Showing papers in "Clinical Journal of The American Society of Nephrology in 2015"
TL;DR: Renal regulation of these ions occurs through glomerular filtration and tubular re absorption and/or secretion and is therefore an important determinant of plasma ion concentration.
Abstract: Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys.
523 citations
TL;DR: This paper reviews key aspects of the normal regulation of potassium metabolism and is designed to serve as a readily accessible review for the well informed clinician as well as a resource for teaching trainees and medical students.
Abstract: Potassium is the most abundant cation in the intracellular fluid, and maintaining the proper distribution of potassium across the cell membrane is critical for normal cell function. Long-term maintenance of potassium homeostasis is achieved by alterations in renal excretion of potassium in response to variations in intake. Understanding the mechanism and regulatory influences governing the internal distribution and renal clearance of potassium under normal circumstances can provide a framework for approaching disorders of potassium commonly encountered in clinical practice. This paper reviews key aspects of the normal regulation of potassium metabolism and is designed to serve as a readily accessible review for the well informed clinician as well as a resource for teaching trainees and medical students.
346 citations
TL;DR: The results underscore the need to adopt a single, universal AKI definition and show AKI was associated with greater mortality and LOS in theICU and greater LOS outside the ICU.
Abstract: Background and objectives Although several standardized definitions for AKI have been developed, no consensus exists regarding which to use in children. This study applied the Pediatric RIFLE (pRIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) criteria to an anonymized cohort of hospitalizations extracted from the electronic medical record to compare AKI incidence and outcomes in intensive care unit (ICU) and non-ICU pediatric populations. Design, setting, participants, & measurements Observational, electronic medical record–enabled study of 14,795 hospitalizations at the Lucile Packard Children’s Hospital between 2006 and 2010. AKI and AKI severity stage were defined by the pRIFLE, AKIN, and KDIGO definitions according to creatinine change criteria; urine output criteria were not used. The incidences of AKI and each AKI stage were calculated for each classification system. All-cause, in-hospital mortality and total hospital length of stay (LOS) were compared at each subsequent AKI stage by Fisher exact and Kolmogorov–Smirnov tests, respectively. Results AKI incidences across the cohort according to pRIFLE, AKIN, and KDIGO were 51.1%, 37.3%, and 40.3%. Mortality was higher among patients with AKI across all definitions (pRIFLE, 2.3%; AKIN, 2.7%; KDIGO, 2.5%; P P Conclusions Application of the three definitions led to differences in AKI incidence and staging. AKI was associated with greater mortality and LOS in the ICU and greater LOS outside the ICU. All three definitions demonstrated excellent interstage discrimination. While each definition offers advantages, these results underscore the need to adopt a single, universal AKI definition.
340 citations
TL;DR: This review covers aspects of protein metabolism and the control of the two major molecules involved in renal nitrogen excretion: urea and ammonia.
Abstract: Renal nitrogen metabolism primarily involves urea and ammonia metabolism, and is essential to normal health. Urea is the largest circulating pool of nitrogen, excluding nitrogen in circulating proteins, and its production changes in parallel to the degradation of dietary and endogenous proteins. In addition to serving as a way to excrete nitrogen, urea transport, mediated through specific urea transport proteins, mediates a central role in the urine concentrating mechanism. Renal ammonia excretion, although often considered only in the context of acid-base homeostasis, accounts for approximately 10% of total renal nitrogen excretion under basal conditions, but can increase substantially in a variety of clinical conditions. Because renal ammonia metabolism requires intrarenal ammoniagenesis from glutamine, changes in factors regulating renal ammonia metabolism can have important effects on glutamine in addition to nitrogen balance. This review covers aspects of protein metabolism and the control of the two major molecules involved in renal nitrogen excretion: urea and ammonia. Both urea and ammonia transport can be altered by glucocorticoids and hypokalemia, two conditions that also affect protein metabolism. Clinical conditions associated with altered urine concentrating ability or water homeostasis can result in changes in urea excretion and urea transporters. Clinical conditions associated with altered ammonia excretion can have important effects on nitrogen balance.
274 citations
TL;DR: The kidneys have the predominant role in regulating the systemic bicarbonate concentration and hence, the metabolic component of acid-base balance, and this function of the kidneys has two components: reabsorption of virtually all of the filtered HCO3(-) and production of new bICarbonate to replace that consumed by normal or pathologic acids.
Abstract: Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and function. The importance of this regulation is evidenced by a variety of physiologic derangements that occur when plasma pH is either high or low. The kidneys have the predominant role in regulating the systemic bicarbonate concentration and hence, the metabolic component of acid-base balance. This function of the kidneys has two components: reabsorption of virtually all of the filtered HCO3(-) and production of new bicarbonate to replace that consumed by normal or pathologic acids. This production or generation of new HCO3(-) is done by net acid excretion. Under normal conditions, approximately one-third to one-half of net acid excretion by the kidneys is in the form of titratable acid. The other one-half to two-thirds is the excretion of ammonium. The capacity to excrete ammonium under conditions of acid loads is quantitatively much greater than the capacity to increase titratable acid. Multiple, often redundant pathways and processes exist to regulate these renal functions. Derangements in acid-base homeostasis, however, are common in clinical medicine and can often be related to the systems involved in acid-base transport in the kidneys.
271 citations
TL;DR: A biomarker-integrated model of AKI is proposed, which summarizes the current state of knowledge regarding the roles of these biomarkers and the molecular and cellular biology ofAKI.
Abstract: AKI is a common clinical condition associated with a number of adverse outcomes. More timely diagnosis would allow for earlier intervention and could improve patient outcomes. The goal of early identification of AKI has been the primary impetus for AKI biomarker research, and has led to the discovery of numerous novel biomarkers. However, in addition to facilitating more timely intervention, AKI biomarkers can provide valuable insight into the molecular mechanisms of this complex and heterogeneous disease. Furthermore, AKI biomarkers could also function as molecular phenotyping tools that could be used to direct clinical intervention. This review highlights the major studies that have characterized the diagnostic and prognostic predictive power of these biomarkers. The mechanistic relevance of neutrophil gelatinase–associated lipocalin, kidney injury molecule 1, IL-18, liver-type fatty acid–binding protein, angiotensinogen, tissue inhibitor of metalloproteinase-2, and IGF-binding protein 7 to the pathogenesis and pathobiology of AKI is discussed, putting these biomarkers in the context of the progressive phases of AKI. A biomarker-integrated model of AKI is proposed, which summarizes the current state of knowledge regarding the roles of these biomarkers and the molecular and cellular biology of AKI.
236 citations
TL;DR: The structure and function of the key transporters and the complex interplay of regulatory factors that modulate principal cell ion and water transport are addressed.
Abstract: The principal cell of the kidney collecting duct is one of the most highly regulated epithelial cell types in vertebrates. The effects of hormonal, autocrine, and paracrine factors to regulate principal cell transport processes are central to the maintenance of fluid and electrolyte balance in the face of wide variations in food and water intake. In marked contrast with the epithelial cells lining the proximal tubule, the collecting duct is electrically tight, and ion and osmotic gradients can be very high. The central role of principal cells in salt and water transport is reflected by their defining transporters-the epithelial Na(+) channel (ENaC), the renal outer medullary K(+) channel, and the aquaporin 2 (AQP2) water channel. The coordinated regulation of ENaC by aldosterone, and AQP2 by arginine vasopressin (AVP) in principal cells is essential for the control of plasma Na(+) and K(+) concentrations, extracellular fluid volume, and BP. In addition to these essential hormones, additional neuronal, physical, and chemical factors influence Na(+), K(+), and water homeostasis. Notably, a variety of secreted paracrine and autocrine agents such as bradykinin, ATP, endothelin, nitric oxide, and prostaglandin E2 counterbalance and limit the natriferic effects of aldosterone and the water-retaining effects of AVP. Considerable recent progress has improved our understanding of the transporters, receptors, second messengers, and signaling events that mediate principal cell responses to changing environments in health and disease. This review primarily addresses the structure and function of the key transporters and the complex interplay of regulatory factors that modulate principal cell ion and water transport.
235 citations
TL;DR: In a large international sample of patients on hemodialysis, parathyroid hormone levels increased in most countries, and secondary hyperparathyroidism treatments changed over time, and very low and very high parathyro hormone levels were associated with adverse outcomes.
Abstract: Background and objectives Elevated parathyroid hormone levels may be associated with adverse clinical outcomes in patients on dialysis. After the introduction of practice guidelines suggesting higher parathyroid hormone targets than those previously recommended, changes in parathyroid hormone levels and treatment regimens over time have not been well documented. Design, setting, participants, & measurements Using data from the international Dialysis Outcomes and Practice Patterns Study, trends in parathyroid hormone levels and secondary hyperparathyroidism therapies over the past 15 years and the associations between parathyroid hormone and clinical outcomes are reported; 35,655 participants from the Dialysis Outcomes and Practice Patterns Study phases 1–4 (1996–2011) were included. Results Median parathyroid hormone increased from phase 1 to phase 4 in all regions except for Japan, where it remained stable. Prescriptions of intravenous vitamin D analogs and cinacalcet increased and parathyroidectomy rates decreased in all regions over time. Compared with 150–300 pg/ml, in adjusted models, all-cause mortality risk was higher for parathyroid hormone=301–450 (hazard ratio, 1.09; 95% confidence interval, 1.01 to 1.18) and >600 pg/ml (hazard ratio, 1.23; 95% confidence interval, 1.12 to 1.34). Parathyroid hormone >600 pg/ml was also associated with higher risk of cardiovascular mortality as well as all-cause and cardiovascular hospitalizations. In a subgroup analysis of 5387 patients not receiving vitamin D analogs or cinacalcet and with no prior parathyroidectomy, very low parathyroid hormone ( Conclusions In a large international sample of patients on hemodialysis, parathyroid hormone levels increased in most countries, and secondary hyperparathyroidism treatments changed over time. Very low and very high parathyroid hormone levels were associated with adverse outcomes. In the absence of definitive evidence in support of a specific parathyroid hormone target, there is an urgent need for additional research to inform clinical practice.
226 citations
TL;DR: There are no pharmacologic agents known to reduce the risk of AKI or treat established AKI, and remote ischemic preconditioning is an exciting future strategy, but more work is needed before widespread implementation.
Abstract: Approximately 18% of patients undergoing cardiac surgery experience AKI (on the basis of modern standardized definitions of AKI), and approximately 2%–6% will require hemodialysis. The development of AKI after cardiac surgery portends poor short- and long-term prognoses, with those developing RIFLE failure or AKI Network stage III having an almost 2-fold increase in the risk of death. AKI is caused by a variety of factors, including nephrotoxins, hypoxia, mechanical trauma, inflammation, cardiopulmonary bypass, and hemodynamic instability, and it may be affected by the clinician’s choice of fluids and vasoactive agents as well as the transfusion strategy used. The risk of AKI may be ameliorated by avoidance of nephrotoxins, achievement of adequate glucose control preoperatively, and use of goal-directed therapy hemodynamic strategies. Remote ischemic preconditioning is an exciting future strategy, but more work is needed before widespread implementation. Unfortunately, there are no pharmacologic agents known to reduce the risk of AKI or treat established AKI.
220 citations
TL;DR: Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness, and the PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.
Abstract: Background and objectives Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. Design, setting, participants, & measurements Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. Results Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%–16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%–45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. Conclusions The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.
219 citations
TL;DR: The risks of adverse maternal and fetal outcomes in pregnancy are higher for women with CKD versus pregnant women without CKD and the risk of CKD progression among pregnant patients versus nonpregnant controls is higher, however, pregnancy was not a risk factor for progression of renal disease in womenWith CKD before pregnancy.
Abstract: Background and objectives We undertook a systematic review and meta-analysis of published cohort studies and case-control studies to estimate ( 1 ) the risk of pregnancy complications among patients with CKD versus those without CKD and ( 2 ) the risk of CKD progression among pregnant patients versus nonpregnant controls with CKD. Design, setting, participants, & measurements We searched electronic databases for studies published between 1946 and 2014, and we reviewed articles using validity criteria. Random-effects analytical methods were used. Results Twenty-three studies (14 with data for adverse pregnancy outcomes and 9 for renal outcomes) with 506,340 pregnancies were included. Pregnancy with CKD had greater odds of preeclampsia (odds ratio [OR], 10.36; 95% confidence interval [95% CI], 6.28 to 17.09), premature delivery (OR, 5.72; 95% CI, 3.26 to 10.03), small for gestational age/low birth weight (OR, 4.85; 95% CI, 3.03 to 7.76), cesarean section (OR, 2.67; 95% CI, 2.01 to 3.54), and failure of pregnancy (OR, 1.80; 95% CI, 1.03 to 3.13). Subgroup analysis showed that odds of preeclampsia ( P 0.01) and premature delivery ( P 0.01) were higher in women with nondiabetic nephropathy compared with diabetic nephropathy, and the odds of preeclampsia ( P =0.01) and premature delivery ( P 0.01) were higher in women with macroproteinuria compared with microproteinuria. The median for follow-up time for renal events was 5 years (interquartile range, 5–14.7 years). There were no significant differences in the occurrence of renal events between CKD pregnant women and those without pregnancy (OR, 0.96; 95% CI, 0.69 to 1.35). Subgroup analysis showed that publication year, sample size, follow-up years, type of primary disease, CKD classification, level of serum creatinine at baseline, proteinuria, and level of systolic BP did not modify the renal outcomes. Conclusions The risks of adverse maternal and fetal outcomes in pregnancy are higher for women with CKD versus pregnant women without CKD. However, pregnancy was not a risk factor for progression of renal disease in women with CKD before pregnancy.
TL;DR: New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.
Abstract: The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell–derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell–mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.
TL;DR: AKI is common in hospitalized adults in China and is associated with significantly higher in-hospital mortality and resource utilization, and was associated with longer length of stay and higher daily costs, even after adjustment for confounders.
Abstract: Background and objectives Comprehensive epidemiologic data on AKI are particularly lacking in Asian countries. This study sought to assess the epidemiology and clinical correlates of AKI among hospitalized adults in China. Design, setting, participants, & measurements This was a multicenter retrospective cohort study of 659,945 hospitalized adults from a wide range of clinical settings in nine regional central hospitals across China in 2013. AKI was defined and staged according to Kidney Disease Improving Global Outcomes criteria. The incidence of AKI in the cohort was estimated using a novel two-step approach with adjustment for the frequency of serum creatinine tests and other potential confounders. Risk factor profiles for hospital-acquired (HA) and community-acquired (CA) AKI were examined. The in-hospital outcomes of AKI, including mortality, renal recovery, length of stay, and daily cost, were assessed. Results The incidence of CA-AKI and HA-AKI was 2.5% and 9.1%, respectively, giving rise to an overall incidence of 11.6%. Although the risk profiles for CA-AKI and HA-AKI differed, preexisting CKD was a major risk factor for both, contributing to 20% of risk in CA-AKI and 12% of risk in HA-AKI. About 40% of AKI cases were possibly drug-related and 16% may have been induced by Chinese traditional medicines or remedies. The in-hospital mortality of AKI was 8.8%. The risk of in-hospital death was higher among patients with more severe AKI. Preexisting CKD and need for intensive care unit admission were associated with higher death risk in patients at any stage of AKI. Transiency of AKI did not modify the risk of in-hospital death. AKI was associated with longer length of stay and higher daily costs, even after adjustment for confounders. Conclusion AKI is common in hospitalized adults in China and is associated with significantly higher in-hospital mortality and resource utilization.
TL;DR: A lower probability of renal recovery was associated with residence in an emerging country, higher APACHE score (emerging countries only) and dialysis, while mechanical ventilation wasassociated with renal recovery (developed countries only).
Abstract: Background and objectives AKI is frequent and is associated with poor outcomes. There is limited information on the epidemiology of AKI worldwide. This study compared patients with AKI in emerging and developed countries to determine the association of clinical factors and processes of care with outcomes. Design, setting, participants, & measurements This prospective observational study was conducted among intensive care unit patients from nine centers in developed countries and five centers in emerging countries. AKI was defined as an increase in creatinine of ≥0.3 mg/dl within 48 hours. Results Between 2008 and 2012, 6647 patients were screened, of whom 1275 (19.2%) developed AKI. A total of 745 (58% of those with AKI) agreed to participate and had complete data. Patients in developed countries had more sepsis (52.1% versus 38.0%) and higher Acute Physiology and Chronic Health Evaluation (APACHE) scores (mean±SD, 61.1±27.5 versus 51.1±25.2); those from emerging countries had more CKD (54.3% versus 38.3%), GN (6.3% versus 0.9%), and interstitial nephritis (7.0% versus 0.6%) (all P P P =0.02). Hospital mortality was 22.0%, and 13.3% of survivors were dialysis dependent at discharge. Independent risk factors associated with hospital mortality included older age, residence in an emerging country, use of vasopressors (emerging countries only), dialysis and mechanical ventilation, and higher APACHE score and cumulative fluid balance (developed countries only). A lower probability of renal recovery was associated with residence in an emerging country, higher APACHE score (emerging countries only) and dialysis, while mechanical ventilation was associated with renal recovery (developed countries only). Conclusions This study contrasts the clinical features and management of AKI and demonstrates worse outcomes in emerging than in developed countries. Differences in variations in care may explain these findings and should be considered in future trials.
TL;DR: Functional activity of these transporters plays a key role in drug handling and nephrotoxicity, and may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.
Abstract: The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liver-derived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.
TL;DR: This review includes recent findings on how intercalated cells regulate their intracellular milieu and contribute to acid-base regulation and sodium, chloride, and potassium homeostasis, thus highlighting their potential role as targets for the treatment of hypertension.
Abstract: Intercalated cells are kidney tubule epithelial cells with important roles in the regulation of acid-base homeostasis. However, in recent years the understanding of the function of the intercalated cell has become greatly enhanced and has shaped a new model for how the distal segments of the kidney tubule integrate salt and water reabsorption, potassium homeostasis, and acid-base status. These cells appear in the late distal convoluted tubule or in the connecting segment, depending on the species. They are most abundant in the collecting duct, where they can be detected all the way from the cortex to the initial part of the inner medulla. Intercalated cells are interspersed among the more numerous segment-specific principal cells. There are three types of intercalated cells, each having distinct structures and expressing different ensembles of transport proteins that translate into very different functions in the processing of the urine. This review includes recent findings on how intercalated cells regulate their intracellular milieu and contribute to acid-base regulation and sodium, chloride, and potassium homeostasis, thus highlighting their potential role as targets for the treatment of hypertension. Their novel regulation by paracrine signals in the collecting duct is also discussed. Finally, this article addresses their role as part of the innate immune system of the kidney tubule.
TL;DR: Elderly patients who choose not to have dialysis as part of shared decision making survive a median of 16 months and about one-third survive 12 months past a time when dialysis might have otherwise been indicated.
Abstract: BackgroundandobjectivesSurvival,symptomburden,andqualityoflife(QOL)areuncertainforelderlypatients with advanced CKD managed without dialysis. We examined these outcomes in patients managed with renal supportive care without dialysis (RSC-NFD) and those planned for or commencing dialysis. Design,setting, participants,m P,0.001) but had similar eGFR at the first clinic visit (16 ml/min per 1.73 m 2 ; P=0.92). Of the predialysis patients, 92 (34%) commenced dialysis. Compared with the RSC-NFD group, the death rate was lower in the predialysis group who did not requiredialysis(hazardratio,0.23;95%confidenceinterval,0.12to0.41]andinthoserequiringdialysis(0.30;0.13 to0.67)butnotindialysispatientswhohadnotattendedthepredialysisclinic(0.60;0.35to1.03).Mediansurvival in RSC-NFD patients was 16 (interquartile range, 9, 37) months and 32% survived .12 months after eGFR fell below10ml/minper 1.73 m2.Forthewholegroup,age, serumalbumin,andeGFR,15 ml/minper 1.73 m2were associated with poorer survival. Of the nondialysis patients, 57% had stable or improved symptoms over 12 months and 58% had stable or improved QOL. Conclusions Elderly patients who choose not to have dialysis as partof shared decision making survive a median of 16 months and about one-third survive 12 months past a time when dialysis might have otherwise been indicated. Utilizing the skills of palliative medicine helps provide reasonable symptom control and QOL without dialysis. Clin J Am Soc Nephrol 10: ccc–ccc, 2015. doi: 10.2215/CJN.03330414
TL;DR: The kidney filters vast quantities of Na at the glomerulus but excretes a very small fraction of this Na in the final urine, so regulation of both filtration and reabsorption through the processes of glomerulotubular balance and tubuloglomerular feedback is required.
Abstract: The kidney filters vast quantities of Na at the glomerulus but excretes a very small fraction of this Na in the final urine. Although almost every nephron segment participates in the reabsorption of Na in the normal kidney, the proximal segments (from the glomerulus to the macula densa) and the distal segments (past the macula densa) play different roles. The proximal tubule and the thick ascending limb of the loop of Henle interact with the filtration apparatus to deliver Na to the distal nephron at a rather constant rate. This involves regulation of both filtration and reabsorption through the processes of glomerulotubular balance and tubuloglomerular feedback. The more distal segments, including the distal convoluted tubule (DCT), connecting tubule, and collecting duct, regulate Na reabsorption to match the excretion with dietary intake. The relative amounts of Na reabsorbed in the DCT, which mainly reabsorbs NaCl, and by more downstream segments that exchange Na for K are variable, allowing the simultaneous regulation of both Na and K excretion.
TL;DR: A higher severity of frailty (as defined by the CFS) at dialysis initiation is associated with higher mortality.
Abstract: Background and objectives Frailty is associated with poor outcomes for patients on dialysis; however, previous studies have not taken into account the severity of frailty as a predictor of outcomes. The purpose of this study was to assess if there was an association between the degree of frailty and mortality among patients on incident dialysis. Design, setting, participants, & measurements A cohort study of incident chronic dialysis patients was conducted between January of 2009 and June of 2013 (last follow-up in December of 2013). On the basis of overall clinical impression, the Clinical Frailty Scale (CFS) score was determined for patients at the start of dialysis by their primary nephrologist. This simple scale allocates a single point to different states of frailty (1, very fit; 2, well; 3, managing well; 4, vulnerable; 5, mildly frail; 6, moderately frail; 7, severely frail or terminally ill) with an emphasis on function of the assessed individual. The primary outcome was time to death. Patients were censored at the time of transplantation. Results The cohort consisted of 390 patients with completed CFS scores (mean age of 63±15 years old). Most were Caucasian (89%) and men (67%), and 30% of patients had ESRD caused by diabetic nephropathy. The median Charlson Comorbidity Index score was 4 (interquartile range =3–6), and the median CFS score was 4 (interquartile range =2–5). There were 96 deaths over 750 patient-years at risk. In an adjusted Cox survival analysis, the hazard ratio associated with each 1-point increase in the CFS was 1.22 (95% confidence interval, 1.04 to 1.43; P=0.02). Conclusions A higher severity of frailty (as defined by the CFS) at dialysis initiation is associated with higher mortality.
TL;DR: In adult incident HD patients, frailty is associated with worse cognitive function, particularly global cognitive function (3MS), particularlyglobal cognitive function in adults of all ages undergoing HD.
Abstract: Background and objectives Patients of all ages undergoing hemodialysis (HD) have a high prevalence of cognitive impairment and worse cognitive function than healthy controls, and those with dementia are at high risk of death. Frailty has been associated with poor cognitive function in older adults without kidney disease. We hypothesized that frailty might also be associated with poor cognitive function in adults of all ages undergoing HD. Design, setting, participants, & measurements At HD initiation, 324 adults enrolled (November 2008 to July 2012) in a longitudinal cohort study (Predictors of Arrhythmic and Cardiovascular Risk in ESRD) were classified into three groups (frail, intermediately frail, and nonfrail) based on the Fried frailty phenotype. Global cognitive function (3MS) and speed/attention (Trail Making Tests A and B [TMTA and TMTB, respectively]) were assessed at cohort entry and 1-year follow-up. Associations between frailty and cognitive function (at cohort entry and 1-year follow-up) were evaluated in adjusted (for sex, age, race, body mass index, education, depression and comorbidity at baseline) linear (3MS, TMTA) and Tobit (TMTB) regression models. Results At cohort entry, the mean age was 54.8 years (SD 13.3), 56.5% were men, and 72.8% were black. The prevalence of frailty and intermediate frailty were 34.0% and 37.7%, respectively. The mean 3MS was 89.8 (SD 7.6), TMTA was 55.4 (SD 29), and TMTB was 161 (SD 83). Frailty was independently associated with lower cognitive function at cohort entry for all three measures (3MS: −2.4 points; 95% confidence interval [95% CI], −4.2 to −0.5; P =0.01; TMTA: 12.1 seconds; 95% CI, 4.7 to 19.4; P P =0.01; all tests for trend, P P =0.03). Conclusions In adult incident HD patients, frailty is associated with worse cognitive function, particularly global cognitive function (3MS).
TL;DR: This large international study indicates best survival in patients with both LTI and FTI in the 10th-90th percentiles of a healthy population of hemodialysis patients.
Abstract: Background and objectives High body mass index appears protective in hemodialysis patients, but uncertainty prevails regarding which components of body composition, fat or lean body mass, are primarily associated with survival. Design, setting, participants, & measurements Data between April 2006 and December 2012 were extracted from the Fresenius Medical Care Europe subset of the international MONitoring Dialysis Outcomes initiative. Fresenius Medical Care Europe archives a unique repository of predialysis body composition measurements determined by multifrequency bioimpedance (BCM Body Composition Monitor). The BCM Body Composition Monitor reports lean tissue indices (LTIs) and fat tissue indices (FTIs), which are the respective tissue masses normalized to height squared, relative to an age- and sex-matched healthy population. The relationship between LTI and FTI and all-cause mortality was studied by Kaplan–Meier analysis, multivariate Cox regression, and smoothing spline ANOVA logistic regression. Results In 37,345 hemodialysis patients, median (25th–75th percentile) LTI and FTI were 12.2 (10.3–14.5) and 9.8 (6.6–12.4)kg/m2,respectively.Median(25th–75thpercentile)follow-uptimewas266(132–379)days;3458(9.2%) patients diedduringfollow-up.MortalitywaslowestwithbothLTIandFTIinthe10th–90thpercentile(reference group)andsignificantlyhigheratthelowerLTIandFTIextreme(hazardratio[HR],3.37;95%confidenceinterval [95% CI], 2.94 to 3.87; P,0.001). Survival was best with LTI between 15 and 20 kg/m2 and FTI between 4 and 15 kg/m 2 (probability of death during follow-up: ,5%). When taking the relation between both compartments into account, the interaction was significant (P=0.01). Higher FTI appeared protective in patients with low LTI (HR, 3.37; 95% CI, 2.94 to 3.87; P,0.001 at low LTI–low FTI, decreasing to HR, 1.79; 95% CI, 1.47 to 2.17; P,0.001 at low LTI–high FTI). Conclusions This large international study indicates best survival in patients with both LTI and FTI in the 10th–90th percentiles of a healthy population. In analyses of body composition, both lean tissue and fat tissue compartments and also their relationship should be considered. Clin J Am Soc Nephrol 10: ccc–ccc, 2015. doi: 10.2215/CJN.08550814
TL;DR: This study assessed how glomerular hyperfiltration is measured and defined in the literature and concluded that an age- and sex-matched control group should be used to define a GH threshold.
Abstract: Background and objectives Evaluation of glomerular hyperfiltration (GH) is difficult; the variable reported definitions impede comparisons between studies. A clear and universal definition of GH would help in comparing results of trials aimed at reducing GH. This study assessed how GH is measured and defined in the literature. Design, setting, participants, & measurements Three databases (Embase, MEDLINE, CINAHL) were systematically searched using the terms “hyperfiltration” or “glomerular hyperfiltration”. All studies reporting a GH threshold or studying the effect of a high GFR in a continuous manner against another outcome of interest were included. Results The literature search was performed from November 2012 to February 2013 and updated in August 2014. From 2013 retrieved studies, 405 studies were included. Threshold use to define GH was reported in 55.6% of studies. Of these, 88.4% used a single threshold and 11.6% used numerous thresholds adapted to participant sex or age. In 29.8% of the studies, the choice of a GH threshold was not based on a control group or literature references. After 2004, the use of GH threshold use increased ( P P 2 (median, 135 ml/min per 1.73 m 2 ). Conclusion Thirty percent of studies did not justify the choice of threshold values. The decrease of GFR in the elderly was rarely considered in defining GH. From a methodologic point of view, an age- and sex-matched control group should be used to define a GH threshold.
TL;DR: Mild hyperuricemia is strongly associated with the risk of CKD in patients with type 2 diabetes and serum uric acid was significantly associated with albuminuria only in presence of eGFR <60 ml/min per 1.73 m2.
Abstract: Background and objective Serum uric acid may predict the onset and progression of kidney disease, but it is unclear whether uric acid is an independent risk factor for diabetic nephropathy. Our aim was to study the relationship between uric acid levels and the development of CKD components in patients with type 2 diabetes. Design, setting, participants, & measurements Longitudinal study of a cohort of patients with type 2 diabetes from the database of the Italian Association of Clinical Diabetologists network. From a total of 62,830 patients attending the diabetes centers between January 1, 2004, and June 30, 2008, we considered those with baseline eGFR values ≥60 ml/min per 1.73 m 2 and normal albumin excretion ( n =20,142). Urinary albumin excretion, GFR, and serum uric acid were available in 13,964 patients. We assessed the association of serum uric acid quintiles with onset of CKD components by multinomial logistic regression model adjusting for potential confounders. We calculated the relative risk ratios (RRRs) for eGFR 2 , albuminuria, and their combination at 4 years. Results At 4-year follow-up, 1109 (7.9%) patients developed GFR 2 with normoalbuminuria, 1968 (14.1%) had albuminuria with eGFR ≥60 ml/min per 1.73 m 2 , and 286 (2.0%) had albuminuria with eGFR 2 . The incidence of eGFR 2 increased in parallel with uric acid quintiles: Compared with the lowest quintile, RRRs were 1.46 (95% confidence interval [CI], 1.14 to 1.88; P =0.003), 1.44 (95% CI, 1.11 to 1.87; P =0.006), 1.95 (95% CI, 1.48 to 2.58; P P 2 . Conclusions Mild hyperuricemia is strongly associated with the risk of CKD in patients with type 2 diabetes.
TL;DR: VC assessment using AS independently predicts death and time to hospitalization and could be a useful index to identify patients with CKD at high risk of death and morbidity as previously reported in patients on dialysis.
Abstract: Background and objectives Vascular calcification (VC) is common in CKD, but little is known about its prognostic effect on patients with nondialysis CKD. The prevalence of VC and its ability to predict death, time to hospitalization, and renal progression were assessed. Design, setting, participants, & measurements The Study of Mineral and Bone Disorders in CKD in Spain is a prospective, observational, 3-year follow-up study of 742 patients with nondialysis CKD stages 3–5 from 39 centers in Spain from April to May 2009. VC was assessed using Adragao (AS; x-ray pelvis and hands) and Kauppila (KS; x-ray lateral lumbar spine) scores from 572 and 568 patients, respectively. The primary end point was death. Secondary outcomes were hospital admissions and appearance of a combined renal end point (beginning of dialysis or drop >30% in eGFR). Factors related to VC were assessed by logistic regression analysis. Survival analysis was assessed by Cox proportional models. Results VC was present in 79% of patients and prominent in 47% (AS≥3 or KS>6). Age (odds ratio [OR], 1.05; 95% confidence interval [95% CI], 1.02 to 1.07; P 6 was independently associated with all-cause (hazard ratio [HR], 2.07; 95% CI, 1.07 to 4.01; P=0.03) and cardiovascular (HR, 3.46; 95% CI, 1.27 to 9.45; P=0.02) mortality as well as a shorter hospitalization event–free period (HR, 1.14; 95% CI, 1.06 to 1.22; P Conclusions VC is highly prevalent in patients with CKD. VC assessment using AS independently predicts death and time to hospitalization. Therefore, it could be a useful index to identify patients with CKD at high risk of death and morbidity as previously reported in patients on dialysis.
TL;DR: How the innate immune system recognizes and responds to nonself and danger signals is discussed and the roles of renal epithelial cells that make them an integral part of the innateimmune apparatus of the kidney are highlighted.
Abstract: The innate immune system is the first line of defense in response to nonself and danger signals from microbial invasion or tissue injury. It is increasingly recognized that each organ uses unique sets of cells and molecules that orchestrate regional innate immunity. The cells that execute the task of innate immunity are many and consist of not only “professional” immune cells but also nonimmune cells, such as renal epithelial cells. Despite a high level of sophistication, deregulated innate immunity is common and contributes to a wide range of renal diseases, such as sepsis-induced kidney injury, GN, and allograft dysfunction. This review discusses how the innate immune system recognizes and responds to nonself and danger signals. In particular, the roles of renal epithelial cells that make them an integral part of the innate immune apparatus of the kidney are highlighted.
TL;DR: HO phenotype was not associated with higher risk of incident CKD, and metabolically healthy nonobesity phenotype after adjustment for confounders was found to be similar.
Abstract: Background and objectives Metabolically healthy obesity (MHO) is a unique obesity phenotype that apparently protects peoplefromthemetaboliccomplications ofobesity. The associationbetween MHO phenotypeandincident CKD is unclear. Thus, this study investigated the association between MHO phenotype and incident CKD. Design, setting, participants, & measurements A total of 3136 Japanese participants were enrolled in an 8-year follow-up cohort study in 2001. Metabolically healthy status was assessed by common clinical markers: BP, triglycerides, HDL cholesterol, and fasting plasma glucose concentrations. Body mass index $25.0 kg/m2 was defined as obesity. CKD was defined by proteinuria or eGFR of ,60 ml/min per 1.73 m2. To calculate the odds ratio for incident CKD, logistic regression analyses were performed. Results The crude incidence proportions of CKD were 2.6% (56 of 2122 participants) in participants with the metabolically healthy nonobesity phenotype, 2.6% (8 of 302) in those with the MHO phenotype, 6.7% (30 of 445) in those with the metabolically abnormal nonobesity phenotype, and 10.9% (29 of 267) in those with the metabolically abnormal obesity phenotype. Compared with metabolically healthy nonobesity phenotype, the odds ratios for incident CKD were 0.83 (95% confidence interval [95% CI], 0.36 to 1.72; P=0.64) for MHO, 1.44 (95% CI, 0.80 to 2.57; P=0.22) for metabolically abnormal nonobesity, and 2.80 (95% CI, 1.45 to 5.35; P=0.02) for metabolically abnormal obesity phenotype after adjustment for confounders, including age, sex, smoking statues, alcohol use, creatinine, uric acid, systolic BP, HDL cholesterol, and impaired fasting glucose or diabetes. Conclusion MHO phenotype was not associated with higher risk of incident CKD.
TL;DR: Lenticonus and central fleck retinopathy strongly suggest the diagnosis of Alport syndrome and are associated with renal failure before the age of 30 years, in males with X-linked disease.
Abstract: Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities Mutations in the COL4A5 (X-linked), or COL4A3 and COL4A4 (autosomal recessive) genes result in absence of the collagen IV α3α4α5 network from the basement membranes of the cornea, lens capsule, and retina and are associated with corneal opacities, anterior lenticonus, fleck retinopathy, and temporal retinal thinning Typically, these features do not affect vision or, in the case of lenticonus, are correctable In contrast, the rarer ophthalmic complications of posterior polymorphous corneal dystrophy, giant macular hole, and maculopathy all produce visual loss Many of the ocular features of Alport syndrome are common, easily recognizable, and thus, helpful diagnostically, and in identifying the likelihood of early-onset renal failure Lenticonus and central fleck retinopathy strongly suggest the diagnosis of Alport syndrome and are associated with renal failure before the age of 30 years, in males with X-linked disease Sometimes, ophthalmic features suggest the mode of inheritance A peripheral retinopathy in the mother of a male with hematuria suggests X-linked inheritance, and central retinopathy or lenticonus in a female means that recessive disease is likely Ocular examination, retinal photography, and optical coherence tomography are widely available, safe, fast, inexpensive, and acceptable to patients Ocular examination is particularly helpful in the diagnosis of Alport syndrome when genetic testing is not readily available or the results are inconclusive It also detects complications, such as macular hole, for which new treatments are emerging
TL;DR: This review describes in broad terms the main divisions of the immune system (innate and adaptive), their cellular and tissue components, and the ways by which they function and are regulated.
Abstract: This review serves as an introduction to an Immunology Series for the Nephrologist published in CJASN. It provides a brief overview of the immune system, how it works, and why it matters to kidneys. This review describes in broad terms the main divisions of the immune system (innate and adaptive), their cellular and tissue components, and the ways by which they function and are regulated. The story is told through the prism of evolution in order to relay to the reader why the immune system does what it does and why imperfections in the system can lead to renal disease. Detailed descriptions of cell types, molecules, and other immunologic curiosities are avoided as much as possible in an effort to not detract from the importance of the broader concepts that define the immune system and its relationship to the kidney.
TL;DR: FRAX was able to predict major osteoporotic fractures in individuals with reduced kidney function; further study is needed before FRAX should be routinely used in Individuals with reducing kidney function.
Abstract: Background and objectives The Fracture Risk Assessment Tool (FRAX) is widely used to predict the 10-year probability of fracture; however, the clinical utility of FRAX in CKD is unknown. This study assessed the predictive ability of FRAX in individuals with reduced kidney function compared with individuals with normal kidney function. Design, setting, participants, & measurements The discrimination and calibration (defined as the agreement between observed and predicted values) of FRAX were examined using data from the Canadian Multicentre Osteoporosis Study (CaMos). This study included individuals aged ≥40 years with an eGFR value at year 10 of CaMos (defined as baseline). The cohort was stratified by kidney function at baseline (eGFR Results There were 320 individuals with an eGFR Conclusions This study showed that FRAX was able to predict major osteoporotic fractures in individuals with reduced kidney function; further study is needed before FRAX should be routinely used in individuals with reduced kidney function.
TL;DR: Higher indices of arterial stiffness are associated with steeper decline in kidney function, which suggests that vascular stiffness could be considered as a target for delaying decline in kidneys function.
Abstract: Background and objectives The independent link between arterial stiffness and CKD remains unknown. We investigated the association of indicators of arterial stiffness with decline in kidney function. Design, setting, participants, & measurements We studied 3666 participants (mean age =65 years old; 58% women) from the Rotterdam Study. Pulse pressure (PP), carotid stiffness, and pulse wave velocity (PWV) were measured.We created genetic risk scores for PP and PWV. Annual declines in kidney function and incident CKD were assessed using eGFR. To put our findings in context of the literature, we performed a meta-analysis of the available population–based studies. Results After a median (interquartile range) follow–up time of 11 (10.7–11.3) years, 601 participantswith incident CKD were recognized. In the model adjusted for age, sex, mean arterial pressure, heart rate, and baseline GFR, each SD higher PP was associated with 0.15-ml/min per 1.73 m2 steeper annual eGFR decline (95% confidence interval [95% CI], 0.10 to 0.20) and 11%higher risk of incident CKD(95% CI, 1.05 to 1.18). Each SD greater carotid stiffnesswas associatedwith 0.08-ml/min per 1.73m2 steeper annual eGFR decline (95%CI, 0.04 to 0.13) and 13% higher risk of incident CKD (95% CI, 1.05 to 1.22). Each SD higher PWV was associated with 7% higher risk of incident CKD (95% CI, 1.00 to 1.14). Incorporating our findings in a meta-analysis, each SD higher PP and PWV were associated with 16% (95% CI, 1.12 to 1.21) and 8% (95% CI, 1.03 to 1.14) higher risks of incident CKD. Each SD higher PP genetic risk score was associated with 0.06-ml/min per 1.73 m2 steeper annual eGFR decline (95% CI, 0.01 to 0.10) and 8%higher risk of incident CKD(95% CI, 1.03 to 1.14). Therewas no association between PWV genetic risk score and kidney function decline. Conclusions Higher indices of arterial stiffness are associated with steeper decline in kidney function. This suggests that vascular stiffness could be considered as a target for delaying decline in kidney function.