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Vascular complications in diabetic kidney disease patients
Clinical Queries: Nephrology 0102 (2012) 178–182
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Clinical Queries: Nephrology j o u r n a l h o m e p a g e : h t t p : / / w w w. e l s e v i e r. c o m / l o c a t e / c q n
Vascular complications in diabetic kidney disease patients Surendra Kumar Agarwal*, Bipin Chandra† *Additional Professor, †Associate Professor, Department of Cardiovascular and Thoracic Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow – , UP, India.
A R T I C L E
I N F O
Article history: Received 18 February 2012 Accepted 3 March 2012
Keywords: Diabetes Renal disease Vascular complications
A B S T R A C T
Patients with diabetic kidney disease develop various vascular complications involving various systems of the body. The pathophysiology involved is the endothelial dysfunction associated with hypertension, dyslipidemia and diabetes, activation of inflammatory pathways, and rennin-angiotensin system resulting in accelerated atherosclerosis due to increased production of reactive oxygen species and increased calcification. These patients have increased cardiovascular morbidity and mortality. In addition, these patients develop more complications related to vascular access needed for dialysis when they develop end-stage renal disease. An understanding of these complications and their pathophysiology will help in the prevention and early management of these complications resulting in better outcome of these patients. Copyright © 2012, Reed Elsevier India Pvt. Ltd. All rights reserved.
Introduction Diabetes and renal disease in isolation are known to be associated with vascular complications like premature atherosclerosis involving coronary arteries, cerebral arteries, peripheral vasculature especially of the lower limbs, and microvascular disease in diabetes.1–3 Additionally, diabetes also causes kidney disease and is a major cause of end-stage renal disease (ESRD) by various mechanisms including renovascular disease and microangiopathy. The renal failure is associated with accelerated calcification, seen especially in the vascular tree.4 Diabetic kidney disease is associated with vascular complications involving all the body systems. It is associated with increased risk of complications of the cardiovascular (CV) system and is a cause of increased morbidity and mortality. The risk factors for mortality due to vascular complications of various systems complement each other and patients with diabetic nephropathy (DN) develop these complications prematurely, even in the asymptomatic stage of the disease.2,3
Definition and stages of diabetic kidney disease Nephropathy seen in patients with diabetes is termed as DN. The diagnosis is made when there is > 500 mg of protein or > 300 mg of albumin in urine in a day and there is no other cause of proteinuria. In the patients with insulin-dependent diabetes (type 1) this occurs late in the course of disease but in patients with non-insulin-dependent diabetes (type 2), it may be seen sometimes at diagnosis as well. Diabetic kidney disease develops slowly in type 2 diabetics. The most rapid increase in diabetic kidney disease is seen during 15–18 years *Corresponding author. E-mail address: [email protected] ISSN: 2211-9477 Copyright © 2012. Reed Elsevier India Pvt. Ltd. All rights reserved. doi: 10.1016/S2211-9477(12)70017-1
of duration of diabetes.5–7 Diabetes may remain undetected for many years despite the presence of symptoms.8,9 This may be one of the reasons of presence of diabetic kidney disease at the time of diagnosis of diabetes in some of these patients. One study found that diabetic kidney disease was a cause of new ESRD in as many as 40% of patients.10 The classification of diabetic kidney disease is based on the degree of proteinuria. As mentioned above, initially there is no kidney disease in patients with diabetes. Microalbuminuria characterizes the first stage of disease and is followed by proteinuria with normal blood urea and/or creatinine. Finally, these patients develop frank kidney failure and may require dialysis therapy or renal transplantation.11,12
Vascular complications and diabetes Vascular complications associated with diabetes can be broadly divided into macrovascular and microvascular. The microvascular complications result in neuropathy, kidney damage, and retinal vascular disease. On the other hand, macrovascular complications result in coronary artery disease (CAD), cardiomyopathy, cerebrovascular disease, and peripheral arterial disease (PAD). Many studies on epidemiology and management of vascular complications take combined CV morbidity and mortality as the clinical end-point without classifying individual vascular diseases separately. The combined CV events occur as a result of both micro as well as macrovascular complications and include myocardial infarction (MI), stroke, lower extremity amputations, and mortality due to CV causes.
Epidemiology of vascular complications in diabetes Cardiovascular disease accounts for approximately two-third of deaths in diabetic patients.13 Most of these deaths and other morbidities are
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a result of CAD and cerebrovascular accidents. Over 70% of the patients with diabetes have either hypertension (HTN) or are on antihypertensive medications. The risk factors for atherosclerosis and CV disease are similar in diabetics but if even one of these risk factors is present, the outcomes are poor in diabetics.14 Peripheral arterial disease in diabetics results from atherosclerosis of the arteries especially the lower limbs, abdominal organs, and kidneys. Longer duration of diabetes, advanced patient age, and presence of neuropathy increases the risk of PAD.15 The PAD presents with intermittent claudication or pain at rest15 and is one of the main causes of amputation of lower extremities. Up to 15% of patients with diabetes develop ulcer/gangrene of lower limbs resulting in amputation in their life. Additionally, presence of diabetes is associated with 10–20 times more chance of these amputations.16,17 The main cause (> 50%) of all amputations in diabetic patients result from the presence of PAD.18
Epidemiology of vascular complications in renal disease The association of increased CV deaths in patients on dialysis was recognized long ago. Over half of patients with ESRD have a CV cause of death.2,3,19 This mortality in diabetic patients is higher than the mortality due to CV diseases seen in general population after adjusting for age.3,20 Although it is seen in all groups, most marked increase is seen in patients between 25 years and 34 years of age. The CV mortality is many times more in young patients with ESRD.1 Coronary artery disease is present in approximately 40% patients with ESRD being started on renal replacement therapy (RRT), with evidence of abnormality of structure and function of the left ventricle in about 85% of these patients.21 Even a moderate degree of abnormality of kidney function is associated with increased mortality due to CV causes. Many of the patients with moderate (stages 3 and 4) kidney disease will die due to CV disease before they progress to ESRD and/or require RRT. Table 1 shows the association of grades of kidney disease and increase in risk of CV disease.
Epidemiology of vascular complications in patients with diabetic nephropathy There are no studies available on the epidemiology of vascular disease in patients with DN. But it can be understood by examining large epidemiological and outcome studies, done in patients with renal dysfunction and also on patients with micro or macroalbuminuria. Heart outcomes and prevention evaluation (HOPE) study enrolled patients with diabetes or evidence of CV disease in association with at least one more CV risk factor. This study evaluated the composite primary outcome (death from CV cause, MI, or stroke) in relation to the baseline value of serum creatinine.22 The exclusion criteria included the presence of heart failure (HF) and a serum creatinine > 2.3 mg/dL. The study found that primary outcome occurred in 22.2% of the patients with mild kidney disease as compared to 15% in patients with normal kidney function. This effect of kidney disease was not related to either the presence of risk factors at enrollment or the treatment group to which the patient was allocated. Similar findings were reported in the Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) trial.23 This trial even demonstrated a stepwise
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increase in composite CV events and degree of decrease in kidney function at baseline as measured by glomerular filtration rate (GFR). In recent years it has been demonstrated that albuminuria is an independent marker of risk of CV complications in patients irrespective of their diabetic status. Albuminuria is measured by urine albumin to creatinine ratio (ACR). An ACR of > 300 mg/g (macroalbuminuria)24,25 and between 30 mg/g and 300 mg/g (microalbuminuria)26 was shown to be associated with increased risk of CV complications. Even the so-called normal level of ACR (< 30 mg/g) is associated with an increased risk of CV disease. It can be said that the presence of albumin in urine is a continuous risk factor for CV complications. Patients with diabetes (type 2), HTN, and presence of albumin in urine were studied in the Irbesartan Diabetic Nephropathy Trial (IDNT).27 The study enrolled 1715 patients. The mean urine ACR was 1416.2 mg/g. The study randomized these patients to treatment with irbesartan, amlodipine, or placebo. There was no significant difference in the CV events in the three treatment groups. An analysis was carried out to study the effect of baseline urine ACR28 on the composite CV outcome (death from a CV cause, MI, HF requiring hospitalization, stroke, amputation, and revascularization of peripheral, or coronary arteries). This analysis showed that with every natural log increase of urinary ACR there was 1.3 times increase in relative risk of these events. Another study evaluated this association. The reduction of endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study enrolled 1513 patients who had diabetes, HTN, and macroalbuminuria. Mean urine ACR was 1810 mg/g at baseline. The patients received losartan or placebo and the follow-up was a mean of 3.4 years. This study again revealed that composite CV end-points (similar to IDNT study) were predicted by the presence of albumin in urine. The urinary ACR at enrollment predicted composite CV end-point very strongly. It has also been shown that if there was a 50% reduction in urine ACR at 6 months as compared to baseline, the end-point also reduced by 18%.29 Similarly, microalbuminuria was seen to be associated with CV complications. In the HOPE study, a baseline urinary ACR of > 2 mg/mmol was shown to be associated with an increased risk of CV end-points. This relative risk was present both in patients with diabetes (1.97) as well as without diabetes (1.61).30 The HOPE study also revealed that so-called normal level of urinary albumin, i.e. the urinary ACR of < 30 mg/g was also associated with increased risk of CV composite end-points and was seen in urinary ACR of even 0.5 mg/mmol which is approximately equal to 4.4 mg/g.31 In the general population also, risk of CV end-points was shown to be increased with the currently defined normal level of urinary ACR.32 The Losartan Intervention for End-point Reduction in Hypertension (LIFE) study also found both the association of microalbuminuria and CV events and role of reduction in urinary albumin on follow-up in reducing these events.33
Pathophysiology The pathophysiological mechanisms that contribute to various complications of vascular system in patients with diabetic kidney disease are a result of both diabetes and renal failure. Both diseases have similar pathophysiological mechanisms which are complex and difficult to separate from each other.
Table 1 Grading of kidney disease and risk of cardiovascular disease in relation to grade of kidney disease. Grade of kidney disease
Definition
1 2 3 4 5 ESRD (need for RRT)
Renal damage with normal or increased GFR Renal damage with mildly decreased GFR Moderately decreased GFR Severely decreased GFR Renal failure On dialysis
GFR (mL/min/1.73 m2) > 90 60–89 30–59 15–29 < 15 –
CV: cardiovascular, ESRD: end-stage renal disease, GFR: glomerular filtration rate, RRT: renal replacement therapy.
Odds ratio of CV disease Depend on degree of microalbuminuria 1.5 2–4 5–10 10–50 20–1000
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Some of these pathophysiological mechanisms are HTN, anemia, dyslipidemia,34 renin-angiotensin system activation,35 calcification of media in the vascular system,36 malnutrition, and inflammation.36 Although many, if not all, of these are seen in patients with ESRD, they may not be seen in patients with normal or mild increase in urinary albumin. The urinary albumin excretion is now regarded to be a marker of damage to vascular system.37,38 Both atherosclerosis and type 2 diabetes were shown to be associated with the presence of inflammation.39,40 The activation of nuclear factor-κB41 a protein regulating various genes associated with inflammation and atherosclerosis in endothelial cells (EC), vascular smooth muscle cells (VSMCs), and macrophages is documented in association with hyperglycemia. Hyperglycemia also results in protein glycation with the resultant formation of free oxygen radicals. Free oxygen radicals cause atherosclerosis by various mechanisms. As the ECs of vascular system come in direct contact with hyperglycemic blood, they bear the maximum brunt of pathological responses to increased blood sugar. The first response is loss of nonadhesive property of these cells. With loss of this property, monocytes get attached to the ECs as documented in the in vitro studies.42 The superoxide production from ECs is also increased.41–43 Increased sugar levels also are associated with the activation of metalloproteinase enzymes. These enzymes were shown to be responsible for the atherosclerotic plaque rupture as well as remodeling of arterial system. There is also the proliferation of ECs along with migration and possible activation of rennin-angiotensin system. In addition to albuminuria, hyperglycemia also strongly correlates with microvascular complications seen in diabetics. It has been documented that tight glucose control is helpful both in prevention as well as decreasing progress of these complications.44 Both microvascular as well as macrovascular complications are thought be due to damage by oxygen free radicals. Reactive oxygen molecules damage both the DNA as well as proteins in the cells. Other pathological mechanisms have also been suggested for the development of vascular complications in diabetic patients.45,46
Novel molecules involved in pathogenesis of vascular complications in patients with diabetic kidney disease As discussed above, there is a strong role of inflammation in the development of atherosclerosis including adhesion of monocytes and other inflammatory cells to ECs and their infiltration within the vascular wall below the endothelium.39 Endothelial cells express the proteins called cell adhesion molecules which help in the adhesion of inflammatory cells to ECs. Two of these are vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1). These molecules have been shown to be expressed in the plaque of atherosclerosis.47 Expression of both these molecules was documented to increase in the presence of high glucose in ECs as evidenced by increased expression of proteins as well as mRNA.48 When the serum of patients with diabetes and kidney disease (both albuminuria and increased serum urea and creatinine) was studied with EC cultures in vitro, again both these adhesion molecules were expressed.49 Although, these molecules are anchored on the membranes of ECs, these may be broken and seen in the circulation. Circulating adhesion molecules may be measured in blood and are called soluble VCAM-1 (sVCAM-1) and soluble ICAM-1 (sICAM-1). These markers may be useful markers for CV disease in patients with diabetes and DN. Various studies have shown a strong relationship between sICAM-1/ sVCAM-1 and DN. There is an increasing trend in plasma levels of these molecules with increasing levels of diabetic kidney disease.49 These molecules also have a good correlation with the CV complications seen in patients with diabetes. Another novel risk factor sparking a lot of research interest is the C-reactive protein (CRP). The significance of CRP and inflammation has become increasingly evident recently, and it now appears that CRP actively contributes to atherosclerotic plaque formation and
thrombotic events. In addition, CRP is associated with the inflammatory states of not only renal failure, but also microalbuminuria. Atherosclerosis with calcification is seen with high frequency in renal disease patients.50 A study done to evaluate presence of coronary artery calcification and kidney disease showed that it was present in 40% of patients with renal dysfunction (mean GFR 33 mL/min) in comparison to 13% in matched control subjects without renal dysfunction.51 Calcification has also been documented in the various CV structures including media of vessels, elastic lamina of both large and medium size arteries, cardiac valves, and atherosclerotic plaque.50 Calciphylaxis (also called calcific uremic arteriopathy) is a syndrome of calcification of vascular system seen in association with dialysis. In this syndrome, diffuse calcification is seen in the media of arteries of small and medium size as well as arterioles. This is associated with the proliferation of intima and thrombosis. The clinical presentation is with skin ulcers, skin necrosis and sometimes gangrene of peripheral tissues which may be life threatening.52 The pathogenesis is raised product of calcium and phosphate in the blood. It should not be confused with the calcification of larger arteries or of skin itself. This complication is rare (seen in approximately 4% patients on hemodialysis [HD]) and is associated with obesity, female gender, and presence of diabetes.52 The pathogenetic mechanisms that have been implicated in calcification of vascular tree in patients with chronic renal failure are precipitation of calcium and phosphate due to high concentration of these in the extracellular space. Various promoters as well as inhibitors of calcification have also been implicated.53
Complications associated with vascular access for dialysis End-stage renal disease patients require HD which requires operational vascular access. Vascular access is the weakest link in providing effective dialysis therapy and is associated with various complications. These complications are seen more commonly in diabetic patients with chronic renal failure due to the presence of atherosclerosis and calcification, and increased risk of infection and thrombosis. Common complications include stenosis, infection, thrombus, and bleeding. Approximately 1 in 5 patients starting HD will die within the first year of dialysis, typically from CV or dialysis complications. In addition, an estimated 25% of all patients starting HD will die because of inadequate vascular access or complications related to vascular access.54 Various access procedures for dialysis are the creation of arteriovenous (AV) fistulas, use of AV grafts, and large bore catheters in central veins. Although the complication rates are similar, there is a higher risk of infection with the use of central venous catheters. These catheters may also result in luminal thrombosis, unreliable blood flows, and central venous stenosis.55 Primary AV fistulas provide excellent HD access and are preferred. But patients with diabetic kidney disease have a limited number of suitable sites for the formation of primary AV fistulas, which restricts their use.54 A significant number of AV fistulas (30–50%) never mature to support dialysis.56 This is supposed to be due to atherosclerosis that accelerates more rapidly. This has resulted in the increased use of AV grafts and a tendency away from AV fistulas. Arteriovenous grafts are equivalent to AV fistulas in long-term patency.57 Although, grafts have a higher incidence of thrombosis, postrevision grafts have a significantly longer patency than the revised fistulas. The graft and fistulas need continuous surveillance and role of pharmacological agents like antiplatelet drugs is being explored. The grafts and fistulas may need revision with surgical revision or angioplasty. Other complications associated with vascular access in patients with diabetic kidney disease are arterial injury resulting in pseudo aneurysm and AV fistula creation, and bleeding complications. These complications require early diagnosis and prompt management by ultrasound guided compression, thrombin glue injection, surgery or endovascular management with covered stent graft or embolization of feeding vessel if the fistula/pseudo aneurysm is arising from a small artery. Some HD patients, especially those with diabetes58 suffer from chronic hand ischemia after AV fistula creation. This is usually caused
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by a very low blood pressure (BP) in forearm and hand with some role of steal (reversal of blood flow). The treatment is aimed at improving the BP in forearm and hand by angioplasty of proximal arteries if there is any stenosis. Sometimes side branches of AV fistula need to be ligated for improving distal BP. If these measures fail, the fistula may need to be taken down with creation at another side. Some patients may even require distal revascularization to save the hand from gangrene.59
Conclusion The patients with diabetic kidney disease are at a high-risk of development of both micro as well as macrovascular complications usually involving coronary, carotid renal, and lower limb arteries. This results in higher mortality and morbidity in these patients. Need for vascular access for dialysis also increases risk of various local complications. The pathophysiological mechanisms involved are atherosclerosis, inflammation, and other neuro-humoral mechanisms. These patients should be properly evaluated for the presence of these complications at diagnosis and put on continuous surveillance program to detect and treat these complications at an early stage. Presence and degree of albuminuria, soluble cell adhesion molecules, and CRPs are some of the easily measurable parameters which predict the development of these complications and may emerge in future as routine follow-up parameters. The strategies at controlling blood sugar, HTN, control of other risk factors, and proper diagnosis and management of vascular access related complications will result in decreasing morbidity and mortality seen in this group of patients. References 1.
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Contents lists available at ScienceDirect
Clinical Queries: Nephrology j o u r n a l h o m e p a g e : h t t p : / / w w w. e l s e v i e r. c o m / l o c a t e / c q n
Vascular complications in diabetic kidney disease patients Surendra Kumar Agarwal*, Bipin Chandra† *Additional Professor, †Associate Professor, Department of Cardiovascular and Thoracic Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow – , UP, India.
A R T I C L E
I N F O
Article history: Received 18 February 2012 Accepted 3 March 2012
Keywords: Diabetes Renal disease Vascular complications
A B S T R A C T
Patients with diabetic kidney disease develop various vascular complications involving various systems of the body. The pathophysiology involved is the endothelial dysfunction associated with hypertension, dyslipidemia and diabetes, activation of inflammatory pathways, and rennin-angiotensin system resulting in accelerated atherosclerosis due to increased production of reactive oxygen species and increased calcification. These patients have increased cardiovascular morbidity and mortality. In addition, these patients develop more complications related to vascular access needed for dialysis when they develop end-stage renal disease. An understanding of these complications and their pathophysiology will help in the prevention and early management of these complications resulting in better outcome of these patients. Copyright © 2012, Reed Elsevier India Pvt. Ltd. All rights reserved.
Introduction Diabetes and renal disease in isolation are known to be associated with vascular complications like premature atherosclerosis involving coronary arteries, cerebral arteries, peripheral vasculature especially of the lower limbs, and microvascular disease in diabetes.1–3 Additionally, diabetes also causes kidney disease and is a major cause of end-stage renal disease (ESRD) by various mechanisms including renovascular disease and microangiopathy. The renal failure is associated with accelerated calcification, seen especially in the vascular tree.4 Diabetic kidney disease is associated with vascular complications involving all the body systems. It is associated with increased risk of complications of the cardiovascular (CV) system and is a cause of increased morbidity and mortality. The risk factors for mortality due to vascular complications of various systems complement each other and patients with diabetic nephropathy (DN) develop these complications prematurely, even in the asymptomatic stage of the disease.2,3
Definition and stages of diabetic kidney disease Nephropathy seen in patients with diabetes is termed as DN. The diagnosis is made when there is > 500 mg of protein or > 300 mg of albumin in urine in a day and there is no other cause of proteinuria. In the patients with insulin-dependent diabetes (type 1) this occurs late in the course of disease but in patients with non-insulin-dependent diabetes (type 2), it may be seen sometimes at diagnosis as well. Diabetic kidney disease develops slowly in type 2 diabetics. The most rapid increase in diabetic kidney disease is seen during 15–18 years *Corresponding author. E-mail address: [email protected] ISSN: 2211-9477 Copyright © 2012. Reed Elsevier India Pvt. Ltd. All rights reserved. doi: 10.1016/S2211-9477(12)70017-1
of duration of diabetes.5–7 Diabetes may remain undetected for many years despite the presence of symptoms.8,9 This may be one of the reasons of presence of diabetic kidney disease at the time of diagnosis of diabetes in some of these patients. One study found that diabetic kidney disease was a cause of new ESRD in as many as 40% of patients.10 The classification of diabetic kidney disease is based on the degree of proteinuria. As mentioned above, initially there is no kidney disease in patients with diabetes. Microalbuminuria characterizes the first stage of disease and is followed by proteinuria with normal blood urea and/or creatinine. Finally, these patients develop frank kidney failure and may require dialysis therapy or renal transplantation.11,12
Vascular complications and diabetes Vascular complications associated with diabetes can be broadly divided into macrovascular and microvascular. The microvascular complications result in neuropathy, kidney damage, and retinal vascular disease. On the other hand, macrovascular complications result in coronary artery disease (CAD), cardiomyopathy, cerebrovascular disease, and peripheral arterial disease (PAD). Many studies on epidemiology and management of vascular complications take combined CV morbidity and mortality as the clinical end-point without classifying individual vascular diseases separately. The combined CV events occur as a result of both micro as well as macrovascular complications and include myocardial infarction (MI), stroke, lower extremity amputations, and mortality due to CV causes.
Epidemiology of vascular complications in diabetes Cardiovascular disease accounts for approximately two-third of deaths in diabetic patients.13 Most of these deaths and other morbidities are
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a result of CAD and cerebrovascular accidents. Over 70% of the patients with diabetes have either hypertension (HTN) or are on antihypertensive medications. The risk factors for atherosclerosis and CV disease are similar in diabetics but if even one of these risk factors is present, the outcomes are poor in diabetics.14 Peripheral arterial disease in diabetics results from atherosclerosis of the arteries especially the lower limbs, abdominal organs, and kidneys. Longer duration of diabetes, advanced patient age, and presence of neuropathy increases the risk of PAD.15 The PAD presents with intermittent claudication or pain at rest15 and is one of the main causes of amputation of lower extremities. Up to 15% of patients with diabetes develop ulcer/gangrene of lower limbs resulting in amputation in their life. Additionally, presence of diabetes is associated with 10–20 times more chance of these amputations.16,17 The main cause (> 50%) of all amputations in diabetic patients result from the presence of PAD.18
Epidemiology of vascular complications in renal disease The association of increased CV deaths in patients on dialysis was recognized long ago. Over half of patients with ESRD have a CV cause of death.2,3,19 This mortality in diabetic patients is higher than the mortality due to CV diseases seen in general population after adjusting for age.3,20 Although it is seen in all groups, most marked increase is seen in patients between 25 years and 34 years of age. The CV mortality is many times more in young patients with ESRD.1 Coronary artery disease is present in approximately 40% patients with ESRD being started on renal replacement therapy (RRT), with evidence of abnormality of structure and function of the left ventricle in about 85% of these patients.21 Even a moderate degree of abnormality of kidney function is associated with increased mortality due to CV causes. Many of the patients with moderate (stages 3 and 4) kidney disease will die due to CV disease before they progress to ESRD and/or require RRT. Table 1 shows the association of grades of kidney disease and increase in risk of CV disease.
Epidemiology of vascular complications in patients with diabetic nephropathy There are no studies available on the epidemiology of vascular disease in patients with DN. But it can be understood by examining large epidemiological and outcome studies, done in patients with renal dysfunction and also on patients with micro or macroalbuminuria. Heart outcomes and prevention evaluation (HOPE) study enrolled patients with diabetes or evidence of CV disease in association with at least one more CV risk factor. This study evaluated the composite primary outcome (death from CV cause, MI, or stroke) in relation to the baseline value of serum creatinine.22 The exclusion criteria included the presence of heart failure (HF) and a serum creatinine > 2.3 mg/dL. The study found that primary outcome occurred in 22.2% of the patients with mild kidney disease as compared to 15% in patients with normal kidney function. This effect of kidney disease was not related to either the presence of risk factors at enrollment or the treatment group to which the patient was allocated. Similar findings were reported in the Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) trial.23 This trial even demonstrated a stepwise
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increase in composite CV events and degree of decrease in kidney function at baseline as measured by glomerular filtration rate (GFR). In recent years it has been demonstrated that albuminuria is an independent marker of risk of CV complications in patients irrespective of their diabetic status. Albuminuria is measured by urine albumin to creatinine ratio (ACR). An ACR of > 300 mg/g (macroalbuminuria)24,25 and between 30 mg/g and 300 mg/g (microalbuminuria)26 was shown to be associated with increased risk of CV complications. Even the so-called normal level of ACR (< 30 mg/g) is associated with an increased risk of CV disease. It can be said that the presence of albumin in urine is a continuous risk factor for CV complications. Patients with diabetes (type 2), HTN, and presence of albumin in urine were studied in the Irbesartan Diabetic Nephropathy Trial (IDNT).27 The study enrolled 1715 patients. The mean urine ACR was 1416.2 mg/g. The study randomized these patients to treatment with irbesartan, amlodipine, or placebo. There was no significant difference in the CV events in the three treatment groups. An analysis was carried out to study the effect of baseline urine ACR28 on the composite CV outcome (death from a CV cause, MI, HF requiring hospitalization, stroke, amputation, and revascularization of peripheral, or coronary arteries). This analysis showed that with every natural log increase of urinary ACR there was 1.3 times increase in relative risk of these events. Another study evaluated this association. The reduction of endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study enrolled 1513 patients who had diabetes, HTN, and macroalbuminuria. Mean urine ACR was 1810 mg/g at baseline. The patients received losartan or placebo and the follow-up was a mean of 3.4 years. This study again revealed that composite CV end-points (similar to IDNT study) were predicted by the presence of albumin in urine. The urinary ACR at enrollment predicted composite CV end-point very strongly. It has also been shown that if there was a 50% reduction in urine ACR at 6 months as compared to baseline, the end-point also reduced by 18%.29 Similarly, microalbuminuria was seen to be associated with CV complications. In the HOPE study, a baseline urinary ACR of > 2 mg/mmol was shown to be associated with an increased risk of CV end-points. This relative risk was present both in patients with diabetes (1.97) as well as without diabetes (1.61).30 The HOPE study also revealed that so-called normal level of urinary albumin, i.e. the urinary ACR of < 30 mg/g was also associated with increased risk of CV composite end-points and was seen in urinary ACR of even 0.5 mg/mmol which is approximately equal to 4.4 mg/g.31 In the general population also, risk of CV end-points was shown to be increased with the currently defined normal level of urinary ACR.32 The Losartan Intervention for End-point Reduction in Hypertension (LIFE) study also found both the association of microalbuminuria and CV events and role of reduction in urinary albumin on follow-up in reducing these events.33
Pathophysiology The pathophysiological mechanisms that contribute to various complications of vascular system in patients with diabetic kidney disease are a result of both diabetes and renal failure. Both diseases have similar pathophysiological mechanisms which are complex and difficult to separate from each other.
Table 1 Grading of kidney disease and risk of cardiovascular disease in relation to grade of kidney disease. Grade of kidney disease
Definition
1 2 3 4 5 ESRD (need for RRT)
Renal damage with normal or increased GFR Renal damage with mildly decreased GFR Moderately decreased GFR Severely decreased GFR Renal failure On dialysis
GFR (mL/min/1.73 m2) > 90 60–89 30–59 15–29 < 15 –
CV: cardiovascular, ESRD: end-stage renal disease, GFR: glomerular filtration rate, RRT: renal replacement therapy.
Odds ratio of CV disease Depend on degree of microalbuminuria 1.5 2–4 5–10 10–50 20–1000
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Some of these pathophysiological mechanisms are HTN, anemia, dyslipidemia,34 renin-angiotensin system activation,35 calcification of media in the vascular system,36 malnutrition, and inflammation.36 Although many, if not all, of these are seen in patients with ESRD, they may not be seen in patients with normal or mild increase in urinary albumin. The urinary albumin excretion is now regarded to be a marker of damage to vascular system.37,38 Both atherosclerosis and type 2 diabetes were shown to be associated with the presence of inflammation.39,40 The activation of nuclear factor-κB41 a protein regulating various genes associated with inflammation and atherosclerosis in endothelial cells (EC), vascular smooth muscle cells (VSMCs), and macrophages is documented in association with hyperglycemia. Hyperglycemia also results in protein glycation with the resultant formation of free oxygen radicals. Free oxygen radicals cause atherosclerosis by various mechanisms. As the ECs of vascular system come in direct contact with hyperglycemic blood, they bear the maximum brunt of pathological responses to increased blood sugar. The first response is loss of nonadhesive property of these cells. With loss of this property, monocytes get attached to the ECs as documented in the in vitro studies.42 The superoxide production from ECs is also increased.41–43 Increased sugar levels also are associated with the activation of metalloproteinase enzymes. These enzymes were shown to be responsible for the atherosclerotic plaque rupture as well as remodeling of arterial system. There is also the proliferation of ECs along with migration and possible activation of rennin-angiotensin system. In addition to albuminuria, hyperglycemia also strongly correlates with microvascular complications seen in diabetics. It has been documented that tight glucose control is helpful both in prevention as well as decreasing progress of these complications.44 Both microvascular as well as macrovascular complications are thought be due to damage by oxygen free radicals. Reactive oxygen molecules damage both the DNA as well as proteins in the cells. Other pathological mechanisms have also been suggested for the development of vascular complications in diabetic patients.45,46
Novel molecules involved in pathogenesis of vascular complications in patients with diabetic kidney disease As discussed above, there is a strong role of inflammation in the development of atherosclerosis including adhesion of monocytes and other inflammatory cells to ECs and their infiltration within the vascular wall below the endothelium.39 Endothelial cells express the proteins called cell adhesion molecules which help in the adhesion of inflammatory cells to ECs. Two of these are vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1). These molecules have been shown to be expressed in the plaque of atherosclerosis.47 Expression of both these molecules was documented to increase in the presence of high glucose in ECs as evidenced by increased expression of proteins as well as mRNA.48 When the serum of patients with diabetes and kidney disease (both albuminuria and increased serum urea and creatinine) was studied with EC cultures in vitro, again both these adhesion molecules were expressed.49 Although, these molecules are anchored on the membranes of ECs, these may be broken and seen in the circulation. Circulating adhesion molecules may be measured in blood and are called soluble VCAM-1 (sVCAM-1) and soluble ICAM-1 (sICAM-1). These markers may be useful markers for CV disease in patients with diabetes and DN. Various studies have shown a strong relationship between sICAM-1/ sVCAM-1 and DN. There is an increasing trend in plasma levels of these molecules with increasing levels of diabetic kidney disease.49 These molecules also have a good correlation with the CV complications seen in patients with diabetes. Another novel risk factor sparking a lot of research interest is the C-reactive protein (CRP). The significance of CRP and inflammation has become increasingly evident recently, and it now appears that CRP actively contributes to atherosclerotic plaque formation and
thrombotic events. In addition, CRP is associated with the inflammatory states of not only renal failure, but also microalbuminuria. Atherosclerosis with calcification is seen with high frequency in renal disease patients.50 A study done to evaluate presence of coronary artery calcification and kidney disease showed that it was present in 40% of patients with renal dysfunction (mean GFR 33 mL/min) in comparison to 13% in matched control subjects without renal dysfunction.51 Calcification has also been documented in the various CV structures including media of vessels, elastic lamina of both large and medium size arteries, cardiac valves, and atherosclerotic plaque.50 Calciphylaxis (also called calcific uremic arteriopathy) is a syndrome of calcification of vascular system seen in association with dialysis. In this syndrome, diffuse calcification is seen in the media of arteries of small and medium size as well as arterioles. This is associated with the proliferation of intima and thrombosis. The clinical presentation is with skin ulcers, skin necrosis and sometimes gangrene of peripheral tissues which may be life threatening.52 The pathogenesis is raised product of calcium and phosphate in the blood. It should not be confused with the calcification of larger arteries or of skin itself. This complication is rare (seen in approximately 4% patients on hemodialysis [HD]) and is associated with obesity, female gender, and presence of diabetes.52 The pathogenetic mechanisms that have been implicated in calcification of vascular tree in patients with chronic renal failure are precipitation of calcium and phosphate due to high concentration of these in the extracellular space. Various promoters as well as inhibitors of calcification have also been implicated.53
Complications associated with vascular access for dialysis End-stage renal disease patients require HD which requires operational vascular access. Vascular access is the weakest link in providing effective dialysis therapy and is associated with various complications. These complications are seen more commonly in diabetic patients with chronic renal failure due to the presence of atherosclerosis and calcification, and increased risk of infection and thrombosis. Common complications include stenosis, infection, thrombus, and bleeding. Approximately 1 in 5 patients starting HD will die within the first year of dialysis, typically from CV or dialysis complications. In addition, an estimated 25% of all patients starting HD will die because of inadequate vascular access or complications related to vascular access.54 Various access procedures for dialysis are the creation of arteriovenous (AV) fistulas, use of AV grafts, and large bore catheters in central veins. Although the complication rates are similar, there is a higher risk of infection with the use of central venous catheters. These catheters may also result in luminal thrombosis, unreliable blood flows, and central venous stenosis.55 Primary AV fistulas provide excellent HD access and are preferred. But patients with diabetic kidney disease have a limited number of suitable sites for the formation of primary AV fistulas, which restricts their use.54 A significant number of AV fistulas (30–50%) never mature to support dialysis.56 This is supposed to be due to atherosclerosis that accelerates more rapidly. This has resulted in the increased use of AV grafts and a tendency away from AV fistulas. Arteriovenous grafts are equivalent to AV fistulas in long-term patency.57 Although, grafts have a higher incidence of thrombosis, postrevision grafts have a significantly longer patency than the revised fistulas. The graft and fistulas need continuous surveillance and role of pharmacological agents like antiplatelet drugs is being explored. The grafts and fistulas may need revision with surgical revision or angioplasty. Other complications associated with vascular access in patients with diabetic kidney disease are arterial injury resulting in pseudo aneurysm and AV fistula creation, and bleeding complications. These complications require early diagnosis and prompt management by ultrasound guided compression, thrombin glue injection, surgery or endovascular management with covered stent graft or embolization of feeding vessel if the fistula/pseudo aneurysm is arising from a small artery. Some HD patients, especially those with diabetes58 suffer from chronic hand ischemia after AV fistula creation. This is usually caused
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by a very low blood pressure (BP) in forearm and hand with some role of steal (reversal of blood flow). The treatment is aimed at improving the BP in forearm and hand by angioplasty of proximal arteries if there is any stenosis. Sometimes side branches of AV fistula need to be ligated for improving distal BP. If these measures fail, the fistula may need to be taken down with creation at another side. Some patients may even require distal revascularization to save the hand from gangrene.59
Conclusion The patients with diabetic kidney disease are at a high-risk of development of both micro as well as macrovascular complications usually involving coronary, carotid renal, and lower limb arteries. This results in higher mortality and morbidity in these patients. Need for vascular access for dialysis also increases risk of various local complications. The pathophysiological mechanisms involved are atherosclerosis, inflammation, and other neuro-humoral mechanisms. These patients should be properly evaluated for the presence of these complications at diagnosis and put on continuous surveillance program to detect and treat these complications at an early stage. Presence and degree of albuminuria, soluble cell adhesion molecules, and CRPs are some of the easily measurable parameters which predict the development of these complications and may emerge in future as routine follow-up parameters. The strategies at controlling blood sugar, HTN, control of other risk factors, and proper diagnosis and management of vascular access related complications will result in decreasing morbidity and mortality seen in this group of patients. References 1.
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