R2 Chronic Kidney Disease

• 1. Kidney damage with normal or high GFR
• -GFR ≥ 90 ml/min
• -5.7% of US population

• 2. Kidney damage with mild decrease in GFR
• -GFR 60-89 ml/min
• -5.4% of US population

• 3. Moderate decrease in GFR
• -GFR 30-59 ml/min
• -5.4% of US population

• 4. Severe decrease in GFR
• -GFR 12-29 ml/min
• -0.2% of US population

• 5. Kidney Failure
• -GFR <15 or Dialysis
• -0.2% of US population

• Diabetes - 45%
• HTN - 26.5%
• Glomerulonephritis - 8.5%

Renal injury leads to adaptations by remaining nephrons that are initially protective, but eventually cause injury

Hypertension - in the presence of CKD is bad prognostically

• Impaired sodium excretion (expansion of ECF volume)
• Activation of RAS (Direct vasoconstriction; sympathetic activation)
• Sympathetic activation (Direct vasoconstriction; sympathetic activation)
• Imbalance in prostaglandins or kinins (vasoconstriction)
• Endothelin (Direct vasoconstriction; renal injury)
• Reduced nitric oxide (Loss of vasodilator effects)

• -Lowering BP does not necessarily lower P_GC; triple therapy does not affect P_GC
• -ACE-Inhibitors do help lower P_GC and Mean Arterial Pressure (MAP); "nephroprotective" drug
• 

ACE-Inhibitors can produce AKI, however: if BP drops to low, P_GC will drop too low

-Tight control on BP reduces risk for: diabetes=related mortality, stroke, microvascular damage, myocardial infarction (more than just CKD complications/progression)

Glomerular-capillary hypertension leads  to increased glomerular permeability to macromolecules

-Increase filtration of plasma proteins --> Proteinuria

• Rate of GFR decline increases as proteinuria increase
• More protein in urine = more rapid decline in kidney function

• Aldosterone levels correlate with rate of progression
• Aldosterone levels are inversely related to GFR
• Dietary protein raises aldosterone in renal disease
• Aldosterone leads to fibrosis
• 
• ACE inhibitors lower aldosterone
• -Aldosterone blocker side effect: hyperkalemia

• Benefit beyond controlling HTN:
• -Improved outcomes in nephropathy in type 1 diabetics; fewer progression to death, dialysis, or transplantation

• irbesartan showed 70% reduction in risk for progression to overt diabetic nephropathy
• -results independent of effects on systemic blood pressure

Losartan improves outcomes (doubling of Cr, ESRD) compared to control

• -These drugs work best if the BP is well controlled:
• -MAP can be used to estimate decline in GFR per year (higher MAP, faster annual decline in GFR)

Kidney is involved in the 1α hydroxilation of 25 VitD (from liver) into the active form: 1,25-Vit D

• Regulation:
• -hydroxilation rxn (generation of active Vit D) is promoted by low Ca2+, Low PO4, high PTH
• -hydroxilation is inhibited by high Ca2+, high PO4, high 1,25-Vit D
• 

-As GFR decreases, there is an inability to secrete phosphorus (PO^4-); increase in PO4 causes a decrease in serum Ca2+ (PO4 binds Ca2+)

• -Decrease in serum Ca2+ causes increase in PTH
• -PTH has detrimental effects on bone (increases osteoclastic activity)

• -Pts used to present with lytic bone lesions
• 

• -Increases serum Ca2+ in order to maintain goal PTH (150-300pg/ml)
• -Goal PTH: stabilizes and improve bone architecture

• -Oversuppression of PTH (<150pg/ml) can cause relative hypoparathyroidism and adynamic bone disease
• -DM, age, aluminum, PTH resistance, malnutrition can also contribute to adynamic bone disease
• 

• Tx:
• -limit phosphate intake in diet
• -phoasphate binding agents (given at same time as meals)
• -Vit D (increases serum Ca and reduces levels of PTH

• -Goal PTH increases (and range broadens) with stage of CKD
• -Treat acidosis
• -Avoid aluminum overload
• -Adjust dialysis calcium in ESRD

• 1. Dietary PO4 restrictions; PO4 binders
• 2. Vit D
• 3. Calcimimetics - binds the calcium-sensing receptor (CaSR)
• 4. Consider parathyroidectomy
• 

Erythropoietin is made in the kidney; promotes production of RBC precursors and increases maturation of the burst forming unit-erythroid (BFU-E) and pro-erythroblast



CKD or ESRD is often complicated by anemia

Tx: target hemoglobin of 11-12g/dL; any higher and pts have problems

• Impaired platelet aggregation is common in CKD
• -Abnormal vWF (various sized vWF fragments) are seen in CKD that (presumably) interfere with platelet adhesion

• Renal failure:
• -Abnormal platelet function
• -Decreased degradation of gastrin → ↑acid → submucosal edema and hyperemia
• -2o hyperparathyroidism → increased secretion → increased gastrin ...
• -Increased Na retention, decreased albumin → submucosal edema and hyperemia
• -Increased urea →decreased mucosal barrier
• -Increased urea → increased urease→ irritability
• 

• CKD can cause CV disease → CV disease accelerates CKD
• 

• *Can have significant loss of function before sx appear
• -Cr as a measure of GFR is inexact; GFR can vary while Cr stays the same (or relatively the same)
• 

• Uremic solute:
• -Urea
• -Creatinine
• -Arginine
• -Dimethylarginine
• -Guanidinosuccinic acid
• -β2-microglobulin
• -Myoinositol
• -Inositol
• -PTH
• -p-cresol sulfate
• -Indican

• Uremic syndrome manifestations:
• 1. Nervous system - seizures, anorexia, RLS, asterixes
• 2. MSK - weaknes, gout, renal osteodystrophy
• 3. Hematologic - Anemia, bleeding disorders, leukocyte dysfunction
• 4. Pulmonary - ARDS, pneumonitis, pleuritis
• 5. CV - cardiomyopathy, arrhythmias, pericarditis
• 6. GI - Anorexia, NausVom, GI bleeding
• 7. Acid base/electrolytes - Anion gap acidosis, hyperkalemia, fluid overload
• 8. Endocrine/metabolism - Hyperparathyroidism, insulin resistance
• 9. Skin - pruritis, yellow pigmentation

• 

• General:
• fatigue, weakness, lethargy
• pruritis, pallor, petechiae
• anorexia, nausvom
• insomnia, irritability, paresthesia, asterixis, seizures, obtunded
• dyspnea, peripheral edema, pericarditis, friction rub may be audible

• 
• -Metabolic acidosis
• -Hyperphosphatemia
• -Hypocalcemia
• -Electrolyte distrubances
• -Normochromic, normocytic anemia
• -Hyperuricemia
• -Broad, waxy casts
• -Periosteal erosions on plain film
• -Small, echogenic (scarred kidneys)

Juxtaglomerular aparatus → Renin → Angiotensin I → Angiotensin II → binds Angiotensin receptors on adrenal gland → releases Aldosterone

Aldosterone binds to aldosterone receptor in collecting duct, leading to K+ secretion

Aldosterone blocking drugs (ACE inhibitors, ARBs, Aldosterone receptor blockers...)  can cause hyperkalemia - hyperkalemia is a common cause of/finding in hospital admission

• Reduce systemic blood pressure (130/80), especially in DM
• ACE-Inhibitors (Proteinuia <1000mg/day)
• Administer ARB (Proteinuia <1000mg/day)
• Reduce proteinuria (diet <1gm protein/kg body weight/day)
• Blood glucose control (HgbA1c <7%)
• Lipid-lowering agent (LDL <100mg/dL)
• Miscellaneous (treat acidosis, corect calcium, phospohrus, vitamin D, and PTH)
• Combination therapy (ACE-In, ARB, lipid-lowering, other antihypertensive)

• Semipermeable membrane
• 

• 1. Hemodialysis
• -need a high pressure/flow vein: "arteriolize" the vein (fistula, graft, or catheter)
• -many more patients on hemodialysis (~350,000)

• 2. Peritoneal dialysis
• -peritoneum used as the semipermeable membrane; dialysate is pumped into peritoneal cavity
• -pts can dialyse from home, even over night
• 
• -fewer patients on Peritoneal dialysis (~25,000)

• Survival at 1 year: 95-98%
• Survival at 10 years: 80%
• ~165,000 transplants each year