Get everything you need to know about chronic kidney disease

1. Chronic Kidney Disease:
Progression-Modifying Therapies
Kyambadde Bonny Bpharm (MUK)

2. Defn…
• Chronic kidney disease, also called chronic renal insufficiency or
progressive kidney disease by some, is defined as a progressive
loss of function occurring over several months to years, and is
characterized by the gradual replacement of normal kidney
architecture with interstitial fibrosis.

3. EPIDEMIOLOGYOFCKD
• The prevalence of CKD is thus similar to that of other chronic conditions
such as hypertension, diabetes mellitus, and cardiovascular disease
• Incidence estimates of stage 5 CKD are obtained from the USRDS.
During the two decades spanning 1980 to 2000, the number of patients
entering stage 5 (and requiring renal replacement therapy) increased by
5% to 10% per year
• However, beginning in 2003 and continuing to the present, the rate of
increase has declined to less than 1%.
• The main factor attributed to this decline has been the implementation
of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin
receptor blocker (ARB) therapy as a standard of care for those with
early stage CKD.
• The four most common causes of incident (new cases of) stage 5 CKD
are diabetes mellitus, hypertension, glomerulonephritis, and polycystic
kidney disease
• It is often assumed that all early stages of CKD progress continuously
toward stage 5.

4. ETIOLOGY
SUSCEPTIBILITY FACTORS
Susceptibility factors to CKD are;
• Advanced age
• Low income or education
• Racial/ethnic minority status
• Reduced kidney mass, low birth weight, and family history of CKD.
These factors have not been proven to directly cause kidney damage.
Novel proposed susceptibility factors are systemic inflammation and
dyslipidemia.
Although most of these susceptibility factors may not be amenable to
pharmacologic or lifestyle interventions, they may be useful for
identifying populations that are at high risk of CKD.

5. Cont…
INITIATION FACTORS
Initiation factors are conditions that directly result in kidney
damage, and are modifiable by pharmacologic therapy.
• Diabetes mellitus
• Hypertension
• Autoimmune diseases
• Polycystic kidney disease, systemic infections, urinary tract
infections, urinary stones, lower urinary tract obstructions, and
drug toxicity are all considered initiation factors.
Because diabetes mellitus, hypertension, and glomerular diseases
are, respectively, the three most common causes of CKD, the
following discussion focuses on these conditions.

6. DiabetesMellitus
• Individuals with type 1 diabetes mellitus have a 40% lifetime risk of
developing CKD of any stage, whereas individuals with type 2 diabetes
mellitus have a 50% lifetime risk.
• Given the greater prevalence of type 2 diabetes mellitus as compared
to type 1—generally a 10:1 ratio exists in most countries—the
majority of CKD from diabetes would be among individuals with type 2
disease.
• Although not all individuals with diabetic nephropathy progress to
stage 5 CKD, the lifetime risk is considerable.
• A prospective study of over 300,000 individuals screened from the
Multiple Risk Factor Intervention Trial estimated that approximately
3% of individuals with diabetes mellitus will develop stage 5 CKD
during their lifetime.
• Thus diabetic subjects have a 12-fold greater relative risk of
developing stage 5 CKD than does someone without diabetes.
• Subjects with diabetes also have an increased risk of nondiabetic
causes of CKD, suggesting an underlying genetic susceptibility to
kidney diseases.

7. Hypertension
• Hypertension also increases the risk of CKD although the exact role
as a cause or consequence is often debated as the kidney has a role
in the development and modulation of high blood pressure.
• Therefore, the interpretation of epidemiologic studies regarding the
presence of high blood pressure and the risk of progressive kidney
disease may be limited by reverse causation.
• Hypertension generally develops concomitantly with progressive
kidney disease.
• Conversely, prospective studies have shown that elevated blood
pressure increases the risk for the development of CKD among
subjects without initial kidney disease.

8. Glomerulonephritis
• Glomerular diseases are also considered initiation factors of CKD.
• The epidemiology and pathophysiology of glomerular diseases are
variable and thus all diseases should not justifiably be lumped into
one disease category.
• Some conditions, such as Goodpasture’s disease or Wegener’s
granulomatosus, may progress rapidly to stage 5 CKD, and thus
may best be categorized as causes of acute renal failure.
• Other conditions, such as immunoglobulin (Ig) A nephropathy,
membranous nephropathy, focal segmental glomerulosclerosis,
lupus nephritis, and others, are more indolent diseases, and are
considered causes of CKD.
• The chronic glomerular diseases progress at variable rates, with the
loss of GFR ranging from 1.4 to 9.5 mL/min per year

9. PROGRESSIONFACTORS
Progression risk factors are those associated with further kidney
damage.
This is generally evident as an increase in the rate of decline in kidney
function in those who already have damaged kidneys.
These include;
• Proteinuria
• Hypertension
• Diabetes Mellitus
• Smoking
• Hyperlipidemia
• Obesity

10. PATHOPHYSIOLOGY
• Kidney damage can result from heterogeneous causes. For example,
diabetic nephropathy is characterized by glomerular mesangial
expansion; in hypertensive nephrosclerosis, the kidney’s arterioles
have arteriolar hyalinosis; and renal cysts are present in polycystic
kidney disease.
• Therefore, the initial structural damage may depend on the primary
disease affecting the kidney.
• However, the majority of progressive nephropathies share a final
common pathway to irreversible renal parenchymal damage and ESRD
• The key elements of this pathway are:
(a) loss of nephron mass;
(b) glomerular capillary hypertension; and
(c) proteinuria.
• The exposure to any of the initiation risk factors can result in loss of
nephron mass. The remaining nephrons hypertrophy to compensate
for the loss of renal function and nephron mass.

11. Cont…
• Initially, this compensatory hypertrophy may be adaptive. Over
time, the hypertrophy can lead to the development of
intraglomerular hypertension, possibly mediated by angiotensin II.
• Angiotensin II is a potent vasoconstrictor of both the afferent and
efferent arterioles, but preferentially affects the efferent arterioles,
leading to increased pressure within the glomerular capillaries and
consequent increased filtration fraction.
• The development of intraglomerular hypertension usually
correlates with the development of systemic arterial hypertension.
• Animal studies have demonstrated that high intraglomerular
capillary pressure impairs the size-selective function of the
glomerular permeability barrier, resulting in increased urinary
excretion of albumin and frank proteinuria.
• Angiotensin II may also mediate renal disease progression through
non hemodynamic effects.
• Proteinuria alone may promote progressive loss of nephrons as a
result of direct cellular damage

12. Proposedmechanismsforprogressionofrenaldisease

13. CLINICALPRESENTATION
General
• CKD development and progression may be insidious in onset, often
without noticeable symptoms.
• The diagnosis of CKD requires measurement of serum creatinine,
estimation of GFR, and assessment of the urine (urinalysis) for
protein and/ or albumin excretion.
• CKD stages 3, 4, and 5 require further workup for CKD complications
of anemia, cardiovascular disease, metabolic bone disease,
malnutrition, and disorders of fluids and electrolytes.

14. Symptoms
• Symptoms are generally absent in CKD stages 1 and 2, and may be
minimal during stages 3 and 4.
• General symptoms associated with stages 1 to 4 include edema,
cold intolerance, shortness of breath, palpitations, cramping and
muscle pain, depression, anxiety, fatigue, and sexual dysfunction.
• Classic symptoms associated with stage 5 CKD are discussed as
complications of CKD

15. Signs
• Cardiovascular–pulmonary: Edema and worsening hypertension,
electrocardiographic evidence of left ventricular hypertrophy,
arrhythmias, hyperhomocysteinemia, and dyslipidemia
• Gastrointestinal: Gastroesophageal reflux disease, weight loss
• Endocrine: Secondary hyperparathyroidism, decreased vitamin D
activation, β2-microglobulin deposition, and gout
• Hematologic: Anemia of CKD, iron deficiency, and bleeding
• Fluid/electrolytes: Hyper- or hyponatremia, hyperkalemia, and
metabolic acidosis
• Malnutrition

16. DefinitionandPrevalenceoftheStagesofChronic
KidneyDisease
Stage Glomerular Filtration Rate
1 ≥90
2 60–89
3 30–59
4 15–29
5 <15 (includes patients on dialysis)

17. TREATMENT
1. Chronic Kidney Disease
GOAL OF THERAPY
• The goal of therapy is to delay the progression of CKD, thereby
minimizing the development or severity of associated
complications including cardiovascular disease
• Non pharmacologic and pharmacologic interventions are
available to slow the rate of CKD progression and they may also
decrease the incidence and prevalence of ESRD.

18. Cont…
NONPHARMACOLOGIC THERAPY
• Dietary Protein Restriction
PHARMACOLOGIC THERAPY
• Guidelines for CKD treatment usually recognize the
differences in pathogenesis and course of diabetic and
nondiabetic CKD.
• Consequently, pharmacologic interventions are discussed
separately for these conditions.
• The major focus is on the impact of ACEI and ARB therapies
on progressive CKD.
• Pharmacologic therapies specific for glomerulonephritis are
to discussed separetely and also therapies for the treatment
of complications of kidney disease are covered in Chap.

19. DiabeticChronicKidneyDisease
• INTENSIVE INSULIN THERAPY
Microvascular complications of D:M
• OPTIMAL HYPERTENSION CONTROL
Reduction of blood pressure in type 1 and type 2 diabetic patients has
been associated with lower rates of CKD progression
Nondiabetic Chronic Kidney Disease
• ANTIHYPERTENSIVE AGENTS
Reduction of blood pressure is key to decreasing cardiovascular and
renal sequelae. However, all antihypertensive agents are not equal in
their ability to preserve kidney function despite similar efficacy in
terms of blood pressure reduction. Among the different
antihypertensives available, ACEIs and ARBs are currently considered
the first choice in patients with CKD because they reduce
intraglomerular pressure.

20. Cont…
OTHER INTERVENTIONS TO LIMIT DISEASE PROGRESSION
• HYPERLIPIDEMIA TREATMENT
• SMOKING CESSATION
• ANEMIA TREATMENT