Sodium Regulation and the Implications in Diabetes Care

1. Sodium Regulation and the Implications in Diabetes Care  Sharon Korhel, MS, FNP-C, CDE February 16, 2011 1

2. OBJECTIVES Review the effects of sodium on the renal and cardiovascular systems Review interventions to lower sodium 2

3. Overview Sodium sources Regulation of Sodium and its effects on arterial blood volume, blood pressure , and insulin resistance Sodium regulation in heart failure Review of dietary and drug interventions to reduce and regulate sodium 3

4. SODIUM Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. 4 Sodium Chloride: Sodium Chloride:

5. Sources of Sodium Sodium can come from natural sources or be added to foods. Most foods in their natural state contain some sodium. Majority (up to 75 percent) of sodium that Americans consume comes from sodium added to processed foods by manufacturers. Medications 5

6. Sodium, chloride and water balance Antidiurectic Hormone (ADH) secretion and perception of thirst are primary regulatory factors in regulating water balance. Kidneys and hormones play a major role in Maintaining sodium and water balance. The Renin-Angiotensin-aldosterone system is the most important hormonal system involved in regulation of sodium. 6 Kidney (Ch 8C: reg of renal Na+ excretion) 80% of the kidney�s total energy requirement is used for Na+ transport. Excess sodium is excreted in the urine. If sodium is depleted, it is reabsorbed. Renal Na+ excretion varies directly with the effective circulating volume. Day to day regulation of sodium excretion is dependant on aldosterone and possibly atrial natruiuretic peptide or related peptides. Decreased sodium intake: volume decrease enhances the activity of the rennin-angiotensin-aldosterone system and reduce the secretion and ANP. Net effect is enhance Na+ reabsorption in the collecting tubules. VOLUME EXPANSION Increase in the secretion of ANP and reduction in aldosterone allowing sodium excretion by the Aldosterone Kidney (Ch 8C: reg of renal Na+ excretion) 80% of the kidney�s total energy requirement is used for Na+ transport. Excess sodium is excreted in the urine. If sodium is depleted, it is reabsorbed. Renal Na+ excretion varies directly with the effective circulating volume. Day to day regulation of sodium excretion is dependant on aldosterone and possibly atrial natruiuretic peptide or related peptides. Decreased sodium intake: volume decrease enhances the activity of the rennin-angiotensin-aldosterone system and reduce the secretion and ANP. Net effect is enhance Na+ reabsorption in the collecting tubules. VOLUME EXPANSION Increase in the secretion of ANP and reduction in aldosterone allowing sodium excretion by the Aldosterone

7. Plasma osmolality maintenance Can by estimated from the plasma sodium concentration is regulated by changes in water intake and excretion, which are mediated by thirst and antidiurectic hormone Electrolyte and fluid abnormalities are due to disorders of osmoregulatin and Effective Arterial Blood Volume (EABV) which result in impaired sodium and water intake excretion 7 Plasma osmolality is a measure of the concentration of substances such as sodium, chloride, potassium, urea, glucose, and other ions in blood. Excess salt must be excreted in order to maintain fluid balance The best known and most important hormonal system involved in the regulation of sodium is the RAS system, which stimulates sodium absorption in the distal and collecting tubules Aldosterone likely plays an important role in modulating Na+ excretionPlasma osmolality is a measure of the concentration of substances such as sodium, chloride, potassium, urea, glucose, and other ions in blood. Excess salt must be excreted in order to maintain fluid balance The best known and most important hormonal system involved in the regulation of sodium is the RAS system, which stimulates sodium absorption in the distal and collecting tubules Aldosterone likely plays an important role in modulating Na+ excretion

8. Plasma osmolality is a measure of the concentration of substances such as sodium, chloride, potassium, urea, glucose, and other ions in blood. It is calculated as the osmoles of solute per kilogram of solvent.Plasma osmolality is a measure of the concentration of substances such as sodium, chloride, potassium, urea, glucose, and other ions in blood. It is calculated as the osmoles of solute per kilogram of solvent.

9. Renal Sodium Excretion Varies directly with the circulating volume Dependant on daily regulation of aldosterone and possibly atrial natruiuretic peptide (ANP) or related peptides Sodium intake effects the renin-angiotensin-aldosterone system and can increase or decrease the secretion of ANP 9 Atrial Natruietic peptide: released by the atrial in response to being stretched as a result of sodium retention, expansion of the extracellular fluid (ECF) volume and increase in arterial pressure; decreases the BP by causing vasodilation and by stimulating the kidneys to excrete more water (decreasing the blood pressure by reducing blood volume) Decreased sodium intake: volume decrease enhances the activity of the renin-angiotensin-aldosterone system and reduce the secretion and ANP. The Net effect is enhance Na+ Reabsorption in the collecting tubulesAtrial Natruietic peptide: released by the atrial in response to being stretched as a result of sodium retention, expansion of the extracellular fluid (ECF) volume and increase in arterial pressure; decreases the BP by causing vasodilation and by stimulating the kidneys to excrete more water (decreasing the blood pressure by reducing blood volume) Decreased sodium intake: volume decrease enhances the activity of the renin-angiotensin-aldosterone system and reduce the secretion and ANP. The Net effect is enhance Na+ Reabsorption in the collecting tubules

10.  Transport across the Proximal Portion  of the Nephron Reabsorption 67% of Na+ is actively reabsorbed, Cl- follows passively All filtered glucose and amino acids reabsorbed by secondary active transport 65% of filtered H2O osmotically reabsorbed Almost all filtered K+ reabsorbed Secretion Variable H+ secretion, depending on the acid-base status of body Organic-ion secretion 10 Active transport is the movement of a substance against its concentration gradient (from low to high concentration). In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine triphosphate (ATP), it is termed primary active transport. The kidneys accordingly adjust the amt. of salt excreted by the controlling two processes: the GFR and the tubular Reabsorption of sodium GFR tends to increase with volume expansion and falls with volume depletion. Alterations in GFR are not required to maintain sodium balance. People with end stage renal disease are usually able to adjust Na+ excretion to match the Na+ intake by decreasing the rate of tubular reabsorption. Can regulate sodium with GFR as low as 10 Active transport is the movement of a substance against its concentration gradient (from low to high concentration). In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine triphosphate (ATP), it is termed primary active transport. The kidneys accordingly adjust the amt. of salt excreted by the controlling two processes: the GFR and the tubular Reabsorption of sodium GFR tends to increase with volume expansion and falls with volume depletion. Alterations in GFR are not required to maintain sodium balance. People with end stage renal disease are usually able to adjust Na+ excretion to match the Na+ intake by decreasing the rate of tubular reabsorption. Can regulate sodium with GFR as low as 10

11. Transport across the Distal  portion of the Nephron Reabsorption Variable Na+ Reabsorption, controlled by aldosterone Cl- follows passively Variable H2O Reabsorption, controlled by vasopressin Secretion Variable H+ secretion; depending on acid-base status of body Variable K+ secretion, controlled by aldosterone Sherwood, L. Human Physiology� 4th edition, 2001. 11

12. 12 The kidneys secrete renin in response to a reduction of NaCl/ECF volume/arterial BP. Renin activates angiotensinogen, a plasma protein produced by the liver, into angiotensin I Agiotensin I is converted into angiotensin II by agiotensin converting enzyme produced by the lungs. Angiotensin II stim the adrenal cortex to secrete the hormone aldosterone, which stimulates sodium reabsorption by the kidneys. Results in Na+ and H2O retention. The osmotic effect holds more H2O in the ECF. This conservation of Na+ and H2O correct the original stimuli that activated RASThe kidneys secrete renin in response to a reduction of NaCl/ECF volume/arterial BP. Renin activates angiotensinogen, a plasma protein produced by the liver, into angiotensin I Agiotensin I is converted into angiotensin II by agiotensin converting enzyme produced by the lungs. Angiotensin II stim the adrenal cortex to secrete the hormone aldosterone, which stimulates sodium reabsorption by the kidneys. Results in Na+ and H2O retention. The osmotic effect holds more H2O in the ECF. This conservation of Na+ and H2O correct the original stimuli that activated RAS

13. Effective Arterial Blood Volume Essential for perfusion of the tissues and oxygen and cell nutrient delivery. Primarily regulated by sodium balance through hormonal changes. Electrolyte and fluid abnormalities are due to disorders of osmoregulatin and EABV which result in impaired sodium and water intake excretion 13 EABV: the arterial volume that perfuses the tissues. The hormonal changes include: atrial natruiuretic peptide, antidiuretic hormone, renin angiotensin aldosterone systemEABV: the arterial volume that perfuses the tissues. The hormonal changes include: atrial natruiuretic peptide, antidiuretic hormone, renin angiotensin aldosterone system

14. Regulation of Effective Arterial Blood Volume Primarily regulated by sodium balance through hormonal changes. Regulated by baroreceptors in three major areas Extrarenal receptors: Located in the carotid sinuses and aortic arch. Regulate sympathetic activity and release of antidiurectic hormone. Atria and ventricles release natruiuretic peptide in response to increased pressure. Renal receptors: Located in the juxtoaglomerular apparatus and the macula densa cells in the kidneys Regulate the renin-angiotensin system and the endothelin and nitric oxide 14 Hormonal changes: i.e. atrial natruiuretic peptide, antidiurectic hormone, rennin-angiotnesion-aldosterone system �regulated by the extra renal baroreceptors Occurs when the secretion of ANP increases and reduction in aldosterone allowing sodium excretion by the aldosterone Plasma osmolality maintenance: which can by estimated from the plasma sodium concentration is regulated by changes in water intake and excretion, which are mediated by thirst and antidiuretic hormone Hormonal changes: i.e. atrial natruiuretic peptide, antidiurectic hormone, rennin-angiotnesion-aldosterone system �regulated by the extra renal baroreceptors Occurs when the secretion of ANP increases and reduction in aldosterone allowing sodium excretion by the aldosterone Plasma osmolality maintenance: which can by estimated from the plasma sodium concentration is regulated by changes in water intake and excretion, which are mediated by thirst and antidiuretic hormone

15. Potential Outcomes of Sodium Imbalance Renal failure Inability of the kidneys to adjust NA+ excretion to balance the changes in Na+ consumption Elevated BP, generalized edema, and congestive heart failure if excessive sodium is consumed Hypotension, and circulatory shock if too little Na+ is consumed 15 Edema: sodium and water retention are contributory factors in several forms of edemaEdema: sodium and water retention are contributory factors in several forms of edema

16. Regulation of Blood Pressure 16 BP goal 130/80, monitor at every visit Home BP, ambulatory BP monitoringBP goal 130/80, monitor at every visit Home BP, ambulatory BP monitoring

17. Other Factors that influence Blood Pressure Regulation Substances that influence blood pressure Epinephrine and norepinephrine Secreted by the Adrenal medulla Increase blood pressure by increasing heart rate and the contractility of the heart Cause vasoconstriction of the arteries and vein Antidiurectic Hormone (ADH) Secreted by the hypothalamus Increases BP by stimulation the kidneys to retain water (increasing volume Nitric oxide (NO) Secreted by the endothelial cells Causes vasodilatation 17

18. Mechanisms of Essential Hypertension Complex disorder that likely has more than one cause Two Pathways are proposed Renal retention of excess sodium Genetic factors may cause reduced renal sodium excretion in the presence of normal arterial pressure Decreased sodium excretion leads to an increase in fluid volume and high cardiac output Peripheral vasoconstriction occurs to prevent over perfusion of the tissues Vasoconstriction and Vascular Hypertrophy Implicates that increased peripheral resistance is a primary cause for hypertension 18 1. Genetic: May be initiated by environmental factors: stress, salt intake, estrogens; which effect blood pressure control in a genetically predisposed individual. 2. Vasoconstriction: influences may consist of behavioral or neurogenic factors, increased release of vasoconstrictor agents such as Renin-which results in increased RAS activity, catecholamines , endothelin, increased sensitivity of vascular smooth muscle to constricting agents. A defect in sodium and calcium across the smooth muscle cell membrane may occur leading to increased intracellular calcium and contraction of the smooth muscle cells. Results in thickening of the resistant vessels, increasing BP In established hypertension, increased CO and increased peripheral resistance contribute to increased BP1. Genetic: May be initiated by environmental factors: stress, salt intake, estrogens; which effect blood pressure control in a genetically predisposed individual. 2. Vasoconstriction: influences may consist of behavioral or neurogenic factors, increased release of vasoconstrictor agents such as Renin-which results in increased RAS activity, catecholamines , endothelin, increased sensitivity of vascular smooth muscle to constricting agents. A defect in sodium and calcium across the smooth muscle cell membrane may occur leading to increased intracellular calcium and contraction of the smooth muscle cells. Results in thickening of the resistant vessels, increasing BP In established hypertension, increased CO and increased peripheral resistance contribute to increased BP

19. Type 2 diabetes, insulin resistance and the effect of sodium on blood pressure Study done in Italy, written up in �Diabetologia�, 2004 Measured the effect of Na+ intake on BP and albuminuria, in relation with insulin sensitivity and kidney hemodynamics, in patients with Type 2 DM with and without micoralbuminuria. Spent two consecutive 7 day periods, one on a high, the other on a low sodium diet Body weight, BP, and albuminuria were measured at the end of each period. At the end of the high sodium period, kidney hemodynamics were measured in 9 of the patients from each group. 19

20. Type 2 diabetes, insulin resistance and the effect of Sodium on blood pressure Results: Switching from low to high sodium diet resulted in: An increase in BP( 7.4+/-4.7mmHg) Increased body weight: (1.9+/-0.4kg) Increased albuminuria (from 80 mcg/min to 101 mcg/min) in patients with micoralbuminuria. Also had increased intraglomerluar pressure (calculated form the glomerular filtration rate, renal plasma flow, plasma protein concentration and the relationship between pressure and natriuresis) No change in patients without albuminuria 20 High sodium+ 250 mmolHigh sodium+ 250 mmol

21. Type 2 diabetes, insulin resistance and the effect of sodium on blood pressure Conclusions of the study Blood pressure and albuminuria increased with high sodium intake in patients with micoralbuminuria. In Type 2 patients, endothelial-dependant vascular relaxation is impaired and associated with insulin resistance. Insulin has a vasodilator effect and the resistance of vessels could account for the increased BP after high sodium intake. Insulin resistance could contribute to greater salt sensitivity, increased glomerular pressure and albuminuria. 21 Increased sodium may contribute to insulin resistance Insulin is a potent antinaturetic. It is known that insulin has the ability to reduce sodium secretion, but the mechanism by which insulin increases sodium reabsorption are not clear. Insulin has vasodilator effect actions on skeletal muscle and the kidney. Studies have shown that insulin resistant humans have impaired vasodilator responses to insulin. Sodium retention results from increased sodium reabsorption. Overtime increased albuminuria: To date, only a few, large prospective trials have substantiated the notion that reduction of albuminuria is linked to improved renal and cardiovascular prognosis. In the LIFE trial, comprising nearly 10,000 hypertensive patients with LVH, reduction of urinary albumin excretion within the first year (most occur even in the normoalbuminuric range) has been found to have a lower incidence of the composite end point of cardiovascular death, stroke, and myocardial infarction . MARPLE Study: In a study analyzing microalbuminuria and tubular proteinuria as risk predictors of cardiovascular morbidity and mortality in essential hypertension (MARPLE study), it was found that conversion of pathological albuminuria to normal-range albuminuria was associated with a reduced cardio- and cerebrovascular morbidity and total mortality . In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, the treatment of hypertensive patients with type 2 diabetes and overt proteinuria by effective blood pressure control with an angiotensin receptor blocker has been analyzed throughout follow-up of 2.6 years. In this trial, reduction of proteinuria of >30% was highly significant and associated with reduced incidence of renal end points (mostly renal replacement therapy) and, in parallel, to improved cardiovascular prognosis with respect to the cardiovascular combined end point, as well as to congestive heart failure Increased sodium may contribute to insulin resistance Insulin is a potent antinaturetic. It is known that insulin has the ability to reduce sodium secretion, but the mechanism by which insulin increases sodium reabsorption are not clear. Insulin has vasodilator effect actions on skeletal muscle and the kidney. Studies have shown that insulin resistant humans have impaired vasodilator responses to insulin. Sodium retention results from increased sodium reabsorption. Overtime increased albuminuria: To date, only a few, large prospective trials have substantiated the notion that reduction of albuminuria is linked to improved renal and cardiovascular prognosis. In the LIFE trial, comprising nearly 10,000 hypertensive patients with LVH, reduction of urinary albumin excretion within the first year (most occur even in the normoalbuminuric range) has been found to have a lower incidence of the composite end point of cardiovascular death, stroke, and myocardial infarction . MARPLE Study: In a study analyzing microalbuminuria and tubular proteinuria as risk predictors of cardiovascular morbidity and mortality in essential hypertension (MARPLE study), it was found that conversion of pathological albuminuria to normal-range albuminuria was associated with a reduced cardio- and cerebrovascular morbidity and total mortality . In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, the treatment of hypertensive patients with type 2 diabetes and overt proteinuria by effective blood pressure control with an angiotensin receptor blocker has been analyzed throughout follow-up of 2.6 years. In this trial, reduction of proteinuria of >30% was highly significant and associated with reduced incidence of renal end points (mostly renal replacement therapy) and, in parallel, to improved cardiovascular prognosis with respect to the cardiovascular combined end point, as well as to congestive heart failure

22. The Metabolic syndrome and the role of aldosterone Aldosterone and Mineral Corticoid receptor (MR) are involved in sodium metabolism. Activation of aldosterone and MR also induce insulin resistance through mechanisms that involve oxidative stress, inflammation and regulation of proteins involved in insulin signaling pathways. Aldosterone plasma levels and obesity are closely related. With a high salt environment, aldosterone induces inflammation and oxidative stress in the vascular wall, in the heart and kidney. 22 Aldosterone, part of the RAS system, is a mineral corticoid that is involved in sodium regulation. Weight loss is associated with a decrease in plasma levels of aldosterone. Adipose tissue contains the complete RAS which could contribute to increased aldosterone levels in obese people. Weight loss can result in decreased levels of aldosterone Clinical studies have shown a strong relationship between plasma aldosterone levels and hyperinsulinemia in obese and hypertensive patients. Inflammation in the vascular walls result in CV fibrosis, and hypertrophy, glomerularsclerosis tubuloiniterstiial fibrosis of podocyte dysfunctionAldosterone, part of the RAS system, is a mineral corticoid that is involved in sodium regulation. Weight loss is associated with a decrease in plasma levels of aldosterone. Adipose tissue contains the complete RAS which could contribute to increased aldosterone levels in obese people. Weight loss can result in decreased levels of aldosterone Clinical studies have shown a strong relationship between plasma aldosterone levels and hyperinsulinemia in obese and hypertensive patients. Inflammation in the vascular walls result in CV fibrosis, and hypertrophy, glomerularsclerosis tubuloiniterstiial fibrosis of podocyte dysfunction

23. Other Large prospective trials LIFE Trial Included nearly 10,000 hypertensive patients with LVH. Showed that reduction of urinary albumin excretion within the first year has been found to have a lower incidence cardiovascular death, stroke, and myocardial infarction . MARPLE Study: Analyzed micoralbuminuria and tubular proteinuria as risk predictors of cardiovascular morbidity and mortality in essential hypertension Found that conversion of pathological albuminuria to normal-range albuminuria was associated with a reduced cardio- and cerebrovascular morbidity and total mortality . RENALL Trial: Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan The treatment of hypertensive patients with type 2 diabetes and overt proteinuria by effective blood pressure control with an angiotensin receptor blocker has been analyzed throughout follow-up of 2.6 years. Reduction of proteinuria of >30% was highly significant and associated with reduced incidence of renal end points and improved cardiovascular prognosis including congestive heart failure . ADVANCE: proved that routine administration of ACEI, perindopril and diuretic indapamide reduced microvascular and macuvascular outcomes, CVD and mortality. ACCOMPLISH: showed a decrease in morbidity and mortality in patients with systolic hypertension treated with benazapril and amlodipine. 23 Trials have documented that reduction of albuminuria is linked to improved renal and cardiovascular prognosis. renin-angiotensin system (RAS) may have unique advantages for initial or early therapy of hypertension. In a nonhypertension trial of high-risk individuals, including a large subset with diabetes, an ACE inhibitor reduced CVD outcomes. In patients with congestive heartfailure (CHF), including diabetic subgroups, ARBs have been shown to reduce major CVD outcomes , and in type 2 patients with significant nephropathy, ARBs were superior to calcium channel blockers for reducing heart failure. Though evidence for distinct advantages of RAS inhibitors on CVD outcomes in diabetes remains conflicting , the high CVD risks associated with diabetes, and the high prevalence of undiagnosed CVD, may still favor recommendations for their use as first-line hypertension therapy in people with diabetes . Recently, the blood pressure arm of the ADVANCE trial demonstrated that routine administration of a fixed combination of the ACE inhibitor perindopril and the diuretic indapamide significantly reduced combined microvascular and macrovascular outcomes, as well as CVD and total mortality. The improved outcomes could also have been due to lower achieved blood pressure in the perindopril-indapamide arm In addition, the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed a decrease in morbidity and mortality in those receiving benazapril and amlodipine versus benazapril and hydrochlorothiazide. The compelling benefits of RAS inhibitors in diabetic patients with albuminuria or renal insufficiency provide additional rationale for use of these agentsTrials have documented that reduction of albuminuria is linked to improved renal and cardiovascular prognosis. renin-angiotensin system (RAS) may have unique advantages for initial or early therapy of hypertension. In a nonhypertension trial of high-risk individuals, including a large subset with diabetes, an ACE inhibitor reduced CVD outcomes. In patients with congestive heartfailure (CHF), including diabetic subgroups, ARBs have been shown to reduce major CVD outcomes , and in type 2 patients with significant nephropathy, ARBs were superior to calcium channel blockers for reducing heart failure. Though evidence for distinct advantages of RAS inhibitors on CVD outcomes in diabetes remains conflicting , the high CVD risks associated with diabetes, and the high prevalence of undiagnosed CVD, may still favor recommendations for their use as first-line hypertension therapy in people with diabetes . Recently, the blood pressure arm of the ADVANCE trial demonstrated that routine administration of a fixed combination of the ACE inhibitor perindopril and the diuretic indapamide significantly reduced combined microvascular and macrovascular outcomes, as well as CVD and total mortality. The improved outcomes could also have been due to lower achieved blood pressure in the perindopril-indapamide arm In addition, the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed a decrease in morbidity and mortality in those receiving benazapril and amlodipine versus benazapril and hydrochlorothiazide. The compelling benefits of RAS inhibitors in diabetic patients with albuminuria or renal insufficiency provide additional rationale for use of these agents

24. Heart Failure Characterized by ventricular dysfunction and associated clinical symptoms. Decreased cardiac output or peripheral vascular resistance lead to inadequate arterial filling. This triggers a response from the neurohormonal systems to maintain arterial pressure and peripheral perfusion of the vital organs. 24

25. Sodium and Heart Failure Patients has a decreased EABV due to primary reduction in cardiac output. The Kidney is the principal organ affected by a decline in Cardiac Output (CO). Reduction in renal perfusion is sensed by the baroreceptors and the renin-angiotensin-aldosterone and sympathetic nervous systems are activated. These changes plus the reduction in renal perfusion promote sodium retention This increases the plasma volume and intracardiac filling pressures, which can increase stroke volume, improve cardiac output (CO)and improved the Effective arterial blood flow (EABV.) 25 The compensatory mechanism of the renin-angiotensin system can contribute to the pulmonary edema in left-sided heart failure. If the perfusion of the kidney becomes severe enough, secretion of nitrogenous waste products can cause azotemia�elevation of the BUN and creatinine levels, related to decreased glomerular filtration rate (GFR)The compensatory mechanism of the renin-angiotensin system can contribute to the pulmonary edema in left-sided heart failure. If the perfusion of the kidney becomes severe enough, secretion of nitrogenous waste products can cause azotemia�elevation of the BUN and creatinine levels, related to decreased glomerular filtration rate (GFR)

26. Heart Failure 26 CO is reduced because of the decrease in EABV The baroreceptors sense then sense low effective perfusion and the RAAS is activated. Angiotensin II mediates sodium and water retention in Heart Failure. NPs (naturetic peptides-promoted excretion of sodium in the urine) are increased in heart failure, but their effect is blunted in patients with heart failure. NPS normally inhibit sodium and water reabsorption induced by angiotensin II action. Sodium transporters These changes plus a reduction in renal perfusion promote sodium retention. These responses can normalize are effective because increased plasma volume raises the intracardiac filling pressures. *with more severe HF, low cardiac output cannot be corrected and the stimulus to retain sodium continues and fluid retention increases and pulmonary congestion results. BP may fall due to a failing heart rather than the salt/fluid level in the body, the salt and fluid retaining reflexes triggered by the low BP are inappropriate. Sodium excretion may drop to zero despite of continued sodium intake. Activation of the RAAS, CO is reduced because of the decrease in EABV The baroreceptors sense then sense low effective perfusion and the RAAS is activated. Angiotensin II mediates sodium and water retention in Heart Failure. NPs (naturetic peptides-promoted excretion of sodium in the urine) are increased in heart failure, but their effect is blunted in patients with heart failure. NPS normally inhibit sodium and water reabsorption induced by angiotensin II action. Sodium transporters These changes plus a reduction in renal perfusion promote sodium retention. These responses can normalize are effective because increased plasma volume raises the intracardiac filling pressures. *with more severe HF, low cardiac output cannot be corrected and the stimulus to retain sodium continues and fluid retention increases and pulmonary congestion results. BP may fall due to a failing heart rather than the salt/fluid level in the body, the salt and fluid retaining reflexes triggered by the low BP are inappropriate. Sodium excretion may drop to zero despite of continued sodium intake. Activation of the RAAS,

27. Heart Failure 27

28. Interventions to Regulate Sodium Dietary Changes Medications 28 Hypertension is a common comorbidity of diabetes, affecting the majority of patients, with prevalence depending on type of diabetes, age, obesity, and ethnicity. Sodium reductions can improve BP and Heart failure and renal function. Hypertension is a major risk factor for both CVD and microvascular complications. In type 1 diabetes, hypertension is often the result of underlying nephropathy, while in type 2 diabetes it usually coexists with other cardiometabolic risk factors. Hypertension is a common comorbidity of diabetes, affecting the majority of patients, with prevalence depending on type of diabetes, age, obesity, and ethnicity. Sodium reductions can improve BP and Heart failure and renal function. Hypertension is a major risk factor for both CVD and microvascular complications. In type 1 diabetes, hypertension is often the result of underlying nephropathy, while in type 2 diabetes it usually coexists with other cardiometabolic risk factors.

29. Dietary Changes 29 Urinary calcium secretion: Alcohol :avoiding excessive alcohol consumption (no more than 2 servings/day in men and no more than 1 serving/day in women) Patients with DM are more prone to kidney stone formation. Insulin resistance leads to increase acidity in urine, an uric acid formation. Calcium containing kidney stones occur more frequently in DM.Urinary calcium secretion: Alcohol :avoiding excessive alcohol consumption (no more than 2 servings/day in men and no more than 1 serving/day in women) Patients with DM are more prone to kidney stone formation. Insulin resistance leads to increase acidity in urine, an uric acid formation. Calcium containing kidney stones occur more frequently in DM.

30. Sodium Intake Recommendations The American Heart Association (AHA) released a call to action on January 13, 2011. American Heart Association�s recommendation for the general population, which is to consume no more than 1500 milligrams (mg) of sodium a day Daily recommended sodium intake Sodium consumption is currently more than two times higher than the recommended upper limit of 1,500 mg daily, with 77 percent of that consumption coming from packaged, processed and restaurant foods. 30 CURRENT RECOMMEDATION: Only 200 mg are needed each day Americans on average consume 3,436 mg sodium daily. The recommendation for sodium intake is less than 2,300 mg/day for adults. This equals about one teaspoon of table saltRead more: http://www.livestrong.com/article/4734-need-recommended-daily-sodium-intake/#ixzz1DO2fOprx The recommendation was made because of the harmful effects of sodium � elevated blood pressure and increased risk of stroke, heart attacks and kidney disease.�Elevated blood pressure (hypertension) is a major public health problem � approximately 90 percent of all Americans will develop hypertension over their lifetime. CURRENT RECOMMEDATION: Only 200 mg are needed each day Americans on average consume 3,436 mg sodium daily. The recommendation for sodium intake is less than 2,300 mg/day for adults. This equals about one teaspoon of table salt

31. DASH Eating Plan Studies Dietary Approaches to Stop Hypertension Two studies sponsored by the National Heart, Lung, and Blood Institute (NHLBI) were done. Tested nutrients as they occur in food 31

32. DASH DIET DASH Diet: Low in saturated fat, cholesterol, and total fat More fruits, vegetables, whole grains, fish, poultry, and nuts Reduced sweets, sugar-containing, and red meats. Rich in nutrients: potassium, calcium, magnesium, protein and fiber. 32

33. DASH DIET STUDY 459 adults with systolic blood pressures <160mmHg and diastolic of 80-95 mmHg. About 27% had hypertension. 50% women, 60% were African Americans. Compared three eating plans 1. Plan similar to the typical American diet 2. Plan similar to the American diet and with higher fruits and vegetable content 3. Dietary Approaches to Stop Hypertension (DASH) eating plan All three plans contained about 3000 mg of sodium/day. 33 Results: showed that reducing dietary sodium lowered Blood pressure for Studies have shown that following a particular diet plan and reducing the amount of sodium can prevent the development of hypertension or reduce hypertension. As sodium intake rises, so does blood pressure and the risk of negative health outcomes. Independent of its effects on blood pressure, excess sodium intake adversely affects the heart, kidneys, and blood vessels. The potential public health benefits of sodium reduction are enormous and extend to all Americans. Scientific evidence on the adverse effects of excess sodium is strong and compelling� The American Heart Association�s 2020 impact goals � to improve the cardiovascular health of all Americans by 20 percent while reducing deaths from cardiovascular diseases and stroke by 20 percent � include a population-wide reduction of sodium consumption to less than 1,500 mg/daily as one of the ways the association will measure the nation�s cardiovascular health.�Furthermore, a normal range blood pressure is another key factor the association will use to measure the nation�s cardiovascular health status. The American Heart Association is part of the National Salt Reduction Initiative, which is working with the food industry to reduce sodium content in packaged and restaurant food. Results: showed that reducing dietary sodium lowered Blood pressure for Studies have shown that following a particular diet plan and reducing the amount of sodium can prevent the development of hypertension or reduce hypertension. As sodium intake rises, so does blood pressure and the risk of negative health outcomes. Independent of its effects on blood pressure, excess sodium intake adversely affects the heart, kidneys, and blood vessels. The potential public health benefits of sodium reduction are enormous and extend to all Americans. Scientific evidence on the adverse effects of excess sodium is strong and compelling� The American Heart Association�s 2020 impact goals � to improve the cardiovascular health of all Americans by 20 percent while reducing deaths from cardiovascular diseases and stroke by 20 percent � include a population-wide reduction of sodium consumption to less than 1,500 mg/daily as one of the ways the association will measure the nation�s cardiovascular health.�Furthermore, a normal range blood pressure is another key factor the association will use to measure the nation�s cardiovascular health status. The American Heart Association is part of the National Salt Reduction Initiative, which is working with the food industry to reduce sodium content in packaged and restaurant food.

34. DASH DIET STUDY Results: Both the fruits and vegetables plan the DASH diet reduced blood pressure DASH had more significant results BP was reduced within two weeks especially in those with high BP 34

35. DASH Sodium Study Evaluated the effect of a reduced dietary sodium intake on blood pressure. 412 participants with systolic blood pressures of 120-159 and diastolic blood pressures of 80-95. 41% had high blood pressure. 57% women, 57% African American Participants were randomly assigned the DASH diet or a typical American eating plan along with one of three sodium levels: 1,500/2,400/or 3,300 mg. per day, at each level for one month. Results: Reduction in dietary sodium reduced the blood pressure on both of the diet plans containing more fruits and vegetables. The biggest blood pressure reductions were for the DASH eating plan at the sodium intake of 1,500 mg per day. 35 Those with hypertension had the biggest reductions in BP. No significant effects on BP were seen in the groups consuming greater that 1500 mg of sodium per day. those on the 1,500 mg sodium diet and the DASH eating plan had fewer headaches DASH Sodium shows the importance of a lowering Na+ intake. Those with hypertension had the biggest reductions in BP. No significant effects on BP were seen in the groups consuming greater that 1500 mg of sodium per day. those on the 1,500 mg sodium diet and the DASH eating plan had fewer headaches DASH Sodium shows the importance of a lowering Na+ intake.

36. Implementing the DASH DIET Tips for reducing sodium in the diet Choose fresh, frozen or canned food items without added salts. Select unsalted nuts or seeds, dried beans, peas and lentils. Limit salty snacks. Avoid adding salt and canned vegetables to homemade dishes. Use unsalted, lower sodium, fat-free broths, soups or bouillons. Choose low-fat or fat-free milk, low-sodium, low-fat cheeses and low-fat yogurt. Season food with herbs and spices to improve tasted.� Instead of salt, add fresh lemon juice to fish and vegetables. When dining out, specify how you want your food prepared. Skip the salt shaker! 36 Most spices naturally contain very small amounts of sodium. Ask for your dish to be prepared without salt. Use the pepper shaker or mill. Rinse canned foods, such as tuna to remove some of the salt.Most spices naturally contain very small amounts of sodium. Ask for your dish to be prepared without salt. Use the pepper shaker or mill. Rinse canned foods, such as tuna to remove some of the salt.

37. Major Food Sources of Sodium Tomato sauce Soups Condiments Canned foods Prepared mixes 37 Sodium can come from natural sources or be added to foods. Most foods in their natural state contain some sodium. Majority (up to 75 percent) of sodium that Americans consume comes from sodium added to processed foods by manufacturers. While some of this sodium is added to foods for safety reasons � the amount of salt added to processed foods is clearly above and beyond what is required for�safety and function of the food supply. The U.S. Food and Drug Administration and U.S. Department of Agriculture state that an individual�food that has the claim "healthy" must not exceed�480 mg sodium per reference amount. "Meal type" products must not exceed�600 mg sodium per labeled serving size. Sodium can come from natural sources or be added to foods. Most foods in their natural state contain some sodium. Majority (up to 75 percent) of sodium that Americans consume comes from sodium added to processed foods by manufacturers. While some of this sodium is added to foods for safety reasons � the amount of salt added to processed foods is clearly above and beyond what is required for�safety and function of the food supply. The U.S. Food and Drug Administration and U.S. Department of Agriculture state that an individual�food that has the claim "healthy" must not exceed�480 mg sodium per reference amount. "Meal type" products must not exceed�600 mg sodium per labeled serving size.

38.  Sodium equivalents 38 1/4 teaspoon salt=�600 mg sodium 1/2 teaspoon salt= 1,200 mg sodium 3/4 teaspoon salt= 1,800 mg sodium 1 teaspoon salt= 2,300 mg sodium 1 teaspoon baking soda= 1,000 mg sodium Baking soda: sodium bicarbonate, not always recognized as a sodium containing productBaking soda: sodium bicarbonate, not always recognized as a sodium containing product

39. Antihypertensive Drugs Direct Effect on Blood Pressure Lowering the sodium intake in conjunction with antihypertensive drugs can result in an enhanced effect of most of these drugs Lower the Extracellular fluid by Response to antihypertensive drugs� 39 �In addition to its direct effect on blood pressure, lowering the extracellular volume by limiting sodium intake can enhance the response to most antihypertensive drugs, except possibly calcium channel blockers. Sodium restriction may also diminish the degree of potassium depletion following treatment with a diuretic . Sodium reduction, by increasing renin release, makes the BP more angiotensin II-dependent and therefore more responsive to therapy with an ACE inhibitor or angiotensin II receptor blocker . BLACKS: A less responsive renin-angiotensin system may be one reason why blacks appear to be more sensitive to sodium restriction than whites . Even patients being treated with the combination of a diuretic and an ACE inhibitor benefit from a reduction in sodium intake (e.g., from 195 down to 105 meq/day). In this setting, the BP has been shown to fall by an average of 9/3 mmHg Diabetes care position statements: Patients with a systolic blood pressure of 130�139 mmHg or a diastolic blood pressure of 80�89mmHgmay be given lifestyle therapy alone for a maximum of 3 months and then, if targets are not achieved, be treated with addition of pharmacological agents. ? Patients with more severe hypertension (systolic blood pressure 140 or diastolic blood pressure 90 mmHg) at diagnosis or follow-up should receive pharmacologic therapy in addition to lifestyle therapy. ? Lifestyle therapy for hypertension consists of: weight loss, if overweight; Dietary Approaches to Stop Hypertension (DASH)-style dietary pattern including reducing sodium and increasing potassium intake; moderation of alcohol intake; and increased physical activity. ? Pharmacologic therapy for patients with diabetes and hypertension should be with a regimen that includes either an ACE inhibitor or an ARB. If one class is not tolerated, the other should be substituted. If needed to achieve blood pressure targets, a thiazide diuretic should be added to those with an estimated GFR (eGFR) 30ml/min/1.73 m2 and a loop diuretic for those with an eGFR 30 ml/min/1.73 m2. ? Multiple drug therapy (two or more agents at maximal doses) is generally required to achieve blood pressure targets. ? If ACE inhibitors, ARBs, or diuretics are used, kidney function and serum potassium levels should be monitored. ? In pregnant patients with diabetes and chronic hypertension, blood pressure target goals of 110�129/65�79 mmHg are suggested in the interest of long-term maternal health and minimizing impaired fetal growth. ACE inhibitors and ARBs are contraindicated during pregnancy. Position Statement care.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 1, JANUARY 2011 S27�In addition to its direct effect on blood pressure, lowering the extracellular volume by limiting sodium intake can enhance the response to most antihypertensive drugs, except possibly calcium channel blockers. Sodium restriction may also diminish the degree of potassium depletion following treatment with a diuretic . Sodium reduction, by increasing renin release, makes the BP more angiotensin II-dependent and therefore more responsive to therapy with an ACE inhibitor or angiotensin II receptor blocker . BLACKS: A less responsive renin-angiotensin system may be one reason why blacks appear to be more sensitive to sodium restriction than whites . Even patients being treated with the combination of a diuretic and an ACE inhibitor benefit from a reduction in sodium intake (e.g., from 195 down to 105 meq/day). In this setting, the BP has been shown to fall by an average of 9/3 mmHg Diabetes care position statements: Patients with a systolic blood pressure of 130�139 mmHg or a diastolic blood pressure of 80�89mmHgmay be given lifestyle therapy alone for a maximum of 3 months and then, if targets are not achieved, be treated with addition of pharmacological agents. ? Patients with more severe hypertension (systolic blood pressure 140 or diastolic blood pressure 90 mmHg) at diagnosis or follow-up should receive pharmacologic therapy in addition to lifestyle therapy. ? Lifestyle therapy for hypertension consists of: weight loss, if overweight; Dietary Approaches to Stop Hypertension (DASH)-style dietary pattern including reducing sodium and increasing potassium intake; moderation of alcohol intake; and increased physical activity. ? Pharmacologic therapy for patients with diabetes and hypertension should be with a regimen that includes either an ACE inhibitor or an ARB. If one class is not tolerated, the other should be substituted. If needed to achieve blood pressure targets, a thiazide diuretic should be added to those with an estimated GFR (eGFR) 30ml/min/1.73 m2 and a loop diuretic for those with an eGFR 30 ml/min/1.73 m2. ? Multiple drug therapy (two or more agents at maximal doses) is generally required to achieve blood pressure targets. ? If ACE inhibitors, ARBs, or diuretics are used, kidney function and serum potassium levels should be monitored. ? In pregnant patients with diabetes and chronic hypertension, blood pressure target goals of 110�129/65�79 mmHg are suggested in the interest of long-term maternal health and minimizing impaired fetal growth. ACE inhibitors and ARBs are contraindicated during pregnancy. Position Statement care.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 1, JANUARY 2011 S27

40. Benefits of Reduction of Sodium Intake in Conjunction with Antihypertensive Drugs 40 Increased renin release make the ACE inhibitor or ARB more effective Patients treated with combination of ACE and diuretic benefit from a reduction in sodium intake. In blacks-have less responsive RAS system and this may be why they are more sensitive to sodium reduction than whites. Increased renin release make the ACE inhibitor or ARB more effective Patients treated with combination of ACE and diuretic benefit from a reduction in sodium intake. In blacks-have less responsive RAS system and this may be why they are more sensitive to sodium reduction than whites.

41. Diuretics Four Classes Each distinguished by the site at which sodium absorption is impaired Diminish sodium reabsorption at different sites of the nephron, increasing urinary sodium and water losses. 41 Beneficial for treatment of a variety of conditions, edema, hypertension Beneficial for treatment of a variety of conditions, edema, hypertension

42. Loop Diuretics Furosemide, Etharcinic Acid, Bumetanide, Torsemide � Reabsorption of sodium by the thick ascending loop of Henle is blocked Inhibit the sodium-potassium-chloride carrier in the luminal membrane 42

43. Thiazide Diuretics Hydrochlorothiazide, Chlorthalodone Block the NaCl-transporter in the distal nephron to cause salt wasting Have less natruiuretic effect than loop diuretics Can affect salt homeostasis 43 Thiazide diuretics: These agents act in the distal convoluted tubule and block a Na+, Cl- symporter that is associated with the luminal membrane. This transport system moves both Na+ and Cl- into the cell using the free energy produced by the Na+, K+, ATPase. The Na+ is pumped out of the epithelial cell via this transport system in the basolateral membrane. Thiazide diuretics: These agents act in the distal convoluted tubule and block a Na+, Cl- symporter that is associated with the luminal membrane. This transport system moves both Na+ and Cl- into the cell using the free energy produced by the Na+, K+, ATPase. The Na+ is pumped out of the epithelial cell via this transport system in the basolateral membrane.

44. Potassium Sparing Diuretics Impair sodium reabsorption in the aldosterone sensitive principal cells of the cortical collecting tubule Amiloride, Triamterene Directly inhibit sodium channel activity Interfere with the sodium-potassium exchange at the distal convoluted tubule of the kidney. Spironolactone Acts as an aldosterone antagonist. This action increases urinary sodium excretion in patients with heart failure. By blocking the actions of aldosterone, spironolactone prevents increases in fluid volume. Spironolactone and Eplerenone Block the mineral corticoid receptor Indicated in patients with primary aldosteronsim or heart failure because they may reduce the adverse effects of excess aldosterone on the heart. 44

45. Osmotic Diuretics Mannitol , Acetazolamide Act in the proximal tubule by inhibiting sodium and water reabsorption 45

46. ACEs/ARBs Antihypertensive and renal protection Mechanism of Action: RAS inhibition Benefits: Block the action of Angiotensin II which mediates sodium and water retention in patient with heart failure. This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials. ACEIs have been shown to cause a central enhancement of parasympathetic activity in healthy volunteers and patients with heart failure. 46 Some clinicians prescribe ACE inhibitors for CV and renal protection for patients with diabetes. Studies indicate these meds may prove to be beneficial even in patients who do not exhibit problems in these systems. Patients prone to hypotension or hyperkalemia, or with a hypersensitivity to other agents in the class, should also avoid ACE inhibitors. http://en.wikipedia.org/wiki/ACE_inhibitor ARBs: By blocking the binding of angiotensin-II to the angiotensin-II receptor, these agents inhibit the vasoconstriction effects of angiotensin-II and prevent the angiotensin-II-mediated release of aldosterone. Aldosterone promotes sodium and water retention. By inhibiting the production of aldosterone, ARBs indirectly inhibit fluid volume increases that result from the actions of aldosterone. Perform an annual test to assess urine albumin excretion in type 1 diabetic patients with diabetes duration of 5 years and in all type 2 diabetic patients starting at diagnosis. Treatment ? In the treatment of the nonpregnant patient with micro- or macroalbuminuria, either ACE inhibitors or ARBs should be used. ? While there are no adequate head-tohead comparisons of ACE inhibitors and ARBs, there is clinical trial support for each of the following statements: ? In patients with type 1 diabetes, with hypertension and any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. (A) Diabetic nephropathy occurs in 20�40% of patients with diabetes and is the single leading cause of end-stage renal disease (ESRD). Persistent albuminuria in the range of 30�299 mg/24 h (microalbuminuria) has been shown to be the earliest stage of diabetic nephropathy in type 1 diabetes and a marker for development of nephropathy in type 2 diabetes. Microalbuminuria is also a well-established marker of increased CVD risk (258,259). Patients with microalbuminuria who progress to macroalbuminuria (300 mg/24 h) are likely to progress to ESRD (260,261). However, a number of interventions have been demonstrated to re-Some clinicians prescribe ACE inhibitors for CV and renal protection for patients with diabetes. Studies indicate these meds may prove to be beneficial even in patients who do not exhibit problems in these systems. Patients prone to hypotension or hyperkalemia, or with a hypersensitivity to other agents in the class, should also avoid ACE inhibitors. http://en.wikipedia.org/wiki/ACE_inhibitor ARBs: By blocking the binding of angiotensin-II to the angiotensin-II receptor, these agents inhibit the vasoconstriction effects of angiotensin-II and prevent the angiotensin-II-mediated release of aldosterone. Aldosterone promotes sodium and water retention. By inhibiting the production of aldosterone, ARBs indirectly inhibit fluid volume increases that result from the actions of aldosterone. Perform an annual test to assess urine albumin excretion in type 1 diabetic patients with diabetes duration of 5 years and in all type 2 diabetic patients starting at diagnosis. Treatment ? In the treatment of the nonpregnant patient with micro- or macroalbuminuria, either ACE inhibitors or ARBs should be used. ? While there are no adequate head-tohead comparisons of ACE inhibitors and ARBs, there is clinical trial support for each of the following statements: ? In patients with type 1 diabetes, with hypertension and any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. (A) Diabetic nephropathy occurs in 20�40% of patients with diabetes and is the single leading cause of end-stage renal disease (ESRD). Persistent albuminuria in the range of 30�299 mg/24 h (microalbuminuria) has been shown to be the earliest stage of diabetic nephropathy in type 1 diabetes and a marker for development of nephropathy in type 2 diabetes. Microalbuminuria is also a well-established marker of increased CVD risk (258,259). Patients with microalbuminuria who progress to macroalbuminuria (300 mg/24 h) are likely to progress to ESRD (260,261). However, a number of interventions have been demonstrated to re-

47. Routine Screening and implications for treatment Blood pressure; monitor at each visit. Urine albumin, GFR; annually and as needed. Goal 130/80 Goal<30; Persistent albuminuria in the range of 30�299 mg/24 hrs(micoralbuminuria) 47 Microalbuminuria has been shown to be the earliest stage of diabetic nephropathy in type 1 diabetes and a marker for development of nephropathy in type 2 diabetes. Patients with microalbuminuria who progress to macroalbuminuria (300mg/24 h) are likely to progress to ESRD Perform an annual test to assess urine albumin excretion in type 1 diabetic patients with diabetes duration of 5 years and in all type 2 diabetic patients starting at diagnosis. ? Measure serum creatinine at least annually in all adults with diabetes regardless of the degree of urine albumin excretion. The serum creatinine should be used to estimate GFR and stage the level of chronic kidney disease (CKD), if present. Treatment ? In the treatment of the nonpregnant patient with micro- or macroalbuminuria, either ACE inhibitors or ARBs should be used. ? While there are no adequate head-to head comparisons of ACE inhibitors and ARBs, there is clinical trial support for each of the following statements: Microalbuminuria has been shown to be the earliest stage of diabetic nephropathy in type 1 diabetes and a marker for development of nephropathy in type 2 diabetes. Patients with microalbuminuria who progress to macroalbuminuria (300mg/24 h) are likely to progress to ESRD Perform an annual test to assess urine albumin excretion in type 1 diabetic patients with diabetes duration of 5 years and in all type 2 diabetic patients starting at diagnosis. ? Measure serum creatinine at least annually in all adults with diabetes regardless of the degree of urine albumin excretion. The serum creatinine should be used to estimate GFR and stage the level of chronic kidney disease (CKD), if present. Treatment ? In the treatment of the nonpregnant patient with micro- or macroalbuminuria, either ACE inhibitors or ARBs should be used. ? While there are no adequate head-to head comparisons of ACE inhibitors and ARBs, there is clinical trial support for each of the following statements:

48. Albuminuria and its Implications for Treatment Clinical findings Treatment In patients with type 1 diabetes, with hypertension and any degree of albuminuria In patients with type 2 diabetes, hypertension and microalbuminuria, In patients with type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine 1.5 mg/dl). ACE inhibitors have been shown to delay the progression of nephropathy. Both ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria. ARBs have been shown to delay the progression of nephropathy. 48 If patient is not tolerating one, switch to the other.If patient is not tolerating one, switch to the other.

49. New treatment for Type 2 diabetesSodium glucose cotransporter 2 inhibitors Sodium-glucose cotransporter 2 (SGLT2) is expressed in the proximal renal tubules and accounts for about 90% of the reabsorption of glucose form the tubular fluid. Genetic defects of SGLT2 result in a benign familial renal glucosuria. These people do not have diabetes. Pharmacological agents that block the SGLT2 are being studied in treatment of type 2 diabetes mellitus. Work by enhancing urinary secretion of glucose independent of insulin action. 49 Low risk of hypoglycemia Associated with weight loss, may assist with a reduction in BP Glucose is excreted from the kidneys when the BG reaches 300 mgdL, Normally no glucose is excreted, it is absorbedLow risk of hypoglycemia Associated with weight loss, may assist with a reduction in BP Glucose is excreted from the kidneys when the BG reaches 300 mgdL, Normally no glucose is excreted, it is absorbed

50. Study of Sodium glucose Cotransporter 2 Wilding et al and Parika et al presented results of a study in abstracts: 808 insulin treated Type 2 diabetic patients with a baseline HbA1c of 8.5%. Randomized to SGLT2 inhibitor, Dapaglifozan at daily doses of 2.5, 5, or 10 mg. or placebo. Results: No increase in the insulin dose was required Placebo group: HbA1C decreased 0.3% 10 mg. dose group: HbA1C decreased by 0.9% Weight loss: 1.7 kg. Bloomgarden, Z. Diabetes Care: February 2011 50 Another SGLT2 under study is CanaglifozanAnother SGLT2 under study is Canaglifozan

51. Conclusions Regulation of sodium relies on a complex system. Sodium regulation be influenced by both environmental and genetic factors. Following a low sodium diet can improve the affects of medical therapies. Regulation and or reduction of sodium can improve outcomes for hypertension, cardiovascular, and renal systems and reduce associated comorbidities. 51

52. Salt Mine in Wieliczka, Poland  Don�t get stuck in the salt mines�. Consider alternatives and enjoy the benefits! 52

53. References American Diabetes Association; �Standards of Medical Care in Diabetes�2011;� Diabetes Care January 26, 2011 vol. 34 no. 2 American Heart Association Presidential Advisory; retrieved from: http://www.newsroom.heart.org; on January 16, 2011 Bailey, C.J.; Renal glucose reabsorption inhibitors to treat diabetes; Breit, M., Schiffrin, E.:�The role of aldosterone in the metabolic syndrome;: Curr Hypertension Rep: DOI 10.1007/s11906-001-0182-2: Published online: January 2001. Bloomgarden, Z;�Type 2 diabetes, uses of thiazolidinediones and insulin: Diabetes Care February 2011; vol. 34. Brater, C.; �Mechanism of action of diuretics�; retrieved from http://www.uptodate.com on January 11, 2011. Burton, et al; �Physiologic regulation of effective arterial blood volume and plasma osmolality�; retrieved from https://uptodate.com on January 13, 2011. Cotran, et el; Pathologic Basis of Disease; The kidney and the heart; pp. 513, 513, 549, 935; copyright 1999, W.B. Saunders Company Eun, H. B, Seong, K.; �water and sodium regulation in heart failure;� Electrolytes Blood Pressure: 7:38-41, 2009. Getting Healthy; retrieved from: http://www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/HealthyDietGoals/Sodium-Salt-or-Sodium-Chloride_UCM_303290_Article.jsp, on January 16, 2011 Glover M, Zuber AM, O'Shaughnessy KM. �Hypertension, Dietary Salt Intake, and the Role of the Thiazide-Sensitive Sodium Chloride Transporter NCCT.� Cardiovascular Ther. 2011 Feb;29(1):68-76. doi: 10.1111/j.1755-5922.2010.00180.x. Epub 2010 Dec 19.PMID: 21167012 Kalambokis, G, Tsatsoulis A, Economou G, Tsianos EV �A case of insulin edema with inappropriate hyperaldosteronism; J Endocrinol Invest. 2004 Nov;27(10):957-60. 53

54. References Sodium (Salt or sodium chloride); retrieved from http://www.americanheart.org on January 12, 2011. McCance, Huether; �Pathophysiology: The Biologic Basis for Disease in Adults and Children; 5th edition; copyright 2006; Mosby; pp. 1256. 1288. National Institutes of Health; National Heart, Lung, and Blood Institute; �The DASH eating plan�; 2005 Nobura, S.; �Renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for new anti-diabetic agent; retrieved from https://www.ncgbi.nlm.nih.gov/pubmed ; on February 1, 2011. Scmieder, R. �Hypertension and diabetes, what are the pros and cons of early surrogates?�; Diabetes Care October 29, 2009 vol. 32 no. suppl 2 S294-S297. Stenvinkel, P.; �Sodium Rose, B. Post, T.; Regulation of renal Na+ excretion, section on Pressure natriuresis. Chapter 8C; retrieved from http://www.uptodate.com on January 11, 2011. U.S. Department of Health and Human Services: National Institutes of Health, National Heart, Lung, and Blood Institute; �The DASH eating plan;� April, 2005. U.S. Department of Health and Human Services: National Institutes of Health, National Heart, Lung, and Blood Institute; �The DASH eating plan;� April, 2005. Vedovato, et al; �Effect of sodium intake on blood pressure and albuminuria in type 2 diabetic patients: the role of insulin resistance; Diabetologia (2004) 47:300-303 Wikipedia.org; �Sodium�; �Sodium regulation�; retrieved on January 12, 2011. 54