Chronic Kidney Disease

Pathophysiology of CKD and Its Complications

Pathophysiology of CKD

CKD can be caused by a multitude of underlying conditions; however, once about half of the total nephrons are lost, CKD progresses similarly, regardless of etiology.

• Underlying etiology: ↓ total number of nephrons (nephron mass), which leads to:
  • ↑ Glomerular permeability → ↑ filtration of proteins, which are lost in the urine (i.e., proteinuria) 
  • Activation of the RAAS
  • Cytokine release
  • ↑ Growth factors
• These changes lead to adaptive hyperfiltration:
  • GFR may actually ↑ during this time.
  • Occurs as a compensatory mechanism
  • Leads to ↑ intraglomerular capillary pressure (i.e., glomerular hypertension)
• ↑ Intraglomerular capillary pressure and inflammatory mediators cause damage to the remaining nephrons.
• Damage to the remaining nephrons continues the positive feedback loop, and CKD progresses.

Pathogenesis of hypertension as a result of CKD

Hypertension is not just one of the most common causes of CKD, it can also result from CKD by the following mechanisms:

• Na⁺ and fluid retention
• ↑ RAAS activity
• ↑ Sympathetic nervous system activity
• Vasoconstriction from ↑ Ca²⁺ due to secondary hyperparathyroidism
• Impaired vasomediators (↓ nitric oxide, endothelium-mediated vasodilation)

Pathogenesis of secondary hyperparathyroidism

Secondary hyperparathyroidism (also known as mineral and bone disease) is an important complication of CKD.

• ↓ GFR → ↓ urinary phosphate excretion → ↑ serum phosphate (PO₄^3–) → ↑ fibroblast growth factor 23 (FGF-23) (a regulatory mechanism) 
• ↑ FGF-23:
  • ↓ PO₄^3– reabsorption:
    • ↑ PO₄^3– excretion
    • Eventually the ↑ serum PO₄^3– overwhelms the FGF-23 regulatory system and leads to ↑ parathyroid hormone (PTH) secretion (i.e., secondary hyperparathyroidism).
  • FGF-23 also inhibits 1?-hydroxylase:
    • 1?-hydroxylase converts 25-hydroxyvitamin D (25(OH)D) into 1,25(OH)D (calcitriol)
    • ↓ Calcitriol → ↓ GI Ca²⁺ absorption → ↓ serum Ca²⁺ → ↑ PTH
• Consequences of secondary hyperparathyroidism:
  • Vascular calcification (↑ morbidity from cardiovascular disease)
  • Renal osteodystrophy (↑ morbidity from trochanteric fractures), which may present as:
    • Osteomalacia
    • Osteitis fibrosa (high-turnover bone disease)
    • Mixed uremic bone disease (osteomalacia + osteitis fibrosa)
    • Adynamic bone disease (iatrogenic from therapeutic oversuppression of PTH)

Pathophysiology of anemia in chronic kidney disease

• Kidney disease → ↓ production of erythropoietin → ↓ production of RBCs
• Defined as a hemoglobin level:
  • < 13 g/dL in men and postmenopausal women
  • < 12 g/dL in premenopausal women

Clinical Presentation

Often, CKD disease remains asymptomatic until the late stages, despite a significant decrease in GFR during the earlier stages. Also, CKD is often either found incidentally on labs or it presents with complications.

• Incidentally discovered on lab work:
  • Routine monitoring of serum creatinine
  • Routine albuminuria screening for diabetics
  • Hematuria and/or proteinuria found on urinalysis for other reasons (e.g., urinary tract infection) 
• Hypertension: 80%–85% prevalence in CKD regardless of etiology 
• Signs of volume overload:
  • Lower-extremity edema
  • Elevated jugular venous pressure 
  • S3 gallop on cardiac auscultation
  • Crackles on pulmonary auscultation
  • New or increasing requirement for supplemental oxygen
  • Ascites
• Signs of uremia:
  • Nausea, vomiting, and anorexia
  • Altered mental status 
  • Asterixis (“flapping tremor” of the hands)
  • Friction rub on cardiac auscultation (sign of pericardial effusion)
  • Skin excoriations from pruritus
  • Uremic frost (urea crystals deposited in the skin)
• Specific exam findings by etiology:
  • Retinopathy (hypertensive nephrosclerosis, diabetes)
  • Abdominal bruit (renal artery stenosis) 
  • Livedo reticularis rash, particularly on the toes (cholesterol emboli)
  • Easily palpable kidneys (PKD)
  • Periorbital edema (nephrotic syndrome)
  • Gross hematuria (IgA nephropathy)
  • Other characteristic signs of autoimmune diseases (e.g., malar rash in SLE)
• Complications:
  • Cardiovascular disease (clinically most important): chest pain, dyspnea on exertion
  • Mineral and bone disease (secondary hyperparathyroidism): bone pain, fractures
  • Anemia: fatigue, dyspnea on exertion, pallor
  • Hyperkalemia: muscle weakness, cardiac arrhythmias

Stages of Chronic Kidney Disease

There are 5 stages of CKD; they are classified using GFR and other markers of kidney damage.

• Stage 1: Normal GFR (≥ 90 mL/min) + other marker of kidney damage; examples include:
  • Proteinuria with normal GFR (e.g., minimal change disease)
  • Isolated hematuria with normal GFR (e.g., IgA nephropathy)
  • Abnormal imaging with normal GFR (e.g., PKD)
• Stage 2: mildly decreased GFR (60–89 mL/min) + other marker of kidney damage. Examples are the same as for stage 1, but with a slight ↓ in GFR.
• Stage 3: moderately decreased GFR (30–59 mL/min): 
  • Other markers of kidney damage are not required.
  • Often the stage at which initial nephrology referral is made.
  • Many drugs begin to require dose adjustments at this level.
  • Subdivided into:
    • Stage 3a (45–59 mL/min)
    • Stage 3b (30–44 mL/min): ↑ risk of death from cardiovascular disease
• Stage 4: severely decreased GFR (15–29 mL/min):
  • Requires close monitoring for signs of uremia and volume overload, which would indicate the need for dialysis
  • Stage at which renal replacement therapy begins to be considered:
    • Counseling regarding the likely future need for transplantation and/or dialysis 
    • Referral to transplant center
    • Referral to vascular surgeon for dialysis access procedure
• Stage 5: ESRD (GFR < 15 mL/min):
  • All patients require renal replacement therapy (dialysis or transplantation).
  • Uremic signs are almost always present.
  • Volume status is difficult to control with diuretics alone.

Management

Other than specific treatments for certain etiologies, it is important to identify and address risk factors for progression of CKD, to address common complications, and to consider preventive measures needed for patients with decreased GFR.

Risk factors for disease progression

• Nonmodifiable risk factors:
  • Underlying genetic disease (e.g., PKD)
  • African descent
  • Male sex
• Modifiable risk factors:
  • Proteinuria > 1 g/day is strongly associated with progression.
  • Hypertension
  • Metabolic acidosis
  • Obesity (↑ glomerular capillary pressure)
  • High-protein diet (↑ glomerular capillary pressure)
  • Smoking (leads to vascular inflammation)

Lifestyle modifications to prevent disease progression

• Smoking cessation
• Dietary changes (assisted by a nutritionist):
  • Low-protein diet:
    • Goal: approximately 0.6–0.8 g/kg/day dietary protein if GFR < 60 mL/min and nonnephrotic
    • Do not restrict intake if nephrotic syndrome (> 3.5 g/day proteinuria) is present.
  • Low-sodium diet (< 2 g of sodium/day or 5 g/day of NaCl)
  • Low-phosphorus diet (or take oral phosphorus binders with meals)
• Exercise
• Weight loss

Medical management to prevent disease progression

• ↓ Proteinuria goal: < 0.5–1 g/day 
  • ACE inhibitor or angiotensin receptor blockers (ARBs):
    • Indicated when albuminuria > 30 mg/day or proteinuria > 150 mg/day
    • Mechanism: vasodilation of efferent arteriole → ↓ glomerular capillary pressure → ↓ hyperfiltration
    • Effect on decreasing proteinuria is independent of blood pressure effect.
    • Must monitor serum potassium closely.
  • Sodium/glucose cotransporter 2 (SGLT2) inhibitors (i.e., dapagliflozin): 
    • Decrease glomerular hyperfiltration
    • Benefit even in nondiabetics (independent of glucose-lowering effect) 
• Control metabolic acidosis: bicarbonate supplementation
• Treat/optimize any underlying medical conditions:
  • Diabetes (goal HbA1c: < 7%): glycemic control, ACE/ARBs, weight control
  • Hypertension (goal: 125–130/< 80 mm Hg): ACE/ARBs preferred agents
  • Autoimmune disease (e.g., SLE, Sjögren syndrome) 
• General management:
  • Avoid nephrotoxins (e.g., IV contrast, NSAIDs).
  • Adjust drug doses for GFR.

Renal replacement therapy

Patients with stage V CKD or signs of uremia require renal replacement therapy. Options include:

• In-center hemodialysis
• Home hemodialysis
• Peritoneal dialysis
• Kidney transplantation

Management of complications

In addition to an overall increase in mortality, there are many other complications of CKD.

• Cardiovascular disease:
  • Reasons to aggressively ↓ cardiovascular disease risk:
    • CKD is an independent risk factor for cardiovascular disease.
    • Patients with ≥ stage 3b CKD are more likely to die from cardiovascular disease than from ESRD.
    • Risk of cardiovascular disease is related to both GFR and proteinuria.
  • Preventive measures include:
    • Statins
    • ACE inhibitors
    • Low-dose aspirin
    • Lifestyle modification (diet, exercise, smoking cessation)
• Mineral and bone disorder:
  • ↓ Phosphorus intake 
  • Oral phosphate binders
  • Calcitriol supplementation
  • Cinacalcet
• Anemia: 
  • Iron supplementation
  • Erythrocyte-stimulating agents (ESAs)
  • Goal hemoglobin in CKD: 10–11.5 mg/dL
• Hypervolemia:
  • Sodium and fluid restriction 
  • Loop diuretics
• Hyperkalemia:
  • Dietary potassium restriction 
  • Loop diuretics
  • Oral potassium-binding resins (e.g., patiromer) 
  • Consider discontinuing ACE inhibitors/ARBs as CKD progresses.

Differential Diagnosis

• Diabetic nephropathy: most common cause of ESRD (approximately 55% of all new dialysis patients). Some stage of CKD will develop in 20%–30% of all diabetics. The pathophysiology is multifactorial and involves glomerular capillary hypertension, which leads to albuminuria and progressive loss of GFR. Kidney biopsy characteristically shows Kimmelstiel-Wilson nodules. Treatment involves glycemic control and ACEis.
• Hypertensive nephrosclerosis: CKD caused primarily by long-standing hypertension. Hypertensive nephrosclerosis is the second most common cause of renal failure in dialysis patients in the United States. Clinical presentation is usually asymptomatic, other than the blood pressure findings. Hypertensive nephrosclerosis is often a diagnosis of exclusion in patients with minimal proteinuria (< 1 g/day), no glomerular hematuria on urinalysis, and no findings of other systemic diseases. Management is aimed at blood pressure control and addressing the other complications and risk factors common to all etiologies of CKD.
• Polycystic kidney disease: Autosomal dominant PKD is the most common genetic cause of kidney disease in adults and is characterized by the progressive development of cysts in the kidneys. Eventually, the burden of cysts results in the loss of nephrons and in GFR. Signs and symptoms include abdominal fullness, easily palpable kidneys, hypertension, hematuria, and recurrent infections of the cysts. Diagnosis is mainly by imaging, and cysts are often also present in the liver. PKD also has a significant association with cerebral aneurysms. Management is primarily supportive, and CKD can progress to ESRD.
• Reflux nephropathy: also known as vesicoureteral reflux. Reflux nephropathy usually presents in childhood and is characterized by the retrograde flow of urine into the kidneys due to inadequate closure at the ureterovesicular junction. This retrograde flow results in tubulointerstitial damage, chronic kidney disease, and the predisposition to recurrent urinary tract infections. Diagnosis is by contrast voiding cystourethrography, and treatment includes prophylactic antibiotics and endoscopic or surgical correction.
• Atherosclerotic CKD (renal artery stenosis): also known as ischemic nephropathy. CKD occurs only with bilateral stenosis of > 70%, as lesser degrees of stenosis, or stenosis to only 1 of 2 functioning kidneys, will be compensated for. Patients may present with refractory hypertension and often have atherosclerosis elsewhere (e.g., coronary artery disease and/or peripheral artery disease) and other general risk factors for vascular disease (i.e., hyperlipidemia and smoking). Management involves blood pressure control and risk reduction.
• Obstructive uropathy: CKD from chronic obstruction of the urinary tract. Obstructive uropathy may be due to BPH, urethral stricture, bilateral obstructing kidney stones, or a pelvic mass. For a rise in serum creatinine to develop, there must be bilateral obstruction, which is most commonly due to BPH in men and to gynecologic pelvic masses in women. Treatment involves relief of the obstruction, which may require surgical intervention, depending on the etiology.
• Nephrotic syndrome: broad category of kidney diseases characterized by very large amounts of proteinuria (> 3.5 g/day). Diseases of this category include focal segmental glomerulosclerosis, membranous nephropathy, minimal change disease, and membranoproliferative glomerulonephritis. The clinical presentation of nephrotic syndrome is notable for volume overload (including periorbital edema) and “frothy urine” due to severe proteinuria. Treatment varies by etiology and often includes glucocorticoids.
• Nephritic syndrome: broad category of kidney diseases characterized by glomerular hematuria and loss of GFR. Diseases of this category include IgA nephropathy, lupus nephritis, postinfectious glomerulonephritis, and many others. Clinical presentation and management vary significantly, depending on etiology.