Chronic Kidney Disease

INTRODUCTION

• The kidney has three primary functions: excretory, metabolic and endocrine.
• As the number of functioning nephrons declines, the production of
erythropoietin, activation of vitamin D, regulation of fluid and electrolyte and
acid–base balance are affected.
• CKD- abnormalities in the structure or function of the kidney, present for 3
months or more.
• Functional abnormalities indicated by a decline in GFR less than 60 mL/min.
• Generally, CKD is a progressive decline in kidney function that occurs over
several months to years.
• Because the decline in kidney function is often irreversible, treatment of CKD
is aimed at slowing the progression to end-stage kidney disease (ESKD).
 ETIOLOGY

• Identifying risk factors is difficult because CKD progresses slowly, classified

into three categories:
• Susceptibility factors with increased risk of developing CKD but are not
directly cause CKD (not modifiable by drug therapy or lifestyle modifications).
✓ Hyperlipidemia, can be modified by drug therapies.
• Initiation factors directly cause CKD (modifiable by therapy).
✓ Diabetes, HTN & glomerulonephritis.
• Progression factors in a faster decline in kidney function and cause
worsening of CKD (modified by therapy).
✓ Proteinuria, elevated BP, elevated blood glucose & AKI.
 Risk Factors Associated with CKD
• Susceptibility: advanced age, reduced kidney mass, low birth weight, FH of
kidney disease, low income or education, systemic inflammation and
dyslipidemia.
• Initiation: diabetes, HTN, autoimmune disease (glomerulonephritis),
polycystic kidney disease, drug toxicity and urinary tract abnormalities
(infections, obstruction, stones).
• Progression: hyperglycemia (in diabetics), HTN, proteinuria, AKI and tobacco
smoking.
 PATHOPHYSIOLOGY

• A number of factors can cause initial damage to the kidney.

• Decrease in the number of functioning nephrons.
• The remaining nephrons hypertrophy to increase GFR and tubular
function.
• Initially, these adaptive changes preserve creatinine and electrolyte
excretion.
• By time progresses, Ang II constrict the efferent arteriole and increase the
pressure in the glomerulus.
• Increased glomerular pressure expands the
pores, and filters the proteins.
• Filtered proteins are reabsorbed in the
tubules, which produce inflammatory
cytokines.
• Cytokines cause interstitial and tubules
damage, leading to loss of more nephrons.
• The number of remaining nephrons is too
small and kidney function declines.
Proposed mechanisms for progression of kidney disease
 ASSESSMENT
• Early treatment of CKD and complications decreases morbidity and
mortality.
• Screening for CKD in increased risk for developing CKD including DM, HTN,
genitourinary abnormalities, autoimmune disease, increased age, FH of
kidney disease, or following AKI.
• Assessment for CKD includes measurement of SCr, urinalysis, BP,
electrolytes, and/or imaging studies.
• A key part of CKD assessment is analysis for proteinuria, which is the
primary marker of structural kidney damage, even in normal GFR.
• Albuminuria should be assessed with GFR at least annually in CKD.
• Assessment of protein excretion is particularly important in patients with
DM, even without CKD.
 Complications

• The decline in kidney function is associated with a number of

complications:
• HTN
• Fluid and electrolyte disorders
• Anemia
• Metabolic bone disease
 CLINICAL PRESENTATION

Symptoms
• Stages 1 and 2 CKD are generally asymptomatic.
• Stages 3 and 4 may be associated with minimal symptoms.
• Stage 5 can be associated with pruritus, dysgeusia, nausea, vomiting,
constipation, muscle pain, fatigue, and bleeding.
Signs
• HTN, edema, dyslipidemia, LV hypertrophy, ECG changes, and chronic HF.
• Cramping.
• Depression, anxiety, impaired mental cognition.
• GERD, GI bleeding, and abdominal distention.
• Changes in urine volume, “foaming” of urine (indicative of proteinuria), and
sexual dysfunction.
 DIAGNOSIS

Laboratory Tests
• Stages 1 and 2 CKD: BUN and SCr are generally within normal limits, despite
mildly decreased GFR.
• Stages 3, 4, and 5 CKD: Increased BUN and SCr; decreased GFR.
• Advanced stages: Increased K, P, and Mg; decreased bicarbonate (metabolic
acidosis); Ca2+ may be elevated in Stage 5, secondary to the use of Ca2+-
containing phosphate binders.
• Decreased albumin, if inadequate nutrition intake in advanced stages.
• Decreased RBC, Hgb, and Hct; Decreased iron stores (iron level, total iron
binding capacity, serum ferritin level, and transferrin saturation).
• Urine positive for albumin or protein.
• Increased PTH; decreased vitamin D (Stages 4 or 5 CKD).
 TREATMENT

Goals of Therapy
• To slow and prevent the progression of CKD.
• To prevent a cardiovascular event, complications and the need for kidney
replacement therapy.
 Non pharmacologic Therapy
• Protein intake lowered to 0.8 g/kg/day in people with diabetes or GFR less
than 30 ml/min/1.73 m2.
• Malnutrition is common in ESKD due to decreased appetite, protein losses in
the urine, and nutrient losses through dialysis.
• For patients receiving dialysis should maintain protein intake of 1.2 g/kg/day.
• Less than 2 g of Na per day (5 g NaCl) will help to control BP and reduce
water retention.
• Increase physical activity, at least 30 minutes 5 times per week, to achieve a
healthy weight.
 Pharmacologic Therapy
CKD with Diabetes
• The target glycated hemoglobin level (HbA1c) should be less than 7.0% in DM
to decrease the incidence of albuminuria.
• Generally involves intensive insulin therapy or optimizing doses of oral
hypoglycemic agents.
• ACEI and ARBs are choice in albumin excretion rate (AER) of 30 mg/day or
more because of greater effect on lowering proteinuria.
• Started at a low dose and the dose should be titrated upward slowly to
minimize the risk of AKI.
Algorithm for management of CKD with DM
 BP Control
• Reductions in BP are associated with a decrease in proteinuria and rate of
progression of kidney disease.
• Patients with AER less than 30 mg/day should achieve a BP target of less than
or equal to 140/90 mm Hg.
• The first-line are ACEIs or ARBs, because of their ability to lower BP and
protein excretion.
• Because HTN and kidney dysfunction are linked, BP control can be more
difficult to attain in patients with CKD.
• All antihypertensive agents have similar effects on reducing BP.
Algorithm for management of HTN in CKD
 Reduction in Proteinuria
• ACEIs and ARBs decrease glomerular pressure and volume, in turn, reduces
the amount of filtered protein, independent of the reduction in BP.
• Combining ACEIs and ARBs should be done with caution (greater reductions
in protein excretion, but leads to faster progression of CKD).
• CCBs also decrease protein excretion with and without diabetes, but the
reduction is related to the reductions in BP (less than 130/80 mm Hg).
• SGLT-2 inhibitors show considerable promise in slowing progression of DCKD
with benefits that seem to be independent of the glucose lowering effect.
• By reducing glucose and Na reabsorption in the proximal tubule, these
agents decrease glomerular hyperfiltration and reduce glomerular HTN.
 Hyperlipidemia Treatment
• Hyperlipidemia plays a role in development of CVD in CKD.
• Primary goal is to decrease the risk of atherosclerotic CVD.
• Secondary goal is to reduce proteinuria and decline in kidney function.
• Treatment of hyperlipidemia increase GFR by 1 mL/min/year of treatment.
• Statins for all patients with non-dialysis dependent CKD aged 50 years and
older.
• Ezetimibe is considered when GFR is less than 60 ml/min.
 CONSEQUENCES OF CKD AND ESKD

Anemia of CKD
• The progenitor cells of the kidney produce 90% of the erythropoietin (EPO),
which stimulates RBC production.
• Reduction in the number of nephrons decreases production of EPO.
• Development of anemia of CKD results in:
✓ decreased O2 delivery and utilization
✓ leading to increased CO and LVH, which increase the cardiovascular risk and
mortality
 Pharmacologic Therapy
• The first-line treatment involves iron supplements.
• If iron alone not increase Hgb, the ESAs (synthetic formulations of EPO) are
necessary to replace erythropoietin.
Iron Supplementation
• Iron supplementation should be considered when:
✓ Serum ferritin level is greater than 500 ng/mL.
✓ Transferrin saturation is greater than 30%.
• A test dose is not required for the newer iron preparations, sodium ferric
gluconate, iron sucrose, ferumoxytol, and ferric carboxymaltose because of
fewer severe reactions and a much lower risk of anaphylaxis, making them
first-line agents in CKD.
• The most common side effects include hypotension, flushing, nausea, and
injection site reactions.
 Erythropoiesis-Stimulating Agents
• ESAs may be considered if Hgb levels remain persistently low.
• Guidelines recommend ESAs when Hgb is less than 10 g/dL.
• The ESAs are as Epoetin alfa (distributed as Epogen and Procrit) and
Darbepoetin alfa (Aranesp)
• Epoetin α and epoetin β, which is available outside the US, have the same
biological activity as endogenous EPO.
• The most common adverse effects- increased BP, which may require
antihypertensive agents.
• Caution should be used when initiating an ESA in very high BP (greater than
180/100 mm Hg).
• If BP are refractory to antihypertensives, ESAs may need to be withheld.
• Seizures and pure red cell aplasia have also been reported in ESA therapy.
 CKD-Mineral and Bone Disorder and Secondary Hyperparathyroidism
• Increases in parathyroid hormone (PTH) occur early as kidney function begins
to decline.
• The actions of PTH on bone turnover lead to CKD-mineral and bone disorders
(CKD-MBD).
• The type of bone disease can vary based on the degree of bone turnover.
• High bone turnover, known as osteitis fibrosa cystica, is generally mediated
by high levels of PTH.
• Adynamic bone disease, characterized by low bone turnover, related to
excessive suppression of PTH.
• The development of CKD-MBD can dramatically affect morbidity in CKD.
 Pathophysiology
• As kidney function declines in CKD, decreased phosphorus excretion disrupts
the balance of Ca2+ and phosphorus homeostasis.
• Decreased vitamin D activation in the kidney also decreases Ca2+ absorption
from the GI tract.
• The parathyroid glands release PTH in response to decreased serum Ca2+ and
increased serum phosphorus levels.
• The actions of PTH include the:
✓ Increasing Ca2+ resorption from bone
✓ Increasing Ca2+ reabsorption from the proximal tubules
✓ Decreasing phosphorus reabsorption in the proximal tubules
✓ Stimulating activation of vitamin D by 1-α-hydroxylase to calcitriol (1,25-
dihydroxyvitmin D3) to promote Ca2+ absorption in the GI tract and increased
Ca2+ mobilization from bone
• All these actions are directed at increasing serum Ca2+ levels and decreasing
serum phosphorus levels.
• Calcitriol also decreases PTH through a negative feedback loop.
• As GFR falls less than 30 mL/min, phosphorus excretion decreases and
calcitriol production decreases, causing PTH levels to rise, leading to sHPT.
• The most dramatic consequence of sHPT is alterations in bone turnover and
the development of renal osteodystrophy (ROD).
• Other complications of CKD including metabolic acidosis also promote ROD:
✓ decreases bone formation by reducing hydroxyapatite solubility
✓ inhibiting osteoblast activity
✓ stimulating osteoclast activity
✓ reducing sensitivity of the parathyroid gland to serum Ca2+ levels
• Excessive aluminum levels cause aluminum uptake into bone in place of
Ca2+, weakening the bone structure.
 Nonpharmacologic Therapy
• The first-line treatment for the management of hyperphosphatemia is
dietary phosphorus restriction to 800 to 1000 mg/day in Stage 3 or higher.
• Hemodialysis and peritoneal dialysis can remove up to 2 to 3 g of phosphorus
per week.
• Restriction of aluminum exposure and parathyroidectomy.
• Chronic ingestion of aluminum-containing antacids and other aluminum-
containing products should be avoided in GFR less than 30 mL/min because
of the risk of aluminum toxicity and potential uptake into the bone.
• Parathyroidectomy is a treatment of last resort for sHPT.
 Pharmacologic Therapy
Phosphate-Binding Agents
• When serum phosphorus levels cannot be controlled by restriction of dietary,
phosphate binding agents are used to bind dietary phosphate in the GI tract.
• Calcium-based phosphate binders, including calcium carbonate and calcium
acetate, are effective in decreasing serum phosphate levels, as well as
increasing Ca2+ levels.
• Calcium citrate is usually not used as a phosphate-binding agent because the
citrate salt can increase aluminum absorption.
• The calcium-containing phosphate binders also aid in the correction of
metabolic acidosis, another complication of kidney failure.
• The most common adverse effects are constipation and hypercalcemia.
• The most common side effects of sevelamer are GI complaints, including
nausea, constipation, and diarrhea.
 Vitamin D Therapy
• Vitamin D regulates many processes in the body, including Ca2+ and
phosphorus absorption from the GI tract and kidney and PTH secretion.
• In CKD, decreases concentrations of calcitriol (1,25-dihydroxyvitamin D) and
its precursor 25-hydroxyvitamin D.
• PTH levels rise as early as Stage 3 as a result of low calcitriol concentrations.
• Exogenous vitamin D decreases PTH secretion by upregulation of vitamin D
receptor in the parathyroid gland, which decreases parathyroid gland
hyperplasia and PTH synthesis and secretion.
• This is particularly useful when reduction of serum phosphorus levels does
not sufficiently reduce PTH levels.
• Ergocalciferol and cholecalciferol have been shown to be effective in lowering
PTH secretion in Stage 3 CKD.
 Calcimimetics
• Cinacalcet is a calcimimetic that increases the sensitivity of receptors on the
parathyroid gland to reduce PTH secretion.
• It has no effect on intestinal absorption of Ca2+ or phosphorus and may even
lower serum Ca2+ levels
• Cinacalcet is beneficial in elevated PTH levels who have increased Ca2+ or
phosphorus levels or cannot use vitamin D therapy.
• Cinacalcet should also be used with caution in patients with seizure disorders
because low serum Ca2+ levels can lower the seizure threshold.
 Impaired Electrolyte and Acid–Base Homeostasis
• The kidney is responsible for regulating homeostasis for Na, K, water, and
acid base.
• Reductions in the number of functioning nephrons decrease glomerular
filtration regulation of electrolytes and acid secretion.
• Na and fluid retention increases intravascular volume and raises systemic BP.
• K excretion occurs in both the distal tubules and in the GI tract, which is
mediated by aldosterone.
• Aldosterone increases in response to rising serum K, which then increases K
excretion in both the nephrons and GI tract.
• This maintains serum K concentrations within the normal range through GFR
categories 1 to 4 CKD.
• Medications can increase the risk of hyperkalemia in patients with CKD,
including ACE-I and ARBs, used for the treatment of proteinuria and HTN.
• H ions are excreted by the kidney via buffers in the urine created by
ammonia generation and phosphate excretion to maintain the pH of body
fluids within a very narrow range.
• As kidney function declines, H excretion is decreased because the ability of
the kidney to generate ammonia is impaired (leads to metabolic acidosis).
• Metabolic acidosis presents when GFR declines below 25 mL/min
(contributes to various complications):
✓ directly cause bone disease, particularly in children, and contribute
significantly to the bone disease induced by secondary hyperparathyroidism.
✓ decreases hepatic albumin synthesis, which contributes to hypoalbuminemia
and muscle wasting.
✓ accelerate progression of CKD by causing tubular injury.
• Reversal of metabolic acidosis decreases progression of CKD, improve bone
disease, and increase serum albumin concentrations.
 Nonpharmacologic Therapy
Sodium and Water
• Changes in Na intake should occur slowly over a period of several days to
allow adequate time for the kidney to adjust urinary Na content.
• Na restriction produces a negative Na balance, which causes fluid excretion
to restore Na balance.
• The resulting volume contraction can decrease perfusion of the kidney and
hasten the decline in GFR.
• Saline-containing IV solutions should be used cautiously in CKD because the
salt load may precipitate volume overload.
• Fluid restriction is generally unnecessary as long as Na intake is controlled.
• Fluid intake should be maintained at the rate of urine output to replace urine
losses, usually fixed at approximately 2 L/day.
• Significant increases in free water intake orally or IV can precipitate volume
overload and hyponatremia.
• Diuretic therapy is often necessary to prevent volume overload in patients
with CKD in those who still produce urine.
• When GFR falls below 30 ml/min, thiazide diuretics alone may not be
effective in reducing fluid retention.
• Loop diuretics are most frequently used to increase Na and water excretion.
• As CKD progresses, higher doses, as much as 80 to 1000 mg/day of
furosemide, or continuous infusion of loop diuretics may be needed, or
combination therapy with loop and thiazide diuretics to increase Na and
water excretion.
 Potassium
• Patients who develop hyperkalemia should restrict dietary intake of K to 50
to 80 mEq (50–80 mmol) per day.
• Severe hyperkalemia is most effectively managed by hemodialysis.
• Acute hyperkalemia can be managed medically until dialysis can be initiated.
• Diuretics, sodium polystyrene sulfonate, and fludrocortisone are useful in the
management of hyperkalemia in CKD.
• Acute hyperkalemia that results in cardiac abnormalities can be managed
with Ca2+, insulin and dextrose.
 Metabolic Acidosis
• Sodium bicarbonate or citrate/citric acid preparations may be needed in
Stage 3 CKD or higher to replenish body stores of bicarbonate.
• Calcium carbonate and calcium acetate, used to bind phosphorus in sHPT,
also aid in increasing serum bicarbonate, in conjunction with other agents.
• Na retention of sodium bicarbonate can cause volume overload, which can
exacerbate HTN and chronic HF.
• Tolerability of sodium bicarbonate is low because of CO2 production in the GI
tract during dissolution.
• Solutions that contain sodium citrate/citric acid provide 1 mEq/L of Na and
bicarbonate.
• Polycitra is a Na/K citrate solution that provides 2 mEq/L of bicarbonate and
1 mEq/L of Na and K, which can promote hyperkalemia in severe CKD.
• The citrate portion is metabolized in the liver to bicarbonate; the citric acid
portion is metabolized to CO2 and water, increasing tolerability compared
with sodium bicarbonate.