Diabetic Nephropathy (DN)

Question 1

Diabetic Nephropathy (define)

Answer 1

• A syndrome seen in patients with all types of diabetes characterized by persistent and increasing albuminuria and proteinuria, hypertension, and progressive renal failure
  
  • 30-40% of daibetic patients develop DN
  • Leading cause of ESRD

Question 2

Structural changes in DN

Answer 2

• DN is defined by characteristic structural and functional changes.
• Main structural changes = mesangial expansion (Kimmelstiel -wilson nodules), glomerular basement membrane thickening, podocyte injury, and glomerular sclerosis.

Question 3

Major clinical manifestations of DN

Answer 3

• Albuminuria
• Hematuria (less often)
• In many cases progresses to chronic kidney disease

Question 4

Hemodynamic changes in DN

Answer 4

• In early stages you see hyperfiltration and increased GFR due to glucose dependent effects resulting in afferent arterioles dilation and constriction of efferent arteriole, resulting in increased pressure and glomerular loss of proteins.
  
  • The hyperfiltration increases colloid osmotic pressure in postglomerular capillaries increasing sodium reabsorption in proximal tubules (means less sodium at macula densa, this dilates afferent arteriole and increases GFR)
  • The leaked proteins also get endocytosed into the proximal tubular cells resulting in inflammation and eventually interstitial fibrosis
  • Glycation of basement membrane results in hyaline aterosclerosis of efferent arteriole. This narrows the efferent arteriole and raises pressure also increasing GFR.
• Overtime, the increases in intraglomarular pressure results in greater mesangial cell production. Expansion of the mesangial matrix results in a reduction of the surface area for filtration and a reduction in GFR. Later, we see thickening of the basement membrane and glomerular sclerosis.

Question 5

Hyperglycemia and AGEs in DN

Answer 5

• Hyperglycemia may cause mesangial expansion and injury. Glycation of tissue proteins also may contribute to development of DN and other microvascular complications. In chronic hyperglycemia, glucose combines with free amino acids on tissue proteins. At first, this forms reversible early glycation products and later irreversible advanced glycation end productions (AGE). Levels of AGE are increased in diabetes especailly in those with renal insufficiency, since AGEs are noramlly excreted in the urine.
• Another way hyperglycemia may contribute to DN is by decreased cell surface heparan sulfate, which may contribute to increases glomerular basement membrane permeability to albumin.

Question 6

Risk factors in the development of DN

Answer 6

• Genetics - changes of developing DN are increases if first degree releatives had DN
• Blood pressure - higher blood pressures may be associated with DN development
• GFR - elevated GFR is associated with increased risk of DN
• Poor glycemic control
• Obesity
• Smoking
• OCPs?
• Best predictor is increased albuminuria
• Patients with DN in DM1 almost always had signs of other microvascular disease, this relationship is less predictable in DM2.

Question 7

Prevention of DN

Answer 7

• Glycemic control - decreases risk for microablumnuria and impaired GFR
• Blood pressure control - if patient has HTN, this should be treated. HTN is assoicated with increasing albuminuria and increased risk of kidney disease.

Question 8

Treatment of DN

Answer 8

• Antihypetensive - uncontrolled HTN is associated with more rapid progession of DN and increased CV events. Antihypertensives lower albuminura, delay progression of nephropathy, postpone renal impairment, and improve survival in patients with DN.
• RAAS blockade - RAAS blockade with ACEi or ARBs is renoprotective independent of BP reduction. This is due tp the intraglomerular hemodynamic and nonhemodynamic renal effects of angiotension II
• Diuretics and reduced sodium - antiproteinuric effects or RAAS blockage is enhanced by reduced sodium and diuretics
• Treament of dyslipidemia with a statin
• Nonpharmacological interventions - dietary protein restriction may reduce proteinuria.
  
  • Restriction of sodium, salt, potassium, and phosphate
  • Smoking cessation and weight loss

Question 9

Diabetic medication in CKD

Answer 9

• Sulfonylurea - binds strongly to albumin, so hypoalubminemia (as seen in DN) may increase plasma concentration and result in hypoglycemia. Furthermore, some of the sulfonylureas have active metabolites that are excreted by the kidneys and these should be avoided.
• DDP4 inhibitors - have not been studied in CKD and should be avoided
• Alpha-glucosidase inhibitors - largely renally excreted and should be avoided.
• Metformin - is excreted unchanged in the urine and should be avoided in CKD due to potential for drug accumulation.
• SGLT2 inhibitors - not recommened with eGFR < 40 and contraindicated with an eGFR <30
• Insulin - dose may need to be lower than those who have normal kidney function, because you see reduced renal metabolism of insulin.

Question 10

Mechanism of hyperkalemia

Answer 10

• Potassium enters the body via oral or IV intake and is mostly stored in cells and excreted via the urine. The main cuases of hyperkalemia are increased potassoim release from the cells or reduced potassium excretion in the urine

Question 11

How is potassium excretion regulated?

Answer 11

• There are 3 main factors that stimulate potassium secretion

1. Increased plasma potassium concentration or intake
2. Increase aldoesterone release
3. Increase delivery of sodium and water to distal potassium secretory sites

• Hyperkalemis is rare because of potassium adaptation - specifically, if potassium levels increase, excretion also increases.

Question 12

Hyperkalemia due to increased potassium release from cells

Answer 12

1. Pseudohyperkalemia - conditions where elevations in measured potassium is due to potassium movement out of the cells during or after the blood speciment has been drawn. This should be suspected when there is no obvious cause for hyperkalemia and patient is asymptomatic.
2. Metabolic acidosis - buffering of excess H⁺ ions into the cells leads to K⁺ movement out of the cells in order to maintain electroneutrality
3. Insulin deficiency , hyperglycemia and hyperosmolality - insulin promotes potassium entry into the cells
4. Increases tissue catabolism - any cause of increased tissue breakdown leads to release of intracellular potassium into extracellular fluid
5. Beta blockers - Increases beta-2-adrenerger activity drives K⁺ into the cells. So, beta-blockers interfere with this process and result in increased serum potassium (seen mainly with nonselective beta-blockers)
6. Exercise - K⁺ is released from muscle cells during exercise. Rarely is this clinically important
7. Hyperkalemic periodic paralysis - autosomal dominant disorder where episodes of weakness or paralysis are prepitated by cold, rest after excersice, fasting, or ingestion of small amounts of potassium

Question 13

Hyperkalemia due to reduced urinary potassium excretion

Answer 13

• Main factors required for adequate potassium secretion are adequate aldosterone secretion, adequate responsiveness to aldosterone, and adequate distal sodium and water delivery

1. Reduced aldosterone secretion - angiotensin inhibitors, NSAIDs, heparin, etc.
2. Reduced reponse to aldosterone - can be due to drugs (potassium sparing diuretics) as well as due to acute and chronic kidney disease
3. Reduced distal sodium and water delivery - most commonly due to arterial volume depletion (GI losses, renal losses, CHF, cirrhosis)