Chronic

Kidney Disease
Review of the Pathophysiology,
Treatment and
Prevention of Progression

Lavadia, Maolenn Karlo P.

Liwanag, Genecarlo
Outline

1. Review the Pathophysiology mechanisms

underlying CKD
2. Understand the importance of slowing the
progression of CKD and its treatment.
ADAPTATION TO RENAL INJURY
AND PATHOPHYSIOLOGY OF CKD
ADAPTATION TO RENAL INJURY

COMPENSATORY RENAL
HYPERTROPHY
The Nephron

Each kidney consist

of 1.2M nephrons
Divided into
segments
• 1) renal corpuscle
(glomerular
capillaries +
bowman’s capsule)
2) proximal tubule,
loop of henle,
distal tubule and
collecting duct
Functional unit of the
kidney
Renal blood flow
enter
Renal blood flow exits

Forms filtration barrier

Charge – selective (-)

Filtratio
n

Collects ultrafiltrate
of plasma
Glomerular Hypertension

VASOCONSTRICTIVE
MECHANISMS
⮚ Blockade of nitric oxide
synthase
⮚ Activation of ANGIOTENSIN II
⮚ Activation of thromboxane
receptors
Pathophysiology of Chronic Kidney
Disease

1. Initiating mechanisms
▪ Genetic abnormalities in kidney
development (dysplastic kidney)
▪ Immune complex deposition (SLE)
▪ Glomerulonephritis
▪ Toxin induced
2. Progressive mechanisms
▪ Hyperfiltration and hypertrophy
 MECHANISMS OF RENAL PROGRESSION

RENAL GLOMERULOSCLEROS
PROGRESSION IS

HYPERTENSION FORMATION OF
OF GLOMERULAR 1. Increase GFR ACELLULAR
TUFTS Interstitial
2. Protein leak SCAR
nephritis
NEPHRITOGENI EPITHELIAL-
CYTOKINE
C IMMUNE MESENCHYMAL
BATH RESPONSE TRANSITIONS
RESPONSE TO REDUCTION IN NUMBER OF
FUNCTIONING NEPHRONS

Renal disease is associated with a reduction in functional nephrons.

1. Glomerular hyperfiltration
▪ Increase renal blood flow and size of remaining glomeruli and tubules
▪ Mediated by local vasoconstriction of efferent arteriole
2. Increase Intraglomerular capillary pressure
▪ According to Robert Platt – high glomerular pressure with nephron loss explains the
peculiarities of renal function in each stage of kidney disease
▪ Brenner hyperfiltration hypothesis – a reduction in nephron 🡪 glomerular hypertension,
hyperfiltration, and enlargement of glomeruli 🡪 decreased kidney function
▪ Disruption of the filtration barrier (endothelium, podocytes, basement membrane)
3. Protein leak from in glomerulus
▪ Proteinuria-linked interstitial mononuclear cell accumulation
▪ Recruitment of chemokines 🡪 further inflammation
Clinical and laboratory
manifestation of Chronic
Kidney Disease
 FLUID, ELECTROLYTE AND ACID BASE
DISORDER

◼ Total body content of sodium and water is

modestly increased
◼ Sodium retention and extracellular fluid
volume expansion (ECFV)
◼ In cases of extrarenal fluid loss, CKD patients
may be prone to ECFV depletion
◼ Depletion of ECFV can cause underperfusion
of the kidneys leading to pre-renal AKI (AKI
on top of CKD)
 FLUID, ELECTROLYTE AND ACID BASE
DISORDER

◼ In CKD, decline in GFR is not necessarily

accompanied by decline in urinary potassium
excretion
◼ Another defense against potassium retention, is
potassium excretion in the GI tract
◼ Hyperkalemia is precipitated in certain settings
▪ (inc dietary potassium intake, hemolysis,
metabolic acidosis)
▪ Medications (ACE-I, ARB’s, spironolactone,
amiloride, eplerenone)
 FLUID, ELECTROLYTE AND
ACID BASE DISORDER

◼ Metabolic acidosis is a common disturbance

in advanced of CKD
◼ Majority can acidify urine but produce less
ammonia
◼ Hyperkalemia, and hyperchloremic metabolic
acidosis (NAGMA) is a common picture in
CKD (S1-3)
◼ Modest degrees of acidosis is associated with
development of protein catabolism.
Treatment

◼ Dietary salt restriction

◼ Loop Diuretics
◼ Avoidance of K-sparing diuretics, ACE, ARBs
◼ Calcium binding agents: Ca Polysterene
◼ Alkali Supplementation: if Serum
Bicarbonate levels <20-23
▪ Rationale: to prevent catabolic state seen even
with mild degrees of metabolic acidosis, and
slows progression of CKD
 DISORDERS OF CALCIUM AND PHOSPHATE
METABOLISM

◼ The pathophysiology of secondary

hyperparathyroidism is related to abnormal mineral
metabolism
1. Declining GFR leads to phosphate retention
2. Retained phosphate stimulates synthesis of PTH and
parathyroid gland hypertrophy
3. Decreased calcitriol production by the kidney causes
decreased levels of ionized calcium
◼ Hyperparathyroidism stimulates bone turnover leading
to osteitis fibrosa cystica
◼ Clinical manifestation includes bone pain and fragility,
compression sndromes
 DISORDERS OF CALCIUM AND PHOSPHATE
METABOLISM

◼ Fibroblast growth factor 23 is a phosphatonin

that promotes renal phosphate excretion
1. Increased renal phosphate excretion
2. Stimulation of PTH
3. Suppression of formation of Calcitriol
leading to diminished phosphorus
absorption from GI tract
Treatment

◼ Phosphate binders: Calcium Carbonate,

Sevelamer
◼ Calcitriol
▪ exerts a direct suppressive effect on PTH secretion
▪ indirectly suppresses PTH secretion by raising the
concentration of ionized calcium.
CARDIOVASCULAR ABNORMALITIES

◼ Leading cause of morbidity and mortality in patients

at every stage of CKD
◼ Hypertension is one of the most common
complications of CKD
◼ Any stage of CKD is a risk factor for ischemic
cardiovascular disease
◼ Inflammatory state in CKD = reflected in increased
circulating acute phase reactants (ex. CRP) and
decrease in negative phase reactant (ex. Albumin)
◼ Cardiac troponin levels are frequently elevated in
CKD without evidence of acute ischemia
Treatment

◼ Management of Hypertension and Heart

Disease
▪ blood pressure should be reduced to <130/80
mmHg
▪ Salt restriction – first line of therapy
▪ Antihypertensives – when volume management is
not sufficient
▪ Any anti-hypertensive of choice similar to that in
the general population.
▪ ACE, ARBs 🡪 delays CKD progression
 HEMATOLOGIC ABNORMALITIES

◼ Anemia is secondary to insufficient production of EPO by

the kidneys
▪ Other factors: 1) iron deficiency, 2) acute and chronic
inflammation with impaired iron utilization, 3) severe
hyperparathyroidism with bone marrow fibrosis, 4) shortened
red cell survival in uremic environment
◼ As early as CKD stage 3: normocytic, normochromic
anemia is observed
◼ Anemia is universal at CKD stage 4
◼ Pathophysiologic consequences: decreased tissue
oxygenation and utilization, increased CO, ventricular
dilatation and hypertrophyAnemia is secondary to
insufficient production of EPO by the kidneys
 HEMATOLOGIC ABNORMALITIES

◼ Later stages of CKD is associated with

1. prolonged bleeding time
2. Decreased activity of platelet factor III
3. Abnormal platelet aggregation and adhesiveness
4. Impaired prothrombin consumption
◼ This increases risk of bleeding and bruising
◼ CKD patients has greater susceptibility to
thromboembolism.
◼ Hypoalbuminemia and renal loss of anticoagulant
factors leads to a thrombophilic state
Treatment

◼ Erythropoietin stimulating Agents

▪ Epoietin alfa
▪ obviated the need for regular blood transfusions in
severely anemic CKD patients
◼ Iron supplementation may be attempted
▪ In CKD patients not on dialysis
Treatment

◼ Anemia resistant to recommended doses of

ESA in the face of adequate iron stores may
be due to some combination of the following:
1. acute or chronic inflammation,
2. inadequate dialysis,
3. severe hyperparathyroidism,
4. chronic blood loss or hemolysis,
5. chronic infection,
6. malignancy.
Caveats to ESA treatment in CKD

◼ ESA in CKD may be associated with an

increased risk of stroke in those with type 2
diabetes, an increase in thromboembolic
events, and perhaps a faster progression of
renal decline.
◼ Target hemoglobin: 110-115 g/L
Slowing Progression of CKD

◼ There is variation in the rate of decline of GFR

among patients with CKD.
◼ The following interventions should be
considered in an effort to stabilize or slow the
decline of renal function.
1. Reducing Intraglomerular Hypertension and
Proteinuria
2. Slowing the progression of Diabetic Nephropathy
3. Managing Complications of CKD
1. Reducing Intraglomerular
Hypertension and Proteinuria
◼ loss of nephron number. 🡪 Increased intraglomerular filtration
pressures and glomerular hypertrophy develop.
◼ Control of glomerular hypertension is important in slowing the
progression of CKD.
▪ elevated blood pressure 🡪 increasing its flux of proteins across the
glomerular capillaries 🡪 proteinuria .
◼ Conversely, the renoprotective effect of antihypertensive
medications is gauged through the consequent reduction of
proteinuria.
▪ Thus, the more effective a given treatment is in lowering protein excretion,
the greater the subsequent impact on protection from decline in GFR.
◼ This observation is the basis for the treatment guideline
establishing 130/80 mmHg as a target blood pressure in proteinuric
CKD patients.
1. Reducing Intraglomerular
Hypertension and Proteinuria
◼ ACE and ARBs
▪ Effective in slowing the progression of renal failure
advanced stages of CKD (both nondiabetic and
diabetic)
▪ Efferent vasodilation 🡪 decline in glomerular
hypertension.
▪ ACEi + ARBs = greater reduction of proteinuria
compared to either agent alone.
▪ However: ACEi + ARBs 🡪 AKI, Adverse cardiac effects.
◼ Nondihydropyridines: Diltiazem, Verapamil
▪ antiproteinuric and renoprotective effects
 2. Slowing the progression of
Diabetic Nephropathy
◼ Diabetic Nephropathy
▪ leading cause of chronic kidney disease (CKD),
ESRD, and CKD requiring renal replacement
therapy.
▪ Albuminuria in individuals with DM is associated
with an increased risk of CV diseases
▪ Individuals with diabetic nephropathy commonly
have diabetic retinopathy.
2. Slowing the progression of Diabetic
Nephropathy
◼ Diabetic Nephropathy
▪ Pathogenesis: chronic hyperglycemia
▪ involve the effects of soluble factors (growth factors, angiotensin II,
endothelin, advanced glycation end products [AGEs]), hemodynamic
alterations in the renal microcirculation (glomerular hyperfiltration or
hyperperfusion, increased glomerular capillary pressure), and structural
changes in the glomerulus (increased extracellular matrix, basement
membrane thickening, mesangial expansion, fibrosis).
Course of Diabetic Nephropathy
thickening of the
glomerular basement
membrane, glomerular
hypertrophy, and
mesangial
volume expansion

Glomerular
hyperperfusion and
renal hypertrophy
Albuminuria in Diabetic Nephropathy

◼ Albuminuria is a risk factor for cardiovascular

disease (CVD) and CKD.
▪ Diabetic kidney disease refers to albuminuria and
reduced GFR (<60 mL/min/1.73 m2);
▪ Marked hyperalbuminemia 🡪 irreversible
◼ American Diabetes Association (ADA) no longer
uses the terms microalbuminuria or
macroalbuminuria.
▪ instead uses albuminuria to refer to increased urinary
protein excretion (spot urinary albumin-to-creatinine
ratio >30 mg/g Cr).
◼ The nephropathy that develops in type 2 DM differs
from that of type 1 DM in the following respects:
1. albuminuria may be present when type 2 DM is
diagnosed, reflecting its long asymptomatic period;
2. hypertension more commonly accompanies
albuminuria
3. albuminuria may be less predictive of diabetic kidney
disease.
◼ albuminuria in type 2 DM may be secondary to factors
unrelated to DM, such as hypertension, congestive heart
failure (CHF), prostate disease, or infection.
Treatment Goals : Glycemic Control
Treatment Goals: BP Control

◼ BP: < 140/90 in patients with DM

◼ BP < 130/80 in patients with increased risk for CVD
and CKD progression
◼ ACE inhibitors or ARBs recommended:
▪ reduce the albuminuria and the associated decline in
GFR in type 1 or type 2 DM patients
▪ ARBS recommended: ACEi induced angioedema or
cough
◼ Other BP lowering agents: diuretics, calcium
channel blockers (nondihydropyridine class), or
beta blockers
Treatment Goals

◼ The ADA suggests a protein intake of 0.8

mg/kg of body weight/day in individuals with
diabetic kidney disease.
◼ Nephrology consultation should be
considered when albuminuria appears and
when the estimated GFR is <30 mL/min per
1.743 m2.
◼ Referral for transplant evaluation should be
made: GFR 20 mL/min per 1.743 m2
3. Managing Complications of CKD

◼ Medication dose adjustment

▪ maintenance doses of many drugs will need to be
adjusted.
▪ Many antibiotics, antihypertensives, and antiarrhythmics
may require a reduction in dosage or change in the dose
interval.
▪ Dose adjustment may not be necessary in agents
>70% excretion by non-renal
▪ Some drugs that should be avoided:
▪ metformin, meperidine, and some OHAs (metformin,
sulfonylureas) that are eliminated by the kidney.
▪ NSAIDs 🡪 risk of further worsening of kidney function.
3. Managing Complications of CKD
◼ Preparation of Renal Replacement Therapy (RRT)
▪ Temporary relief of symptoms and signs of impending uremia, such as
anorexia, nausea, vomiting, lassitude, and pruritus, may sometimes be
achieved with dietary protein restriction
▪ Clear indications for initiation of RRT
▪ Uremic pericarditis
▪ Uremic encephalopathy
▪ Intractable muscle cramping
▪ Anorexia and nausea 🡪 not attributable to reversible causes
(PUD)
▪ Evidence of malnutrition
▪ Fluid and electrolyte abnormalities (principally
hyperkalemia)
▪ Volume overload
3. Managing Complications of CKD

◼ Recommendations for the Optimal Time for

Initiation of Renal Replacement Therapy
▪ studies suggested that starting dialysis before the
onset of severe symptoms and signs of uremia
was associated with prolongation of survival
▪ Practically: advanced preparation may help to
avoid problems with dialysis process
▪ temporary access entails risk for sepsis, bleeding,
thrombosis.
 Reducing
Intraglomerular
Hypertension
and Proteinuria
Slowing the
progression of
Diabetic
Nephropathy
Managing
Complications
of CKD

CKD-MBD: Use of
phosphate binders, anti-
PTH: calcitriol
References
● Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, L. J., &
Loscalzo, J. (2019). Harrisons Manual of Medicine, 20th Edition
(20th ed.). McGraw-Hill Education / Medical.
● Fatehi p., Hsu C., (2021), Chronic kidney disease (newly
identified): Clinical presentation and diagnostic approach in
adults UpToDate. Retrieved March 14, 2021.
https://www.uptodate.com/contents/chronic-kidney-disease-
newly-identified-clinical-presentation-and-diagnostic-
approach-in-adults.
● KDIGO Executive Committee. (2017). CKD, 101(8S), S1.
https://doi.org/10.1097/01.tp.0000522276.01738.f0.