Maturitas 71 (2012) 94– 103
`
`Contents lists available at SciVerse ScienceDirect
`
`Maturitas
`
`j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m a t u r i t a s
`
`Review
`Chronic kidney disease and diabetes
`Ronald Pyram a,b, Abhishek Kansara a,b,c, Mary Ann Banerji a,c, Lisel Loney-Hutchinson a,c,∗
`
`a Division of Endocrinology SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, United States
`b Division of Endocrinology Brooklyn VA Medical Center, Brooklyn, NY, United States
`c Kings County Hospital Center, Department of Medicine, 451 Clarkson Ave, Brooklyn, NY 11203, United States
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`Article history:
`Received 28 October 2011
`Received in revised form 9 November 2011
`Accepted 9 November 2011
`
`Keywords:
`Chronic renal disease
`Diabetes
`Glomerular filtration rate
`Nephropathy
`Renal failure
`
`Contents
`
`Chronic kidney disease has a significant worldwide prevalence affecting 7.2% of the global adult popu-
`lation with the number dramatically increasing in the elderly. Although the causes are various, diabetes
`is the most common cause of CKD in the United States and an increasing cause of the same worldwide.
`Therefore, we chose to focus on diabetic chronic kidney disease in this review.
`The pathogenesis is multifactorial involving adaptive hyperfiltration, advanced glycosylated end-
`product synthesis (AGES), prorenin, cytokines, nephrin expression and impaired podocyte-specific insulin
`signaling. Treatments focus on lifestyle interventions including control of hyperglycemia, hypertension
`and hyperlipidemia as well treatment of complications and preparation for renal replacement ther-
`apy. This review examines the current literature on the epidemiology, pathogenesis, complications and
`treatment of CKD as well as possible areas of future disease intervention.
`Published by Elsevier Ireland Ltd.
`
`1.
`
`2.
`
`3.
`
`4.
`
`94
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1.1.
`95
`Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`95
`Diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.1.
`95
`Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.2.
`96
`Pathological disease progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.3. Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`96
`2.4.
`97
`Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`97
`Evidence of modifiable risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.1.
`97
`Diet, weight reduction, exercise and smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.2.
`Blood glucose control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`98
`3.3.
`98
`Blood pressure control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.4. Management of complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`98
`3.5. Medication management of hypertension in patients with CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`99
`3.6.
`Preparation for initiation of renal replacement therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
`Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
`Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
`Competing interests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
`Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
`
`∗ Corresponding author at: Kings County Hospital Center, Department of
`Medicine, 451 Clarkson Ave, Brooklyn, NY 11203, United States.
`Tel.: +1 718 270 6324.
`E-mail address: lisel.loney-hutchinson@downstate.edu (L. Loney-Hutchinson).
`
`0378-5122/$ – see front matter. Published by Elsevier Ireland Ltd.
`doi:10.1016/j.maturitas.2011.11.009
`
`1. Introduction
`
`Chronic kidney disease (CKD) affects a significant portion of the
`world population with a prevalence of 7.2% in adults over age 30
`and dramatically increasing to 23.4–35.8% over age 65 [1]. Further-
`more, population based studies in the United States reveals a CKD
`prevalence ranging from 1.4 to 43.3% [2]. The causes of CKD are
`
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`R. Pyram et al. / Maturitas 71 (2012) 94– 103
`
`95
`
`various and include glomerular kidney disease, tubular and inter-
`stitial kidney disease, obstructive uropathy, pre renal and vascular
`disorders, diabetes and hypertension. Globally, diabetes is the most
`common cause of CKD.
`There are multiple etiologies involved in the pathogenesis of
`diabetic CKD. The initial mechanism of damage involves adaptive
`hyperfiltration which leads to long term damage of functioning
`nephrons. Additional mechanisms of disease include advanced
`glycosylated end products (AGEs), vascular endothelial growth fac-
`tor (VEGF), prorenin and the renin–angiotensin system, cytokines,
`nephrin expression and impaired podocyte signaling. Importantly,
`CKD is associated with an increased risk of cardiovascular disease,
`mortality and end stage renal disease. Most patients are likely to
`die than develop end stage renal disease. Treatments are limited
`but focus on treatment of associated causes including diabetes and
`hypertension, slowing progression of disease, treatment of compli-
`cations and preparation for renal replacement therapy. This review
`examines the current literature on the epidemiology, pathogene-
`sis, complications and treatment of CKD as well as possible areas of
`future disease intervention.
`
`1.1. Epidemiology
`
`Diabetes mellitus is a disease that affects over 23.5 million
`American adults [3] and type 2 diabetes accounts for over 90%
`[4,5]. Diabetes is the most common cause of CKD. The prevalence
`of some degree of CKD among adults with type 2 diabetes is 40%
`[3,6–11]. The 2009 annual report published by the United States
`Renal Data Systems, reports the prevalence rate of CKD in type 2
`diabetes according to stage was 8.9% for stage I, 12.8% for stage
`II, 19.4% for stage III, and 2.7% for stages IV and V combined. The
`lifetime risk of developing CKD in type 1 diabetes is 25% [5,12–17].
`The older population is especially affected by diabetic nephropa-
`thy. The incidence of end stage renal disease (ESRD) related to
`diabetes among the elderly markedly increased from the 1980s
`up until the late 1990s at which time there was slight decrease
`and leveling off to approximately 350–370/100,000 [4,18,19]. This
`more recent decline in CKD is likely due to earlier recognition and
`interventions.
`In the 2010 Annual report published by the United States Renal
`Data Systems, the median age of incident ESRD population was
`64.2 in 2008 which varied by race; the median age ranged from
`59.2 among African Americans to 66.8 among whites. The rate of
`prevalence of CKD remains highest among the African American
`and Native American population, and lowest among the Caucasian
`and Asian population paralleling the rate of diabetes in these pop-
`ulations [20,21]. The trend of increasing prevalence is expected to
`continue to grow as the elderly population continues to rise with
`increased life expectancy.
`CKD in diabetes causes significant disability and contributes
`greatly to health care costs; annually approaching $23 billion with
`ESRD in the US [22]. McFarlane et al. [23] evaluated the risk of hos-
`pitalization, cardiovascular risk and death in patients with chronic
`kidney disease and reported that the adjusted risk of hospitaliza-
`tion increased as the estimated glomerular filtration rate (eGFR)
`decreased ranging from an increase of 14% with an estimated GFR
`of 45 to 59 ml/min/1.73 m2 to an increase of 315% with an estimated
`GFR of less than 15 ml/min/1.73 m2.
`
`2. Diabetic nephropathy
`
`CKD
`in kidney
`loss
`irreversible
`is defined as progressive,
`function. The National Kidney Foundation (NKF) Kidney Disease
`Outcomes Quality Initiative (K/DOQI) defined CKD as lasting three
`or more months with either kidney damage defined by structural or
`
`Table 1
`Stages of chronic kidney disease.
`
`Stage
`
`Description
`
`eGFR (ml/min/1.73 m2)
`
`I
`II
`III
`IV
`V
`
`Normal or increased eGFRa
`Mildly decreases eGFRa
`Moderately reduced eGFR
`Severely reduced eGFR
`Kidney failure
`
`>90
`60–89
`30–59
`15–29
`<15 or dialysis
`
`a With evidence of structural kidney damage such as albuminuria, abnormal uri-
`nary sediment (i.e. casts, tubular epithelial cells), abnormal imaging studies, renal
`transplant recipients [26].
`
`functional abnormalities of the kidney with or without decreased
`eGFR, or a GFR of less than 60 ml/min/1.73 m2. These abnormal-
`ities include markers of kidney damage [1] such as albuminuria,
`abnormal urinary sediment (casts, epithelial cells), abnormal imag-
`ing (polycystic kidneys, hydronephrosis), blood and urine markers
`of ‘tubular syndromes’ and renal transplant recipients. In addi-
`tion to the gold standard isotopic measures, several equations
`are used to estimate GFR. The Modification of Diet in Renal Dis-
`ease (MDRD) equation [1], validated in patients with diabetic
`(type 2) and non-diabetic kidney disease and in transplant recip-
`ients is most commonly used. It is verified in US and European
`whites and African-Americans, but not with other racial/ethnic
`groups, extremes of age, pregnancy and certain other conditions
`[1]. The Chronic Kidney Disease Epidemiology Collaboration (CKD-
`EPI) equation is a new estimate of glomerular filtration and may be
`more accurate [24,25] at higher levels of eGFR.
`Stages of chronic kidney disease: The stages of chronic kidney
`disease as described in Table 1 are defined on the basis of eGFR [26]
`with evidence of kidney damage.
`
`2.1. Risk factors
`• Elevated blood pressure: Elevated systolic blood pressure is well
`known to accelerate diabetic nephropathy [27–29]. The devel-
`opment of impaired renal function was associated with higher
`mean blood pressures even in patients who were normotensive
`with and without proteinuria [28] in long-term follow-up of type
`2 diabetes patients.
`• Diabetes: Strong evidence for the role of glycemia was provided
`by the DCCT (type 1 diabetes) and the UKPDS (type 2 diabetes)
`intervention trials where improved glycemia resulted in signifi-
`cantly lower progression rates for albuminuria [30]. The duration
`of diabetes is associated with progression of nephropathy in long-
`term follow-up in Saudis with duration of diabetes >10 years
`[31]. The odds of nephropathy were 4.6-fold higher in urban
`African-Americans with duration of diabetes greater than 5 years
`as compared to <1 year [32].
`• Cholesterol: Elevated levels are associated with increased risk of
`nephropathy [26].
`• Microalbuminuria: The prevalence of microalbuminuria
`in
`South
`Indian diabetics was 36%, similar to urban African-
`Americans with type 2 diabetes for <1 year [32,33]. Microal-
`buminuria predicts progression to clinical proteinuria and
`decreased renal function in patients with type 2 diabetes [34–36]
`as well as increased CVD and mortality [30,37,38]. The rate
`of progression in UKPDS, from diagnosis of diabetes without
`microalbuminuria to microalbuminuria is 2% per year; from
`microalbuminuria to macroalbuminuria is 2.8% per year; and
`macroalbuminuria to elevated creatinine or renal replacement
`therapy
`is about 2.3% per year. Patients without microal-
`buminuria at diagnosis remained free of nephropathy for a
`median period of about 19 years, while those who developed
`microalbuminuria progressed to macroalbuminuria (or worse)
`in 11 years [39]. Microalbuminuria is infrequently reversible to
`
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`R. Pyram et al. / Maturitas 71 (2012) 94– 103
`
`Table 2
`Effects of RAAS in pathogenesis of diabetic nephropathy.
`
`Aldosterone
`
`Profibrotic
`
`Mitogenic
`
`Angiotensin II
`
`↑
`
`Production of reactive
`oxygen species
`↓ Nitric oxide production
`↑ Glomerular hypertension
`↑ Vascular endothelial growth
`factor
`
`Prorenin
`
`Elevated in type 1 diabetics
`with microalbuminuria
`
`increased VCAM expression causing vascular injury, mesangial
`cell growth, enhanced expression of growth factors, extracellu-
`lar membrane proteins, ROS and activation of protein kinase C,
`releasing cytokines and growth factors.
`• Protein kinase C (PKC): Hyperglycemia activates isoforms of
`protein kinase C through diacylglycerol (DAG), which activates
`MAP kinase and vasotropic substances such as angiotensin II,
`endothelin and prostanoids causing glomerular hyperfiltration.
`PKC activation increases ROS and the actions of fibrotic factors
`such as TGF-beta and connective tissue growth factor (CGTF)
`resulting in glomerular hypertrophy and mesangial expansion.
`ROS increases cytokines and extracellular membrane proteins
`type IV collagen leading to glomerulosclerosis and renal failure
`[59].
`• Vascular endothelial growth factor (VEGF) expression
`in
`podocytes is upregulated by hyperglycemia, increasing vascular
`permeability in the nephron [60].
`• Aldose reductase pathway: Its role in CKD is unclear [61,62].
`
`Nephrin: Nephrin, a protein found in podocytes is crucial in
`maintaining an intact filtration barrier. Lower renal expression of
`nephrin in kidney biopsies of patients with diabetes is reported
`[63].
`mTOR (mammalian Target Of Rapamycin) is a serine/threonine
`protein kinase which integrates multiple signals including insulin,
`energy balance and oxidative stress and regulates cell growth
`and survival. In glomeruli from patients with diabetic nephropa-
`thy, mTOR activated target genes were increased including VEGF,
`SREBP, mitochondrial genes as well as mTOR mRNA [64]. mTOR may
`play a role in glomerular hypertrophy and podocyte enlargement.
`Renin–Angiotensin System Aldosterone (RAAS) (see Table 2):
`
`• Prorenin: Increased serum prorenin levels precede and predict
`the onset of microalbuminuria in normotensive type 1 diabetes
`[65]. Levels were also higher in non-diabetic siblings of these
`patients [66,67] and may be a marker for increased risk of
`nephropathy in non-diabetic patients at high risk for diabetes.
`• Angiotensin II (Ang II) Ang II stimulates synthesis of matrix
`proteins, increases VEGF, oxidative stress, and decreases NO pro-
`duction and loss of endothelial integrity. Ang II causes efferent
`arteriolar vasoconstriction and increased intraglomerular pres-
`sure leading to renal hyperfusion [68,69].
`• Aldosterone is known to be mitogenic and increases renal fibro-
`sis through profibrotic TGF-beta [70,71].
`
`Microalbuminuria: Elevated levels of inflammatory markers
`are proportional to the degree of albuminuria [68]. In patients with
`type 2 diabetes and persistent microalbuminuria, elevated levels
`of biomarkers of inflammation and endothelial dysfunction pre-
`dicted development of nephropathy over a 2-year follow-up period
`[72]. Inflammatory factors lead to accumulation of macrophages
`in the tubular interstitium, producing free radicals, inflammatory
`cytokines and proteases that induce tubular damage [18,71].
`
`normoalbuminuria in type 2 diabetes (21% over 2 years) [40]. In
`contrast, this occurs in up to 50% of type 1 diabetes with short
`duration microalbuminuria [41]. Thus, although microalbumin-
`uria precedes proteinuria and decreased renal function, not all
`microalbiminuria will progress. The challenge is in identifying
`those with microalbuminuria who are likely to progress from
`those who will not. The GFR may also decline in the absence of
`any microalbuminuria [36,42].
`• Smoking: In types 1 and 2 diabetes, albuminuria was greater in
`smokers [43].
`• Genetic factors:
` An insertion /deletion polymorphism (specif-
`ically the deletion allele) of the ACE gene predicted severe
`structural kidney changes in patients with microalbuminuria
`[44]. Not all studies confirm this. Identifying the genetic risk of
`diabetic nephropathy [45] requires further study.
`• Age and BMI:
` Advancing age and obesity are also risk factors [28].
`
`2.2. Pathological disease progression
`
`Classical hemodynamic and structural causes of diabetic
`nephropathy, best characterized in type 1 diabetes are summarized
`below [46–49]:
`• Glomerular hyperfiltration: Vasodilatation and glomerular
`hyperfiltration, resulting in increased glomerular filtration rate,
`are known to occur early in type 1 diabetes, but not always in type
`2 diabetes [46,49–52]. While hyperfiltration frequently predicts a
`decline in renal function, it is not invariable.
`• Glomerular lesions without clinical disease: This stage
`is
`characterized by glomerular lesions-glomerular basement mem-
`brane thickening and mesangial expansion; without excess
`albumin excretion. Typical Kimmelstiel–Wilson lesions (nodular
`glomerulosclerosis) are found in only a small proportion early in
`nephropathy [49].
`• Incipient diabetic nephropathy: This stage develops after about
`10–15 years of type 1 diabetes characterized by microalbu-
`minuria and structural lesions [53,54]; the GFR may be well
`preserved. It is of clinical interest because interventions, espe-
`cially blood pressure control may prevent progression to overt
`nephropathy.
`• Overt diabetic nephropathy: There is persistent and progres-
`sively worsening proteinuria, a decline in GFR, frequently leading
`to ESRD. This stage is characterized by advanced glomerular
`lesions-diffuse and nodular glomerulosclerosis, fibrinoid caps,
`capsular drops and arteriolar hyalinosis [49].
`
`2.3. Mechanisms
`
`The mechanisms by which diabetes induces renal damage are
`not adequate to formulate a cohesive model of nephropathy.
`Various physical and metabolic factors together result in mesan-
`gial hypertrophy, glomerular basement thickening, podocyte and
`endothelial dysfunction.
`Glomerular hyperfiltration
`[55–57]: Various mediators
`include
`system, vascular endothelial
`the
`renin–angiotensin
`growth
`factor (VEGF), nitric oxide and transforming growth
`factor-beta (TGF-B).
`Hyperglycemia: Hyperglycemia is linked to multiple metabolic
`perturbations (Fig. 1).
`• Advanced glycosylated end-products (AGEs) are covalently
`glycosylated proteins [58] whose synthesis increases with hyper-
`glycemia. These accumulate in the extracellular matrix and the
`glomerular basement membrane altering the elasticity, ionic
`charge and thickness [59]. AGEs bind with cell surface receptors
`(RAGE) and initiate cellular signaling cascades associated with
`
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`R. Pyram et al. / Maturitas 71 (2012) 94– 103
`
`97
`
`Hyperglycemia
`
`se Reducta
`Aldo
`
`
`Pathway
`
`se
`
`d Glycation
`Advance
`
`
`VCAM-1
`
`s
`
` End-product
`
`
`RAGERAGE
`
`Protein Kinase C
`
`DAG
`
`Diminished
`NO
`production
`
`Increased AGEs
`
`Increased
`prostaglandins
`
`Increased PKC
`
`Abnormal
`glomerular
`
`filtrati
`on
`
`
`
`
` injury
`
`Vascular
`
`
`Accumulation
`in ECM,
`
`
`
`GGBM
`
` elasticity,
`Altered
`
`
`ionic charge,ionic charge,
`
` of GBM
`thickness
`
`
`
`Renal dysfunctionRenal dysfunction
`
`
`
`
`
`AGE-RAGE
`-mesangial
` cell growth
`
`-stimulati
`
`on of GFs
`
`
`-ROS activation
`releasing
` cytokines
`
`
`Fibrotic factors
`
`
`
`
`Vasotropic
`substances
`-Ang,
`VEGF,
`PGE2
`
`ROS
`
`Increased
`cytokines,
`ECM
`proteins
`
`Glomerular
`hyperfiltratio
`n
`
`
`GlomerularGlomerular
`
`n,
`hyperfiltratio
`
`mesangial
`expansion
`
`Glomerulosclerosis
`
`Fig. 1. Pathways of hyperglycemia causing renal damage. AR: aldose reductase; NO: nitric oxide; AGEs: advanced end-glycation products; PKC: protein kinase C; VCAM:
`1-vascular cell adhesion molecule-1; RAGE: receptor for AGE; ECM: extracellular matrix; GBM: glomerular basement membrane; GFs: growth factors; ROS: reactive oxygen
`species; Ang: angiotensin; VEGF: vascular endothelial growth factor; PGE2: prostaglandin E2; DAG: diacylglycerol.
`
`2.4. Complications
`
`Anemia: Nearly 1 in 5 patients with stage III chronic kidney
`disease have anemia and likely due to decreased erythropoietin.
`Anemia is associated with a poor quality of life, increased fatigue,
`weakness, cognitive dysfunction, memory impairment and pro-
`gression of renal disease (ESRD) and increased mortality from CVD
`[73–76].
`Cardiovascular disease: As shown in Fig. 2, the prevalence
`of atherosclerotic vascular disease, congestive heart failure, renal
`replacement therapy and death was significantly higher in patients
`with both CKD and diabetes (49.1%, 52.3%, 3.4%, and 19.9%, respec-
`tively) compared with patients with neither underlying disease
`[77] in 1 million US elderly Medicare patients. The devastating CV
`consequences of CKD have been confirmed in numerous studies
`[78,79].
`Bone disease: Renal osteodystrophy or chronic kidney disease-
`mineral and bone disorder (CKD-MBD) encompasses all disorders
`of bone and mineral metabolism that are associated with CKD.
`
`CHF
`
`PVD
`
`ASCVD
`
`RRT
`
`Death
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`2000-2001/ 100 patient-years
`
`Incident events:
`
`The spectrum ranges from high bone turnover secondary to ele-
`vated PTH levels (secondary hyperparathyroidism) to those with
`low bone turnover associated with normal-to-low PTH levels (ady-
`namic bone disease, osteomalacia), including abnormal mineral
`metabolism, altered bone structure and composition, and extra-
`skeletal calcification.
`Secondary hyperparathyroidism ensues with a decline in GFR,
`secondary phosphorus retention, hypocalcemia and
`impaired
`1,25-dihydroxyvitamin-D production [80]. FGF-23 plays a key
`role in renal phosphate excretion and homeostasis; and sup-
`presses 1,25(OH)2-vitamin D3. Persistent hyperphosphatemia and
`1,25(OH)2-vitamin D3 are principal stimuli for its production. In
`patients with CKD, FGF-23 levels increase in response to phosphate
`retention which in turn suppresses 1-alpha-hydroxylase and renal
`synthesis of 1,25(OH)2-vitamin D3 which then leads to increased
`secretion of PTH. FGF-23 has been positively associated with left
`ventricular hypertrophy and CV mortality, especially in patients
`with low eGFR [81,82]. Recently, Klotho has been identified as a cru-
`cial cofactor essential for the biological effect of FGF-23 [80]. CKD
`may be a state of Klotho deficiency [83], with the lowest values in
`CKD stage V patients. Klotho protein may have anti-apoptotic and
`anti-senescent effects on endothelial cells including effects on vas-
`cular calcifications, endothelial dysfunction and kidney injury and
`repair. The ultimate role of FGF23 and its cofactor, Klotho protein,
`await further study.
`The prevalence of adynamic bone disease or bone’s resis-
`tance to the action of PTH ranges from 5% to 70% with a higher
`prevalence
`in advanced stages of CKD [84]. The CKD milieu
`promotes low bone formation. This milieu includes altered vitamin-
`D/calcium/phosphorus metabolism, acidosis, diabetes, age and
`AGEs (which increase circulating cytokines) [85–89].
`
`3. Evidence of modifiable risk factors
`
`3.1. Diet, weight reduction, exercise and smoking
`
`Epidemiological studies reveal a relationship between lifestyle
`variables including diet, obesity, exercise and smoking and CKD.
`
`DM-/CKD-
`
`DM+/CKD-
`
`DM-/CKD+
`
`DM+/CKD+
`
`
`Fig. 2. Incident event rates in 2000–2001 in over 1 million elderly US Medicare ben-
`eficiaries (over age 67 years). CHF: congestive heart failure; PVD: peripheral vascular
`disease; ASCVD: atherosclerotic cardiovascular disease; RRT: renal replacement
`therapy; DM: diabetes mellitus; CKD: chronic kidney disease.
`
`MPI EXHIBIT 1145 PAGE 4
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`98
`
`R. Pyram et al. / Maturitas 71 (2012) 94– 103
`
`moderate blood pressure group. This was not the case in patients
`who had already displayed overt macroalbuminuria at baseline, as
`their renal function continued to decline regardless of which blood
`pressure group they were enrolled in [106].
`Further data from the ABCD study using hypertensive patients,
`treated also with Nisoldipine or Enalapril (switched to solely
`Enalapril during course of trial due to its cardiovascular bene-
`fit). After 5-year follow up, the intensive (mean BP 133/78) and
`moderate (mean BP 139/86) groups’ results were similar to the
`prior mentioned normotensive study arm. Renal function remained
`stable for those who had normoalbuminuria or microalbumin-
`uria at baseline, independent of initial therapy (Nisoldipine or
`Enalapril). Once again, those with overt macroalbuminuria con-
`tinued to show decline in renal function, with the rate of decline
`of about 5 ml/min/year. This decline was still markedly less than
`untreated hypertensives (10–12 ml/min/year), hence, very much
`suggestive of a significant benefit even in more advance CKD [106].
`Ravid et al. conducted a 5-year randomized study of 94 type
`2 diabetes with normal blood pressure and renal function but
`with microalbuminuria. Even in these normotensive patients there
`was a benefit of tighter blood pressure control with enalapril
`on renal function. In the enalapril group, the initial 24 h urine
`microalbumin of 143 mg/24 h initially decreased to a mean of
`123 mg/24 h, but rose to 140 mg/24 h after 5 years of treatment.
`In contrast, the placebo group began with a mean microalbumin
`level of 123 mg/24 h with an astonishing increase in microal-
`buminuria to a mean of 310 mg/24 h [107]. Additionally, there
`were significant differences in kidney function which decreased
`by 13% in the placebo group over the course of 5 years, while
`remaining stable in the enalapril group. These findings lead to
`the conclusion that intensive blood pressure control is benefi-
`cial for renal protection, especially when started early and may
`be less valuable in advanced CKD. Currently, the recommenda-
`tions from the American Society of Hypertension [3], patients with
`hypertension with eGFR > 50 ml/min/1.73 m2 or greater, should be
`started on anti-hypertensive medications. The medication regimen
`for patients with systolic blood pressures >20 mm Hg above goal
`should include an angiotensin converting enzyme inhibitor (ACEI)
`or an angiotensin receptor blocker (ARB) plus a thiazide diuretic or
`a calcium channel blocker. Patients with a systolic blood pressures
`<20 mm Hg above goal can be started just on an ACE inhibitor or
`ARB.
`
`3.4. Management of complications
`
`Management is focused on correcting or stabilizing the follow-
`ing complications.
`Treatment for hyperkalemia includes potassium restriction
`<60 mmol/d, and kayexalate, a potassium binder that lowers serum
`potassium levels via GI loss. Additional interventions include the
`re-evaluation and/or adjustment of medications with the potential
`to induce or exacerbate hyperkalemia (i.e. ACEi, potassium sparing
`diuretics, beta-blockers) [108].
`Volume overload can best be managed with fluid restriction
`and diuretic therapy [108,109].
`Although still somewhat controversial, many studies have
`shown the potential benefit of aggressive treatment of metabolic
`acidosis. Sodium bicarbonate supplementation resulted in a sig-
`nificant decrease in progression to dialysis at the end of 2 years
`[96,97]. Therefore, sodium bicarbonate may be a safe and effective
`treatment for metabolic acidosis, with the possible added benefit
`of reducing the rate of decline in renal function.
`Controlling hyperphosphatemia is important because of the
`increased risk development of secondary hyperparathyroidism,
`renal osteodystrophy and cardiovascular mortality, mostly seen in
`the hemodialysis population [109,110]. This can be achieved with
`
`However, evidence of benefit is limited as there are few robust
`intervention studies [90–98].
`The diet recommended is low protein and low carbohydrate
`diet. In the early stages of CKD, protein intake should not exceed
`0.8–1.0 g kg/wt d, while in later stages of CKD protein should be
`limited to 0.8 g kg/wt d. Dietary restriction can help improve renal
`function by decreasing urinary albumin excretion, presumably
`reducing the decline in eGFR [90,91]. In addition, a diet consist-
`ing of no more than 130 g of carbohydrates per day ha