Do ultrasound renal resistance indices reflect systemic rather than renal vascular damage in chronic kidney disease?

BACKGROUND: In patients suffering from chronic kidney disease (CKD), ultrasound renal resistance indices predict progression of kidney disease and death. Although ultrasound resistance indices were initially considered to directly reflect intrarenal vascular resistance, they are complex composite parameters that are influenced by various vascular factors. We hypothesized that renal resistance indices reflect systemic vascular disease rather than local renal damage in patients with CKD. METHODS: In 140 patients suffering from CKD not receiving renal replacement therapy, intrarenal resistance indices were measured in interlobar arteries. For assessment of systemic atherosclerotic disease, common carotid intima-media thickness (IMT) and ankle-brachial blood pressure index were determined. Categories of risk for coronary heart diseases were defined by Framingham risk scoring. RESULTS: Increased renal resistance indices were associated with high Framingham risk scores and with the presence of atherosclerotic disease. In addition, ultrasound renal resistance indices progressively increased with the stage of renal function impairment, and patients suffering from diabetic nephropathy had higher resistance indices than patients suffering from other renal diseases. In a multivariate linear regression analysis, IMT, Framingham risk score, renal function, presence of diabetic nephropathy and pulse pressure independently predicted resistance indices. However, when additionally adjusting for age, IMT and Framingham risk score were no longer independent predictors of resistance indices. CONCLUSIONS: In patients suffering from CKD, intrarenal resistance indices are independently associated with cardiovascular risk score and systemic vascular disease as well as with aetiology and stage of CKD. This may explain their strong association with both impaired renal outcome and death.     

Arsenic-mediated nephrotoxicity

Abstract

Chronic kidney disease (CKD) is an important global health problem that affects 8–15% of the population according to epidemiological studies done in different countries. Essential to prevention is the knowledge of the environmental factors associated with this disease, and heavy metals such as lead and cadmium are clearly associated with kidney injury and CKD progression. Arsenic is one of the most abundant contaminants in water and soil, and many epidemiological studies have found an association between arsenic and type 2 diabetes mellitus, hypertension and cancer; however, there is a scarcity of epidemiological studies about its association with kidney disease, and the evidence linking urinary arsenic excretion with CKD, higher urinary excretion of low molecular proteins, albuminuria or other markers of renal in injury is still limited, and more studies are necessary to characterize the role of arsenic on renal injury and CKD progression. Global efforts to reduce arsenic exposure remain important and research is also needed to determine whether specific therapies are beneficial in susceptible populations.     

How Do Living Kidney Donors Develop End‐Stage Renal Disease?

The clinical course and risk factors for developing end-stage renal disease (ESRD) after heminephrectomy in living kidney donors have scarcely been investigated. We reviewed medical records and identified eight case donors who developed chronic kidney disease (CKD) stage 5 or ESRD, and subsequently investigated the association between postoperative clinical courses and changes in renal function. To conduct a case-control study, we also selected a control group comprising 24 donors who had maintained stable renal function and were matched for age, sex and follow-up time since donation. Except for one donor who developed ESRD caused by a traffic accident, none of the donors developed progressive renal dysfunction immediately after donation. Their renal functions remained stable for a long period of time, but started to decline after developing new comorbidities, especially risk factors known as progression factors (proteinuria or hypertension) or accelerating factors (cardiovascular [CV] event or infection) of CKD. As compared with the control donors, incidence of postoperative persistent proteinuria, acute CV event, severe infection and hospitalization due to accelerating factors of CKD were significantly higher in the case donors. These results suggest the importance of long-term (more than 10 years) follow-up of donors with special attention on the risk factors of CKD.     

Dyslipidemia and the progression of renal disease in chronic renal failure patients

Dyslipidemia is a common complication of progressive kidney disease and contributes to the high cardiovascular morbidity and mortality of chronic kidney disease (CKD) patients. Recent evidence also suggests a role for dyslipidemia in the development and progression of renal disease. Experimental studies have demonstrated that lipids may induce glomerular and tubulointerstitial injury, and that lipid-lowering treatments ameliorate renal injury. Various lipid abnormalities have been associated with the development and progression of renal disease in diabetic and nondiabetic patients. Population-based studies and studies of diabetic patients have reported associations of various lipid abnormalities with the development of renal disease. In patients with CKD, lipid abnormalities have also been associated with renal disease progression. Post hoc analyses of some large clinical trials on patients with vascular disease, diabetes, or dyslipidemia, and a meta-analysis of small, prospective, controlled studies on patients with CKD (diabetics and nondiabetics) suggest that statins may slow the progression of kidney disease. It is unclear whether the beneficial renal effects of statins are due to the reduction of serum cholesterol levels and/or their pleiotropic effects. There is also evidence for synergistic renoprotective effects between statins and renin-angiotensin system inhibitors. According to the results of post hoc analysis of several studies, treatment with fibrates does not seem to confer renoprotection, but evidence is scarce. In summary, there is growing evidence that lipid abnormalities may be a risk factor for renal disease, and that statins appear to confer a renoprotective effect.     

Renin-angiotensin system blockers-SGLT2 inhibitors-mineralocorticoid receptor antagonists in diabetic kidney disease: A tale of the past two decades!

Several pharmacological agents to prevent the progression of diabetic kidney disease (DKD) have been tested in patients with type 2 diabetes mellitus (T2DM) in the past two decades. With the exception of renin-angiotensin system blockers that have shown a significant reduction in the progression of DKD in 2001, no other pharmacological agent tested in the past two decades have shown any clinically meaningful result. Recently, the sodium-glucose cotransporter-2 inhibitor (SGLT-2i), canagliflozin, has shown a significant reduction in the composite of hard renal and cardiovascular (CV) endpoints including progression of end-stage kidney disease in patients with DKD with T2DM at the top of renin-angiotensin system blocker use. Another SGLT-2i, dapagliflozin, has also shown a significant reduction in the composite of renal and CV endpoints including death in patients with chronic kidney disease (CKD), regardless of T2DM status. Similar positive findings on renal outcomes were recently reported as a top-line result of the empagliflozin trial in patients with CKD regardless of T2DM. However, the full results of this trial have not yet been published. While the use of older steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone in DKD is associated with a significant reduction in albuminuria outcomes, a novel non-steroidal MRA finerenone has additionally shown a significant reduction in the composite of hard renal and CV endpoints in patients with DKD and T2DM, with reasonably acceptable side effects.     

Risk factors for progression of chronic kidney disease: An investigation in prepubertal children

Aim

Previous studies on progression of chronic kidney disease (CKD) in children have included older post-pubertal subjects. This study attempted to evaluate risk factors for progression of CKD in pre-pubertal children.

Methods

An observational study of children aged 2–10 years with an eGFR within the limits of >30 and <75 mL/min/1.73 m² was performed. Presenting clinical and biochemical risk factors, as well as diagnosis, were analysed for their association with progression to kidney failure, time to kidney failure and for the rate of decline of kidney function.

Results

One hundred and twenty-five children were studied of whom 42 (34%) had progressed to CKD stage 5 during the median period of follow up of 3.1 (IQR = 1.8–6) years. Hypertension, anaemia and acidosis at entry were associated with progression but they did not predict reaching the end point. Only glomerular disease, proteinuria and stage 4 kidney disease were independent predictors of kidney failure and the time to kidney failure. The rate of kidney function decline was greater in patients with glomerular than non-glomerular disease.

Conclusions

Common modifiable risk factors, when present at initial evaluation, were not independently associated with CKD progression to kidney failure in prepubertal children. Only non-modifiable risk factors and proteinuria predicted eventual stage 5 disease. The physiological changes of puberty may be the major precipitator of kidney failure during adolescence.     

Cardiovascular changes during chronic hypertensive states

It is well established that elevated blood pressure constitutes a major risk factor for coronary heart disease, arrythmias, heart failure, cerebrovascular disease, peripheral artery disease and renal failure. Blood pressure level and the duration of arterial hypertension (HTN) impact target organ damage. Many studies in adults have demonstrated the role of antihypertensive therapy in preventing cardiovascular (CV) events. The so-called hard end-points, such as death, myocardial infarction (MI) or stroke, are rarely seen in children, but intermediate target organ damage, including left ventricular hypertrophy, increased intima-media thickness and microalbuminuria, is already detectable during childhood. The goal of antihypertensive treatment is to reduce the global risk of CV events. In the adult population stratification of CV risk is based on blood pressure level, risk factors, subclinical target organ damage and established CV and kidney disease. Increased CV risk begins early in the course of kidney disease, and CV diseases are the most frequent cause of morbidity and mortality in patients with chronic kidney disease (CKD). Children with CKD are especially prone to the long-term effects of CV risk factors, which result in high morbidity and mortality in young adults. To improve the outcome, pediatric and adult CKD patients require nephro- and cardioprotection.     

Understanding the role of genetic polymorphisms in chronic kidney disease

Although no valid studies clearly indicate increasing or decreasing numbers of incident paediatric patients, the prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) is growing worldwide. This is mainly due to improved access to renal replacement therapy (RRT), increased survival after dialysis and kidney transplantation and an increase in diagnosis and referral of these patients. Although the increase in CKD prevalence is mainly caused by environmental factors, genetic factors may also influence the incidence and/or the progression of CKD and its complications. As CKD patients might be more sensitive to genetic effects due to the exposure to a uraemic milieu, this makes studies of genetic factors especially interesting in this population. The goal of identifying genetic factors that contribute to the outcome of CKD is to gain further understanding of the disease pathogenesis and underlying causes and, possibly, to use this knowledge to predict disease or its complications and to identify a risk population. Therefore, genetic screening of paediatric CKD patients may enhance the impact of preventive measures that could have a positive effect on outcome. Furthermore, by identifying patients’ genetic backgrounds, it is possible that a more individualised therapy could be designed.     

Quality of Life and Outcomes in African Americans with CKD

Low health-related quality of life (HRQOL) has been associated with increased risk for hospitalization and death in ESRD. However, the relationship of HRQOL with outcomes in predialysis CKD is not well understood. We evaluated the association between HRQOL and renal and cardiovascular (CV) outcomes in 1091 African Americans with hypertensive CKD enrolled in the African American Study of Kidney Disease and Hypertension (AASK) trial and cohort studies. Outcomes included CKD progression (doubling of serum creatinine/ESRD), CV events/CV death, and a composite of CKD progression or death from any cause (CKD progression/death). We assessed HRQOL, including mental health composite (MHC) and physical health composite (PHC), using the Short Form-36 survey. Cox regression analyses were used to assess the relationship between outcomes and five-point decrements in MHC and PHC scores using measurements at baseline, at the most recent annual visit (time-varying), or averaged from baseline to the most recent visit (cumulative). During approximately 10 years of follow-up, lower mean PHC score was associated with increased risk of CV events/CV death and CKD progression/death across all analytic approaches, but only time-varying and cumulative decrements were associated with CKD progression. Similarly, lower mean MHC score was associated with increased risk of CV events/CV death regardless of analytic approach, while only time-varying and cumulative decrements in mean MHC score was associated with CKD progression and CKD progression or death. In conclusion, lower HRQOL is associated with a range of adverse outcomes in African Americans with hypertensive CKD.     

Chronic kidney disease in children: the global perspective

In contrast to the increasing availability of information pertaining to the care of children with chronic kidney disease (CKD) from large-scale observational and interventional studies, epidemiological information on the incidence and prevalence of pediatric CKD is currently limited, imprecise, and flawed by methodological differences between the various data sources. There are distinct geographic differences in the reported causes of CKD in children, in part due to environmental, racial, genetic, and cultural (consanguinity) differences. However, a substantial percentage of children develop CKD early in life, with congenital renal disorders such as obstructive uropathy and aplasia/hypoplasia/dysplasia being responsible for almost one half of all cases. The most favored end-stage renal disease (ESRD) treatment modality in children is renal transplantation, but a lack of health care resources and high patient mortality in the developing world limits the global provision of renal replacement therapy (RRT) and influences patient prevalence. Additional efforts to define the epidemiology of pediatric CKD worldwide are necessary if a better understanding of the full extent of the problem, areas for study, and the potential impact of intervention is desired.     

Disordered mineral metabolism and vascular calcification in nondialyzed chronic kidney disease patients.

It is well established that abnormalities in mineral metabolism are apparent early in the course of chronic kidney disease (CKD) and result in clinically relevant consequences such as renal osteodystrophy. Furthermore, there is emerging evidence linking some of these abnormalities (hyperphosphatemia) to the high cardiovascular morbidity and mortality experienced by nondialyzed patients with CKD. Most studies have evaluated vascular calcification in patients with stage 5 CKD. Reports published over the last 2 years show that the process begins rather early in CKD and is particularly severe among elderly and type 2 diabetic patients. Furthermore, "calcium begets calcium", such that the calcification burden in early CKD is an important predictor of subsequent progression, including the rapid increase seen in stage 5 CKD. There is an increasing body of evidence that supports the thesis that elevated serum levels of phosphorus and calcium and deficiency of inhibitors of calcification (for example, fetuin-A) are important in the progression of vascular calcification in patients with end-stage renal disease. However, the concentrations of calcium and phosphorus shown to induce mineralization in cell culture studies are not observed in most patients until late in stage 4 or stage 5 CKD. Cross-sectional and longitudinal studies have also been unable to show a correlation between serum levels of markers of disordered mineral metabolism and severity of vascular calcification. Future studies should evaluate the pathogenetic role of phosphorus retention, which occurs early in the course of CKD, in the induction and/or progression of vascular calcification. Finally, there is a need to identify alternative pathogenetic mechanisms that may be important causes of the high calcification burden observed early in CKD.     

Chronic kidney disease

Chronic kidney disease (CKD) is a common disorder as currently defined. Patients with CKD face two major hazards: cardiovascular disease and – in a minority – progression to end-stage renal disease (ESRD). Advanced CKD also causes numerous metabolic and other complications. The management of CKD involves excluding acute kidney injury, diagnosing the cause of CKD, slowing progression and detecting and treating complications. Surgeons seeing patients with CKD should aim to optimize fluid balance in the perioperative period, avoid nephrotoxic agents and ensure drug doses are appropriate for the level of renal function. Nephrological input should be sought early if required.     

The lipid story in chronic kidney disease: a long story with a happy end?

Cardiovascular (CV) morbidity and mortality increase with the severity of kidney disease, reaching 30 times higher mortality rates in dialysis patients compared with the general population. Although dyslipidemia is a well-established CV risk factor in the general population, the relationship between lipid disorders and CV risk in patients with chronic kidney disease (CKD) is less clear. Despite the clear evidence that statins reduce the risk of atherosclerotic events and death from cardiac causes in individuals without CKD, the use of statins in patients with kidney disease is significantly less frequent. For a long time, one of the explanations was the lack of a prospective, randomized, controlled study designed specifically to CKD patients. After recent publication of the data from Study of Heart and Renal Protection trial, given the safety and potential efficacy of statins, this lipid-lowering treatment should be administered more frequently to individuals with CKD stage 1–4, as well as those undergoing dialysis.     

Paradigm Shifts in Atherosclerotic Renovascular Disease: Where Are We Now?

Results of recent clinical trials and experimental studies indicate that whereas atherosclerotic renovascular disease can accelerate both systemic hypertension and tissue injury in the poststenotic kidney, restoring vessel patency alone is insufficient to recover kidney function for most subjects. Kidney injury in atherosclerotic renovascular disease reflects complex interactions among vascular rarefication, oxidative stress injury, and recruitment of inflammatory cellular elements that ultimately produce fibrosis. Classic paradigms for simply restoring blood flow are shifting to implementation of therapy targeting mitochondria and cell-based functions to allow regeneration of vascular, glomerular, and tubular structures sufficient to recover, or at least stabilize, renal function. These developments offer exciting possibilities of repair and regeneration of kidney tissue that may limit progressive CKD in atherosclerotic renovascular disease and may apply to other conditions in which inflammatory injury is a major common pathway.     

Biomarkers in chronic kidney disease: a review

Chronic kidney disease (CKD) is a major public health problem. The classification of CKD by KDOQI and KDIGO and the routine eGFR reporting have resulted in increased identification of CKD. It is important to be able to identify those at high risk of CKD progression and its associated cardiovascular disease (CVD). Proteinuria is the most sensitive marker of CKD progression in clinical practice, especially when combined with eGFR, but these have limitations. Hence, early, more sensitive, biomarkers are required. Recently, promising biomarkers have been identified for CKD progression and its associated CVD morbidity and mortality. These may be more sensitive biomarkers of kidney function, the underlying pathophysiological processes, and/or cardiovascular risk. Although there are some common pathways to CKD progression, there are many primary causes, each with its own specific pathophysiological mechanism. Hence, a panel measuring multiple biomarkers including disease-specific biomarkers may be required. Large, longitudinal observational studies are needed to validate candidate biomarkers in a broad range of populations prior to implementation into routine CKD management. Recent renal biomarkers discovered include neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and liver-type fatty acid-binding protein. Although none are ready for use in clinical practice, it is timely to review the role of such biomarkers in predicting CKD progression and/or CVD risk in CKD.     

Metabolic syndrome in children with chronic kidney disease and after renal transplantation

Visceral obesity and metabolic abnormalities typical for metabolic syndrome (MS) are the new epidemic in adolescence. MS is not only the risk factor for cardiovascular disease but also for chronic kidney disease (CKD). Thus, there are some reasons to recognize MS as a new challenge for pediatric nephrologists. First, hypertensive and diabetic nephropathy, the main causes of CKD in adults, both share the same pathophysiological abnormalities associated with visceral obesity and insulin resistance and have their origins in childhood. Secondly, as the obesity epidemic also affects children with CKD, MS emerges as the risk factor for progression of CKD. Thirdly, metabolic abnormalities typical for MS may pose additional risk for cardiovascular morbidity and mortality in children with CKD. Finally, although the renal transplantation reverses uremic abnormalities it is associated with an exposure to new metabolic risk factors typical for MS and MS has been found to be the risk factor for graft loss and cardiovascular morbidity after renal transplantation. MS is the result of imbalance between dietary energy intake and expenditure inducing disproportionate fat accumulation. Thus, the best prevention and treatment of MS is physical activity and maintenance of proper relationship between lean and fat mass.     

Chronic kidney disease and inflammation in pediatric patients: from bench to playground

Signs of an activated immune system can be observed already in the early stages of chronic kidney disease (CKD). Markers of a chronically activated immune system are closely linked to several complications of CKD, such as accelerated atherosclerosis, vascular calcification, insulin resistance, increased muscle catabolism, loss of appetite, bone remodeling, and increased peritoneal permeability. Interestingly, all the aforementioned pathological states resemble a state of accelerated ageing and are strongly associated with increased morbidity and mortality in CKD patients. In recent studies, signs of inflammation have been shown as predictors for mortality in dialysis patients, and the role of inflammation as a risk factor for complications of CKD in children has emerged. Although preliminary findings suggest that inflammation is highly prevalent in the pediatric population with CKD, information related pathogenic links and to clinical outcomes is lacking. For the future, it is crucial for investigations to address the mechanisms and complications of inflammation that are manifested in pediatric patients with CKD in all stages. Since early identification and intervention may generate the most efficient strategies for prevention and treatment of cardiovascular disease in CKD patients, the pediatric population deserves special attention in future studies. In this review, we discuss the mechanisms involved in the inflammatory activation and the main causes and consequences of the inflammatory state observed in the CKD patient, with special emphasis on the pediatric population.     

Chronic kidney disease after liver,cardiac, lung,heart–lung,and hematopoietic stem cell transplant

Patient survival after cardiac, liver, and hematopoietic stem cell transplant (HSCT) is improving; however, this survival is limited by substantial pretransplant and treatment-related toxicities. A major cause of morbidity and mortality after transplant is chronic kidney disease (CKD). Although the majority of CKD after transplant is attributed to the use of calcineurin inhibitors, various other conditions such as thrombotic microangiopathy, nephrotic syndrome, and focal segmental glomerulosclerosis have been described. Though the immunosuppression used for each of the transplant types, cardiac, liver and HSCT is similar, the risk factors for developing CKD and the CKD severity described in patients after transplant vary. As the indications for transplant and the long-term survival improves for these children, so will the burden of CKD. Nephrologists should be involved early in the pretransplant workup of these patients. Transplant physicians and nephrologists will need to work together to identify those patients at risk of developing CKD early to prevent its development and progression to end-stage renal disease.