CHRONIC RENAL FAILURE

 The term chronic renal failure (CRF) describes a worsening, progressive and irreversible loss of a
patient’s kidney function.Unlike acute renal failure, where a complete recovery of renal function is
possible, in CRF the kidneys are permanently damaged, potentially leading to dialysis or transplantation.
The incidence of CRF increases with age. 150–200 cases per million people = new cases each year
Chronic Renal Failure Causes

 Diabetic Nephropathy

 Hypertension

 Glomerulonephritis

 HIV nephropathy

 Reflux nephropathy in children

 Polycystic kidney disease

 Kidney infections & obstructions

CRF Symptoms
• Malaise • Weakness • Fatigue • Neuropathy • CHF • Anorexia
• Nausea • Vomiting ----All these due to uremic toxins
• Seizure • Anemia • Pruritus • Jaundice
Abnormal hemostasis

 CRF is significant as it indicates the possibility of progression to end stage renal failure and strong
association with accelerated cardiovascular disease. Progression to more severe stages and ESRD may
occur if the blood pressure is inadequately controlled. However many patients with mild CRF remain
stable for years or decades
Function of Kidneys

 Remove toxic waste products

 Remove excess water and salts

 Play a part in controlling blood pressure

 Produce erythropoetin (epo) which stimulates red cell production

 Helps to keep calcium and phosphate in balance for healthy bones

 Maintains proper pH for the blood

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 The MDRD(Modification of Diet in Renal Disease) equation is as follows:

An abbreviated version has also been developed1:

Classification Damage GFR (mL/min)

Increased risk of kidney Risk factors for CKD (diabetes, HTN, ≥90
disease family history of CKD)

Stage I Kidney damage with normal GFR ≥90

Stage II Kidney damage with mild decrease in 60–89

GFR

Stage III Moderate decrease in GFR 30–59

Stage IV Severe decrease in GFR 15–29

Stage V Kidney failure <15

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PATHOPHYSIOLOGY
Glomerular Hyperfiltration and Intraglomerular Hypertension
 When the number of functioning nephrons is reduced the remaining nephrons compensate by enlarging
in size and by increasing their individual GFRs.
 Through escalation of glomerular blood flow and intraglomerular capillary pressure, a state of increased
glomerular perfusion can be attained.
 This occurs with simultaneously induction of a degree of intraglomerular hypertension(renal reserve
capacity)these glomerular adaptations accomplish the short-term goal of improving or restoring total
GFR.
Unfortunately, sustained elevations of blood flow and pressure within the glomeruli cause damage to remaining
nephrons, ultimately leading to their demise.
Glomerular injury is also believed to result from increased capillary permeability which allows proteins and
other macromolecules to leak through capillaries into the renal tubules.
Microalbuminuria is one of the earliest clinical manifestations of glomerular damage.
• Because protein (mostly albumin) is a relatively large molecule, it generally is not filtered in the
glomerulus but is returned to systemic circulation via the efferent arteriole.
• The presence of small amounts of protein in the urine (microalbuminuria) or larger amounts
(proteinuria) is due to damage within the glomerulus.
• Although this may be the result of a self-limiting situation (e.g., acute muscle breakdown), it occurs
more often as a result of injury caused by a disease process such as diabetes or hypertension.
This process in turn may promote the secretion of proinflammatory mediators and induce renal mesangial cells
to deposit an extracellular glycoprotein matrix,leading to a type of renal fibrosis and scarring called sclerosis.
Sclerosis may involve the entire nephron (nephrosclerosis), extending from the glomerulus
(glomerulosclerosis) to the tubules and interstitium.
Diabetic Nephropathy
• The pathophysiology of diabetic nephropathy is complex and involves the formation of advanced
glycation end products (AGEs).
• Hyperglycemia leads to a nonenzymatic reaction between sugar and protein.
• AGEs cause expansion of the mesangium, damage to the glomerular basement membrane, cytokine
release, and gene expression.
• Changes in Endothelium-dependent vasodilatation, may play a role in the development of diabetic
nephropathy.
• The ultimate result of these changes is glomerulosclerosis.

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 Hypertension
• Hypertension is an important risk factor for the progression of renal disease. Renal damage is thought to
result from exaggerated intraglomerular hypertension and hyperfiltration, perhaps in conjunction with
ischemic damage caused by arteriosclerotic changes in renal vasculature.
• The kidney plays a major role in the control of blood pressure by regulating sodium retention,
extracellular fluid volume, and the renin-angiotensin system. Expanded extracellular fluid (ECF) volume
is presumed to be a major factor contributing to hypertension in most patients with CKD, followed by
elevated renin-angiotensin activity.
• Imbalances between endogenous vasoconstrictive (e.g., endothelin) and vasodilatory substances (e.g.,
nitric oxide) have also been recognized as a probable factor underlying hypertension in CKD.this explns
hw HTN occurs in ckd
• Left ventricular hypertrophy (LVH) may begin early in the course of kidney disease and is correlated
with a decline in hemoglobin levels or an increase in systolic blood pressure.One study found that for
every 1 mg per dL decrease in hemoglobin, a 6% increase in the risk of LVH occurred. Other risk
factors for LVH include age, hypertension, volume overload.
• Dysregulation of calcium and phosphorus may be yet another risk factor for the development of CVD.
• An increase in serum phosphorous levels has been shown to stimulate vascular calcification. In addition
to serum phosphorus, serum calcium and the calcium × phosphorous product may play a role in vascular
calcification.
Dyslipidemia
• Dyslipidemia may lead to the progression of CKD caused by oxidation and deposition of lipoproteins in
the glomerulus and the mesangial cells. Oxidized low-density lipoprotein (LDL) may cause synthesis of
inflammatory cytokines, vasoactive substances, and macrophage chemotactic factors.These changes
eventually lead to glomerular scarring.
Drugs or Abnormalities That Cause Renal Dysfunction

Reduction in Renal Blood Flow Direct Nephrotoxin

Diuretics Antimicrobials: amphotericin, indinavir, tenofovir, aminoglycosides

ACE-Is/ARBs Radiocontrast dyes (high-osmolar, high-volume)

NSAIDs Anticancer agents: cisplatin, ifosfamide, high-dose methotrexate

Volume loss, dehydration Immunosuppressants: cyclosporine, tacrolimus

Metabolic and Systemic Consequences of Chronic Kidney Disease

1. Because daily sodium intake usually exceeds requirements, the kidneys are able to maintain sodium
balance by simply reducing urinary Na-reabsorption

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• Conversely, if sodium intake is below output, the kidney is usually able to increase its conservation of
sodium
• In CRF the kidney becomes unable to concentrate or dilute urine efficiently
• Roughly 90% to 95% of K-daily intake is excreted in the urine via tubular secretion; 5% to 10% is
eliminated in the feces.
• As the degree of kidney failure progresses, an adaptive increase in colonic elimination of potassium
occurs; in patients with ESKD
• This increased gastrointestinal secretion and an increase in distal tubular secretion prevent hyperkalemia
until kidney function declines to 10 to 15 mL per minute.
• Factors that increase the risk of hyperkalemia include an increase in potassium intake and use of drugs
that impair potassium excretion (ACE-Is, potassium-sparing diuretics),
PATHOPHYSIOLOGY

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 • Or drugs or conditions that shift potassium to the extracellular fluid from the intracellular fluid (β-
blockers, metabolic acidosis).
• For each 0.1 unit change in blood pH, an average corresponding opposite change of approximately 0.6
mEq/L in serum K level occurs.
• The primary route of magnesium excretion is renal. Mild, asymptomatic elevations in serum magnesium
may occur in patients with advanced CKD.
• Provided that dietary intake is not unusually excessive, life-threatening hypermagnesemia is uncommon.
• Pharmaceutical sources of magnesium such as antacids and magnesium-based cathartics can markedly
elevate serum magnesium levels when used on a long-term basis or in large quantities.
2. Anemia of Chronic Kidney Disease
• Erythropoietin (EPO) is a hormone that is produced and secreted by the granular cells of the kidney in
response to hypoxia or ischemia.
• When secreted, EPO travels to the bone marrow and causes the proliferation and differentiation of
committed erythroid progenitor cells.
• Additionally, EPO prevents apoptosis of these cells, allowing them to mature.
• The primary cause of anemia in CKD is the diminished production of EPO by the failing kidneys.
• Another contributing factor to anemia is the shortened life cycle of red blood cells in uremia.
3. Calcium, Phosphorus, and Bone Homeostasis
• Abnormalities of bone metabolism and bone disease of CKD are complex
As GFR decreases, Phosphorus may begin to accumulate in the early stages of CKD—stages 3 and 4.
Hyperphosphatemia causes a decrease in serum calcium brought about through a physiochemical interaction
and complexation.
\Reduction in serum calcium triggers the parathyroid gland to synthesize and secrete more parathyroid hormone
(PTH). PTH in turn causes an increase in osteoclast activity in the bone, breaking down bone to release calcium
and restore serum levels.
• These abnormalities are compounded by a relative deficiency of vitamin D.
• The failing kidneys are not able to convert vitamin D to the active form—1,25-dihydroxycholecalciferol
(vitamin D3).
• Under normal conditions, active vitamin D facilitates the absorption of calcium in the gastrointestinal
tract (raising serum calcium levels) and also acts as a negative feedback loop to downregulate the
production of PTH. In normal subjects hydroxylation of vit d hydroxylation take place in 1 positn in
kidney and 25 position hydroxylation in liver.
• In gastric paresis metoclopromide,erythromycin 250 mg once daily
• Thiazide like diuretic metalazone can work if crea clr < 30(pct)

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• In normal kidney function, elevated PTH levels cause increased secretion of phosphate in the tubule and
hence, increased excretion of phosphate.The failing kidneys, however, are unable to increase excretion,
and hyperphosphatemia continues.
• The end results of this dysfunction often include hyperphosphatemia, hypocalcemia or hypercalcemia,
hyperparathyroidism, and the bone disease called osteitis fibrosa cystica. This is one of the types of
bone disease that are collectively known as renal osteodystrophy.
4. Uremic Bleeding
• It has long been known that uremia can lead to an increased propensity for bleeding.
• Purpura, epistaxis, and bleeding from venous and arterial access sites have been reported.
• More serious, life-threatening bleeding includes hemorrhaging from gastrointestinal and genitourinary
sites, as well as subdural hematomas.
• The exact cause of uremic bleeding is still unknown but appears to be multifactorial. Some possible
causes are
• Defects in platelet function and cellular metabolism
Defects of vascular endothelial/smooth muscle cell metabolism
Defects of platelet-vessel wall interactions
Anemia of chronic kidney disease
• Guanidinosuccinic acid, a uremic agent causes an increase in nitric oxide, which has been shown to
decrease platelet function by interfering with the interaction of fibrinogen and the platelet GP IIb/IIIa
receptor.
5. Endocrine and Hormonal Abnormalities
• Abnormalities in female and male gonadal hormones are common in ESKD and result in high
incidences of infertility and sexual dysfunction.
• Hyperprolactinemia is common, and gonadotropin, follicle-stimulating hormone (FSH), and luteinizing
hormone (LH) levels may be low in both men and women.
• Many patients with ESKD exhibit a form of secondary hypothyroidism called sick euthyroid syndrome,
which is characterized by low T3 and total T4 levels, but normal free T4 index and thyroid-stimulating
hormone (TSH) levels.
• Insulin metabolism(in normal 20% takes place in kidney, in renal failure patients it is delayed)
6. Gastrointestinal Disease
• Patients with advanced renal failure commonly have gastrointestinal complications such as anorexia,
nausea, and vomiting. Uremic patients have high concentrations of urea in their saliva, which undergoes
conversion to ammonia in the presence of bacterial ureases. As a consequence of the irritating effects of
ammonia and probably other factors, mucosal and submucosal ulcerations often develop along the
alimentary tract;
• In diabetic patients with uremia, it is not uncommon for gastroparesis to be superimposed on the
aforementioned abnormalities, compounding nausea, vomiting, and gastroesophageal reflux.

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 • Constipation is a nearly universal complaint in ESKD, which partly stems from the use of constipating
medications, along with fluid and dietary restrictions.
7. Pruritus and Dermatologic Abnormalities
• The cause of pruritus is still not well understood, and a large number of factors have been implicated.
Some of these include dry skin, accumulation of uremic wastes, elevations in serum calcium ×
phosphate product (leading to integumentary calcification), increased levels of histamine and serotonin,
alterations in opioid receptors, and alterations in the immune system.
8. Musculoskeletal and Neurologic Issues
• Uric acid is the end product of purine metabolism. It circulates primarily as urate, is filtered at the
glomerulus, and is almost completely reabsorbed in the proximal tubules. Renal excretion of uric acid is
impaired when the GFR falls to below 25 to 30 mL per minute, resulting in elevated serum uric acid
levels. Potential complications from hyperuricemia include gouty attacks, uric acid kidney stones, and
urate nephropathy
DIAGNOSIS
• Functional assessment of the kidney may be performed by testing serum creatinine & urea
• Hyperkalemia,low bicarbonate level,hypocalcemia & hyperphosphatemia may be presnt
• Urine analysis
• Structural assessmnet of kidney may be performed using
1. USG 2. Intravenous urography 3. Plain abdominal radiography 4. CT 5. MRI 6. MRA
Therapeutic Plan
Slowing the Progression of Chronic Kidney Disease
• Strategies for slowing kidney disease progression are often divided into measures for patients with
diabetes versus those for nondiabetic individuals.
• It is important residual kidney function be preserved at all stages of CKD.
• In addition to treating patients with risk factors and comorbid diseases, minimizing exposure to
nephrotoxins is recommended .
Monitoring Progression of Chronic Kidney Disease
• When a patient is identified to have renal disease, regular periodic assessments should be performed to
determine the rate of GFR decline and to confirm the efficacy of interventions intended to slow renal
demise.
• Regular monitoring also facilitates the detection of sudden deteriorations in GFR due to reversible
factors.
• Early detection and management of complications that begin to develop before ESKD (e.g., anemia,
bone disease, malnutrition, hypertension, heart disease) may help minimize morbidity and mortality.

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 • Maintaining an accurate gauge of renal status should help prompt the adjustment of dose or regimen for
renally eliminated drugs, preventing toxicity or dangerous drug accumulation.

Nephrotoxin Possible Alternative or Kidney-Sparing Approach*

Aminoglycoside Fluoroquinolones, aztreonam, imipenem, meropenem, ceftazidime, cefepime

Once-daily “pulse” dosing strategies

Cyclosporine, tacrolimus Sirolimus

Amphotericin B Liposomal or lipid complex formulations

Itraconazole, fluconazole, voriconazole
Caspofungin, micafungin

Cisplatin Carboplatin
Nephroprotection with amifostine

Radiocontrast media Low-osmolality or nonionic contrast agents, low volume

Nephroprotection protocols (hydration, bicarbonate, N-acetylcysteine,
theophylline)

TREATMENT
1. Treatment of Diabetic Nephropathy
• Diabetic nephropathy is caused mainly by the presence of hyperglycemia
• DCCT (for type 1 DM) trial demonstrated that patients with type 1 diabetes who maintain hemoglobin
A1C levels at approximately 7% (vs. 9%) delayed the onset and progression of retinopathy,
nephropathy, and neuropathy. Another study in type 2 diabetes showed similar results.
• It is interesting to note that in this study the difference in hemoglobin A1C was very small—7% vs.
7.9%. This small difference resulted in a decrease of 35% in the relative risk of microvascular disease.
• In vitro as well as in vivo studies have shown that ACE-Is prevent the formation of AGEs, regardless of
glycemic control. The mechanism may be secondary to chelation or a decrease in reactive oxygen
species. Other studies using angiotensin receptor antagonists have shown similar benefits.
• Both classes of drugs—ACE-Is and ARBs—appear to be efficacious in slowing the progression of
albuminuria and nephropathy.
• Second-line therapy for the treatment of patients with diabetic nephropathy and proteinuria is the use of
nondihydropyridine calcium channel blockers
• Diltiazem and verapamil have been shown to attenuate permeability changes in the glomerulus and to
have an effect on rates of decline in GFR similar to that associated with treatment with an ACE-I.
Because these agents have not been shown to significantly decrease proteinuria, they should not be used
in the management of diabetic nephropathy

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 • Multifactorial interventional studies designed to control diet, exercise, smoking cessation,
hyperglycemia, and dyslipidemia, and to administer ACE-Is, vitamins, and low-dose aspirin have shown
a decrease in the progression of microvascular and macrovascular disease.
Treatment Goals:
2. Hypertension in CRF patients
• Decrease blood pressure to less than 130/80 mm Hg.
• Reduce proteinuria.
• Slow progression of kidney disease.
• Reduce CVD risk.
• It has been proven that treatment with ACEI-ARBs slows the progression of CKD even in the absence
of hypertension. (delay microalbumiuria)
• Patients who have a spot urine total protein-to-creatinine ratio greater than 200 mg per g, or
microalbuminuria, should be treated with moderate to high doses of an ACE-I or ARB, regardless of
whether or not they are diabetic or hypertensive.
• Patients who do not have proteinuria or diabetes, should be treated first with a diuretic.
• A combination of a thiazide and a loop diuretic may be necessary for patients with significant edema or
hyporesponsiveness to a single agent. Calcium channel blockers are the preferred agents in transplant
patients with CKD, followed by β-blockers and ACE-Is
K/DOQI, Kidney Disease Outcomes Quality Initiative Recommendations for Antihypertensive Therapy

Type of Kidney Disease Preferred Other Agents

Agents

Diabetic nephropathy or spot urine total protein-to- ACE-I or ARB Diuretic, then β-blocker or CCB
creatinine ratio ≥200 mg/g

Nondiabetic CKD with spot urine total protein-to- Diuretic ACE-I, ARB, β-blocker, or CCB
creatinine ratio <200 mg/g

CKD in the transplant recipient None preferred CCB, diuretic, β-blocker, ACE-I, or
ARB

• β-Adrenergic blocking agents lower blood pressure primarily by reducing cardiac output.
• They also inhibit renin release and thus may be especially useful in the setting of renovascular
hypertension or renal failure, or in combination with renin-activating agents (such as diuretics).
• Other Adrenergic Blocking Agents

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• The centrally acting α2-adrenergic agonists (methyldopa, clonidine, guanabenz, and guanfacine) are
useful in reducing blood pressure in patients with chronic renal failure.
• The α1-adrenergic antagonists (prazosin, terazosin, doxazosin) reduce blood pressure by producing
arterial and venous vasodilation.
• Because of an association with increased mortality, these agents are generally not used unless there is a
compelling indication
• The direct-acting vasodilators, hydralazine and minoxidil, decrease peripheral vascular resistance.
• Blood pressure reduction is usually accompanied by compensatory activation of the sympathetic nervous
system and renin release, leading to reflex tachycardia, increased cardiac output, and fluid retention.
• Because of these secondary effects, hydralazine and minoxidil are commonly used in combination with
agents that counteract fluid retention (e.g., diuretics) and tachycardia

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 3. Treatment of Proteinuria
• Given the detrimental effects of proteinuria, much research has been undertaken to evaluate the benefits
of lowering total daily protein excretion in the urine and the use of different agents and therapies to
achieve this goal.
TREATMENT: MANAGEMENT OF COMPLICATIONS
• Progression of CKD to ESRD can occur over years to decades, dependent on the etiology of the disease.
• No single toxin is responsible for all of the signs and symptoms of uremia observed in stage 4 or 5 CKD.
• Toxins accumulate as a result of increased secretion, decreased clearance secondary to reduced
metabolism within the kidney, and/or decreased renal clearance of by-products of protein metabolism.
• Patients who reach CKD stage 4 almost inevitably progress to ESRD, requiring dialysis to sustain life.
FLUID AND ELECTROLYTE ABNORMALITIES
• Serum sodium concentration is generally maintained by an increase in fractional excretion of sodium,
resulting in a volume-expanded state.
• The most common manifestation of increased intravascular volume is systemic hypertension.
• The kidney’s ability to adjust to abrupt changes in sodium intake is diminished in patients with ESRD.
• Sodium restriction beyond a no-added salt diet is not recommended unless hypertension or edema is
present.
• A negative sodium balance can decrease renal perfusion and cause a further decline in GFR.
• Loop diuretics, particularly when administered by continuous infusion,increase urine volume and renal
sodium excretion.
• Although thiazide diuretics are ineffective when creatinine clearance is less than 30 mL/min,adding
them to loop diuretics can enhance excretion of sodium and water.
• Calcium glu is used to treat hyprkalemia which leads to arrythmia(this can be reversed)
POTASSIUM HOMEOSTASIS
• The definitive treatment of severe hyperkalemia in ESRD is hemodialysis.
• Temporary measures include-
1. calcium gluconate
2. insulin and glucose
3. nebulized salbutamol
4. sodium polystyrene sulfonate.
5. Loop diuretics

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• Chronic hyperkalemia is managed by-
1. dietary potassium restriction to approximately 1 mEq/kg/day
2. curtailing the use of medications that can interfere with potassium excretion (e.g., ACE-Is, ARBs,
potassium-sparing diuretics, β-blockers, trimethoprim)
ANEMIA
• The primary cause of anemia in patients with CKD or ESRD is erythropoietin deficiency.
• Other contributing factors include decreased lifespan of red blood cells, blood loss, and iron deficiency
• Iron supplementation is necessary to replete iron stores.
• Parenteral iron therapy improves response to erythropoietic therapy and reduces the dose required to
achieve and maintain target indices.
• In contrast, oral therapy is often inadequate.
• Subcutaneous (SC) administration of epoetin alfa is preferred because IV access is not required, and the
SC dose that maintains target indices is 15% to 50% lower than the IV dose
• Darbepoetin alfa has a longer half-life than epoetin alfa and prolonged biologic activity.
• Doses are administered less frequently, starting at once a week when administered IV or SC.
• Erythropoietic agents are well tolerated. Hypertension is the most common adverse event.
• Iron indices (transferrin saturation [TSat]; ferritin) should be evaluated before initiating an
erythropoietic agent.
• To avoid errors, clinicians should wait at least 2 weeks after a loading dose of IV iron to reassess iron
indices.
• For monitoring purposes, hemoglobin is preferred to hematocrit because the latter fluctuates with
volume status. The target hemoglobin is 12 g/dL.
• After an erythropoietic agent is initiated, hemoglobin response is typically delayed.
• Steady-state hemoglobin levels do not occur until after the life span of a red blood cell
• To avoid making premature dosing changes, clinicians should evaluate response over several weeks
• Patients should be monitored for potential complications, such as hypertension, which should be treated
before starting an erythropoietic agent.
• Epoetin –alpha & beta were thought to be indistinguishable in practical terms
• Antierythropoietin antibodis developed and lead to severe anemia unresponsive to exogenous
erythropoietin known as pure red cell aplasia(PRCA)(mainly by alpha)
• More common if epoetin –alpha used by SC route
• Only epoetin- beta is recommended for SC administration.

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• Novel erythropoisis stimulating protein(NESP) is a recombinant hyper glycosylated analogue of epoetin
• Half life of NESP is 3 times longer than epoetin so only once weekly administered
• Epoetin therapy aims a slow rise in hemoglobin level to avoid CVS side effects due to rapid increase in
red cell mass-HTN, increased blood volume/viscocity, seizures,clotting of vascular accesses.
• Hg rise should not exceed 2gm/dl per month.
(Dipiro--FIGURE 47-2. Guidelines for iron therapy in the management of the anemia of chronic kidney disease.)
REFER
SECONDARY HYPERPARATHYROIDISM AND RENAL OSTEODYSTROPHY
• As kidney disease progresses, renal activation of vitamin D is impaired, which reduces gut absorption of
calcium.
• Low blood calcium concentration stimulates secretion of parathyroid hormone (PTH).
• As renal function declines, serum calcium balance can be maintained only at the expense of increased
bone resorption, ultimately resulting in renal osteodystrophy
 Secondary hyperparathyroidism can cause
 altered lipid metabolism
 altered insulin secretin
 resistance to erythropoietic therapy
 impaired neurologic and immune functions
 increased mortality.
• ROD progresses insidiously for several years before the onset of symptoms such as bone pain and
fractures.
• When ROD symptoms appear, the disease isnot easily amenable to treatment.
• Preventive measures should be initiated in patients in early stages of CKD to improve outcomes by the
time they reach stage 5 CKD or ESRD.
• The K/DOQI guidelines provide desired ranges of calcium, phosphorus, calcium–phosphorus product,
and intact PTH based on the stage of CKD
• Measurements should be repeated every 12 months for stage 3, every 3 months for stage 4, and more
frequently for stage 5.
• Dietary phosphorus restriction (800 to 1,000 mg/day) should be first-line intervention for stage 3 or
higher CKD.
• By the time ESRD develops, most patients require a combination of phosphate-binding agents, vitamin
D, and calcimimetic therapy to achieve K/DOQI goals.
• Phosphate-Binding Agents(cal acetate,caco3 also)
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 • Phosphate-binding agents decrease phosphorus absorption from the gut and are first-line agents for
controlling both serum phosphorus and calcium concentrations .
• K/DOQI guidelines recommend that elemental calcium from calcium containing binders should not
exceed 1,500 mg/day and the total daily intake from all sources should not exceed 2,000 mg.
• combination of calcium- and noncalcium-containing products (e.g., sevelamer HCL, lanthanum
carbonate) are used
• Adverse effects of calcium-containing phosphate binders, as well as sevelamer and lanthanum, include
constipation, diarrhea, nausea, vomiting, and abdominal pain.
• The risk of hypercalcemia is also a concern.
• To avoid potential drug interactions, phosphate binders should be administered 1 hour before or 3 hours
after other oral medications.
• Vitamin d therapy
• Calcium and phosphorus must be controlled before vitamin D therapy is initiated.
Calcitriol- 1,25-dihydroxyvitamin D3 directly suppresses PTH synthesis ,secretion and upregulates vitamin D
receptors, which ultimately may reduce parathyroid hyperplasia.
• The newer vitamin D analogs paricalcitol and doxercalciferol may be associated with less hypercalcemia and,
for paricalcitol, hyperphosphatemia.
• Vitamin D therapy, regardless of agent, is associated with decreased mortality.
• Calcimimetics
• Cinacalcet -reduces PTH secretion by increasing the sensitivity of the calcium-sensing receptor.
• The starting dose is 30 mg daily, which can be titrated to the desired PTH and calcium concentrations
every 3 to 4 weeks and to a maximum of 180 mg daily.
METABOLIC ACIDOSIS
• A clinically significant metabolic acidosis is commonly seen when the GFR drops below 20 to 30
mL/min . The goals of therapy in CKD are to normalize the blood pH (7.35 to 7.45) and serum
bicarbonate (22 to 26 mEq/L).
• Consequences of metabolic acidosis include renal bone disease, reduced cardiac contractility,
predisposition to arrhythmias, and protein catabolism.
• Oral alkalinizing salts (e.g., sodium bicarbonate, Shohl solution, and Bicitra )can be used in patients
with stage 4 or 5 CKD.
HYPERLIPIDEMIA
• The prevalence of hyperlipidemia increases as renal function declines.
• Hyperlipidemia should be managed aggressively in patients with ESRD to a low-density lipoprotein
cholesterol goal of less than 100 mg/dL.

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• Statins are the drugs of first choice.
PRURITUS
• Pruritus is a common problem in patients with ESRD.
• The pathogenesis has been attributed to inadequate dialysis, skin dryness, secondary
hyperparathyroidism, and histamine, and increased sensitivity to histamine etc.
• Oral antihistamines are used
• Non sedating antihistamines are less effective than sedating antihistamines like CPM.
NUTRITIONAL STATUS
• Protein-energy malnutrition is common in patients with stage 4 or 5 CKD.Food intake is often
inadequate because of anorexia, altered taste sensation(due to pdctn of ammonia by urease enzyme),
intercurrent illness, and unpalatability of prescribed diets.
• Daily protein intake should be 1.2 g/kg for patients undergoing hemodialysis and 1.2 to 1.3 g/kg for
those undergoing peritoneal dialysis.
• Daily energy intake should be 35 kcal/kg for patients undergoing any type of dialysis. Vitamins A and
E are elevated in ESRD whereas water-soluble vitamins should be supplemented to replace dialysis-
induced loss.
UREMIC BLEEDING
• The pathophysiology of uremic bleeding is multifactorial. The primary mechanisms are platelet
biochemical abnormalities and alterations in platelet-vessel wall interactions.
• Nondialytic therapies that may temporarily shorten increased bleeding time include cryoprecipitate,
desmopressin (1-deamino-8-D-arginine vasopressin), and estrogens. Decreased platelet numbers and
platelet adhesion and aggregation all play a key role in bleeding .
• Degree of platelet dysfunction and risk of bleeding are best measured by a skin bleeding time test.
Bleeding risk is not correlated with coagulation tests, the findings of which are generally within normal
limits. The compound that is responsible for platelet abnormalities include -guanidinosuccinic acid, a
byproduct of ammonia detoxification.
• Accumulation causes an increase in nitric oxide, which has been shown to decrease platelet function by
interfering with the interaction of fibrinogen and the platelet GP IIb/IIIa receptor.
ENDOCRINE AND HORMONAL ABNORMALITIES
• Abnormalities in female and male gonadal hormones are common in ESKD and result in high
incidences of infertility and sexual dysfunction.
• Hyperprolactinemia is common, and gonadotropin, follicle-stimulating hormone (FSH), and luteinizing
hormone (LH) levels may be low in both men and women.