chronic kidney disease

Edited byDr. Luca Di Lullowww.esciencecentral.org/ebooks

Ultrasound Approach to

Chronic Kidney Disease

and its Complications

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Ultrasound Approach to Chronic Kidney Disease and its Complications

Chapter: Chronic Kidney Disease

Edited by: Luca Di Lullo

Published Date: June 2014

Published by OMICS Group eBooks

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Ultrasound Approach to Chronic Kidney Disease and its ComplicationsEdited by: Luca Di Lullo

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IntroductionChronic kidney disease (CKD) is a pathophysiologic process characterized by progressive

loss of nephrons and function due to multiple etiologies and frequently leading to end stage renal disease (ESRD). The incidence and prevalence of CKD are increasing every year all over the world mainly driven by the ageing of the general population, rising incidence of obesity as well as type 2 diabetes mellitus and improved survival from cancer as well as major cardiovascular accidents. The clinical and public health importance of CKD is well established. CKD in the long run progresses to ESRD and eventual need for renal replacement therapy. It also predispose to increased risk of cardiovascular disease. This has impact not only on the economy but also place a formidable effect on the mortality especially cardiovascular mortality. Major causes of CKD include hypertension, diabetes mellitus, glomerulonephritis, cystic kidney disease, urinary tract obstruction, interstitial nephritis, vesico-ureteric reflux, nephrolithiasis and recurrent kidney infection. At the same time it is important to emphasize that there is a natural physiological reduction in glomerular filtration rate (GFR) with aging which behaves differently from the various etiologies mentioned above in terms of progression of the disease. Although the renal prognosis is favorable in most patients who demonstrate age related drop in GFR, even a modest reduction in GFR in this population is associated with increased risk of cardiovascular morbidity and mortality [1].

Epidemiology of chronic kidney diseaseCKD affects almost 14–15% of the adult United States (U.S) population [2]. The prevalence

of CKD is highest in the elderly population especially those above the age of 65 years [3]. While the incidence and prevalence of CKD is increasing every year, not all patients with CKD progress to ESRD. This is mostly because of the fact that a significant proportion of patients with CKD die before reaching dialysis [4]. Currently almost 600000 people in U.S are undergoing hemodialysis for ESRD [2].

Pathophysiology of Chronic Kidney DiseaseThe pathophysiology of CKD involves initiating mechanisms specific to the underlying

etiology as well as a set of progressive mechanisms viz, glomerulosclerosis and tubulo-

Bijin Thajudeen*Assistant Professor, University of Arizona, Department of Nephrology, Tucson, USA*Corresponding author: Bijin Thajudeen, Assistant Professor, University of Arizona, Department of Nephrology, PO box 245022, Room 6325, 1501, North Campbell Ave, Tucson, AZ 85724, USA, Tel: 5206266371; Fax: 5206262024; E-mail: [email protected], [email protected]

Chronic Kidney Disease

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interstitial fibrosis that are common consequences following long term reduction in renal mass, irrespective of the etiology [5]. Structural and functional changes in surviving nephrons lead to hypertrophy and hyper filtration of the surviving nephrons. This compensatory hypertrophy mediated by vasoactive molecules, cytokines, growth factors and renin angiotensin axis mediators eventually lead to intra-glomerular hypertension and accelerated sclerosis of surviving nephrons. Raised intra-glomerular hypertension will lead to reduction of glomerular permeability and filtration surface area resulting in decreased GFR [6] (Figure 1).

Initiating factors

Diabetes, hypertension,

glomerulonephritis, gcystic

kidney disease

Figure 1: Stages of progression of glomerular injury following the initial insult.

In addition to glomerulosclerosis all forms of CKD are associated with tubulointerstitial injury manifested by tubular dilatation and interstitial fibrosis. The degree of tubulointerstitial disease is a better predictor of glomerular filtration rate decline and long term prognosis than the severity of injury. The major hallmark of tubulointerstitial fibrosis is the progressive accumulation of extracellular matrix (ECM). This expansion of the ECM is marked by accumulation of mainly interstitial collagens and fibronectin (In normal kidney, the ECM is composed of a variety of macromolecules including collagens, fibronectin, elastin, laminin, proteoglycans and non-collagenous glycoproteins). In addition to expansion of ECM, modification of proteins such as crosslinking of collagens may alter the mechanical properties of the matrix and render it resistant to normal degradative process. Thus both increased production and decreased turnover of ECM proteins contribute to matrix accumulation [5]. Other factors that play a role in the initiation and pathogenesis of fibrosis in CKD include [5]:

1) Upregulation of profibrotic factors such as transforming growth factor beta 1 (TGF-β1), platelet derived growth factor, fibroblast growth factor, osteopontin and endothelin.

2) Down regulation of anti-fibrotic factors like hepatocyte growth factor and bone morphogenic protein.

3) Dysregulation of vasoactive factors with an increase in vasoconstrictors such as angiotensin II, and a decrease in vasodilators such as nitric oxide (NO).

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4) Microvascular injury and obliteration (due to hypoxia).

5) Disruption of normal homeostatic interactions between adjacent cell populations, especially the one between tubular epithelial cells and interstitial fibroblasts.

Role of renin angiotensin-aldosterone system in CKDThe renin-angiotensin-aldosterone system (RAAS) plays a major role in maintaining the

blood volume and salt-water balance. It has effect on the blood pressure and tissue perfusion through a number of multiple complex actions including vasoconstriction and sodium retention. Despite its role in maintaining homeostasis, long-lasting stimulation of RAAS can lead to development of kidney lesions and progression of CKD. An excess of angiotensin II increases intraglomerular pressure by preferentially constricting the efferent arterioles, thus promoting glomerular hypertension and protein trafficking through the glomerular basement membrane. Additionally angiotensin II can stimulate aldosterone production which triggers the activation of a cascade of profibrotic cytokines resulting in glomerular sclerosis and tubulointerstitial fibrosis. Prorenin and renin can stimulate TGF-β1 production via the activation of p42/p44 mitogen-activated protein kinase (p42/p44MAPK), which sub¬sequently result in the up-regulation of profibrotic and prothrombotic molecules, such as fibronectin, collagen-1, and plasminogen activator inhibitor-1 (PAI-1) inducing renal fibrosis. A high prorenin level is also associated with complications like micro¬albuminuria, and development of nephropathy especially in diabetic patients [7,8].

Role of proteinuria in CKDProteinuria is an important risk factor for the progression of CKD. Increased protein

filtration results in excess reabsorption of filtered proteins by proximal tubular cells. The reabsorbed proteins eventually leak into the renal tubular interstitium through focal breaks in tubular basement membrane attracting macrophages. These macrophages can promote tubulointerstitial fibrosis by release of proinflammatory mediators like endothelin, MCP and RANTES) [9].

Role of sympathetic system in progression of chronic kidney diseaseHyperactivity of the sympathetic nervous system has been found to have considerable

adverse consequences on progression of CKD and cardiovascular disease. Sympathetic activation aggravates hypertension and proteinuria, two important factors associated with progression of CKD. Other consequences of sympathetic activation related to progression of renal damage include accelerated atherosclerosis, vasoconstriction and proliferation of smooth muscle cells as well as adventitial fibroblasts in the vessel wall [10].

Ischemic nephropathy and chronic kidney diseaseIschemic nephropathy is a common cause of renal disease especially in the elderly

population. It is defined by the gradual reduction of the GFR or a loss of renal parenchyma resulting from vascular occlusion and not explained by other etiologies. The pathogenesis of this disease involves not only the narrowing of the major renal artery due to atherosclerosis but also renal microvascular disease. The role of microvascular disease is supported by the fact that the severity of renal vascular disease on imaging has not been found to correlate with the onset or progression or time to reach ESRD in patients with atherosclerotic renal vascular disease. Microvascular involvement can result from vascular rarefaction within interstitium

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(reduced number or length of peritubular capillaries), increased vascular wall to lumen ratio and atheroembolic renal vascular disease. Induction of hypoxia secondary to these, results in activation of renin-angiotensin system, growth factors, different cytokines and chemokines playing a major role in the pathogenesis of ischemic nephropathy. Hypoxia additionally promotes fibrosis by up regulating extracellular matrix production, suppressing turnover of collagen and promoting epithelial-to mesenchymal transition. The other mechanisms responsible for renal injury in ischemic nephropathy include aldosterone–mediated damage, sympathetic over activity, increased release of reactive oxygen species (ROS) and reduction in NO activity. ROS increases renal vascular tone, sensitivity to vasoconstrictors and leads to endothelial dysfunction. Similarly reduction of NO activity permits vasopressors like angiotensin II and endothelin-1(ET-1) to dominate resulting in vasoconstriction and consequent reduction in GFR. Prolonged periods of vasoconstriction and ischemia can also lead to permanent structural changes in endothelium. Histology of ischemic nephropathy shows tubular atrophy, glomerular collapse, irreversible glomerulosclerosis and interstitial fibrosis. Chronic ischemic injury resulting from tubulointerstitial injury and loss of peritubular capillaries is the final common pathway to ESRD [11,12].

Role of endothelial dysfunction in CKDIt is recognized that endothelial dysfunction takes place from the early stages of CKD and

play a role in the pathogenesis of CKD and cardiovascular disorders. Atherosclerotic lesions in the arterial system are initiated by this functional disorder of the vascular endothelium. Additionally endothelium has reduced capacity to generate nitric oxide in response to various stimuli resulting in impaired endothelium-dependent vasorelaxation. Aging, smoking and lifestyle-related diseases such as diabetes, hypertension and dyslipidemia contribute to the development of endothelial dysfunction. In addition to these classical risk factors, novel factors such as inflammation and oxidative stress are also thought to participate in the etiology and pathogenesis of endothelial dysfunction in CKD patients [13,14].

Role of genetics in chronic kidney diseaseGenetic disorders of kidney leading to CKD can be divided into diseases of monogenic

inheritance like polycystic kidney disease, focal segmental glomerulosclerosis (FSGS), congenital nephrotic syndrome, Fabry’s disease, Alport disease, nephronophthisis as well as medullary cystic kidney disease and diseases of polygenic inheritance like diabetic nephropathy and hypertensive nephropathy. Polycystic kidney disease (PKD) is the best-known and most easily recognizable inherited kidney disease. There are mainly two genetic variants of PKD-PKD1 and PKD2. Point mutations in the Alpha-actinin-4 (ACTN4), Transient Receptor Potential Cation Channel Type 6 (TRPC6), and Inverted Formin 2 (INF2) genes can lead to phenotypes characterized by injury to glomerular podocyte associated filtration barrier and cause progressive deterioration in renal filtration function resulting in FSGS. Recent genome-wide association studies have identified several genetic loci that may affect renal function. UMOD gene is the most important among them which is strongly linked to effects on CKD and GFR. The other major genetic locus associated with progression of kidney disease especially in the African American population is the APOL-1(discussed elsewhere) [15-17].

Definition of Chronic DiseaseChronic kidney disease is defined as presence of following for three months or more [18].

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1) Structural and functional abnormalities of the kidney (with or without reduction in the GFR manifested by any of the following abnormalities.

a) Pathological abnormalities.

b) Clinical markers of renal damage in the form of proteinuria (more than 150 mg/gm creatinine) or albuminuria (more than 30 mg/gm creatinine) or abnormalities of urine sediment.

c) Abnormal imaging studies (for example: polycystic kidneys or small hypo echoic kidneys on ultrasound).

d) Tubular syndromes.

e) Kidney transplant recipient.

2) GFR less than 60 ml/min/1.73 m2 with or without kidney damage.

Staging of CKDIn 2002 national kidney foundation put forward staging of chronic kidney disease which

established the 5 stages based on estimation of GFR (G1 to G5) without regards to cause of CKD. Staging of CKD helps in predicting the risk of cardiovascular disease and mortality. It is important in monitoring dosage of medications cleared by kidneys and safety of diagnostic tests as well as procedures which can damage kidneys. Staging is also important in terms of promoting early referral to nephrologists and for kidney transplantation [18] (Table 1).

Stage GFR Description Intervention

G1 >90 normal GFRConfirm diagnosis,

retard progression.G2 60-89 mild functional impairment Retard progression.

G3a 45-59 moderate functional impairment Confirm diagnosis, retard progression and treat secondary complications.

G3b 30-44 Moderate to severe functional impairment

Confirm diagnosis, retard progression and treat secondary complications

G4 15-29 severe functional impairment Prepare for renal replacement therapy, referral for transplantationG5 <15 ESRD Initiate renal replacement therapy

Table 1: Stages of CKD and interventions at each stage.

Methods of estimating GFRThere are several methods of estimating GFR. The most reliable markers of GFR estimation

include inulin clearance and use of radionuclides like iothalamate and iodohexol [19]. The latter is considered as the gold standard for estimation of glomerular filtration rate. Both these methods are useful only in the research setting and not in clinical practice. The most commonly used methods for estimating GFR is based on creatinine. Creatinine is a protein derived from metabolism of creatine in skeletal muscle and dietary meat intake. It must be in a steady state to estimate GFR. Levels can be altered by medications interfering with measurement (cephalosporin, ketone) or reduced secretion by medications (cimetidine, Bactrim). It can also be altered by factors like variability in muscle mass (myasthenics, leg amputees and paraplegics), presence of liver disease, age, sex, race and weight, chronic illness, and consumption of cooked meat. An ideal estimation of GFR should incorporate all these factors into account [20].

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The various creatinine based formula for estimating GFR include

1) Modification of Diet in Renal Disease (MDRD) formula (takes into account age, gender and race).

2) Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (takes into account age, gender and race).

3) Cockcroft-Gault (CG) equation (takes into account the age, weight and gender).

4) 24 hour urine estimation of creatinine clearance.

These formulas differ in both the estimates of CKD prevalence and ability to predict consequences associated with CKD. The MDRD equation was found to be less accurate than CKD-EPI in predicting risk for those with GFR more than 45-60 ml/min/1.73 m2 [19]. But at the same time CKD –EPI was not superior in estimating GFR in the elderly or those with extreme body mass. MDRD and CKD-EPI are more accurate in young compared to CG equation. In terms of gender, CKD-EPI was most accurate in women whereas MDRD was most accurate in men [19].

Estimation of GFR using serum creatinine has drawbacks. Creatinine does not fulfill the criteria of an ideal marker for estimating GFR, since creatinine is excreted not only via glomer¬ular filtration but also via secretion in the proximal tubule. Moreover creatinine based estimation of GFR is not validated in patients above the age of seventy years, children, pregnant women, diabetics, Native Americans and Hispanics. Although creatinine clearance based on 24 hour urine collection is rec¬ommended in situations like extremes of age as well as body size, severe malnutrition, disease of skeletal muscle, para¬plegia or quadriplegia, vegetarian diet, rapidly chang-ing kidney function, and calculation for adjustment of dosage of potentially nephrotoxic drugs the main problem is the requirement for urine collection over 24 hours; patients find this inconvenient and, therefore, collections are often inaccurate especially in patients who are elderly and having cognitive impairment [19].

More recently cystatin C has been used for estimation of GFR. Cystatin C is involved in antigen presentation, protein catabolism, tissue remodeling and pathogenesis of atherosclerosis. It is freely filtered by glomerulus, reabsorbed and metabolized by proximal tubules and there is no urinary excretion. Cystatin C has advantage over creatinine in conditions of decreased mass including older adults, those with chronic diseases (such as heart failure, cirrhosis, AIDS) and in those without established CKD and diabetics. In terms of assessing mortality risk, cystatin C maintains a linear association across its entire distribution and is superior to creatinine based GFR and iothalamate based GFR(Creatinine based glomerular filtration rate has a J-shaped relation with mortality with only the lowest quintile of glomerular filtration rate associated with increased mortality risk). The superiority of cystatin C GFR compared to iothalamate GFR in the assessment of all-cause and cardiovascular mortality is due to two reasons; 1) Cystatin C has non-kidney influences that are independent of GFR, which are associated with mortality risk. 2) The coefficient of variation of measurement of iothalamate GFR is higher than that of cystatin C. The use of cystatin C also has its own limitations. Among patients with a GFR <60 ml/min/ 1.73 m2, cystatin C offers only a moderate gain over creatinine for approximating renal function. A combined serum cystatin C and creatinine based formula is sometimes used in practice [19-21].

The different modalities of GFR estimation and advantages as well as disadvantages are represented in Table 2

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Method Agent/agents used Advantages DisadvantagesExogenous substances.

Inulin, iohexol, chromium labeled ethylenediamine tetraacetic acid (Cr-EDTA), 131I-iothalamate, 99mTc diethylenetriaminepentaacetic acid (DTPA).

Precise and accurate (gold standard). Costly, time consuming, and labor-intensive.

Endogenous substance

(Creatinine).

24 hour creatinine clearance.

Cockcroft-Gault equation.

MDRD equation.

CKD-EPI equation.

Used for patients with highly abnormal muscle mass or on vegetarian diet.

Well suited for estimation of GFR changes during pharmacotherapy.

Most accurate in men.

Most accurate in female and cases where GFR is more than 60 ml/min/ m2.

In accuracies due to errors in urine collection.

Only suitable for adults, slightly overestimates GFR.

Less accurate in cases where GFR is more than 60 ml/min/m2 and children.

Less accurate in elderly and patients with extremes of body mass.

Endogenous substance

(Cystatin C).

Cystatin C based GFR estimation. No patient specific data required. More accurate than creatinine based formula in diabetics and elderly. Equally accurate in pediatric patients. Gives better risk factor estimates for death and metabolic abnormalities.

Levels can vary with age, gender, ethnicity, body mass index, diabetes and inflammation.

Table 2: Different modalities of estimation of GFR with their advantages and disadvantages.

Role of proteinuria in the classification of CKDUntil recently proteinuria was not incorporated into the classification of CKD. It is already

known proteinuric patients with early stage CKD have higher risk for progression of renal function than patients classified in more advanced stages of CKD but less proteinuria. Additionally the presence of increased albuminuria especially in presence of CKD, involves a manifold higher risk of unfavorable cardiovascular events well before they reach ESRD. Hence recent classification of CKD incorporates proteinuria (Figure 2) [22].

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Figure 2: Prognosis of CKD based on GFR and albuminuria categories. Red represents the group with very high risk for adverse renal and cardiovascular outcomes; orange rep-resents the group with high risk; yellow represents the group with moderately increased risk; green represents the group with low risk.

Biomarkers in CKDEffective CKD screening and management should ideally involve accurate, non-invasive

indicators that reflect the pathophysiologic mechanisms underlying CKD. Given the inherent limitations of proteinuria assessments and GFR estimations, several potential novel biomarkers that correlate with histopathological findings are actively being investigated for their utility in determining the underlying renal pathological processes and in predicting CKD progression prior to the development of overt clinical evidence of CKD. These include neutrophil gelatinase- associated lipocalin (NGAL), asymmetric dimethylarginine (ADMA), and liver-type fatty acid binding protein (L-FABP). NGAL is produced by neutrophils and various epithelial cell types, including those composing the renal distal tubules. It has been shown as an early, sensitive marker of acute kidney injury. Another promising biomarker for CKD is ADMA, which functions as a nitric oxide synthase inhibitor reflecting endothelial function. ADMA levels have been associated with faster progression to dialysis and death in individuals with CKD. Similarly, L-FABP, a marker of proximal tubule integrity, has also been associated with progressive CKD. In non-diabetic CKD patients, urinary L-FABP concentrations correlated with proteinuria as well as serum creatinine levels in addition to progression of CKD [23].

Who should be screened for CKD?According to Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, all individuals

with risk factors for CKD like history of diabetes, cardiovascular disease, hypertension, hyperlipidemia, obesity, metabolic syndrome, smoking, HIV or hepatitis C virus infection,

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malignancy, family history of kidney disease and treatment with potentially nephrotoxic drugs should be screened [16]. The Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference suggested screening all patients over age 60 years [24]. The preferred screening tests are urine albumin/creatinine ratio and serum creatinine (to calculate estimated GFR or creatinine clearance) [25].

Clinical features of CKDClinical symptoms of CKD arise from accumulation of nitrogenous and non-nitrogenous

toxic substances. Urea the major nitrogenous toxic substance contributes to symptoms including anorexia, malaise, vomiting and headache. Additional categories of nitrogenous toxic substances include guanido compounds, urates, hippurates, phenol, benzoate and indoles. Nitrogenous substances with molecular weight in the 500-12000 (so called middle molecules) also accumulate in CKD. These middle molecules are believed to be associated with morbidity and mortality. In addition a host of metabolic and endocrine abnormalities accompany CKD which are represented in Table 3 [26].

Fluid and electrolyte abnormality

Volume expansion and contraction

Hypernatremia and hyponatremia

Hyperkalemia and hypokalemia

Metabolic acidosis

Hyperphosphatemia

Hypocalcemia

Hematologic abnormalities

Anemia

Leucopenia

Thrombocytopenia

Infection

Platelet dysfunction

Pulmonary abnormalities

Pulmonary edema

Uremic lung

Pleural effusion

Endocrine-metabolic abnormalities

Renal osteodystrophy

Adynamic bone disease

Osteomalacia

Osteoporosis

Impaired glucose tolerance

Hypoglycemia

Hyperuricemia

Hypertriglyceridemia

Low HDL cholesterol

Impaired growth and development

Infertility

Sexual dysfunction

Amyloidosis

Gastrointestinal abnormalities

Anorexia

Nausea

Vomiting

Gastroenteritis

GI bleeding

Neuromuscular disturbances

Fatigue

Sleep disorders

Headache

Asterexis

Neuropathy

Restless leg syndrome

Myoclonus

Seizure

Muscle cramps

Myopathy

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Dermatologic abnormalities

Hyperpigmentation

Pruritus

Ecchymosis

Uremic frost

Cardiovascular abnormalities

Hypertension

Congestive heart failure

Pericarditis

Cardiomyopathy

Atherosclerosis

Vascular calcification

Table 3: System wise representation of clinical features in CKD.

Risk Factors for CKDDiabetes and CKD

Type 2 diabetes mellitus is the leading cause of CKD in developed countries and accounts for 45% of all cases of kidney failure [18]. Diabetic nephropathy complicates 30% of patients with type 1 diabetes and 20% of patients with type 2 diabetes mellitus. Risk factors for prevalence of CKD in diabetic patients include hyperglycemia, hypertension, proteinuria, smoking, dyslipidemia and gene polymorphism affecting the renin angiotensin-aldosterone system [26]. Pathogenesis of nephropathy in diabetes mellitus progresses through various stages starting from stage of hyperfiltration to microalbuminuria, macroalbuminuria, overt nephropathy and ESRD. In the early stage there is hyperfiltration due to renal vasodilation [26]. The precise mechanisms underlying diabetes associated glomerular hyperfiltration remain inconclusive, but it is thought to be due to reduced delivery of salt to the macula densa, as a consequence of increased proximal reabsorption of glucose and sodium, reducing afferent arteriolar resistance leading to increased glomerular blood flow and GFR via attenuated tubuloglomerular feedback. In addition, afferent vasodilation and efferent vasoconstriction due to circulating or locally formed vasoactive factors (e.g. angiotensin II and endothelin) produced in response to hyperglycemia or shear stress is also believed to contribute to the development of diabetes-associated glomerular hyperfiltration [27].

Hypertension and CKDHypertension is the most commonly treated chronic disease. It is a major risk factor for heart

disease, kidney failure and stroke. In relation to renal system, hypertension has been regarded as a special condition since it is known to be both a cause and a consequence of renal damage. The underlying pathophysiology of hypertensive nephropathy is related to the glomerular ischemia resulting from afferent arteriolar narrowing. This arteriolar narrowing is mediated by a myogenic contractile response to increased afferent arteriolar flow (due to hypertension) and a tubuloglomerular feedback signal from the macula densa (resulting in auto regulation of glomerular capillary pressure and flow). The histological lesion of hypertensive nephrosclerosis is characterized by myointimal hyperplasia of interlobular and afferent arteriolar vessels, hyaline arteriolosclerosis especially of the latter and wrinkling collapse of the glomerulus [28].

Race and CKDAlthough the prevalence of early CKD is comparable across racial and ethnic groups in

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the United States, CKD progression to ESRD is far more rapid in African American compared to White Americans. Moreover the onset of CKD is earlier in African Americans. Part of the reason for these differences is that compared with whites, African Americans have higher rates of diabetes and hypertension which is more severe. While diabetes accounts for nearly half of new cases of kidney failure in African Americans, hypertension accounts for nearly a third. This is compounded by the lower rate of blood pressure control in African Americans which contribute to the more rapid progression of CKD to ESRD. The greater risk of proteinuria in African Americans at any given level of higher blood pressure is thought to contribute as well. High rates of low socioeconomic status, low health literacy, being underinsured or uninsured, and lack of awareness of risk factors also contribute to the increased risk. A unique genetic variation, originally linked to the MYH9 gene and now attributed to the APOL1 gene, is another important factor associated with the rapid progression of non-diabetic ESRD in African Americans ( details discussed elsewhere) [29].

Role of klotho and FGF 23 in CKDKlotho is a protein present in various tissues including kidneys which functions as a humoral

factor exerting biologic functions like ion transport, anti-oxidation and anti-senescence. Klotho functions as co-receptor for FGF23 which plays an important role in the homeostasis of phosphorus. Its co receptor action amplifies and confers specificity of FGF23 action. Klotho usually functions as a renoprotective factor especially against vascular calcification. Klotho deficiency can be associated with elevated serum levels of FGF23 and phosphate predisposing to vascular calcification [30].

FGF-23 is a phosphaturic peptide hormone derived from osteocytes and osteoblasts and has multiple tissue effects influencing bone metabolism. The rise in FGF-23 corresponds to decline in the number of intact nephrons as well as renal phosphate retention and appears to precede the development of secondary hyperparathyroidism. Serum FGF-23 levels have been reported to be persistently increased as early as stage 3 CKD and as CKD progresses, it continues to increase with reduced responsiveness in late stages of CKD. FGF-23 elevation may inhibit parathyroid hormone (PTH) mRNA activity, osteoblast differentiation, and bone matrix maturation. Elevated FGF-23 levels are also associated with more rapid CKD progression to ESRD, left ventricular hypertrophy, and premature mortality [30].

APOL 1 gene and CKDApolipoprotein L1 (APOL1) is the region on chromosome 22 containing the genes encoding

non-muscle myosin heavy chain 9 (MYH9) and it has been implicated in the increased risk among African American patients of human immunodeficiency virus (HIV) nephropathy, FSGS, CKD attributed to hypertension and ESRD not related to diabetes. Recent data suggest that this risk is strongly associated with two common variants (G1 and G2) in the last exon of APOL1 that confer resistance to lethal Trypanosoma brucei infections. The G1 and G2 variants are common in populations of recent African descent but are very rare or absent in most other populations. About 50 % of African Americans are carriers of at least one or the other allele; 10–15 % is carriers of two alleles, whereas White Americans are carriers of neither. APOL1 cause autophagy in podocytes or cause renal vascular endothelial inflammation as a response to the synthesis of dysfunctional HDL particle formation [31].

CKD and dyslipidemiaThe dyslipidemia picture in CKD patients is characterized by low high-density lipoprotein

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(HDL), accumulation of small, dense highly atherogenic low-density lipoprotein (LDL), decreased metabolism of chylomicrons as well as remnants of chylomicrons and reduced catabolism of lipoprotein(a) [32]. This abnormal lipid metabolism facilitates glomerular, tubular and interstitial injuries in the kidney [33]. The deposition of lipoprotein especially in glomerular structures stimulates factors that excite inflammation and fibrogenesis [32]. Dyslipidemia also leads to oxidative stress and inflammatory reactions which result in endothelial dysfunction eventually leading to the development of arteriosclerosis and atherosclerosis in patients with CKD [33].

Metabolic acidosis and CKDMetabolic acidosis due to CKD has been associated with progressive deterioration of kidney

function in experimental animals and human beings. A typical diet of individuals living in industrialized societies produces about 1 mEq of hydrogen ions (protons)/kilogram body weight/day. This is mainly derived from the high acid-producing animal proteins. It is the function of the kidney to eliminate the protons and regenerate the alkali. Dietary acid by itself can augment kidney acidification through increased production of endothelin, aldosterone, and angiotensin II. Although these agents can augment distal nephron acidification in the short term, they might increase kidney inflammation and fibrosis over the longer term if increased dietary acid intake is sustained. A U-shaped association was found between serum bicarbonate concentration and all-cause mortality in CKD patients [34].

Cardiovascular risk factors associated with progression of CKDA number of cardiovascular related risk factor associated with progression of CKD has

been studied. These include highest and lowest heart rate variability which predicted ESRD, aortic stiffness measured by pulse wave velocity which showed independent association with progression of CKD ( especially stage 3,4) and silent brain infarction which predicted CKD progression [35-37].

Socioeconomic status and CKDLow socioeconomic status (SES) is considered as an independent potential risk factor for

CKD [38]. SES can have direct and indirect effect on the progression of CKD [39]. Access to nutrition, physical activity, health information and treatment are the major direct factors influencing CKD whereas obesity, diabetes and hypertension are the important indirect factors affecting CKD [38]. In United States low income additionally affects health care access, health lifestyle choices which in turn increase the prevalence of CKD [39].

AKI and CKDAcute kidney injury (AKI) is increasingly been recognized as a risk factor for development

and progression of CKD. Renal parenchymal injury sustained during episodes of AKI may lead to permanent tubulointerstitial fibrosis and a reduction in the number of functioning nephrons. Additionally, an episode of AKI may lead to permanent damage to the renal microvasculature, and trigger inflammatory and fibrotic signaling pathways that predispose to future accelerated declines in GFR. It has also been found that ischemic insult can result in persistent changes at the gene transcription level in the kidneys of animals even after serum creatinine levels had recovered. Each additional episode of AKI is associated with an independent and cumulative increase in the risk for the development of CKD. This relation between AKI and progression of CKD is independent of the underlying GFR which makes us think whether AKI is simply a

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marker or causal of progressive kidney disease. But at the same time its presence identifies a high-risk population of patients likely to have progressive kidney disease. Determining a history of AKI in CKD patients may be comparable to proteinuria especially in patients with diabetes [40].

CKD and uric acidThe end product of purine metabolism, uric acid, is produced mainly by the liver, bowel

and peripheral tissues like muscles, endothelium and kidneys. Plasma urate is readily filtered by the human glomerulus, but filtered uric acid is reabsorbed mainly by the selective urate transport protein URAT1 in proximal convoluted tubules [41]. Hyperuricemia which is defined as serum concentration of urate exceeding the solubility of urate in water (6.8 mg/day) may result from uric acid overproduction, reduced excretion, or both. Uric acid can act as both a risk factor and a biomarker for renal progression and/or cardiovascular outcomes among patients with CKD. The mechanisms responsible for development of CKD in hyperuricemia include:

1) Hyperuricemia leads to microvascular changes in the glomerular afferent arterioles which induce the development of a glomerular arteriolopathy impairing renal autoregulation and causing glomerular hypertension, eventually leading to glomerulosclerosis and interstitial fibrosis.

2) Intraluminal uric acid crystals attaching to the epithelial renal cells in the collecting ducts induce an acute inflammatory response.

3) Endothelial dysfunction 4) Activation of the renin angiotensin system. In addition to CKD progression, increase in uric acid has been found to be associated with rise in all-cause mortality, and cardiovascular mortality. There is a J-shaped mortality relationship for CKD patients with higher and lower tertiles of serum uric acid [41,42].

Gender and CKDThere is role for gender in the progression of CKD. Most of the existing data regarding

potential sex differences suggest that women have lower risk of cardiovascular mortality, all-cause mortality and progression to ESRD compared to men [43]. It has been postulated that hormones play a role, with estrogen having a protective effect and testosterone having a detrimental effect.

Smoking and CKDCigarette smoking is a risk factor for accelerated progression of renal disease and

cardiovascular disease in patients with diabet¬ic nephropathy. Smoking, along with hypertension and vascu¬lar disease, is a strong predictor of increased serum creatinine levels in non-diabetic patients over the age of 65 years. It is also regarded as an independent risk factor for renal failure in males with kidney dis¬eases. It predisposes to vasoconstriction, thromboembolism as well as vascular endothelial damage [44].

Obesity and CKDObesity is an important risk factor for genesis as well as progression of CKD. Development

of CKD and eventual ESRD in obesity is also mediated though risk factors including diabetes, hypertension and other elements of the metabolic syndrome including body mass index (BMI).

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Although BMI is considered as an independent risk factor for progression of renal disease, it is also known that patients with higher BMI on hemodialysis have better survival. In this context, several studies have highlighted the importance of visceral or central obesity, rather than BMI in the pathogenesis of incident CKD and increased cardiovascular risk in CKD patients. Pathophysiology of obesity-related renal disease evolves in a sequence of stages beginning with initial increase in GFR and intraglomerular capillary pressure, glomerular hypertrophy, proteinuria and overt nephropathy. The mechanisms underlying obesity-related glomerular hyperfiltration, is the increased sodium reabsorption by the proximal tubule or loop of Henle, leading to tubuloglomerular feedback mediated reduction in afferent arteriolar resistance. This tubuloglomerular feedback driven dilation of afferent arterioles and resultant impairment of renal autoregulation, in turn, allows increases in blood pressure to be transmitted to the glomerulus causing injury to glomerulus. This is especially important in individuals with reduced nephron number. The higher preglomerular vasodilatation in this situation leads to enhanced blood pressure transmission to glomerulus. Obesity also predisposes to increased activation of the RAAS and renal sympathetic tone resulting in increased sodium reabsorption exacerbating the renal hemodynamic changes associated with obesity [45,46].

Complications of CKDElectrolyte abnormalities

The major electrolyte abnormalities seen in CKD patients are related to sodium and potassium. Normal kidneys filter almost all of the sodium and reabsorb almost 99 percent of the filtered sodium. With progressive deterioration in kidney function, the kidneys compensate by increasing fractional excretion of sodium to maintain the sodium balance. But in advanced renal disease states and in presence of disease process that tends to retain sodium (glomerulonephritis) or excess dietary intake of sodium this compensation can be offset resulting in a positive sodium balance state and attendant extracellular volume expansion. This in turn contributes to hypertension and further damage to nephrons. Some CKD patients on the other hand will have impairment in conserving sodium and water leading to volume depletion especially in presence of extra renal cause for volume depletion (like vomiting, diarrhea). Depletion of extracellular volume can in turn worsen the renal function. Hyponatremia and hypernatremia seen in CKD is mainly due to impaired handling of free water in relation to water intake [26].

Decline in renal function may not be necessarily accompanied by concomitant decline in potassium excretion. The kidneys can efficiently handle potassium until late in CKD. Additionally potassium excretion through gastrointestinal tract is augmented. But at the same time hyperkalemia can be precipitated by a number of factors like increase dietary intake, protein catabolism, hemolysis, hemorrhage, transfusion of stored red blood cells, metabolic acidosis, exposure to medications like angiotensin converting enzyme inhibitors, angiotensin receptor blocker, potassium sparing diuretics and NSAIDS. Sometimes impaired excretion of potassium might be a feature of underlying disease responsible for CKD like hyporeninemic hypoaldosteronism seen in diabetic nephropathy. Hypokalemia can also be occasionally seen in relation to disorders where potassium wasting is part of the underlying disease process like Fanconi’s syndrome, renal tubular acidosis and some hereditary and acquired forms of tubulointerstitial diseases [26].

Vitamin D deficiency and CKD

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Vitamin D deficiency is very common among CKD patients. Possible explanations for this high prevalence of nutritional vitamin D deficiency in patients are reduced sunlight exposure (e.g., in the elderly, the sick, dark-skinned people, those who wear a veil for cultural reasons), losses of vitamin D–binding protein in proteinuric states [25 (OH) D is lost in the urine bound to vitamin D–binding protein] and a reduced endogenous synthesis of vitamin D from the skin in the uremic state [47].

Anemia and CKDAnemia is one of the major complications of CKD. It is also an independent modifiable

risk factor of cardiovascular and renal damage. Both deficiency and hyporesponsiveness to erythropoietin contribute to anemia in CKD. The cause of erythropoietin deficiency in patients with CKD is mainly due to the reduced renal mass with consequent depletion of the hormone. Additionally there are various other explanations for erythropoietin deficiency in CKD:

1) Human erythropoietin (EPO) which is a 165-amino acid glycoprotein is mainly produced by the liver during fetal life and by fibroblast-like peritubular interstitial cells (pericytes) in the kidney in adulthood. In the progression of CKD, the EPO producing abilities of pericytes are decreased (due to pericyte-myofibroblast transition) leading to the decreased production of EPO. 2) Uremic toxins can induce deoxyribonucleic acid (DNA) methylation leading to silencing of the EPO gene. 3) Defective hypoxic signaling leading to defective stimulation of EPO synthesis [48,49].

Hyporesponsiveness to EPO is defined clinically as a requirement for high doses of EPO in order to raise blood hemoglobin level in the absence of iron deficiency. It is believed to represent impaired antiapoptotic action of EPO on proerythroblasts. Possible causes of this EPO hyporesponsiveness include systemic inflammation, microvascular damage in the bone marrow and deficiency as well as impaired utilization of iron [50].

Another major cause of anemia in CKD patients is iron deficiency. According to analyses of the National Health and Nutrition Examination Survey IV, prevalence of iron deficiency (both functional and absolute) is around 50% in patients with CKD. Absolute iron deficiency is defined as a diminution of tissue iron stores demonstrated by a serum ferritin level <100 ng/ml or a transferrin saturation of <20%. Functional iron deficiency anemia is defined as reduction in iron saturation in presence of adequate tissue iron (established by a serum ferritin level ≥ 100 ng/ml). The latter is closely related to up regulation of inflammatory cytokines and impaired tissue responsiveness to EPO, which inhibit iron transport from tissue stores to erythroblasts [50].

Other causes of anemia in CKD include proteinuria and use of angiotensin-converting enzyme (ACE) inhibitors. In CKD patients with nephrotic syndrome there is excretion of transferrin and EPO which can predispose to anemia. The mechanisms responsible for anemia with use of ACE inhibitors and angiotensin receptor blockers (ARB) include a direct blockade of the proerythropoietic effects of angiotensin II on red cell precursors, degradation of physiological inhibitors of hematopoiesis, and suppression of insulin-like growth factor 1 [50].

Anemia in turn can result in progression of renal failure. The mechanisms include renal ischemia caused by reduced oxygen delivery due to low hemoglobin as well as heart failure and increased renal sympathetic nerve activity. Renal medullary hypoxia resulting from renal ischemia up regulates hypoxia-inducible factor-1α (a transcriptional regulator of the erythropoietin gene) as well as heme oxygenase, nitric oxide synthases, extracellular matrix,

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and apoptosis genes. This up regulation results in induction of collagen gene expression in renal fibroblasts, thereby increasing interstitial fibrosis. Additionally anemia can increase sympathetic nerve activity, which leads to increased glomerular pressure and proteinuria contributing to worsening of kidney function [48].

Cognitive impairment/frailty in CKDPatients with CKD especially older adults with CKD face a high risk for cognitive

impairment, frailty and physical disability. Presence of frailty among CKD and among those without CKD was associated with about a twofold higher risk for mortality. CKD shares risk factors with cerebrovascular small vessel disease such that the development or progression of CKD parallels the development of physical or cognitive impairment. Alternatively CKD is a potential accelerant of decline in physical and cognitive functions through associated anemia, mineral-bone disease, or inflammation [51].

Cardiovascular complications of CKDMajor cardiovascular complications of CKD include accelerated atherosclerosis,

sudden cardiac death, cardiac arrhythmias, vascular stiffness, vascular calcification, left ventricular hypertrophy (LVH) and cardiac fibrosis. Accelerated atherosclerosis has close association with impaired kidney function. Common risk factors associated with accelerated atherosclerosis include dyslipidemia, hypertension, diabetes, acid–base imbalance, calcium phosphate metabolism, anemia, high prevalence of vasoconstrictive agents like angiotensin II, blood clotting factors, hyperhomocysteinemia and inflammatory factors. Elevated levels of inflammatory mediators along with accumulation of asymmetric dimethylarginine, high levels of homocysteine as well as raised levels of calcification promoters (e.g. osteopontin), diminished levels of calcification inhibitors (e.g. feutin-A) and abnormal calcium–phosphate metabolism act as promoters of atherosclerosis. The other risk factors include cigarette smoking, male gender, family history and lack of physical activity [52].

Common triggers for sudden cardiac death in patients with CKD include premature atherosclerosis, cytokine-induced plaque instability and direct effect of inflammation on the myocardium and the electrical conduction system. Ventricular arrhythmia due to inflammatory involvement of electrical conduction system and myocardial ischemia is a common cause of sudden cardiac death in patients with CKD. Fatal ventricular arrhythmias can also occur in patients with CKD due to metabolic disorder (hyperphosphatemia and hyperparathyroidism), electrolyte (potassium, pH) alterations, sympathetic overactivity, autonomic nerve dysfunction, concomitant obstructive sleep apnea, acquired or hereditary QT interval prolongation, systolic and/or diastolic dysfunction, acute volume overload and valvular calcification [52].

Increased arterial stiffness is an important factor associated with cardiovascular morbidity as well as mortality and progression of kidney disease. Arterial stiffness is also associated with abnormalities in microcirculation leading to poor wound healing and infection-related deaths. The factors associated with arterial stiffness include matrix metalloproteinases (MMP), advanced glycation end-products (AGE), endothelial dysfunction, RAAS and dietary sodium. Increased MMP production promotes vascular stiffness by causing weakness of the extracellular matrix (by enhancing collagen and elastin turnover). Accumulation of AGE leads to modification of collagen making blood vessels stiffer and less susceptible to slow hydrolytic degradation. Additionally glycation can also cause arterial stiffening through generation of reactive oxygen species and nitric oxide deactivation. Endothelial dysfunction in CKD patients is

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characterized by impairment in endothelium dependent and independent vasodilatation which usually is a reflection of the high oxidative stress. Risk factors like hypertension, diabetes and the reduced clearance of uremic toxins, such as asymmetrical dimethylarginine (an effective inhibitor of nitric oxide synthase) are risk factors associated with endothelial dysfunction. Angiotensin II contributes to vascular stiffness by stimulating vascular smooth muscle cells (VSMC) hypertrophy as well as proliferation and increasing the production of collagen as well as MMP. Mechanisms of dietary sodium induced vascular stiffness include increase in VSMC hypertrophy as well as tone, increase in collagen cross-linking and facilitation of aldosterone-induced oxidative stress and inflammation [53].

In addition to vascular stiffness, vascular calcification (VC) also plays a major role in the pathogenesis of cardiovascular disease in CKD patients. VC can either take place in the intima or in the media of the vessel wall with former common in atherosclerosis and latter common in arteriosclerosis. Key risk factors associated with progressive cardiovascular calcification are age, diabetes, hyperphosphatemia, hypercalcemia, high intake of calcium (by calcium containing phosphate binders), secondary hyperparathyroidism and inflammation. Other risk factors associated with VC include osteoprotegerin, feutin-A, pyrophosphates, matrix Gla protein, osteopontin, FGF 23 and bone morphogenic protein. Under the influence of these factors the vascular tissue acquires bone cell characteristics resulting in deposition of calcium in arterial walls. Calcification of blood vessels leads to arterial stiffening, increased pulse pressure, decreased coronary perfusion and LVH. The high cardiovascular mortality seen in uremic patients is directly related to the magnitude of vascular calcification (VC) [53,54].

The cardiovascular mortality in CKD patients is attributed to the traditional cardiovascular risk factors (diabetes, hypertension, obesity and hypercholesterolemia), non-traditional risk factors (such as hyperhomocysteinemia, abnormal lipoprotein levels and chronic inflammation and oxidant stress). Some CKD patients are at an increased risk of mortality even with low blood pressure and reduced cholesterol, which has been referred to as ‘reverse epidemiology’. The mechanism involved includes malnutrition and vascular calcification. Abnormalities in bone mineral disorder like hyperphosphatemia, PTH excess and vitamin D deficiency are also associated with increased cardiovascular morbidity and mortality. Excess phosphate influences cardiovascular risk by increasing PTH or decreasing 1,25-dihydroxyvitamin D3 levels. PTH excess has been implicated in cardiac fibrosis, impaired cardiac contractility, impaired endothelial vasodilatory function and LVH. Lower levels of vitamin D may decrease cardiac contractility, increase coronary calcification and up regulation of the renin-angiotensin axis, resulting in the development of hypertension and LVH [55].

LVH and cardiac fibrosis are well described pathologies associated with CKD and ESRD. They have major impact on morbidity and mortality of CKD and ESRD patients especially those who have coexisting congestive heart failure and arrhythmias. The major factors determining the extent of LVH include systemic arterial resistance, elevated systolic (and diastolic) arterial blood pressure, and large vessel compliance which are closely related to the aortic calcification seen in CKD and in ESRD. These afterload-related factors result in myocardial cell thickening and concentric left ventricular remodeling. Preload-related factors related to LVH include expansion of intravascular volume (salt and fluid loading) and anemia. These latter factors result in myocardial cell lengthening and eccentric or asymmetric left ventricular remodeling. Both afterload- and preload-related factors may operate independently or have synergistic effects. Activation of the intracardiac renin-angiotensin system and aldosterone are also involved in myocardial cell hypertrophy and fibrosis, independent of afterload.

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Hyperaldosteronemia, consequent to activation of renin-angiotensin system or through non-renin-angiotensin system dependent factors, promotes cardiac fibrosis, perhaps through generation of signals promoting profibrotic TGF β production, deficiency of iron as well as erythropoietin (with attendant anemia), carnitine deficiency, vitamin D deficiency (which can activate the intracardiac renin-angiotensin system) elevated PTH, hypoalbuminemia and albuminuria. Non-angiotensin II–dependent pathways like oxidative stress and xanthine oxidase activation have also been implicated in LVH. LVH and myocardial fibrosis lead to progressive impairment in contractility and stiffening of the myocardial wall, leading to systolic and diastolic dysfunction and ultimately to dilated cardiomyopathy and diastolic and/or systolic congestive heart failure. Intramyocardial fibrosis also leads to disturbances in the electrical conduction system (through superimposition of high-resistance pathways for ventricular electrical conductance and the encouragement of re-entry pathways of the heart) leading to ventricular arrhythmogenesis (e.g. ventricular fibrillation). Additionally increased cardiac work and oxygen consumption due to hypertrophy of myocardium can aggravate ischemic heart disease from coronary atherosclerosis which in turn can aggravate the myocardial cell loss and fibrosis [56].

CKD and cardiovascular disease markersIn patients with CKD the various markers of myocardial injury like troponin and N-terminal

pro-brain natriuretic peptide (NT-proBNP) should be interpreted with caution because of the variation in levels depending on the level of renal function. The increased plasma NT-proBNP levels is either related to the hemodynamic stimuli or may relate to anemia, obesity, cachexia, impaired renal clearance of natriuretic peptides, despite similar hemodynamic stimuli. There is conflicting reports in literature regarding the usage of NT-proBNP in patients with CKD and heart failure. While some studies showed an inverse moderate, but significant, correlation between GFR and NT-proBNP concentrations, others indicated that NT-proBNP is related to presence and extent of cardiac pathology rather than impaired renal clearance. Based on these the utility of using NT-proBNP for monitoring treatment in heart failure patients is uncertain. On the other hand measurement of cardiac troponins in patients with CKD has been found to have prognostic significance. Base-line measurement of cardiac troponin T is strongly predictive of the risk of death or myocardial infarction [57,58].

CKD and infectionsInfections are supposed to be a major factor responsible for the increased risk of morbidity

and mortality in patients with CKD. The susceptibility of CKD patients to infections results from defective phagocytosis promoted by a variety of factors, including uremic toxins, iron overload and anemia of renal disease. Risk factors associated with infection in CKD patients include advanced malnutrition, age, diabetes, hypoalbuminemia, iron therapy, increased intracellular calcium, and immunosuppressive therapy. CKD patients are also predisposed to zinc, vitamin B6 (pyridoxine), vitamin C and folic acid deficiencies which can lead to alterations in host defense. This alteration in the host defense function affects all cell lines of white blood cells; polymorphonuclear cells, lymphocytes, and monocyte. Two proteins that have been found to have association with increased risk of infection include leptin and resistin. Leptin, which accumulates in CKD patients, plays a role in innate and acquired immunity by regulating T lymphocyte responses, increasing secretion of several cytokines and by positively modulating mononuclear cell survival by interfering with the apoptotic process. Resistin, a 12-kDa protein expressed in inflammatory cells, impair polymorphonuclear leukocyte function in

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CKD patients [59,60].

CKD and bone mineral disordersDisturbances of bone mineral metabolism and regulatory hormones may occur early in the

course of CKD, with changes occurring as early as stage 2 CKD, and progressing as kidney function worsens [61]. The various bone mineral disorders associated with CKD include decreased levels of 1,25-dihydroxy vitamin D as well as 25-hydroxy vitamin D, increased levels of FGF-23 as well as PTH.

The elevation in PTH is due to reduction in calcium as well as 1, 25-dihydroxy vitamin D and increase in phosphorus. In addition, as kidney function declines a corresponding decrease in vitamin D receptors (VDR) and calcium-sensing receptors (CaSR) occurs in the parathyroid glands making them less responsive to the actions of circulating vitamin D and calcium [62].

Reduced levels of 1,25-dihydroxy vitamin D seen in CKD patients is due to decreased production of 1,25-dihydroxyvitamin D (calcitriol) resulting from a loss of functioning proximal renal tubules and reduced activity of renal 1-alpha-hydroxylase. The combination of low calcitriol and elevated PTH in CKD is now recognized as a cause of bone loss and a major contributor to bone disease in CKD patients. 25-hydroxy vitamin D deficiency is also commonly observed in CKD patients. The degree of decline in serum levels of 25-hydroxyvitamin D has been found to be related directly with decreases in GFR, and indirectly with increases in PTH and bone alkaline phosphatase. Hypovitaminosis D contributes to bone loss through decreased intestinal calcium absorption, lowered bone formation, and increased osteoclastogenesis. Hence 25-hydroxyvitamin D level should be measured in all patients at any stage of CKD [63].

Another major bone mineral disorder seen in CKD patients is hyperphosphatemia. Phosphate homeostasis is primarily regulated by the kidney. Phosphate is filtered by the renal glomerulus and 80% is then reabsorbed mostly by the proximal nephron’s brush border membrane type IIa sodium-phosphate co-transporter (NaP2a). Retention of phosphorus lead to compensatory increases in FGF23 and PTH leading to decreased renal tubular reabsorption of phosphate and increased urinary phosphate excretion (PTH increases urinary phosphate excretion via cyclic-AMP dependent inhibition of NaP2a expression). Phosphate retention can predispose to hypocalcemia by interfering with the kidney’s ability to produce calcitriol (creating a state of vitamin D deficiency and decreased intestinal absorption of calcium) and by direct suppression of blood calcium which in turn can act directly on the parathyroid causing elevated PTH. Hyperphosphatemia also has a direct effect on post-transcriptional increases in PTH synthesis and secretion inducing parathyroid hyperplasia independent of low blood levels of calcium or calcitriol [30,54].

The nature and type of bone disease that develops in CKD may vary among patients. Four types of bone disease, as defined by quantitative bone histomorphometry, may be encountered in patients with CKD: a) Increased bone turnover and resorption due to secondary hyperparathyroidism with or without marrow fibrosis (osteitis fibrosa) b) Decreased bone turnover and formation (termed adynamic bone) and c) Defective bone mineralization (osteomalacia) and d) Osteoporosis [64].

Chronic kidney disease and role in activation of sympathetic systemCKD can activate the sympathetic system through its communication with the integrative

structures in the brain. Activation of sympathetic system in CKD patients can exert trophic

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effects on cardiac myocytes leading to LVH in patients with essential hypertension. Additionally it can predispose to cardiac arrhythmias, which, in concert with the aforementioned factor, is partly responsible for the high rate of sudden cardiac death in patients with CKD. Treatment strategies targeting the inhibition of sympathetic nervous system should become an integral part of the standard therapy in CKD to slow down the progression of renal failure and improve cardio vascular prognosis in this high-risk patient group [65].

Coagulopathy in chronic kidney diseaseThrombotic events and coagulopathy are two major issues associated with CKD. Patients

with CKD have increased tendency for bleeding due to decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness and impaired prothrombin consumption. Hence use of medications like warfarin and aspirin can predispose those patients to high risk of bleeding. CKD patients also have high predisposition to venous thromboembolism (VTE) especially in presence of nephrotic syndrome. This is mostly related to the increase in procoagulant markers, decreased endogenous anticoagulants, enhanced platelet activation as well as aggregation and decreased activity of the fibrinolytic system. Other factors responsible for increased procoagulant activity in CKD patients include increased levels of D-dimer, C-reactive protein, fibrinogen, factor VII, factor VIII and von Willebrand factor [66].

Nutrition in CKDThe prevalence of protein energy wasting (PEW), a condition of loss of muscle and visceral

protein stores not entirely accounted for by inadequate nutrient intake increases progressively as the renal function deteriorates. PEW appears to be the strongest predictor of survival in CKD patients. Biochemical markers that are directly or indirectly linked to PEW and outcomes include testosterone, leptin, visfatin, adiponectin, thyroid hormones, C-reactive protein and interleukin 6 levels. Progressive increase in the levels of these factors with the decline of GFR in CKD patients cause anorexia, induce resistance to growth hormone as well as insulin like growth factor -I and increase energy expenditure. Additionally uremia-induced alterations in protein metabolism and gastrointestinal tract dysfunction can result in poor nutritional status, which in turn increases the risks of cardiovascular disease and infection [67,68].

Special CircumstancesHuman immunodeficiency virus and CKD

The prevalence of impaired kidney function in human immunodeficiency virus (HIV) patients can range between 2.4% and 10%. The majority of CKD cases in HIV infection are purportedly due to HIV associated nephropathy (almost 50%). Other causes include pathologies resulting from underlying coexisting diseases such as diabetes, hypertension, hepatitis C infection, toxicity related to the medications used in the treatment of HIV which simultaneously contribute to the development and progression of kidney disease in the setting of HIV infection. Risk factors associated with development of CKD in these patients include intravenous drug abuse (especially cocaine), family history of kidney disease, dyslipidemia and cigarette use. The impact of CKD on mortality in HIV infected individuals is related to the severity of renal dysfunction and insufficient use of highly active antiretroviral therapy and doses. Among the HIV-positive individuals, proteinuria and impaired kidney function are associated with faster progression to CKD and death. In agreement with the national kidney foundation, current guidelines provided by the HIV Medicine Association of the IDSA advocate evaluation for both

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proteinuria and kidney dysfunction as CKD screening in HIV-infected individuals [69].

Because of lack of data, ideal method of estimation of GFR in the HIV patients is not clear. Serum creatinine based estimated GFR among HIV infected persons may be particularly biased due to altered metabolism; body mass abnormalities and exposure to multiple medications known to affect renal tubular creatinine secretion. But at the same time until adequate validation of these equations occurs in HIV infected patients, the re-expressed MDRD equation should be the preferred GFR estimating equation used in this patient population, despite its shortcomings, since it is the most widely accepted GFR estimating equation in clinical practice and appears to be the most reliable of the available formulas studied thus far in HIV-positive persons [69].

CKD in elderlyThe prevalence of CKD is increasing in U.S elderly population especially those above the

age of 60 years [70]. Between 1988 and 1994 National Health and Nutrition Examination Survey (NHANES) study and the 2003–2006 NHANES study, the prevalence of CKD in people ages 60 and older increased from 18.8 to 24.5 percent. But at the same time, the prevalence of CKD in people between the ages of 20 and 39 stayed consistently below 0.5 percent [4]. Although only a minority of elderly patients with CKD progress to ESRD, renal impairment is associated with high cardiovascular mortality in this population. Renal impairment affects the safety of many drugs used in older people. Most of the formulas used for estimating GFR are not validated in elderly. It is unclear at this point which creatinine based formula is best for GFR estimation in the elderly or in those with extremes of body mass. Cystatin C based glomerular filtration rate estimation seems to be more accurate than any creatinine based formula in elderly. A multidisciplinary care approach focusing especially on the cardiovascular risk factor modification should be among the goals of treatment for this population [71].

Evaluation and Management of Patients with CKDCare of CKD patients

Patients with CKD should receive multidisciplinary comprehensive clinical management by kidney disease professionals for at least 6 months before requiring renal replacement therapy (RRT). There is near-universal consensus that patients should be referred to a nephrologist when glomerular filtration rate drops below 60 ml/min per 1.73 m2. Late referral results in poor outcomes after dialysis initiation, increased mortality, higher hospitalization rates, lower rate of renal transplantation and higher rate of dialysis catheter use at initiation of dialysis. In addition to dietary instruction and modality education, recommended care includes counseling on cardiovascular disease risk factors, management of blood pressure, screening for bone and mineral disease of CKD and anemia, hepatitis B immunization and administration of nephroprotective agents (renin-angiotensin system antagonists). Consensus guidelines also emphasize placement of permanent dialysis access that is functional at the time of initiation, as well as assessment and referral for preemptive transplantation, if possible. A multidisciplinary team should include or have access to dietary counseling, education and counseling about different RRT modalities, transplant options, vascular access surgery and ethical, psychological as well as social care.

When to refer patients

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Referral to nephrology service should be considered in the following circumstances [24].

1) Acute kidney injury or abrupt sustained fall in glomerular filtration rate (GFR).

2) GFR <30 ml/min/1.73 m2.

3) A consistent finding of significant albuminuria (albumin-creatinine ratio ≥ 300 mg/g creatinine [≥ 30 mg/mmol] or albumin excretion rate ≥ 300 mg/24 hours, approximately equivalent to protein-creatinine ratio ≥ 500 mg/g creatinine [≥ 50 mg/mmol] or protein excretion rate ≥ 500 mg/24 hours).

4) Rapid progression of CKD.

5) Presence of microscopic hematuria.

6) CKD and hypertension refractory to treatment with 4 or more antihypertensive agents.

7) Persistent abnormalities of serum potassium.

8) Recurrent or extensive nephrolithiasis.

9) Hereditary kidney disease.

10) Abnormal structural findings in kidney on imaging.

Effective management should include the following steps:

1) History, physical examination and laboratory studies to establish the diagnosis of CKD.

2) Modification of risk factors.

3) Treatment of complications.

4) Preparation for renal replacement therapy.

5) Patient education.

History and physical examinationA proper history taking in CKD should focus on the establishing the etiology of CKD.

This include history of diabetes, hypertension, systemic inflammatory disorders, nephron/urolithiasis, metabolic diseases, exposure to drugs as well as toxins, exposure to intravenous contrast, herbal medications (Chinese herb containing aristocholic acid), exposure to phosphate containing enema and family history of renal diseases (polycystic kidney disease)and urologic disorders. Drugs which are of particular importance are the NSAIDS, antimicrobials, ACE inhibitors and lithium. In evaluating risk factors and complications ask about history of smoking, drug abuse (mainly cocaine), uremia related symptoms like appetite, diet, nausea, vomiting, and shortness of breath, edema, weight change, pruritus, skin rash, mental acuity and activities of daily living. Physical examination should focus on blood pressure, fundoscopy (hypertensive retinopathy and diabetic retinopathy), precordial examination (fourth heart sound, murmurs, pericardial rub), abdomen (renal bruit, aortic bruit, palpable masses), edema, peripheral pulses, central nervous system (asterixis, muscle weakness, neuropathy), rectum (prostate size) and vagina (pelvic masses) [26].

Pertinent laboratory testing include tests to determine the stage and chronicity of the disease (including complications of uremic syndrome) like plasma creatinine, estimated GFR, urea, electrolytes (sodium, potassium, chloride, bicarbonate), calcium, phosphorus, alkaline

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phosphatase, PTH, 25-hydroxy vitamin D and hemoglobin. Urine analysis should include urine dipstick (pH, specific gravity, blood, leucocyte esterase, nitrates, glucose and protein), urine protein to urine creatinine ratio, urine albumin to creatinine ratio and urine microscopy (dysmorphic red blood cells, white blood cells, white blood cell casts, red blood cell casts, broad casts, cellular casts and granular casts). In certain situation a 24 hour urine collection may be mandatory. Other tests depend on the necessity based on the history, physical examination and abnormalities in above laboratory tests. This includes workup for collagen vascular disease, vasculitis, plasma cell dyscrasias, viral hepatitis and HIV [26].

Most useful and commonly obtained imaging study is a simple ultrasound of renal system. This can verify the presence of symmetric kidneys, estimate size of the kidneys, assess echogenicity, corticomedullary differentiation as well as extent of intact cortex and rule out renal masses as well as obstructive nephropathy. Presence of symmetric small kidneys, increased echogenicity, loss of corticomedullary differentiation and thinning of cortex are some of the signs of chronic kidney disease. Presence of large kidneys in the presence of abnormal renal function indicates disorders like polycystic kidney disease; amyloidosis, diabetes and HIV associated nephropathy. Presence of asymmetry in kidney size indicates unilateral developmental abnormality, chronic unilateral obstruction or infection and chronic renovascular disease. In cases where there is suspicion for renal vascular disease vascular imaging such as renal duplex sonography of renal vessels, radionuclide scintigraphy or magnetic resonance angiography should be strongly considered if revascularization is feasible. Similarly a spiral computed tomography scan without contrast can pick up renal stone disease. A voiding cystourethrography is indicated in the presence of history of enuresis or family history of vesicoureteric reflux disease. In any case avoidance of intravenous contrast exposure should be contemplated because of nephrotoxicity [26].

A renal biopsy is indicated in presence of near normal size kidneys without any changes consistent with advanced structural damage of kidneys. It should also be considered in clinical situations where there is absence of clear cut diagnosis by less invasive means and when there is possibility of reversible underlying disease process. The extent of tubulointerstitial disease on biopsy gives us the most reliable pathologic correlate indicating prognosis in a CKD patient [26].

The information gathered from above should be put into the right perspective to establish the diagnosis of CKD. Past medical records documenting serial measurements of plasma creatinine, GFR and urine analysis can give an idea in terms of the duration of renal dysfunction. In the absence of such information sometimes a urine analysis (presence of broad casts and proteinuria), hyperphosphatemia, hypocalcemia, elevated PTH levels, radiologic evidence of bone disease, normocytic normochromic anemia supported by imaging evidence of long standing renal damage help in the diagnosis of CKD. Constellation of history, clinical findings, laboratory and imaging tests can also facilitate the diagnosis of underlying disease process (For example a 15-20 years history of type 1 diabetes mellitus, nephrotic range proteinuria in the absence of hematuria and diabetic retinopathy favor a diagnosis of CKD from diabetic nephropathy) [26].

Modification of Risk FactorsTreatment of hypertension

Effective antihypertensive treatment in CKD patients has clearly been shown to attenuate

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the worsening of renal function and to reduce proteinuria. At the same time progressively lower blood pressures have been found to be associated with paradoxical increase in mortality (so called J curve phenomenon) especially in diabetics and coronary artery disease patients [8].

The agents of choice in treatment of hypertension are the renin-angiotensin-aldosterone (RAAS) blockers. Antihypertensive agents which specifically inhibit RAAS activity at various levels exert antiproteinuric and renoprotective effects even beyond their systemic hemodynamic effect on blood pressure [72]. These agents prevent progression of renal disease by ameliorating intraglomerular hypertension as well as hypertrophy and consequently proteinuria [7]. Best renal outcomes might be achieved in patients who have maximum reduction in proteinuria. Even though ACE inhibitors and ARBs are equally effective in achieving this based on available data, guidelines indicate ARBs as the preferred choice in type 2 diabetes mellitus patients, and ACE inhibitors for type 1 diabetic as well as non-diabetic renal patients [8]. But at the same time, despite the substantial use of ACE inhibitors and ARBs in the protection of CKD, large fraction of CKD patients progressed to ESRD over time. This was attributed to the non ACE-dependent angiotensin II formation pathways or counter regulatory supramaximal angiotensin II production in the presence of angiotensin II type I receptor blockade (so called aldosterone escape phenomenon). This results in incomplete blockade of the RAAS both under ACE inhibitor or ARB treatment [7].

Although the concept of dual blockade was introduced to resolve this issue, trials using dual blockade showed that on one hand there was reduction in proteinuria and on the other hand use of dual agents resulted in hyperkalemia, hypotension and acute worsening of renal function, especially in the subgroup with impaired renal function. Moreover it did not have any impact on cardiovascular outcomes. Use of direct renin inhibitor with ACE inhibitor or ARB entailed unfavorable outcomes [7]. Single agent high dose therapy came up with encouraging results in terms of reduction in proteinuria which in turn can result in slowing of progression of CKD [8]. The use of combined aldosterone receptor antagonist and ACE inhibitor /ARB did not document any impact on renal function or survival but at the same time demonstrated untoward effects including hyperkalemia when GFR was less than 30 ml/min/1.73 m2. But at the same time the combination showed reduction in proteinuria [8].

Ambulatory blood pressure (particularly nighttime blood pressure) has been found to be a significant and an independent predictor of renal function in both cross-sectional and longitudinal studies. The other factors found to have association with impaired renal function include elevated nighttime blood pressure, non-dipping and decreased circadian variation. Additionally, the risk for micro-albuminuria was 70% lower in dippers (night/day blood pressure ratio ≤ 0.90) compared with non-dippers which means that lowering nighttime blood pressure in patients with CKD is associated with decreased urinary protein excretion and improvement in renal function. Nighttime blood pressure also seems to be a good predictor of adverse cardiovascular events in patients with hypertension and CKD [73].

The optimal goals of therapy and current guidelines (KDIGO) for treatment of blood pressure are represented at the end of this chapter.

Control of diabetic renal diseaseSince diabetes being the most common cause of renal disease progressing to ESRD, control

of diabetes should be given equal importance as management of hypertension. There has been mixed findings in literature regarding the benefit of tight glycemic control and risk for

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renal disease progression. Beneficial effects of intensive glycemic control at reducing risk of nephropathy and retinopathy has been demonstrated in both type 1 and type 2 diabetic patients. Also there has been some data favoring delayed development of microalbuminuria and overt proteinuria in these patients. But at the same time aggressive glycemic control was also found to be associated with side effects like weight gain (leading to increased insulin resistance) and severe hypoglycemia [74]. Hence current guidelines recommend achieving glycosylated hemoglobin of around 7 [24].

Protein restrictionProtein restriction is an important intervention in preventing progression of CKD. Low

protein diet has been found to retard the decline of renal function and alleviate uremic symptoms caused by the accumulation of urea, phosphorus, sulphates, and organic acids. Low protein diet can lead to attenuated protein mediated hyperfiltration in progressive renal injury. It can result in the reduction of sodium and phosphorus intakes and a low acidic content favoring correction of several hormone and metabolic disorders responsible for uremic symptoms. Moreover consuming low protein diet lower urea generation and therefore these patients become less symptomatic and hence low protein diet may delay initiation of renal replacement therapy especially in the elderly. However, long-term dietary restrictions expose older individuals to inadequate protein-energy and micronutrient intake, which may cause a deterioration of nutritional status. It can contribute to the development of sarcopenia, frailty, and functional impairment, which eventually can result in the deterioration of quality of life leading to deprivation, frustration, and social isolation. Hence it has been recommended that protein restriction should be assisted by providing proteins of high biologic value, maintaining sufficient caloric intake, maintaining adequate physical activity to prevent sarcopenia and nutritional monitoring. Based on KDIGO guidelines, a moderate reduction of protein intake to 0.8 g/kg/day may be recommended in individuals with GFR less than 30 ml/min/m2 [24,75].

Treatment of dyslipidemiaThe major modality of treatment of dyslipidemia in CKD patients is using statins. Its major

action is by reducing the level of LDL. In addition to role in improving lipid metabolism, statins also have pleiotropic effects like anti-inflammatory and anti-oxidative actions. They reduce inflammatory markers such as highly sensitive C-reactive protein and improve endothelial function. Meta-analysis studies have shown beneficial role of anti-dyslipidemic drug therapy, mostly using statins, in reducing proteinuria and deterioration of renal function. Improvement in renal function and reduction in proteinuria as well as LDL cholesterol result in decrease number of coronary events and revascularization. At the same time statins have been associated with complications like rhabdomyolysis, liver dysfunction and diarrhea. Use of combination of statins and ezitimibe (which inhibits cholesterol absorption in the jejunum) can reduce the risk of adverse events associated with use of high dose statins and at the same time reduce risk of cardiovascular events [33].

Treatment of metabolic acidosisSince metabolic acidosis has been associated with renal injury and progression of kidney

disease, correction of acidosis might reduce this injury directly by ameliorating the acid environment. Therefore, alkalization that reduces acid retention might be equivalent to drug therapies that reduce kidney levels and effects of angiotensin II, endothelin, and aldosterone. Short-term and long-term studies also show that bicarbonate therapy can reduce serum

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potassium, an outcome that can be beneficial in CKD patients who are at increased risk of hyperkalemia, particularly in the later stages of CKD and in such patients taking ACE inhibitors. Although there is data saying that bicarbonate supplementation in the form of sodium bicarbonate will not elevate blood pressure or require increased dose of anti-hypertensive agents, higher alkali doses might cause sodium-water retention and affect blood pressure control in patients with advanced renal failure. Sodium bicarbonate is contraindicated in patients with metabolic or respiratory alkalosis and in those with hypocalcaemia in whom alkalosis may induce tetany and hypokalemia. It should also be used with caution in patients with chronic obstructive pulmonary disease, because alkalization can reduce the sensitivity of the respiratory regulatory center. The National Kidney Foundation recommends 0.5–1.0 mEq of NaHCO3/kg body weight in patients with bicarbonate less than 22 mmol/L [76].

Treatment of hyperuricemiaTargeting uric acid has also been found to have impact on the progression of CKD. The

most common agent used for this purpose in addition to diet restriction is allopurinol. Allopurinol treatment resulted in a decrease of uric acid that was associated with improvement of endothelial function, GFR and systolic blood pressure. The effect of allopurinol effect is either due to reduction of uric acid per se or because of the antioxidant effect produced when xanthine oxidase is inhibited. Similarly another xanthine oxidase inhibitor febuxostat treatment protected against renal damage and progression of proteinuria, maintaining the morphology of glomerular vessels and glomerular pressure independent of effect on uric acid [77,78].

Treatment of ComplicationsTreatment of bone mineral disorders

Vitamin D has potent anti-proliferative, pro-differentiative, and immuno-modulating activities modulated via vitamin D receptor–dependent genomic effects [44]. This seems to provide the biologic basis for salutary effects of vitamin D receptor agonists (VDRA) in patients with kidney disease. Use of oral VDRA is associated with significantly better survival, and a lower risk of initiating dialysis. Inactive forms of supplementary vitamin D, ergocalciferol (vitamin D2), and cholecalciferol (vitamin D3), significantly increase 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D levels in patients with stages 3 and 4 CKD. Markers of bone formation, such as bone-specific alkaline phosphatase, will also be significantly reduced by VDRA treatment. Although these supplements are generally considered ineffective for PTH suppression in usual doses, in patients with stage 5 CKD (before or in those receiving dialysis), they may prevent osteomalacia due to vitamin D deficiency. Hence depending on the stage of kidney dysfunction, repletion of both inactive 25-hydroxy vitamin D and active 1,25-dihydroxy vitamin D is needed. In patients with stage 3 and 4 CKD and secondary hyperparathyroidism, it is recommended to correct vitamin D deficiency with cholecalciferol (vitamin D3). Supplementation of oral vitamin D should be done in patients who have 25- hydroxy vitamin D levels less than 30 ng/ml. Use of calcitriol or VDRA is recommended only if the PTH remains elevated inspite of correcting the vitamin D deficiency. Major side effects with use of vitamin D include hypercalcemia, hyperphosphatemia and over suppression of PTH leading to adynamic bone disease [62].

Treatment of secondary hyperparathyroidism is carried out with use of vitamin D

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supplementation, phosphate binders and calcimimetics (not FDA approved for non- dialysis CKD patients). This might have beneficial effects for the vascular mineralization and mortality in CKD, an effect that can be at least be partly mediated through the reduction of arterial stiffness and arterial calcification [62].

Treatment of hyperphosphatemia includes dietary phosphate restriction and the use of phosphate binders. This eventually will result in control of secondary hyperparathyroidism with secondary lowering of FGF23. Lowering serum phosphorus also increases production of calcitriol, which has a direct effect on the parathyroid glands to decrease PTH production and secretion. The traditionally used phosphate binders include calcium based binders like calcium acetate as well as non-calcium based binders like sevelamer carbonate and lanthanum carbonate. Sevelamer can reduce FGF-23 levels irrespective of the changes in serum phosphorus or 1,25-dihydroxyvitamin D [79].

KDIGO guidelines suggest measurement of serum total calcium, phosphorus, 25- hydroxyvitamin D, PTH, and bone alkaline phosphatase as baseline values if patients are diagnosed with stage 3 CKD (GFR 30-59 mL/min). Measurement of alkaline phosphatase should be done on a regular basis since it is a readily available biochemical marker for assessing bone formation in CKD and it is not excreted by the kidney. Although alkaline phosphatase elevation in CKD likely reflects secondary hyperparathyroidism, it may also signify recent fracture, hypovitaminosis D, osteomalacia, or other metabolic bone disorders. Increased levels virtually exclude the presence of adynamic bone disease (ABD). But at the same time normal alkaline phosphatase and normal to slightly elevated PTH levels in late CKD need to be viewed with caution for possible ABD [80].

Bone mineral density (BMD) measurement may be done in stage 3 CKD (GFR30-59 mL/min/m2), especially in patients with laboratory or other risk factors for osteoporosis. A DEXA scan can assess fracture risk and bone loss over time in patients with stage 3-4 CKD. It can also measure changes in bone mass following parathyroid surgery for hyperparathyroidism. But at the same time it can be highly unreliable especially when GFR is less than 45 ml/min/m2. The gold standard for the diagnosis and classification of CKD-MBD is the tetracycline double-labeled bone biopsy (iliac crest biopsy) for histomorphometric analysis. Current KDIGO guidelines do not recommend bone mineral density measurements for CKD but do suggest that stages 3 to 5 CKD patients be measured for serum PTH or bone-specific alkaline phosphatase to predict for low or high bone turnover [24]. Clinical practice guidelines (KDOQI) for bone metabolism and disease in CKD are represented in Table 3.

CKD stage Phosphorus (mg/dL) Calcium( mg/dL) PTH (pg/ml)Stage 3 2.7-4.6 8.4-10.2 35-70Stage 4 2.7-4.6 8.4-10.2 70-110Stage 5 3.5-5.5 8.4-9.5 150-300

Table 3: Clinical practice guidelines (KDOQI) for bone metabolism and disease in CKD.

Treatment of anemiaTreatment of anemia in CKD includes correction of iron deficiency and erythropoietin

deficiency. The ideal goal of hemoglobin in patients with CKD is a matter of debate. The target hemoglobin and threshold for use of erythropoietin is based on three major trials viz CHOIR, CREATE and TREAT. In the CHOIR study the patients treated for the higher hemoglobin target experienced a 34% increased risk of a composite cardiovascular endpoint compared to those

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treated for a lower hemoglobin target. In addition, quality of life did not differ between the groups. In the CREATE study the composite cardiovascular endpoint did not differ between the two groups. However, the risk of ESRD increased in the higher target group. In TREAT, a large trial of 4038 patients with diabetes, CKD (GFR 20-60 mL/min/1.73 m2) and anemia, participants were randomly assigned into receiving darbopoetin for a hemoglobin target of 13 g/dL, or matching placebo with rescue darbopoetin treatment below hemoglobin of 9 g/dL. Even though there was a significant improvement in quality of life, the incidence of the composite cardiovascular endpoint did not differ between the groups. At the same time a doubling in the risk of stroke in the normal hemoglobin arm and increased cancer-related mortality were observed. Based on the increased risk of adverse outcomes at higher hemoglobin concentrations, the Food and Drug Administration (FDA) recommended more conservative dosing guidelines for erythropoiesis stimulating agents (ESA) when used to treat anemia in patients with CKD. On the same tune the KDIGO anemia guidelines also recommended that for patients with CKD not on dialysis and anemia, ESA treatment should only be considered when the hemoglobin level is < 10 g/dL and be individualized based on the rate of fall of hemoglobin, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy, and the presence of symptoms attributable to anemia. In general, ESAs should not be used to maintain a hemoglobin concentration > 11.5 g/dL in adult patients with CKD. It is unclear whether the negative effects of complete correction of anemia are due primarily to high hemoglobin levels per se, to excessive ESA doses, or to both. Higher doses of ESAs might be associated with toxicities, which include erythropoietic and non-erythropoietic effects most important being the increase in blood viscosity. Increased blood viscosity also predisposes patients to increased vascular resistance and the development of hypertension [81,82].

Prevention of infectionBecause of increased risk of infections seen in CKD patients it has been recommended to

take appropriate measures for prevention of infection. As part of this effort KDIGO has made the following recommendations [24].

1) Annual vaccination with influenza vaccine, unless contraindicated.

2) CKD patients with GFR less than 30 and those at high risk of pneumococcal infection (e.g., nephrotic syndrome, diabetes, or those receiving immunosuppression) receive vaccination with polyvalent pneumococcal vaccine unless contraindicated. Additionally all adults with CKD who have received pneumococcal vaccination should be offered revaccination within 5 years.

3) CKD patients who are at high risk of progression of CKD and have GFR <30 ml/min/1.73 m2 be immunized against hepatitis B and the response confirmed by appropriate serological testing.

In addition to this early detection and treatment of urinary tract infection is also important in preventing progression of CKD.

Dietary sodium restriction in CKDDietary sodium intake in CKD patients has been found to influence a number of uremia

related risk factors including oxidative stress, proteinuria, inflammation, and endothelial cell damage. Additionally it has been found to increase blood pressure, cardiovascular risk (independent of blood pressure changes), proteinuria and intraglomerular pressure and decrease GFR. As sodium handling is primarily the role of the kidney those with CKD may have

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a reduced ability to excrete sodium, making them less able to compensate for the high sodium load that is characteristic of the Western diet. Hence a diet low in sodium is essential for better control of hypertension as well proteinuria and improvement in GFR and cardiovascular outcomes. Current guidelines recommend salt restriction amounting to less than 90 mmol/day (<2 gm/day) [83].

Medication use in CKDThe medical management of CKD patients involve complex and highly variable

pharmacotherapy, including frequent monitoring as well as evaluation to ensure optimal pharmacotherapy and adherence to medication. A high number of prescribed medications, poor medication adherence, and frequent dosage changes may contribute to drug-related morbidity and related problems. Drug related side effects are very frequently reported in CKD patients because of the complexity of dosing emanating from the changes in drug pharmacodynamics and pharmacokinetics in the presence of CKD. NKF-KDOQI guidelines explicitly highlight the need for regular medication reviews, including dosage adjustment, adverse drug event detection, drug interaction detection, and therapeutic drug monitoring. One way of dealing with this is by utilizing the service of a clinical pharmacist who can work with the physician closely in outpatient clinics. A higher proportion of CKD patients achieve haemoglobin target, increased medication knowledge, decreased hospitalisation rates, and an overall improvement in the quality of life in such clinical pharmacist led programs [84].

Other interventions that can potentially prevent progression of renal disease include immunosuppressive medications for autoimmune glomerular diseases, antibiotics for urinary tract infections, removal of urinary stones, relief of obstruction, and cessation of toxic drugs, avoidance of phosphate containing enema.

Monitoring in CKDKDIGO guidelines for management of chronic kidney disease.

Proteinuriaa) During evaluation of CKD check for proteinuria using albumin to creatinine (ACR) ratio.

If ACR > 30 mg/g (>3 mg/mmol) on a random untimed urine, confirm it with a subsequent early morning urine sample. If a more accurate estimate of albuminuria or total proteinuria is required, measure albumin excretion rate or total protein excretion rate in a timed urine sample.

b) Assess GFR and albuminuria at least annually in people with CKD. Assess GFR and albuminuria more often for individuals at higher risk of progression (sustained decline in GFR of more than 5 ml/min/1.73/m2/year), and/or where measurement will impact therapeutic decisions.

Hypertensiona) For diabetic and non-diabetic adults with CKD and urine albumin excretion < 30

mg/24 hours (or urine ACR < 30 mg/g) start treatment for hypertension if blood pressure is consistently more than 140 mmHg systolic or 90 mmHg diastolic.

b) For diabetic and non-diabetic adults with CKD and urine albumin excretion ≥ 30 mg/24 hours (or urine ACR ≥ 30 mg/g) start treatment for hypertension if blood pressure

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is consistently more than 130 mmHg systolic or 80 mmHg diastolic to achieve a goal blood pressure of ≤ 130 mm Hg systolic and ≤ 80 mm Hg diastolic.

c) An ARB or ACE inhibitor can be used in diabetic adults with CKD and urine albumin excretion 30–300 mg/ 24 hours.

d) An ARB or ACE inhibitor should be used in both diabetic and non-diabetic adults with CKD and urine albumin excretion > 300 mg/24 hours.

Dietary intervention/ Protein intakea) Restrict protein intake to 0.8 g/kg/day in adults with diabetes or without diabetes and

GFR <30 ml/min/ 1.73 m2 with appropriate education.

b) High protein intake of > 1.3 g/kg/day in adults with CKD at risk of progression should be avoided.

c) Dietary advice and information in the context of an education program, tailored to severity of CKD and the need to intervene on salt, phosphate, potassium, and protein intake should be provided where indicated.

Glycemic controlTarget hemoglobin A1C to ~7.0% to prevent or delay progression of the micro vascular

complications of diabetes, including diabetic kidney disease.

Salt intakeLower salt intake to <90 mmol (<2 g) per day of sodium in adults, unless contraindicated.

Metabolic acidosisIn the presence of CKD and serum bicarbonate concentrations <22 mmol/L, treatment

with oral bicarbonate supplementation can be given to maintain serum bicarbonate within the normal range, unless contraindicated.

Miscellaneous interventionsa) Encourage people with CKD to undertake physical activity compatible with cardiovascular

health and tolerance (aiming for at least 30 minutes 5 times per week)

b) Encourage to achieve a healthy weight (body mass index of 20-25) based on exercise and diet

c) Encourage to stop smoking.

d) Avoid use of phosphate enema

e) Refer for preemptive renal transplantation when the GFR is <20 ml/min/1.73 m2, and when there is evidence of progressive and irreversible CKD over the preceding 6–12 months.

The following interventions should be avoided:

a) Perform bone mineral density testing routinely in those with GFR <45 ml/min/1.73 m2 as information may be misleading or unhelpful.

b) Prescribing bisphosphonate treatment in people with GFR <30 ml/min/1.73 m2 without

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a strong clinical rationale.

c) Use of gadolinium-containing contrast media in people with GFR <15 ml/min/1.73 m2 unless there is no alternative appropriate test. If there is need for using gadolinium in people with GFR <30 ml/min/1.73 m2, a macrocyclic chelate preparation should be preferred.

Monitoring of laboratory testsI. GFR

a) For GFR categories G1 &2, GFR can be tested annually if CKD is present in the absence of microalbuminuria or 1-2 times per year if there is micro or macro albuminuria.

b) For GFR categories G3a & G3b, GFR should be tested at 1-3 times per year depending on the severity of albuminuria.

c) For GFR categories G4 & G5, GFR should be tested at least 3-4 times per year depending on the severity of albuminuria.

d) Assess GFR more often for individuals at higher risk of progression, and/or where measurement will impact therapeutic decisions.

II. Metabolic bone disease and laboratory monitoring

a) For GFR categories G3a & G3b, serum calcium, phosphorus every 6-12 mos and PTH based on baseline level and CKD progression.

b) For GFR categories G4, serum calcium, phosphorus every 3-6 mos and PTH every 6-12 months.

c) For GFR categories G5 (including dialysis), serum calcium, phosphorus every 1-3 mos and PTH every 3-6 months.

III. Albuminuria

a) Assess Albuminuria at least annually irrespective of the stage of kidney disease.

b) Assess albuminuria more often for individuals at higher risk of progression, and/or where measurement will impact therapeutic decisions.

IV. Hemoglobin

a) CKD and GFR categories G1 &2 when clinically indicated.

b) For GFR categories G3a & G3b: annually.

c) For GFR categories G4 &G5 twice per year.

Renal replacement therapyPatients with CKD should be referred well in advance for placement of arteriovenous fistula

so that they will have mature fistula by the time they are on the point of initiation of renal replacement therapy. This is preferably done at stage 4 when glomerular filtration rate (GFR) is around 20 ml/min/1.73 m2. The decision to start dialysis treatment depends on the severity of uremic symptoms. Clear indications for initiation of dialysis include pericarditis, progressive neuropathy attributable to uremia, encephalopathy, muscle irritability, anorexia and nausea attributable to uremia and that are not ameliorated by reasonable protein restriction, evidence

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of protein-energy malnutrition, and fluid and electrolyte imbalance refractory to conservative treatment. Patients who have questionable history of compliance with conservative treatment should be also considered for early initiation of dialysis treatment. The optimal timing of initiation of dialysis based on absolute GFR is still not known at this point. Early initiation of dialysis has not been found to be superior to late initiation based on available data [24,26].

Patient educationWhile conservative and supportive treatment is being carried out, simultaneous educational

program focusing on social psychological and physical preparation for transition to renal replacement therapy should be initiated. This should include information regarding timing of initiation of renal replacement therapy, various modalities of therapy available for dialysis. Patient’s family should also be involved in the discussion especially of those who are planning home hemodialysis, peritoneal dialysis and transplantation. The risk and benefits of each dialysis modality and renal transplantation should be explained in detail. The potential psychological impact that the patients could develop in this process should also be addressed accordingly.

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17. Gbadegesin R, Lavin P, Foreman J, Winn M (2011) Pathogenesis and therapy of focal segmental glomerulosclerosis: an update. Pediatr Nephrol 26: 1001-1015.

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55. Covic A, Kothawala P, Bernal M, Robbins S, Chalian A et al. (2009) Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease. Nephrol Dial Transplant 24(5): 1506-1523.

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