Pathogenesis, Clinical Manifestations, and Natural History of Diabetic Kidney Disease

John Feehally DM, FRCP , in Comprehensive Clinical Nephrology , 2019

Measurement of Albuminuria or Proteinuria

As alluded to earlier, moderately increased albuminuria (previously microalbuminuria) is arbitrarily defined equally excretion of 30 to 300 mg albumin/24 h in at least two of 3 consecutive urine samples ( Table 30.1). There is substantial private twenty-four hours-to-day variation in albumin excretion (coefficient of variation, 30% to fifty%) and also between day and night collections (Fig. 30.eighteen). Even in the upper quantiles of so-called normoalbuminuria, the risk for progression and cardiovascular events is elevated. At concentration of 30 to 300 mg/24 h, albumin is normally not detected by nonspecific tests for poly peptide (e.g., Biuret reaction). Albumin can be detected, however, by use of specific techniques such as dipstick, enzyme-linked immunosorbent analysis, nephelometry, and radioimmunoassay. Instead of difficult-to-obtain 24-hr urine collections, the albumin concentration can be determined in spot urine or, better, first-void morn urine samples. The normal range is less than twenty µg/ml.

The detection of urinary albumin is a specific indicator of DN only if confounding factors such as fever, physical practice, urinary tract infection, nondiabetic renal disease, hematuria from other causes, heart failure, uncontrolled hypertension, and uncontrolled hyperglycemia have been excluded. 78

The main advantage of searching for microalbuminuria early on in the course of diabetes is that it predicts a high renal and cardiovascular adventure and thus allows targeted intervention. The American Diabetes Association (www.diabetes.org) and other societies recommend annual testing of all diabetic patients.

By definition, in that location is clinically overt DKD (severely increased albuminuria; formerly macroalbuminuria) if the charge per unit of albumin excretion exceeds 300 mg/twenty-four hours. At this point, serum proteins other than albumin are normally excreted in the urine as well (nonselective proteinuria).

Although at that place are few guidelines regarding repeated measures of albuminuria or proteinuria after a diagnosis of diabetic kidney disease has been established, Kidney Affliction: Improving Global Outcomes (KDIGO) recommends using the albumin-to-creatinine ratio or protein-to-creatinine ratio annually to determine if there is disease progression, 78 although assaying the urine ratio of albumin to creatinine can be much more expensive in sure countries.

Albuminuria

Hiddo J. Lambers Heerspink , ... Dick de Zeeuw , in Chronic Renal Disease, 2015

Changes in Albuminuria Predict Changes in Renal Outcome

Not only the level of urinary albuminuria excretion itself simply besides changes in urinary albumin excretion over time predict renal risk changes. Regression or progression of albuminuria frequently occurs, every bit shown in studies of patients with type 2 diabetes and in the general population. 35,36 Patients with type 2 diabetes in whom albuminuria declined by more than 50% over 2 years' follow-up had a subsequent balmy eGFR turn down (-i.8   mL/min/year). 37 In contrast, in subjects in whom albuminuria stayed high, long-term renal office decline was substantial (-3.ane   mL/min/yr). These information imply that albuminuria should be regularly measured to monitor the individual renal risk prediction.

Given that albuminuria regression and progression frequently occur and that progression of albuminuria precedes a progressive decline in renal function, it is of interest to analyze which factors predict progression or regression of albuminuria. In blazon i diabetes, baseline albuminuria, blood force per unit area, HbA1c, and male gender predicted progression of albuminuria. 38 In patients with type 2 diabetes, baseline albuminuria and blood pressure level correlated with progression in albuminuria. 39 Factors that independently predict progression in albuminuria in the general population evidence not bad overlap with factors identified in diabetic populations. In the PREVEND study (a general population report), higher baseline albuminuria, age, body mass alphabetize, and male gender predicted progressive albuminuria. twoscore In these studies the baseline albuminuria level itself was a strong contained predictor of progressive albuminuria. 38,39 These data imply that monitoring of albuminuria over time, even in the absenteeism of other renal or cardiovascular risk factors, is important to place individuals at run a risk of renal disease.

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Biomarkers in Acute and Chronic Kidney Diseases

Alan S.L. Yu MB, BChir , in Brenner and Rector's The Kidney , 2020

Albuminuria

Albuminuria is recognized equally 1 of the well-nigh important take a chance factors for the progression of CKDs. Albumin is a major serum protein with a size slightly larger than the pores of the glomerular filtration membrane, and so albuminuria is best known as a biomarker of glomerular dysfunction; its appearance in large amounts in urine represents compromised integrity of the glomerular basement membrane. 366 In smaller amounts, however, the presence of albumin in the urine may reverberate tubular injury. Albuminuria is classified in the KDIGO classification system equally A1 (UAE < 30 mg/day or urine ACR [uACR] < 30 mg/g creatinine), A2 (previously termed "microalbuminuria"; urinary albumin excretion, 30–300 mg/mean solar day, or uACR, 30–300 mg/1000 creatinine) and A3 (previously termed "macroalbuminuria"; urinary albumin excretion > 300 mg/day or uACR > 300 mg/thou creatinine). In a number of clinical studies, albuminuria has been shown to be a sensitive biomarker of drug-induced tubular injury. 367,368 It is routinely used every bit a marker of kidney damage for making a CKD diagnosis at eGFR levels above 60 mL/min/1.73 grandtwo. 359 Guidelines of the National Kidney Foundation (NKF) and American Centre Clan (AHA) include microalbuminuria, too as an increase in the urinary full protein excretion, as a risk gene for renal and cardiovascular disease. Both NKF and AHA guidelines propose measurement of the uACR in an untimed spot urine sample. Ideally, the uACR should be assessed in at least 3 different samples to decrease intraindividual variation. 369 Albuminuria is a continuous hazard factor for ESRD and cardiovascular mortality, with no lower limit, even after aligning for the eGFR and other established risk factors. 370–372 Urinary albumin has been used as a biomarker for monitoring CKD progression and potential therapeutic efficacy, although the FDA does not take albuminuria equally a surrogate marker. Using microalbuminuria as a marking, Levin and colleagues have demonstrated that N-acetylcysteine may benumb contrast-induced glomerular and tubular injury. 373

In the past several years, in that location have been increased investigations of albuminuria equally a biomarker for AKI. In a large-scale, collaborative meta-analysis, Grams and colleagues combined data from viii full general population cohorts (ane,285,049 subjects) and v CKD cohorts (79,519 subjects) to investigate the association of albuminuria and other factors with AKI. 374 The primary consequence for this written report was hospitalization for AKI. Using Cox proportional hazards models, they demonstrated that the incidence of AKI was higher in those with CKD (2.6%) compared with the general population (ane.3%). Additionally, compared with those with an uACR < 5 mg/grand, the risk of AKI with uACR > 300 mg/g was 2.73 (2.18–3.43]. 374 Thus, increased uACR is a strong risk factor for the long-term risk of developing of AKI.

Chronic kidney disease, end-phase renal disease, and os marrow transplant

CLAUDE BASSIL , in Onco-Nephrology, 2020

Albuminuria and chronic kidney illness after hematopoietic stalk prison cell transplantation

Albuminuria, defined as a urine albumin:urine creatinine ratio (ACR) of 30 to 300 mg/g, is commonly used as a surrogate marker of systemic endothelial dysfunction and inflammation, affecting many organs, including the kidney. Albuminuria occurs frequently after HSCT and it correlates with acute GVHD (aGVHD), bacteremia, hypertension (HTN), and progression of renal disease. 10 Albuminuria at day 100 mail-HSCT was associated with CKD at 1 yr, 10 as defined past a glomerular filtration charge per unit (GFR) beneath 60 mL/min/1.73 m2, using the abbreviated modification of diet in renal disease equation, afterward adjusting for chronic GVHD (c-GVHD), HTN, diabetes, and age. In addition, Hingorani and colleagues proposed a possible intrarenal inflammation later HSCT, by identifying elevated urinary levels of proinflammatory cytokines (interleukin [IL]-6, IL-xv, and elafin), which were associated with the evolution of albuminuria and proteinuria (Table 15.i and Fig. 15.i). Urinary elafin is an endogenous serine protease inhibitor, produced by epithelial cells and macrophages in response to tissue inflammation. 11 An elevated urinary elafin level is associated with both acute kidney injury and CKD. 11 Furthermore, albuminuria and proteinuria inside the get-go 100 days postal service-HSCT are associated with decreased overall survival. 12

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Cardiorenal Syndromes

Alan S.L. Yu MB, BChir , in Brenner and Rector's The Kidney , 2020

Albuminuria

Albuminuria and proteinuria oftentimes develop and are hallmarks of CKD. Every bit such, in patients who have AKI or CKD complicated by HF (CRS blazon three or 4), albuminuria is often present and has been the focus of all-encompassing research. In patients with HF complicated by CKD, worsening renal function, or AKI, albuminuria has been observed equally well. 67,68 In patients with chronic HFREF or HFPEF, three retrospective analyses from randomized studies accept shown that albuminuria is present in upward to 41% of patients (20%−xxx% microalbuminuria, 5%−eleven% macroalbuminuria). 67,69 Like prevalences were observed in ane single-center written report of stable HFPEF patients. 70 In astute HF, fewer data are available. Using a dipstick test to evaluate proteinuria, 55% of patients with astute HF had a positive dipstick examination in a Chinese cohort. 71 In a pocket-sized cohort of 100 acute HF patients from Portugal, only 26% to 40% of patients with acute HF presented with normoalbuminuria. 72 In all these analyses, including whatsoever HF phenotype, the presence of albuminuria was associated with a college chance of cardiovascular events, independent of baseline eGFR. Furthermore, neither ARB nor statin treatment was able to reduce the urinary albumin excretion rate significantly. 67,68

The pathophysiology of increased albumin excretion in HF, as discussed earlier, is probably different from albuminuria in hypertension, diabetes, and other cardiovascular disease, including CKD without HF. Whereas in these conditions it is thought that college intraglomerular pressures (either primarily or as an adaptive process) induce structural glomerular changes, podocyte dysfunction, and somewhen leakage of macromolecules such as albumin, in HF the intraglomerular pressures are (probably) low. The reasons for low intraglomerular pressures are a depression RBF, a low efferent arteriolar tone in the presence of RAAS inhibitor therapy, and probably loftier afferent arteriolar tone in very low cardiac output states. Indeed, in the most severe chronic HFREF patients, RBF, GFR, and FF are low, whereas renal vascular resistance and albumin excretion are high. 32 This suggests that the pathophysiology of albumin excretion in HF must exist distinctly different from that observed in hypertension, diabetes, and intrinsic renal disease. Proposed mechanisms include endothelial dysfunction and inflammation, structural glomerular harm, and changes in the glycocalyx, as well as podocyte dysfunction.

Whether higher renal venous pressure and associated college renal interstitial pressures also contribute to albuminuria is unknown. Most interestingly, and reinforcing the notion that albuminuria must be different in HF compared with CKD, sacubitril/valsartan treatment in HFPEF and HFREF actually increases urinary albumin excretion, only leads to substantially reduced rates of agin cardiovascular outcomes. 73,74 This essentially indicates that together with a lack of upshot of both statin and ARB treatment on albumin levels, albuminuria by itself serves as a risk marker, rather than as a run a risk factor, in HF. 75

Diabetes

Daniel Y. Li BSc , W.H. Wilson Tang Doc , in Glucose Intake and Utilization in Pre-Diabetes and Diabetes, 2015

Albuminuria

Albuminuria, previously termed microalbuminuria, is a status where moderately raised albumin levels can be detected in the urine [188]. Traditionally, increased levels of urine albumin have been considered to exist a precursor of diabetic nephropathy but studies now have also demonstrated that albuminuria is besides linked to adverse cardiovascular outcomes and death [189]. A majority of proteins in urine is albumin that is filtered from the plasma, and a normal healthy individual will be expected to lose <xxx   mg in a twenty-four hours [190]. Even so, the mechanism by which albuminuria is reflective of CVD is not well understood. Evidence to appointment associates any level of albuminuria to a loss of vascular endothelial office in many organs. Impaired endothelial synthesis of nitric oxide has been independently associated with albuminuria and diabetes [191–193]. This provides a common mechanism for both increased cardiovascular and renal risk in patients with elevated albuminuria. Additionally, depression levels of heparan sulfate in the glomerular glycocalyx lining as a result of low chronic inflammation in atherosclerosis could lead to increased glomerular permeability and albumin secretion [194]. Furthermore, there is an clan of moderately elevated albuminuria with agin risk factors such as age, increased claret pressure, and increased inflammatory markers in patients with or without diabetes [195,196].

One of the benefits of albuminuria is that it is easily measured in the urine with 24-h urine albumin excretion being the gold standard. Although this method is more cumbersome and fourth dimension-consuming, information technology can exist more reliable than the albumin–creatinine ratio (ACR) across historic period, weight, and serum creatinine concentrations. The 24-h method quantifies moderate pinnacle of albumin as ≥30   mg/twenty-four hours and severe meridian every bit ≥300   mg/twenty-four hour period [188]. Urine ACR tin can be used to eliminate confounding values of urine volume on albumin concentration. Some confounding factors to consider for ACR would be differing creatinine ratios with race, diet, and musculus mass. Yet, this test is fourth dimension-saving, well correlated with the 24-h urine albumin excretion, and the preferred screening strategy for moderately increased albuminuria [197]. Normal or slightly increased ratios are defined as <30   mg/g of creatinines. Moderately increased levels are ≥xxx   mg/g of creatinine and severely increased levels are considered to be ≥300   mg/g of creatinine [188]. It is important to annotation that the terms micro- and macroalbuminuria refer to albumin secretions of 30–299   mg/24   h and more than 300   mg/24   h, respectively [198]. However, the lack of pathologic basis to these thresholds has caused guidelines to modify their recommendation of using these terms.

Epidemiological evidence has established that diabetes is ane of the most mutual causes for end-stage renal disease. NHANES Iii data has found that 28.2% of patients with T2DM take moderately elevated albuminuria [199]. Of these patients, approximately 20–twoscore% will develop renal failure. However, this total may be college if the patients did non die due to cardiovascular complications first. Convincing evidence in recent years has independently associated albuminuria with adverse cardiovascular outcomes. Population studies accept observed moderately elevated albuminuria to exist significantly correlated with cardiovascular risk. In one study of a Prevention of REnal and Vascular ENdstage Illness (PREVEND) population, twoscore,000 patients were observed for a median of 2.6 years [200,201]. A 1.35-fold increase of cardiovascular mortality was documented for each doubling of urine albumin excretion. Later on, analysis of the trial also observed that the risk of MACE was reduced among the participants whose albuminuria decreased later on one-twelvemonth follow-up [202]. Furthermore, college levels of albumin excretion even in the "normal" range have also been shown to be associated with increased cardiovascular risk. In the Third Copenhagen Heart Study, healthy patients within the top quartile of albumin excretion with 6.nine   mg/day had an RR=2 for CAD [203]. Similar findings from the Framingham Heart Report subgroup saw healthy participants with higher-than-median ACR developing a greater adventure for offset cardiovascular upshot afterwards 6 years follow-up [204]. Finally, a meta-analysis involving over 1 meg participants in the general population saw increased risk of MI, heart failure, stroke, or sudden cardiac expiry associated with rising levels of ACR [205].

Potent observations of albuminuria and association of center disease exist, but several trials testing the treatment of albuminuria take been conducted without parallel benefit demonstrated across these studies. The Losartan Intervention for Endpoint Reduction (LIFE) in hypertension trial suggested a decreased adventure for cardiovascular events when utilizing the magnitude of albuminuria as a guide to angiotensin-converting enzyme receptor blocker (ARB) therapy [206,207]. The results from LIFE were more striking from the diabetes subgroup, in which losartan was associated with a reduction of 24% in the primary endpoint, and a meaning reduction of 37% in CV and 39% in all-cause mortality. Meta-analysis of over 8000 patients by Maione et al. saw reduced risk of nonfatal cardiovascular outcomes with ACEi or ARB in patients with at least 1 cardiovascular risk factor and albuminuria [208]. All the same, Maione et al. did not observe any reduced rates of cardiovascular mortality. Furthermore, a meta-analysis for the USPSTF by Fink et al. looking at 18 trials of ACEi and 4 of ARB observed the aforementioned lack of association betwixt therapeutics and cardiovascular death [209]. Finally, the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) trial evaluated the combination of ACEi and ARB in patients with diabetes or pre-existing peripheral vascular illness [210]. They observed that increased baseline albuminuria was associated with worse cardiovascular outcomes only not beyond ACR baseline values of ten   mg/g of creatinine.

In the absenteeism of clear data for improved cardiovascular outcomes with albuminuria-guided therapy, it is difficult to make clear recommendations on cardiovascular management strategies utilizing this marker. The improver of ACEi or ARB appears to improve nonfatal cardiac endpoint. However, the other deleterious effects of these drugs such as hyperkalemia may affect the overall mortality of these patients. Despite these observations, monitoring levels of albuminuria is still important for the development of other pathologies. Because albuminuria has been besides demonstrated to be independently associated with increased mortality independent of diabetes, many guidelines recommend annual screening for albuminuria in diabetes patients or patients already at high risk for albuminuria [viii,211,212].

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Volume ii

Erik Ilsø Christensen , ... Henrik Birn , in Seldin and Giebisch's The Kidney (Fifth Edition), 2013

Introduction

Albuminuria is one of the oldest nonetheless remains ane of the nearly sensitive and widely used markers of kidney dysfunction. Albumin is the most abundant plasma protein 1 and its urinary excretion is determined by the combined effects of glomerular filtration and renal tubular processing (Fig. 73.1). Dysfunction of both these processes may result in increased excretion of albumin, and glomerular injuries as well as tubular harm accept been implicated in the initial events leading to albuminuria. Albuminuria non only indicates acute or chronic renal damage but is also a well established and independent marker of progression in chronic kidney disease (CKD). Interventions aimed at reducing albuminuria have proved effective in ameliorating the continuous loss of renal function in various form of CKD suggesting that albuminuria not merely is a marking of kidney illness but in fact involved in the pathophysiology of progression. Experimental bear witness points to direct and deleterious effects of albumin on renal tubular cells and identifies a number of downstream mediators initiating inflammation and eventually renal fibrosis.

Effigy 73.1. Renal albumin handling. Plasma albumin is filtered in the glomeruli (A). Filtered albumin may exist taken up by podocytes (B) maybe by a megalin mediated process. Information technology is not clear whether albumin is taken up from the subepithelial space or from the urinary space, or both. Filtered albumin is reabsorbed in the proximal tubule by megalin and cubilin/AMN mediated endocytosis (C). Albumin is degraded inside the lysosomal compartment and amino acids are released at the basolateral cell surface. Nether proteinuric weather, albumin, not reabsorbed by the proximal tubule, may be taken up by more than distal nephron segments or collecting ducts (D) past an unknown mechanism (see also figure 74.half-dozen). Depending on the balance between glomerular filtration of albumin and the tubular reabsorptive and degradative capacity, albumin and albumin fragments may exist excreted in the urine (E). Urinary albumin fragments accept been identified, however, the origin and significance of these remain unclear.

Factor analyses in man diseases and beast knockout models accept identified a number of key molecules regulating glomerular filtration and tubular reabsorption of albumin. In most cases of human disease, however, both the precipitating events and the accelerating mechanisms associated with albuminuria are unknown and may include several, different pathways. The relative importance of the various molecular mechanisms regulating glomerular filtration and tubular handling of albumin remain controversial both in normal physiology and in disease and the show for an contained pathogenic role of albumin in the development and progression of renal disease is debated.

This chapter will review the structures controlling glomerular filtration of albumin and discuss the molecular and pathophysiological mechanisms causing changes in glomerular permselectivity. Furthermore, the receptors regulating tubular reuptake of filtered albumin are presented and the possible pathways by which filtered albumin may cause tubular and interstitial damage are discussed in relation to acute and chronic kidney disease.

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Volume I

Yan Chun Li , in Vitamin D (Tertiary Edition), 2011

Renoprotection of Vitamin D Therapy in Chronic Kidney Disease

Albuminuria is a major risk factor for progressive renal function decline and is believed to be the initial step in an inevitable progression to proteinuria and renal failure in humans. Thus reduction of albuminuria is a major target for renoprotective therapy in CKD. A number of epidemiological and clinical studies have demonstrated stiff antiproteinuric activity of vitamin D and vitamin D analogs. In a big accomplice cross-sectional assay of information from the NHANES 3, vitamin D insufficiency was institute to be associated with increased prevalence of albuminuria [148], suggesting that vitamin D has an intrinsic antiproteinuric property. The therapeutic antiproteinuric activity of vitamin D analogs was first reported in a retrospective assay of patients with CKD [149]. In that report the antiproteinuric outcome of paricalcitol was seen even in subjects already treated with ACEI or ARB, indicating that the effects of vitamin D analogs are on superlative of those of ACEI and ARB. A recent randomized double-blinded pilot trial in patients with stage ii–3 CKD (n   =   24) showed that paricalcitol treatment for 1   month significantly reduced albuminuria and inflammation status in the drug-treated subjects, and these effects were independent of its effects on hemodynamics and PTH suppression [99]. Again, every bit the CKD patients in this study were already on ACEI or ARB treatment, the benign furnishings of vitamin D analogs are additive or synergistic to those of RAS inhibitors. These clinical information warrant larger and long-term randomized, controlled trials to ostend the therapeutic benefits of vitamin D and its analogs.

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Vitamin D and the Renin-Angiotensin System

Yan Chun Li , in Vitamin D (Fourth Edition), 2018

Vitamin D Therapy of Chronic Kidney Disease

Albuminuria is a major risk factor for progressive renal function decline and is believed to be the initial step in an inevitable progression to proteinuria and renal failure in humans. Thus reduction of albuminuria is a major therapeutic target in the direction of CKD. A number of epidemiological and clinical studies accept demonstrated potent antiproteinuric activity of vitamin D and vitamin D analogs. In a large accomplice cross-sectional analysis of the NHANES (1988–94) data, vitamin D insufficiency was found to exist associated with increased prevalence of albuminuria [214], suggesting that vitamin D has an intrinsic antiproteinuric holding. A post hoc analysis of the Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of CKD in Pediatric Patients (ESCAPE) cohort (n   =   167) showed that normal serum 25(OH)D levels are associated with less proteinuria and greater preservation of renal part in children with CKD [215]. Moreover, vitamin D deficiency was found to be independently associated with a higher take a chance of affliction progression of diabetic nephropathy in patients with type 2 diabetes and CKD [216].

The therapeutic antiproteinuric activeness of activated vitamin D analogs was starting time reported in a retrospective analysis of patients with CKD [217]. In that study the antiproteinuric effect of paricalcitol was seen even in subjects already treated with ACEI or ARB, indicating that the consequence of vitamin D analogs is in improver to those of ACEI and ARB. A subsequent randomized double-blinded pilot trial in patients with stage 2–3 CKD (n   =   24) showed that paricalcitol treatment for 1   calendar month significantly reduced albuminuria and inflammation status in the drug-treated subjects, and these effects were independent of its effects on hemodynamics and PTH suppression. Again, every bit the CKD patients in this study were already on ACEI or ARB treatment, the beneficial effects of vitamin D analogs are additive or synergistic to those of RAS inhibitors [113]. Another trial also reported that calcitriol reduced albuminuria too as urinary AGT in patients with type ii diabetes who were on RAS inhibitors (north   =   98) [218]. The larger VITAL randomized trial (north   =   281) confirmed that paricalcitol was able to safely reduce residual albuminuria in patients with type 2 diabetes who were receiving ACEIs or ARBs, suggesting that agile vitamin D analogs could exist a novel approach to lower residual renal risk in diabetes [114]. In fact, rest proteinuria, the amount of proteinuria that remains during optimally dosed RAS blockade, is an contained take a chance factor for progressive renal function loss and cardiovascular complications in CKD patients, and it has been proposed that agile vitamin D or its analogs be used to target balance proteinuria as an adjunct to RAS blockade in the management of CKD patients [219,220]. It is believed that in this state of affairs, vitamin D acts at least partially through suppressing the reactive induction of renin in humans. Indeed, paricalcitol has been reported to essentially reduce plasma renin activity in hemodialysis patients [107].

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The Glomerulus: Mechanisms and Patterns of Injury☆

B. Bikbov , ... G. Remuzzi , in Reference Module in Biomedical Sciences, 2014

Markers of Increased Glomerular Permeability to Macromolecules

The glomerular capillary wall consists of endothelium, the glomerular basement membrane (GBM), and podocytes, which make up one's mind the size- and accuse-selective properties of the glomerular barrier to macromolecules ( Table one ).

In intact kidneys, as much as 0.12   g of albumin per day in rats (Sangalli et al., 2011) and 0.6   g of albumin per day in normal humans (Comper et al., 2008) are idea to be filtered through the glomerular capillary wall. This amount is reabsorbed by proximal tubules. With usual laboratory methods, proteins are undetectable in the urine of good for you persons. Increases in glomerular permeability due to alterations in the properties of glomerular capillary wall, or tubular dysfunction due to a disturbance of protein reabsorption, could lead to detectable proteinuria.

Injury of any component of glomerular capillary wall could lead to loss of its selective properties with passage of increased amounts of proteins in the Bowman's space. In disease, insults usually touch on the podocyte, but in some weather such equally anti-GBM illness, thrombotic microangiopathy, or handling with anti-vascular endothelial growth factor (VEGF) antibodies, selective injury of GBM or endothelium occurs.

Podocyte foot processes form slit diaphragms, and many proteins that contribute to sustain the normal structure of the slit diaphragm have been identified: nephrin, podocin, CD-2-associated protein (CD2AP), protocadherin Fat, P-cadherin, and Zonula occludens protein 1 (ZO-ane) (Boute et al., 2000; Inoue et al., 2001; Reiser et al., 2000; Ruotsalainen et al., 1999; Shih et al., 1999). Some of these proteins as well play an important role in signal transduction regulating podocyte polarity, survival, and cytoskeleton organization (Shankland, 2006). Many nephrotoxic substances lead to podocyte injury resulting in foot process effacement, which is associated with disruption of the actin cytoskeleton network (Benzing, 2004). Nephrin, the podocyte-specific protein that constitutes the major office of the filtration slit diaphragm (Ruotsalainen et al., 1999), participates in the regulation of actin cytoskeleton organization of the podocyte. Recently, in puromycin aminonucleoside (PA)-induced nephrosis, the phosphorylation of nephrin was shown to be decreased, and this effect preceded the development of overt proteinuria (Uchida et al., 2008).

Anionic apical podocyte proteins, podocalyxin and podoplanin, also play important roles in both GBM charge selectivity and cytoskeleton organisation (Shankland, 2006). The cytoplasmic domain of podocalyxin is linked to the actin cytoskeleton through Na+/H+ exchanger regulatory gene (NHERF)/ezrin, and their dissociation leads to pes procedure effacement (Takeda et al., 2001). This result is oft associated with detachment of podocytes from the GBM, loss of slit diaphragms, and replacement of slit diaphragms past tight junctions, and as such is a major ultrastructural hallmark of clinical proteinuria (Shankland, 2006).

Albuminuria

Albuminuria is a sensitive marking of changes in glomerular permeability to macromolecules. In more than than 500 patients, two contained groups ( Gosling et al., 2006; Thorevska et al., 2003) plant spot urine albumin/creatinine ratios to be a prognostic marker of illness severity and bloodshed in patients with AKI and this ratio had a similar predictive value of astute physiology and chronic wellness evaluation scale (APACHE) Ii or sequential organ failure assessment score (SOFA) scores. In these patients, serial measurement of the albumin/creatinine ratio could aid in monitoring the effect of systemic inflammation on glomerular microvasculature (Gosling et al., 2006).

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