Chronic Kidney Disease

Pathof

- Two broad set:

o Initiating mechanism specific to the underlying etiology (immune complexes, inflammation, toxic)
o Set of progressive mechanism (hyperfiltration and hypertrophy of remaining nephron)

Stage

Diagnostic

- GFR
- Albuminuria
o 24-h collection of urine as “gold standard”
 Cockroft-gault
o Albumin-to-creatinine ratio in morning urine more practical
 >17mg albumin per 1g creatinine (males)
 >25mg albumin per 1g creatinine (females)
o Microalbuminuria = kalau jmlh albumin tidak bisa dideteksi urinary dipstick

UREMIA SYNDROME
Pathof :

1. Penumpukan toxin yang biasa dibuang melalui ginjal seperti urea

2. Kerusakan dari fungsi ginjal yang lain seperti hormonal atau electrolyte homeostasis
3. Progressive systemic inflammation
Disturbances of function:

- Fluid, electrolytes, acid-base disorder

o Water dan Na
 Water and na increase karena ada sodium retention diikuti air (ECFV / extracellular fluid
volume)  hypertension  accelerate nephron injury
 Jika ada ECFV clinical manifestation  harus salt restriction
 Jika ECFV tinggi, bisa melarutkan Na  hyponatremia (harus restrict water)
o Potassium
 Homeostasis dari kalium biasa tidak terganggu karena ada ekskresi kalium dengan bantuan
aldosterone di DCT & ekskresi di GI Tract
 Namun Hyperkalemia masi bisa terjadi karena dietary intake, protein catabolism, hemolysis,
hemorrhage, transfusion RBC, metabolic acidosis, medication (ACEI, ARB, potassium-sparing
diuretic)
 Hypokalemia (not common)
 Biasa karena ada primary potassium wasting (Fanconi syndrome, renal tubular
acidosis, hereditary diseases)
o Metabolic acidosis
 Pasien DM (diabethic nephropathy) biasanya hyperkalemia  metabolic acidosis
 Early CKD biasa non-anion-gap metabolic acidosis, tapi lama2 jadi anion-gap metabolic
acidosis
o Treatment:
 Adjustment in salt intake, use of loop diuretic + metolazone, but with caution karena bisa
ECFV depletion
 Water restriction if hyponatremia (rare)
 Dietary restriction of potassium, avoidance of potassium supplement or medication
 Alkali supplementation for metabolic acidosis
- Disorders of calcium and phosphate metabolism
o Bone manifestation of CKD
 Bisa :
 High bone turnover bcs increased PTH (osteitis fibrosa cystica, secondary
hyperparathyroid)
 Low bone turnover bcs low-normal PTH (osteomalacia (vit D deficiency jadinya
unmineralized bone matrix)
 Secondary parathyroidism (high PTH):
 GFR rendah akan menyebabkan retensi dari fosfat (hyperphosphatemia)
 Phosphate yang diretensi meningkatkan sintesis PTH dan pertumbuhan dari
parathyroid gland
 Kidney yang gagal fungsi dan retensi fosfat akan mengurangi produksi calcitriol 
meningkatkan produksi PTH (hyperparathyroidism  bone fragile, brown tumour,
bone marrow fibrosis)
 Parathyroid gland akan bertumbuh sesuai dengan CKD, pertumbuhan bisa:
 Diffuse hyperplasia (polyclonal)
 Nodular growth (monoclonal) within diffuse hyperplasia
 Diffuse monoclonal hyperplasia (adenoma)
o Calcium, phosphorus, cardiovascular system
 Hypercalcemia dan hyperphosphatemia berpengaruh besar thd cardiovascular mortality,
mungkin karena meningkatnya kalsifikasi dari vascular
 Calciphylaxis (calcification of vascular  patches of ischaemic necrosis)
o Treatment: dietary restriction, oral phosphate binders (calcium or noncalcium), correction of
acidosis, parathyroidectomy, calcimimetic agent
- Cardiovascular abnormalities
o Ischaemic vascular disease:
 Traditional (classic):
 Hypertension
 Hypervolemia
 Dyslipidemia
 Sympathetic overactivity
 Hyperhomocysteinemia
 Non-traditional (CKD-related)
 Anemia
 Hyperphosphatemia
 Hyperparathyroidism
 Sleep apnea
 Generalized inflammation
o Heart failure
 Salt & water retention, myocard ischaemia, left ventricular hypertrophy  heart failure
 Heart failure bisa terjadi karena systolic or diastolic dysfunction
 Di advanced CKD, “low pressure” pulmo edema juga bisa terjadi  Shortness of breath dan
“bat wing” distribution of alveolar edema fluid on chest X-ray
o Hypertension dan Left ventricular hypertrophy
 Hypertension : most common complications seen in CKD
 Biasa terjadi early during course of CKD, associated with development of LVH
 Chronic Extra Cellular Fluid Volume (ECFV) overload mempengaruhi hipertensi
 Namun, aktifasi dari RAAS, juga bisa menyebabkan hypertension tidak sembuh walaupun
sudah ada penanganan ECFV
o Pericardial Disease
 Uremic pericarditis :
 Pericardial pain saat bernafas
  Friction rub
o Treatment:
 Slow progression of kidney disease and prevent extrarenal complications of high BP
 125/75 mg goal for patients with diabetes or proteinuria >1 g/24h
 Salt restriction and diuretics as first line
 Modification of RF, lifestyle changes, statins
- Hematologic Abnormalities
o Anemia
 Normocytic, normochromic anemia umum terjadi di CKD stage 3 dan 4
 Terjadi karena kekurangan produksi erythropoietin (EPO)
 Faktor pendukung lain:
 Iron deficiency
 Hyperparathyroidism
 Folate and vitamin B12 deficiency (jarang)
 Aluminium toxicity (jarang)
 Manifestations: angina, HF, decreased cognition, impaired host defense
 Treatment: Exogenous EPO, iron supplementation, pemberian folate
o Abnormal hemostasis
 Pasien CKD stage akhir-akhir, dapat terjadi prolonged bleeding time, decreased activity of
platelet factor III, abnormal platelets aggregation, impaired prothromi, consumption
 Manifestations: increased bleeding + bruising tendency, prolonged bleeding, spontaneous GI
bleed
- Neuromuscular abnormalities
o Biasa baru muncul pada CKD stage 3
o Early manifestation:
 Mild disturbance in memory, concentration, and sleep
o Later stage: (neuromuscular irritability)
 Hiccup, cramps, twitching muscle
o Peripheral neuropathy biasa terjadi pada CKD stage 4
o Asterixis, myoclonus, seizure, coma in advanced untreated kidney failure
- Gastrointestinal and nutritional abnormalities
o Uremic fetor : Uremic odor of breath karena ada breakdown urea to ammonia di saliva, biasa
muncul bersama dengan metallic taste (dysgeusia)
o Retention of uremic menyebabkan anorexia, nausea, vomiting
o Protein restriction may be useful to decrease nausea vomit, tapi hati-hati karena resiko protein-
energy malnutrition
o Metabolic acidosis + inflammation bisa promote protein catabolism
- Endocrine metabolic disturbances
o Glucose metabolism impaired in CKD
 Fasting glucose biasa normal
 Insulin biasa dibuah melalui ginjal, kalau ginjal rusak, insulin tidak dapt dibuang
o Estrogen in women are low
 Menstrual abnormalities
 Inability to carry pregnancies
 GFR <40 mL/min  20% pregnancies leading to live birth
o Testosterone in men are low
 Sexual dysfunction
 Oligospermia
- Dermatologic Abnormalities
o Skin abnormalities prevalent in progressive CKD
o Anemic patients  pale
o Defective hemostasis  multiple ecchymoses (bruise)
o Pruritus (gatal)
 o More pigmented (karena ada urochrome  retained pigmented metabolites)
o Nephrogenic fibrosing dermopathy (esp. on arms and legs)
o Treatment: control phosphate conc, EPO therapy, local moisturizer, antihistamine

Progression of Chronic Kidney Disease

- Progresi CKD considered glomerular adaptation, characterized by increased workload per nephron or single
nephron GFR/SNGFR

1. Hemodynamic hypothesis
- Karena CKD, jumlah nephron fungsional akan berkurang, sisa nephron akan hyperfiltration dan
glomerular capillary hypertension sebagai kompensasi
- Awal2 hal tersebut untuk maintain GFR, tapi lama2 maladaptive karena pressure yg tinggi
menyebabkan pressure-induced capillary stretch akan membuat injury di glomerulus
- Histopathology : glomerular and tubular hypertrophy  focal glomerular sclerosis, tubular atrophy,
interstitial fibrosis
- Glomerular hyperfiltration sangat penting di diabetic nephropathy
o Karena kondisi hyperglycemia induce hyperfiltration -> aktivasi RAAS juga
o RAAS further increase glomerular capillary pressure by Angiotensin II
2. Abnormal permeability to macromolecules
- Renal injury dan RAAS menyebabkan proteinuria karena increased glomerular permeability
- Selain membesarkan pore size, RAAS juga mengganggu expression dari nephrin (transmembrane
protein di antara celan podocyte).
o Normalnya nephrin menjaga slit integrity untuk mencegah protein lewat, tapi kalau nephrin
berkurang, integritas terganggu dan protein bisa lewat
- Protein di tubule bersifat toxic, menyebabkan injury, tubulointerstitial inflammation, scarring
o Karena overload dari lysosome (organelle dengan digestive enzyme), cytokine expression,
dan ECM production
3. Growth Factor Hypothesis
- Selain increased capillary pressure and stretch leads to scarring, ada pengaruh lain seperti proinflammatory
+ profibrotic effect of Angiotensin II and aldosterone
- Pada basien diabetic nephropathy, ada pengaruh AGEs (Advanced Glycation End-products / glycoprotein,dll)
yang bisa cause renal injury
a. AGEs interfere with ECM proteins (collagen, elastinin, laminin)  alteration in structure (fibrosis) and
function (hydrophobic, charge, elasticity)
b. AGE-RAGE interaction: AGE induce injury through cascade of receptor-dependent (RAGE) event ->
transformation of tubular cell into myofibroblast, leading to tubular atrophy and interstitial fibrosis
c. Receptor-independent reaction that lead to intracellular ROS -> proinflammatory (TNF-a, MCP-1, NF-kB)
and profibrotic (TGF-B, PDGF)
d. AGEs accumulation cause endothelial dysfunction, increased thrombogenicity and atherosclerotic ->
subsequent end-organ hypoperfusion
- Another mechanism: Increased ammoniagenesis in remaining nephron
o Promotes complement cascade -> enhance injury to tubulointerstitium
o Related to actions of excess aldosterone and endothelin-1 akibat acid retention
o Makanya, dietary alkali therapy may preserve GFR and delay CKD progression

Dialysis in Treatment of Renal Failure

Hemodialysis

- Mengandalkan solute diffusion from circulation to dialysate across semipermeable membrane, yang
dipengaruhi faktor seperti magnitude of concentration gradient, membrane surface area, mass transfer
coefficient of membrane (porosity and thickness, size of solute, condition of flow)
- Selain diffuse, waste bisa move melalui ultrafiltration atau convective clearance (solute mengikuti air)
- Hemodialysis terdiri dari Dialyzer, dialysate, and blood delivery system
 a. Dialyzer
- Bundles of capillary tubes in which blood circulates while dialysate travels outside of bundle
- Membrane material: cellulose, substituted cellulose, cellulosynthetic, synthetic
- Sekarang lebih sering synthetic, karena more biocompatible (ability of membrane to activate complement
cascade)
o Ada free hydroxyl group di cellulose, sedangkan di synthetic tidak
- Sekarang lebih banyak disposable dialyzers yang digunakan dibandingkan reuse karena costs
- In centers with reuse, only dialyzer unit is reprocessed
o Sequential rinsing of blood and dialysate with water, chemical cleaning with reverse ultrafiltration,
disinfection, testing of patency
o Agents: Formaldehyde, Bleach, glutaraldehyde
b. Dialysate: water for dialysate used for filtration, softening, deionization, reverse osmosis
c. Blood Delivery System: Negative hydrostatic pressure on dialysate side to achieve fluid removal or
ultrafiltration

Goals of Dialysis

- Removing both low (urea) and high (creatinine) molecular weight molecules
- Pump heparinized blood through dialyzer while dialysate flow counter-current
o Efficiency tergantung blood+dialysate flow and dialyzer characteristics
- Majority of ESRD patient given 9-12 h dialysis each week, divided into three sessions
Complications during Hemodialysis

- Hypotension is most common complication, due to excessive ultrafiltration, impaired vasoactive or

autonomic response, overuse of antihypertensive, osmolar shifts
- Muscle cramps also a common complication
o Change in muscle perfusion due to aggressive volume removal or low-sodium diasylate
- Anaphylactoid reactions (reported in cellulose membrane, which is now uncommon)
1. Type A: Ig-E hypersensitivity to ethylene oxide for sterilization
2. Type B: Nonspecific chest & back pain due to complement activation and cytokine release

Peritoneal Dialysis

- 1.5-3L dextrose solution infused into peritoneal cavity through catheter, dwelled for 2-4h
- Absorption of solutes and water across peritoneal membrane into circulation and via lymph
- Rate of transport tergantung infection (peritonitis), drugs, physical factors (position, exercise)
- Complications: peritonitis, catheter-associated infection, weight gain, residual uremia
- Broad spectrum antibiotics administered to prevent infection

Advantage & Disadvantage

- Neither hemodialysis or peritoneal dialysis have advantage in terms of survival

- Disadvantage of hemodialysis: low blood pressure, lightheadedness, SoB, abdominal cramp, nausea, vomit,
more time for travel and treatment
- Advantage of Peritoneal Dialysis compared to hemodialysis: more uninterrupted time for work & family,
users are able to continue working
- Disadvantage of peritoneal dialysis: person must know how to set equipment up to connect and disconnect
small tubes (karena biasanya done at home), increased risk of hernia from fluid pressure in abdominal cavity,
peritonitis, weight gain
- Transplant advantage: treatment of choice for ESRD patient, paling bagus untuk improve quality of life, do
not require hours of dialysis treatment, biasa sudah dilakukan sebelum dialysis
- Transplant disadvantage: major surgical procedure with risks, such as infection, bleeding, damage to
surrounding organs, require medications and frequent monitoring for chance of organ rejection
Anemia Classification

1. Decreased production vs RBC Loss (increased destruction or bleeding) -> Reticulocyte/immature RBC count
2. RBC Size: Macro/micro/Normocytic (RBC indices)
3. Hemoglobin content: hypochromic (iron deficiency, thalassemia) vs normochromic (hemolytic anemia) (RBC
indices)
4. Shape: Normal or abnormal (Peripheral blood smear)

Anemia of CKD
- Anemia is an early, common complication of CKD
o Anemia commonly occurs when GFR reaches 30-40ml/min, tapi bisa di 60ml/min juga
o Mild anemia: Hb level < 12g/dL
o Normochromic normocytic RBCs
o Anemia workup recommended for Stage 3-4 CKD patients, with Hb being recommended parameter
because Hct has wider variation and instability of samples
o No optimal target Hb levels, in fact can be harmful
- Decreased RBC production, survival, and blood loss all contribute to anemia
- Primary cause: low erythropoietin production by diseased kidney
o Makanya RBC count improve following exogenous erythropoietin therapy/Erythropoietin-stimulating
Agent (ESA)
- Secondary cause: iron deficiency
o Bisa karena occult GI bleeding, blood loss from phlebotomies, decreased iron absorption, dietary
restriction, iron usage by exogenous erythropoietin
- Acute and chronic inflammation (including infection) can also cause anemia
o Increased cytokines -> reduce erythropoietin production, decrease marrow response to
erythropoietin (reduce ESA response), and increase production of hepcidin, which sequesters iron in
RES
- Other secondary cause: hypothyroidism, severe HyperPTH, folate and B12 deficiency, hemoglobinopathy,
shortened RBC survival
- Diagnosis of Iron deficiency
o Biasanya pasien CKD ada functional iron deficiency, dimana serum ferritin normal tapi TSAT <20%
karena inadequate iron incorporation for erythropoiesis
 o Serum ferritin <100ng/mL usually diagnostic for iron deficiency, equal or less than 30ng/mL = severe
iron deficiency, tapi ferritin bisa naik due to inflammatory process, jadinya not reliable
o TSAT/Transferrin Saturation: reflects amount of available iron necessary for erythropoiesis Formula:
(serum iron/TIBC/total iron binding capacity)*100
 <20% indicate functional iron deficiency
 Target TSAT: 30-50%
Effect of Anemia Correction in CKD Patient

- ESAs: Recombinant human erythropoietin (rHuEpo) and darbepoietin

o Subcutaneous injection preferred route, bisa self-administration karena simple
o rHuEpo given 1-2x per week, sedangkan darbepoietin frequency should be less
o Darbepoetin: longer serum half life
o Patient will require iron supplementation to maintain erythropoietic responsiveness (karena ESA
stimulate RBC production by bone marrow which requires iron) -> diberikan ketika TSAT <30% or
ferritin <500ng/mL
o Bisa oral atau IV pada pasien ESRD (sodium ferric gluconate, iron sucrose, ferumoxytol)
- Correction with ESAs has not improved CVD outcomes
- Decline in Hb by 1g/dL associated with 6% increased risk for LVH
- Anemia may also increase oxidative stress
- Correction of anemia in ESRD patient improve left ventricle mass index, ejection fraction, mitigates ischemic
changes
- Other benefits of anemia correction:
o Improved well-being and work capacity, reduce needed for RBC transfusion, reduced hospitalization
- Benefits of anemia correction to kidney function: correction of hypoxia-induced interstitial fibrosis and
antiapoptotic effect of erythropoietin
o Tapi pada pasien CKD masih tidak ada keuntungan atau kerugian to kidney function
Anemia correction may increase BP in CKD patients due to systemic vascular resistance and pressor effects of ESAs,
tapi dengan slowed Hb correction to 1g/dl/month alleviates rise