaucoma or retinopathy and CKD. RESULTS AND CONCLUSION: Multiple shared pathophysiological events have been implicated in the pathogenesis in the alterations at eye and kidney including renin-angiotensin-aldosterone system. Patients with CKD are more likely to experience glaucoma, age-related macular degeneration, cataracts, uremic optic neuropathy and retinopathy. To establish the role of ocular manifestations in predicting CKD progression, it is crucial to address the limitations of correlation and explore the underlying causality with further research on common disease pathogenesis. Additionally, specific methods for risk stratification based on retinal changes, the effectiveness of timely interventions, and the development of predictive tools combining ocular and renal data are of utmost importance research topics to enlighten the bidirectional causality.

Physical activity and exercise in chronic kidney disease: consensus statements from the Physical Exercise Working Group of the Italian Society of Nephrology.

The Italian Society of Nephrology has tasked its Working Group on Physical Exercise with developing a consensus statement document on physical activity and exercise in patients with chronic kidney disease (CKD). This paper consists of 16 points that were discussed, and approved using the mini-Delphi method by 15 members of the working group. Each statement is based on a comprehensive review of the literature, clinical experience, and expert opinions. Overall, the statements affirm that regular physical activity and exercise training offer numerous benefits to CKD patients, including improved physical function, enhanced cardiometabolic and neuromuscular function, cognitive benefits, and an overall improvement in quality of life. Furthermore, exercise may provide nephroprotection and reduce mortality. These advantages are observed across all CKD stages, whether on conservative therapy or kidney replacement therapy (hemodialysis or peritoneal dialysis), and in kidney transplant recipients. Moreover, when physical activity and exercise training are implemented with appropriate precautions, they are safe in CKD patients. Gradual physical activity and customized exercise programs should be tailored to the patient's exercise tolerance, potentially enhancing compliance. Clinicians are encouraged to use a series of questionnaires and tests to assess the patient's level of physical activity and performance. However, exercise and physical activity are poorly implemented in clinical practice due to many barriers related to patients and healthcare staff. Overcoming these barriers requires the proactive role of the nephrologists, who should actively incorporate exercise training and promote physical activity within routine care plans. Adopting a multidisciplinary team approach, which includes nephrologists, nurses, exercise professionals, and dietitians, is crucial for providing comprehensive rehabilitation for CKD patients. Integrating new technologies and remote check ups could further enhance the effectiveness of these interventions.

8-hydroxy-2'-deoxyguanosine, a biomarker of oxidative DNA injury, in diabetic kidney disease.

BACKGROUND AND AIMS: To gain insight into the extent of oxidative stress and DNA damage in diabetic kidney disease (DKD), a serious complication of diabetes, we compared the levels of the oxidative stress-related metabolite 8-hydroxy-2'-deoxyguanosine (8-OHdG) in a case-control study accurately matching diabetic patients with and without renal complications. METHODS AND RESULTS: We analyzed serum 8-OHdG in relation to clinical indicators of kidney function in a group of type-2 diabetes patients including 33 patients with DKD and 33 without DKD. Circulating levels of 8-OHdG were higher in patients with DKD than in those without (4.6 ± 0.7 ng/mL vs 4.0 ± 0.8 ng/mL, p = 0.002). In a logistic regression analysis adjusting for potential confounders, 8-OHdG was associated with DKD (OR: 2.90, 95%CI:1.15-7.34; p = 0.02) and in a linear regression model, a 1 ng/mL increase of this biomarker entailed a reduction of 11.5 mL/min/1.73 m2 in the renal filtration rate. Furthermore, an interaction analysis showed that glycated hemoglobin was a modifier of the relationship between 8-OHdG and study outcomes (p for effect modification = 0.02). CONCLUSION: This study supports the role of oxidative stress in the pathogenesis of diabetic nephropathy and highlights the potential of serum 8-OHdG as a biomarker for assessing oxidative stress and DNA damage in patients with diabetes and renal complications.

Decoy receptors as biomarkers for exploring aetiology and designing new therapies.

Soluble decoy receptors (DR) are circulating proteins that act as molecular traps for ligands that modulate various signalling pathways. These proteins can be exploited as biomarkers and, in some cases, as drugs in various disease contexts. Inflammation is a key area where DRs have shown significant potential. By binding to pro-inflammatory cytokines, inflammatory DRs, such as soluble tumour necrosis factor receptors (sTNFRs), can inhibit downstream inflammatory signalling. This modulation of the inflammatory response holds promise for therapeutic interventions in various inflammatory conditions, including cardiovascular and chronic kidney diseases. Soluble DRs for advanced glycation end products (sRAGE) bind to advanced glycation end products (AGEs), reducing their detrimental effects on vascular function and atherosclerosis. High circulating sRAGE levels are associated with a lower risk for CV events, highlighting the potential of these soluble receptors for assessing the role of AGEs in CV diseases and managing the attendant risk. DRs may serve as biomarkers and therapeutic agents to advance our understanding of disease mechanisms and improve patients' outcomes. Their ability to modulate signalling pathways in a controlled manner opens up new opportunities for therapeutic interventions in various diseases, ranging from inflammation to cardiovascular and renal disorders.

Risk of Cardiovascular Events in Metabolically Healthy Overweight or Obese Adults: Role of LDL-Cholesterol in the Stratification of Risk.

The objective of this study was to investigate the longitudinal association of metabolically healthy overweight/obese adults with major adverse cardiovascular events (MACE) and the effect of LDL-cholesterol levels on this association. This study was conducted with 15,904 participants from the URRAH study grouped according to BMI and metabolic status. Healthy metabolic status was identified with and without including LDL-cholesterol. The risk of MACE during 11.8 years of follow-up was evaluated with multivariable Cox regressions. Among the participants aged <70 years, high BMI was associated with an increased risk of MACE, whereas among the older subjects it was associated with lower risk. Compared to the group with normal weight/healthy metabolic status, the metabolically healthy participants aged <70 years who were overweight/obese had an increased risk of MACE with an adjusted hazard ratio of 3.81 (95% CI, 1.34-10.85, p = 0.012). However, when LDL-cholesterol < 130 mg/dL was included in the definition of healthy metabolic status, no increase in risk was found in the overweight/obese adults compared to the normal weight individuals (hazard ratio 0.70 (0.07-6.71, p = 0.75). The present data show that the risk of MACE is increased in metabolically healthy overweight/obese individuals identified according to standard criteria. However, when LDL-cholesterol is included in the definition, metabolically healthy individuals who are overweight/obese have no increase in risk.

Plasma levels of myeloperoxidase and resistin independently predict mortality in dialysis patients.

BACKGROUND: In patients with kidney failure (KF) undergoing dialysis, neutrophils are dysfunctionally activated. Such chronic activation does not correspond to increased protection against infections and is thought to cause direct vascular damage accounting for the higher incidence of cardiovascular (CV) events. We hypothesized that circulating levels of neutrophil degranulation products (i.e. myeloperoxidase (MPO) and resistin) can predict overall and CV-specific mortality in dialysis patients. METHODS: MPO and resistin levels were assessed in plasma samples from n = 1182 dialysis patients who were followed-up for median 2.9 years (IQR: 1.7-4.2). RESULTS: Patients were 65 ± 14 (SD) years old and 36 % women. Median value of MPO and resistin were 78 ng/mL (IQR: 54 - 123) and 72 ng/mL (IQR: 46 - 110), respectively. MPO and resistin levels correlated with biomarkers of organ damage, nutritional status and inflammation. Both MPO and resistin levels predicted all-cause mortality even after adjustment for traditional risk factors and inflammation, nutritional and KF-related indexes (MPO, HRfor 1 ln unit increase: 1.26, 95 %CI 1.11 - 1.42, P < 0.001; Resistin, HRfor 1 ln unit increase: 1.25, 95 %CI 1.09 - 1.44, P = 0.001). Similarly, their predictive ability held true also for CV death (MPO, HRfor 1 ln unit increase: 1.19, 95 %CI 1.01 - 1.41, P = 0.04; Resistin, HRfor 1 ln unit increase: 1.29, 95 %CI 1.07 - 1.56, P = 0.007). CONCLUSION: Plasma levels of MPO and resistin correlate with prospective overall and CV-specific mortality risk in KF patients undergoing dialysis and might be useful prognostic tools. Mediators of inflammation may be potential target to improve survival of those patients.

Proximal tubule hypertrophy and hyperfunction: a novel pathophysiological feature in disease states.

The role of proximal tubules (PTs), a major component of the renal tubular structure in the renal cortex, has been examined extensively. Along with its physiological role in the reabsorption of various molecules, including electrolytes, amino acids and monosaccharides, transcellular transport of different hormones and regulation of homeostasis, pathological events affecting PTs may underlie multiple disease states. PT hypertrophy or a hyperfunctioning state, despite being a compensatory mechanism at first in response to various stimuli or alterations at tubular transport proteins, have been shown to be critical pathophysiological events leading to multiple disorders, including diabetes mellitus, obesity, metabolic syndrome and congestive heart failure. Moreover, pharmacotherapeutic agents have primarily targeted PTs, including sodium-glucose cotransporter 2, urate transporters and carbonic anhydrase enzymes. In this narrative review, we focus on the physiological role of PTs in healthy states and the current understanding of the PT pathologies leading to disease states and potential therapeutic targets.

Biomarkers in clinical epidemiology studies.

This paper discusses the use of biomarkers in clinical practice and biomedical research. Biomarkers are measurable characteristics that can be used to indicate the presence or absence of a disease or to track the progression of a disease. They can also be used to predict how a patient will respond to a particular treatment. Biomarkers have enriched clinical practice and disease prognosis by providing measurable characteristics that indicate biological processes. They offer valuable insights into disease susceptibility, progression, and treatment response, aiding drug development and personalized medicine. However, developing and implementing biomarkers come with challenges that must be addressed. Rigorous testing, standardization of assays, and consideration of ethical factors are crucial in ensuring the reliability and validity of biomarkers. Reliability is vital in biomarker research. It ensures accurate measurements by preventing biases and facilitating robust correlations with outcomes. Conversely, validation examines which and how many biomarkers correspond to theoretical constructs and external criteria, establishing their predictive value. Multiple biomarkers are sometimes necessary to represent the complex relationship between exposure and disease outcomes accurately. Susceptibility factors are pivotal in disease states' complex interaction among genetic and environmental factors. Gaining a comprehensive understanding of these factors is essential for effectively interpreting biomarker data and maximizing their clinical usefulness. Using well-validated biomarkers can improve diagnoses, more effective treatment evaluations, and enhanced disease prediction. This, in turn, will contribute to better patient outcomes and drive progress in medicine.

Management of patients with hypertension and chronic kidney disease referred to Hypertension Excellence Centres among 27 countries. On behalf of the European Society of Hypertension Working Group on Hypertension and the Kidney.

Objective Real-life management of patients with hypertension and chronic kidney disease (CKD) among European Society of Hypertension Excellence Centres (ESH-ECs) is unclear : we aimed to investigate it. Methods A survey was conducted in 2023. The questionnaire contained 64 questions asking ESH-ECs representatives to estimate how patients with CKD are managed. Results Overall, 88 ESH-ECS representatives from 27 countries participated. According to the responders, renin-angiotensin system (RAS) blockers, calcium-channel blockers and thiazides were often added when these medications were lacking in CKD patients, but physicians were more prone to initiate RAS blockers (90% [interquartile range: 70-95%]) than MRA (20% [10-30%]), SGLT2i (30% [20-50%]) or (GLP1-RA (10% [5-15%]). Despite treatment optimisation, 30% of responders indicated that hypertension remained uncontrolled (30% (15-40%) vs 18% [10%-25%]) in CKD and CKD patients, respectively). Hyperkalemia was the most frequent barrier to initiate RAS blockers, and dosage reduction was considered in 45% of responders when kalaemia was 5.5-5.9 mmol/L. Conclusions RAS blockers are initiated in most ESH-ECS in CKD patients, but MRA and SGLT2i initiations are less frequent. Hyperkalemia was the main barrier for initiation or adequate dosing of RAS blockade, and RAS blockers' dosage reduction was the usual management.

What is the context? Hypertension is a strong independent risk factor for development of chronic kidney disease (CKD) and progression of CKD to ESKD. Improved adherence to the guidelines in the treatment of CKD is believed to provide further reduction of cardiorenal events. European Society of Hypertension Excellence Centres (ESH-ECs) have been developed in Europe to provide excellency regarding management of patients with hypertension and implement guidelines. Numerous deficits regarding general practitioner CKD screening, use of nephroprotective drugs and referral to nephrologists prior to referral to ESH-ECs have been reported. In contrast, real-life management of these patients among ESH-ECs is unknown. Before implementation of strategies to improve guideline adherence in Europe, we aimed to investigate how patients with CKD are managed among the ESH-ECs.What is the study about? In this study, a survey was conducted in 2023 by the ESH to assess management of CKD patients referred to ESH-ECs. The questionnaire contained 64 questions asking ESH-ECs representatives to estimate how patients with CKD are managed among their centres.What are the results? RAAS blockers are initiated in 90% of ESH-ECs in CKD patients, but the initiation of MRA and SGLT2i is less frequently done. Hyperkalemia is the main barrier for initiation or adequate dosing of RAAS blockade, and its most reported management was RAAS blockers dosage reduction. These findings will be crucial to implement strategies in order to improve management of patients with CKD and guideline adherence among ESH-ECs.

Serum Uric Acid, Hypertriglyceridemia, and Carotid Plaques: A Sub-Analysis of the URic Acid Right for Heart Health (URRAH) Study.

High levels of serum uric acid (SUA) and triglycerides (TG) might promote high-cardiovascular-risk phenotypes, including subclinical atherosclerosis. An interaction between plaques xanthine oxidase (XO) expression, SUA, and HDL-C has been recently postulated. Subjects from the URic acid Right for heArt Health (URRAH) study with carotid ultrasound and without previous cardiovascular diseases (CVD) (n = 6209), followed over 20 years, were included in the analysis. Hypertriglyceridemia (hTG) was defined as TG ≥ 150 mg/dL. Higher levels of SUA (hSUA) were defined as ≥5.6 mg/dL in men and 5.1 mg/dL in women. A carotid plaque was identified in 1742 subjects (28%). SUA and TG predicted carotid plaque (HR 1.09 [1.04-1.27], p < 0.001 and HR 1.25 [1.09-1.45], p < 0.001) in the whole population, independently of age, sex, diabetes, systolic blood pressure, HDL and LDL cholesterol and treatment. Four different groups were identified (normal SUA and TG, hSUA and normal TG, normal SUA and hTG, hSUA and hTG). The prevalence of plaque was progressively greater in subjects with normal SUA and TG (23%), hSUA and normal TG (31%), normal SUA and hTG (34%), and hSUA and hTG (38%) (Chi-square, 0.0001). Logistic regression analysis showed that hSUA and normal TG [HR 1.159 (1.002 to 1.341); p = 0.001], normal SUA and hTG [HR 1.305 (1.057 to 1.611); p = 0.001], and the combination of hUA and hTG [HR 1.539 (1.274 to 1.859); p = 0.001] were associated with a higher risk of plaque. Our findings demonstrate that SUA is independently associated with the presence of carotid plaque and suggest that the combination of hyperuricemia and hypertriglyceridemia is a stronger determinant of carotid plaque than hSUA or hTG taken as single risk factors. The association between SUA and CVD events may be explained in part by a direct association of UA with carotid plaques.

Socioeconomic Status and Clinical Outcomes in Chronic Kidney Disease: Bootstrap Validation of a Simple Indicator.

Background: Chronic Kidney Disease (CKD) is a complex health condition that interacts significantly with socioeconomic determinants, particularly income status and education. This study developed a simple indicator of socioeconomic status (SES), which is composed of income status and education in CKD patients, and evaluated its impact on health outcomes in this population. Methods: This study was conducted on 561 CKD patients, stages 2-5. The composite SES score was developed by combining the regression coefficients of income and education as predictors of the study endpoint in a multivariable Cox model, normalizing these coefficients to derive weights, and then using these weights to calculate an individual percentage score based on each person's income and education. The composed SES indicator was internally validated through bootstrap analysis. Over a median follow-up time of 36 months, we tracked all-cause death and non-fatal cardiovascular events. Results: Both lack of income (p = 0.020) and low educational level (p = 0.034) were independently related to the combined endpoint. Based on these covariates' regression coefficients, a composite socioeconomic score considering income and educational level was generated. In a Cox regression model, a 10% increase in this composite risk score entailed a 25% increase in the hazard ratio (HR) of the combined endpoint [HR (10% increase): 1.25], and the internally validated 95% CI ranged from 1.14 to 1.41 (p < 0.001). Conclusions: This study underscores the significant impact of a simple, bootstrap-validated composite SES indicator on CKD patients' health outcomes. These findings highlight the importance of considering education and socioeconomic factors in managing and treating CKD patients and inform future research and policy considerations for this population.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) and clinical outcomes in dialysis patients.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9), a factor accelerating the degradation of LDL receptors, was associated with a gender-dependent risk for cardiovascular (CV) events in the general population and with all-cause and CV mortality in two relatively small studies in black Africans and South Korean haemodialysis patients. The effect modification by gender was untested in these studies. METHODS: The study enrolled 1188 dialysis patients from the Prospective Registry of The Working Group of Epidemiology of Dialysis Region Calabria (PROGREDIRE) cohort. PCSK9 was measured by colorimetric enzyme-linked immunosorbent assay. The primary outcomes were all-cause and CV mortality. Statistical analysis included Cox regression analysis and effect modification analysis. RESULTS: During a median 2.9-year follow-up, out of 494 deaths, 278 were CV-related. In unadjusted analyses, PCSK9 levels correlated with increased all-cause (HRfor1ln unit increase: 1.23, 95% CI 1.06-1.43, p =.008) and CV mortality (HRfor1ln unit increase: 1.26, 95% CI 1.03-1.54, p =.03). After multivariate adjustment, these associations were no longer significant (all-cause mortality, HRfor 1 ln unit increase: 1.16, 95% CI .99-1.36, p =.07; CV mortality, HRfor1ln unit increase: 1.18, 95% CI .95-1.46, p =.14). However, in fully adjusted interaction analyses, a doubling in the risk of this outcome in women was registered (Women, HRfor1ln unit increase: 1.88, 95% CI 1.27-2.78, p =.002; Men, HRfor1ln unit increase: 1.07, 95% CI .83-1.38, p =.61; p for effect modification: .02). CONCLUSIONS: PCSK9 levels are unrelated to all-cause mortality in haemodialysis patients but, like in studies of the general population, independently of other risk factors, entail a doubling in the risk of CV events in women in this population.

Screening and management of hypertensive patients with chronic kidney disease referred to Hypertension Excellence Centres among 27 countries. A pilot survey based on questionnaire.

OBJECTIVE: Real-life management of hypertensive patients with chronic kidney disease (CKD) is unclear. METHODS: A survey was conducted in 2023 by the European Society of Hypertension (ESH) to assess management of CKD patients referred to ESH-Hypertension Excellence Centres (ESH-ECs) at first referral visit. The questionnaire contained 64 questions with which ESH-ECs representatives were asked to estimate preexisting CKD management quality. RESULTS: Overall, 88 ESH-ECs from 27 countries participated (fully completed surveys: 66/88 [75.0%]). ESH-ECs reported that 28% (median, interquartile range: 15-50%) had preexisting CKD, with 10% of them (5-30%) previously referred to a nephrologist, while 30% (15-40%) had resistant hypertension. The reported rate of previous recent (<6 months) estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) testing were 80% (50-95%) and 30% (15-50%), respectively. The reported use of renin-angiotensin system blockers was 80% (70-90%). When a nephrologist was part of the ESH-EC teams the reported rates SGLT2 inhibitors (27.5% [20-40%] vs. 15% [10-25], P  = 0.003), GLP1-RA (10% [10-20%] vs. 5% [5-10%], P  = 0.003) and mineralocorticoid receptor antagonists (20% [10-30%] vs. 15% [10-20%], P  = 0.05) use were greater as compared to ESH-ECs without nephrologist participation. The rate of reported resistant hypertension, recent eGFR and UACR results and management of CKD patients prior to referral varied widely across countries. CONCLUSIONS: Our estimation indicates deficits regarding CKD screening, use of nephroprotective drugs and referral to nephrologists before referral to ESH-ECs but results varied widely across countries. This information can be used to build specific programs to improve care in hypertensives with CKD.

A new era in the science and care of kidney diseases.

Notable progress in basic, translational and clinical nephrology research has been made over the past five decades. Nonetheless, many challenges remain, including obstacles to the early detection of kidney disease, disparities in access to care and variability in responses to existing and emerging therapies. Innovations in drug development, research technologies, tissue engineering and regenerative medicine have the potential to improve patient outcomes. Exciting prospects include the availability of new drugs to slow or halt the progression of chronic kidney disease, the development of bioartificial kidneys that mimic healthy kidney functions, and tissue engineering techniques that could enable transplantable kidneys to be created from the cells of the recipient, removing the risk of rejection. Cell and gene therapies have the potential to be applied for kidney tissue regeneration and repair. In addition, about 30% of kidney disease cases are monogenic and could potentially be treated using these genetic medicine approaches. Systemic diseases that involve the kidney, such as diabetes mellitus and hypertension, might also be amenable to these treatments. Continued investment, communication, collaboration and translation of innovations are crucial to realize their full potential. In addition, increasing sophistication in exploring large datasets, implementation science, and qualitative methodologies will improve the ability to deliver transformational kidney health strategies.