CHRONIC KIDNEY

DISEASE
Chronic Kidney Disease: Introduction

 CKD encompasses different pathophysiologic

processes associated with abnormal kidney
function and a progressive decline in GFR.

 Based on guidelines of the National Kidney

Foundation , stages of CKD are defined
according to the estimated GFR.
Classification of CKD

Stage GFR, mL/min per 1.73 m2

0 >90a
1 90b
2 60–89
3 30–59
4 15–29
5 <15
CKD – Introduction…

 The term chronic renal failure applies to the process of continuing

irreversible reduction in nephron number & corresponds to CKD
stages 3–5.

 ESRD represents a stage of CKD where the accumulation of

toxins, fluid, and electrolytes results in the uremic syndrome.

 This syndrome leads to death unless the toxins are removed by

renal replacement therapy, using dialysis or kidney
transplantation.

 ESRD will be supplanted by the term stage 5 CKD.

Pathophysiology - CKD

 Involves two broad sets of mechanisms of damage:

 (1) Initiating mechanisms specific to the underlying etiology (e.g., genetically

determined abnormalities , immune complex deposition and inflammation in
GN , or toxin exposure) and

 (2) A set of progressive mechanisms, involving hyperfiltration and

hypertrophy of the remaining viable nephrons, irrespective of underlying
etiology.

 Eventually, these short-term adaptations of hypertrophy and hyperfiltration

become maladaptive

 Increased intrarenal activity of the renin-angiotensin axis appears to

contribute both to the initial adaptive hyperfiltration and to the subsequent
maladaptive hypertrophy and sclerosis.
Identification of Risk Factors and Staging of CKD

 Risk factors include :

 Hypertension,
 Diabetes mellitus,
 Older age,
 African ancestry,
 A family history of renal disease,
 A previous episode of acute kidney injury, and
 The presence of proteinuria, abnormal urinary sediment, or
structural abnormalities of the urinary tract.

 In order to stage CKD, it is necessary to estimate the GFR.

Recommended Equations for Estimation of GFR Using Serum Creatinine
Concentration (PCr), Age, Sex, Race, and Body Weight

1.Equation from the Modification of Diet in Renal Disease study*

Estimated GFR (mL/min per 1.73 m2) = 1.86 x (PCr)–1.154 x (age)–0. 203
Multiply by 0.742 for women
Multiply by 1.21 for African Americans

2. Cockcroft-Gault equation

Estimated creatinine clearance (mL/min)

= (140–age) x body weight (kg)
72 x PCr (mg/dL)
Multiply by 0.85 for women
Leading Categories of Etiologies of CKD*

 Diabetic glomerular disease

 Glomerulonephritis

 Hypertensive nephropathy
Primary glomerulopathy with hypertension
Vascular and ischemic renal disease

 Autosomal dominant polycystic kidney disease

 Other cystic and tubulointerstitial nephropathy

Pathophysiology and Biochemistry of Uremia

 Serum urea and Cr are measures of the excretory capacity of the

kidneys,
 Their accumulation on its own do not account for the many
symptoms and signs of uremic syndrome

 Hundreds of toxins that accumulate in renal failure have been

implicated in the uremic syndrome.

 A host of metabolic and endocrine functions normally

performed by the kidneys is also impaired or suppressed, and
this results in anemia, malnutrition, and abnormal metabolism
of CHOs, fats, and proteins.
Pathophysiology and Biochemistry of Uremia…

 Plasma levels of many hormones, including PTH, insulin, glucagon, steroid

hormones including vitamin D , change with renal failure as a result of urinary
retention, decreased degradation, or abnormal regulation.

 Progressive renal impairment is associated with worsening systemic

inflammation.

 Elevated levels of C-reactive protein are detected along with other acute-phase
reactants, while levels of so-called negative acute-phase reactants, such as
albumin , decline even in nonproteinuric kidney disease.

 The inflammation associated with renal impairment is important in the

malnutrition-inflammation-atherosclerosis/calcification syndrome, which
contributes in turn to the acceleration of vascular disease and comorbidity
 The pathophysiology of the uremic syndrome can be divided into
manifestations in three spheres of dysfunction:

 (1) those consequent to the accumulation of toxins that normally

undergo renal excretion, including products of protein metabolism;

 (2) those consequent to the loss of other renal functions, such as

fluid and electrolyte homeostasis and hormone regulation; and

 (3) progressive systemic inflammation and its vascular and

nutritional consequences.
Sodium and Water Homeostasis in CKD

 As long as water intake does not exceed the capacity for water
clearance, the ECFV expansion will be isotonic and the patient will
have a normal plasma Na concentration and effective osmolality .

 Hyponatremia is not commonly seen in CKD but, when present, can

respond to water restriction.

 If the patient has evidence of ECFV expansion ( edema, HTN poorly

responsive to Rx), salt should be restricted.

 Thiazide diuretics have limited utility in stages 3–5 CKD, such that
administration of loop diuretics may also be needed.
Sodium and Water Homeostasis in CKD…

 Resistance to loop diuretics in renal failure often mandates use of higher doses
 Diuretic resistance with intractable edema and HTN in advanced CKD may
serve as an indication to initiate dialysis.

 Some patients with CKD may have impaired renal conservation of sodium and
water.

 Furthermore, depletion of ECFV(GI loss or excess diuretic), can further

compromise kidney function through under perfusion, or a "prerenal" basis,
leading to acute-on-chronic kidney failure.

 In this setting, cautious volume repletion may return the ECFV to normal and
restore renal function to baseline.
Potassium Homeostasis in CKD

 In CKD hyperkalemia may be precipitated in certain settings.

 These include increased dietary K intake, protein catabolism, hemolysis,

hemorrhage, transfusion of stored RBCs, and metabolic acidosis.

 In addition, a host of medications can inhibit renal potassium

excretion(ACEIs , ARBs, and spironolactone and other potassium-
sparing diuretics such as amiloride, eplerenone, and triamterene).

 Hypokalemia is not common in CKD and usually reflects markedly

reduced dietary potassium intake, especially in association with
excessive diuretic therapy or concurrent GI losses.
Evaluation and Management of Patients with CKD

History
 Symptoms and overt signs of kidney disease are often subtle or absent until

renal failure supervenes.

 History of hypertension (which can cause CKD or more commonly be a

consequence of CKD),

 Hx of diabetes mellitus
 A careful drug history should be elicited.

 Uremic syndrome - appetite, weight loss, nausea, hiccups, peripheral edema,

muscle cramps, pruritus, and restless legs

 Family history of kidney disease

 P/E - CKD

Physical examination

 Blood pressure and target organ damage from hypertension.

 Funduscopy and precordial examination (LV heave, a 4TH heart sound)

should be carried out.

 Funduscopy is important in the diabetic patient, as it may show evidence of

diabetic retinopathy, which is associated with nephropathy.

 Edema and sensory polyneuropathy.

 The finding of asterixis or a pericardial friction rub not attributable to

other causes usually signifies the presence of the uremic syndrome
Laboratory Investigation - CKD

 Laboratory studies should focus on a search for an underlying

causative or aggravating disease & on the degree of renal damage
and its consequences.

 Serum and urine protein electrophoresis, looking for multiple

myeloma, in all patients >35 with unexplained CKD, especially if
there is associated anemia and elevated serum calcium in the face of
renal insufficiency.

 In the presence of GN, autoimmune diseases such as lupus and

underlying infectious etiologies such as hepatitis B and C and HIV
should be assessed.
Laboratory tests – CKD…

 Serial measurements of renal function - to determine the pace of

renal deterioration and ensure that the disease is truly chronic.

 Serum concentrations of calcium, phosphorus, vitamin D, and

PTH - to evaluate metabolic bone disease.

 Hgb , iron, B12, and folate.

 A 24-h urine collection - as protein excretion >300 mg may be an

indication for therapy with ACE inhibitors or ARBs.
Imaging Studies - CKD

 Most useful is a renal ultrasound (verify the presence of 2 kidneys, determine if

they are symmetric, estimate kidney size, & R/O renal masses and evidence of
obstruction).

 The finding of bilaterally small kidneys supports the Dx of CKD, with an

irreversible component of scarring.
 Normal kidney size - acute or sub acute renal disease.
 The exceptions are diabetic nephropathy , amyloidosis, and HIV nephropathy,
where kidney size may be normal in the face of CKD.

 Polycystic kidney disease - enlarged kidneys with multiple cysts.

 A discrepancy >1 cm in kidney length - either a unilateral developmental

abnormality or disease process or renovascular disease with arterial insufficiency
affecting one kidney more than the other.
Imaging Studies – CKD…

 The diagnosis of renovascular disease can be made by Doppler

sonography, nuclear medicine studies, or CT or MRI studies.

 Radiographic contrast imaging studies are not helpful in CKD.

 IV or intraarterial dye should be avoided where possible in the

CKD patient, especially with diabetic nephropathy.

 When unavoidable, avoidance of hypovolemia , minimization of

the dye load, and choice of radiographic contrast with the least
nephrotoxic potential are important
Renal Biopsy - CKD

 In the patient with bilaterally small kidneys, renal biopsy is not advised
because

 (1) it is technically difficult and has a greater likelihood of causing bleeding

and other adverse consequences,

 (2) there is usually so much scarring that the underlying disease may not be
apparent, and

 (3) the window of opportunity to render disease-specific therapy has passed.

 Other contraindications to renal biopsy include uncontrolled hypertension,

active urinary tract infection, bleeding diathesis (including ongoing
anticoagulation), and severe obesity.
Establishing the Diagnosis and Etiology of CKD

 The most important initial step in the evaluation of a

patient with elevated SCr is to distinguish newly
diagnosed CKD from acute or sub acute renal failure

 Previous measurements of SCr are helpful.

 Even if there is evidence of chronicity, there is the

possibility of a superimposed acute process (e.g., ECFV
depletion, urinary infection or obstruction, or
nephrotoxin exposure).
Establishing the Diagnosis and Etiology of CKD…

 Evidence of metabolic bone disease with hyperphosphatemia, hypocalcemia, and

elevated PTH and bone ALP suggests chronicity.

 Norm chromic, normocytic anemia suggests that the process has been ongoing
for some time.

 The finding of bilaterally reduced kidney size (<8.5 cm) favors CKD.
 Renal biopsy can usually be performed in early CKD (stages 1–3)

 In type 1 DM for 15–20 yrs with retinopathy, nephrotic-range proteinuria, and

absence of hematuria or WBC cast, diabetic nephropathy is very likely and
biopsy is usually not necessary.

 In the absence of a clinical diagnosis, renal biopsy may be the only recourse to
establish an etiology in early-stage CKD
Treatment: Chronic Kidney Disease

 Rx aimed at specific causes of CKD.

 Optimized glucose control in DM,
 Immunomodulatory agents for GN.

 The optimal timing of both specific and nonspecific Rxy is well before there has
been a measurable decline in GFR and certainly before CKD is established

 It is helpful to sequentially measure and plot the rate of decline of GFR in all
patients.

 Acceleration in the rate of decline of GFR - search for superimposed acute

processes that may be reversible.

 These include ECFV depletion, uncontrolled HTN, UTI , new obstructive uropathy,
exposure to nephrotoxic agents , & flare of the original disease, such as lupus or
vasculitis
Slowing the Progression of CKD

Reducing Intraglomerular Hypertension and Proteinuria

 Control of systemic and glomerular HTN is important in slowing the progression of

CKD.
 It also reduce cardiovascular disease risk

 Elevated BP increases proteinuria by increasing its flux across the glomerular

capillaries.

 Conversely, the renoprotective effect of antihypertensive medications is gauged through

the consequent reduction of proteinuria.

 Thus, the more effective a given Rx is in lowering protein excretion, the greater the
impact on protection from decline in GFR.

 This observation is the basis for the Rx guideline establishing 125/75 mmHg as the
target BP in proteinuric CKD patients.
 ACE inhibitors and ARBs inhibit the angiotensin-induced
vasoconstriction of the efferent arterioles of the glomerular
microcirculation.

 This inhibition leads to a reduction in both intraglomerular filtration

pressure and proteinuria.

 These drugs are effective in slowing the progression of renal failure in

patients with advanced stages of both diabetic and nondiabetic CKD.
 Adverse effects from these agents include cough and angioedema with
ACE inhibitors, anaphylaxis, and hyperkalemia with either class.
Slowing Progression of Diabetic Renal Disease

 Diabetic nephropathy is now the leading cause of CKD

requiring renal replacement Rxy.

 The prognosis of diabetic patients on dialysis is poor, with

survival comparable to many forms of cancer.

 Excellent glycemic control reduces the risk of kidney disease

and its progression in both type 1 and type 2 diabetes.

 It is recommended that pre-prandial glucose be kept in the

90–130 mg/dL range & Hgb A1C should be < 7%.
Diabetes and CKD…

 As the GFR decreases with progressive nephropathy, the use and dose
of oral hypoglycemics needs to be reevaluated.

 For example, chlorpropamide - prolonged hypoglycemia;

 Metformin can cause lactic acidosis in the patient with renal
impairment

 Thiazolidinediones , may increase renal salt and water absorption and

aggravate volume-overload states.

 As renal function declines, renal degradation of insulin will also

decline - less insulin may be required for glycemic control.
Diabetes and CKD…

Control of Blood Pressure and Proteinuria

 Microalbuminuria precedes the decline in GFR and heralds renal and

cardiovascular complications.

 Testing for microalbumin is recommended in all diabetic patients, at least

annually.

 Antihypertensive Rx reduces albuminuria & diminishes its progression even

in normotensive diabetic patients.

 In addition to treatment of hypertension in general, the use of ACE inhibitors

and ARBs in particular is associated with additional renoprotection
 Diabetes and CKD…

Protein Restriction
 Protein restriction has been advocated to reduce symptoms of uremia.

 It may be effective in slowing the progression of CKD, especially proteinuric

and diabetic renal diseases

 A daily protein intake of b/n 0.60 and 0.75 g/kg per day is recommended ,
depending upon patient adherence, co morbid disease, presence of proteinuria,
and nutritional status.

 It is advised that at least 50% of the protein intake be of high biologic value.
 As patients approach stage 5 CKD, spontaneous protein intake tends to
decrease, and patients may enter a state of protein-energy malnutrition.

 In these circumstances, a protein intake of up to 0.90 g/kg per day might be

recommended
Medication Dose Adjustment - CKD

 For those agents in which >70% excretion is by a nonrenal route, such

as hepatic elimination, dose adjustment may not be needed.

 Some drugs that should be avoided include metformin, meperidine,

and oral hypoglycemics that are eliminated by the kidney.

 NSAIDs should be avoided because of the risk of further worsening of

kidney function.

 Many antibiotics, antihypertensives, and antiarrhythmics may require

a reduction in dosage or change in the dose interval.