Last edited: 11/12/2021

CHRONIC KIDNEY DISEASE (CKD)

Chronic Kidney Disease (CKD) Medical Editor: Donya Moslemzadeh

OUTLINE Mesangial cells

Interglomerular
I) INTRODUCTION Extraglomerular
II) CAUSES
o part of Juxtaglomerular complex
III) PATHOPHYSIOLOGY & CLINICAL FEATUERES
IV) DIAGNOSIS Overall function of Mesangial cells is protection of
V) TREATMENT Kidneys
VI) APPENDIX o Phagocytosis and Endocytosis
VII) REVIEW QUESTIONS o Structural Support
VIII) REFERENCES o Secretion of TGF-B and other Cytokines
o Etc.
I) INTRODUCTION
Juxtaglomerular Complex
Components

(i) Juxtaglomerular cells

 Modified smooth muscle cells located in the
afferent arterioles
 Renin Synthesis

(ii) Macula Densa

 Monitors the NaCl concentration within the lumen
of the DCT

(iii) Extraglomerular Mesangial cells

 Autoregulation of Blood flow
Afferent arteriole → Brings blood in
Efferent arteriole → Drains blood

(B) BASIC KIDNEY FUNCTIONS

Waste removal
o Drugs, Urea, Creatinine, etc.
Water balance
Electrolyte Balance
Figure 1. Structure of the Renal Corpuscle and the structures
o Ca2+, Na+, K+, PO43-
associated with it [Ross & Pawlina, 2015]
Acid-Base Balance
(A) REVIEW OF THE IMPORTATN KIDNEY Hormones
STRUCTURES o Erythropoietin
Nephron
(C) DEFINITIONS
Definition
Acute Kidney Injury, AKI
o Structural and Functional unit, o Abrupt Decrease in Renal Function
o composed of Renal Corpuscle and Renal Tubule
Chronic Kidney Disease, CKD
(i) Renal Corpuscle o ↓ Renal Function ≥ 3 months
o The renal corpuscle contains the filtration apparatus o ↓↓ Glomerular Filtration Rate =GFR (< 90)
of the kidney=Glomerular filtration barrier → 3
components
i. Glomerular Endothelium
ii. Glomerular Basement Membrane, GBM
iii. Visceral layer of Bowman's capsule

o Function: Filters fluid and produce ultrafiltrate

(ii) Renal Tubule

o Segments:
 Proximal Convoluted Tubule
 Loop of Henle
 Distal Convoluted Tubule (DCT)
 Connecting Tubule and collecting duct
o Function:
 resorbs and secretes substances from the
ultrafiltrate, producing urine

Chronic Kidney Disease (CKD) RENAL PATHOLOGY: NOTE #8. 1 of 15

 II) CAUSES
(A) HYPERTENSION (B) DIABETES
Second most common cause Most Common Cause
= Diabetic Nephropathy
Mechanism:
Mechanism:
High BP
(i) N.E.G
Non Enzymatic Glycosylation (also called Glycation) :

Consistent High BP o Glucose in the blood

(ii) Arteriolosclerosis
o Mesangial cells = Supportive cells o Diabetic Patients
 Very sensitive to low O2

o Hyaline → protein deposition

o Atherosclerotic → fat deposition

(iii) Glomerulosclerosis
o arteriolosclerosis of the Efferent arteriole

(iv) Tubular Disease

o Arteriolosclerosis of the Efferent arteriole

Kimmelstiel-Wilson nodules[Klatt, n.d.]

= Nodular glomerulosclerosis

Nodules of pink hyaline material form in regions of

glomerular capillary loops in the glomerulus. This is due
to a marked increase in mesangial matrix from damage
as a result of non-enzymatic glycosylation of proteins.

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 (C) GLOMERULONEPHRITIS Glomerulosclerosis [AMBOSS, 2021]
A scarring of the renal glomeruli with deposition of
3 common cause
rd
extracellular matrix, which leads to impaired glomerular
Various Types filtration and proteinuria. Can occur in a segmental
pattern (e.g., in focal segmental glomerulosclerosis) or
o Secondary to autoimmune disease ,Lupus,
nodular pattern (e.g., in diabetic nephropathy).
rheumatoid arthritis
o Secondary to Infections like HIV, Hepatitis
Mechanism (D) POLYCYSTIC KIDNEY DISEASE
Antigen-Antibody complex Inherited disorder
multiple cysts in the kidneys
2 Types:
o Autosomal Dominant Polycystic Kidney Disease
(ADPKD)
 Glomerular Endothelium o Autosomal Recessive Polycystic Kidney Disease
 Glomerular Basement Membrane, GBM
 Visceral layer of Bowman's capsule Mechanism:
• Contains Visceral Epithelial cells = o Cysts
Podocytes
 ↓ O2 Delivery to the tubular cells
↑ damage to GBM

 ↓Blood flow

(E) ACUTE KIDNEY INJURY

Prolonged AKI

Frequent AKIs over time

Prostaglandins

Mechanism of NSAIDs
o Acts on COX enzyme

Chronic Kidney Disease (CKD) RENAL PATHOLOGY: NOTE #8. 3 of 15

 III) PATHOPHYSIOLOGY & CLINICAL FEATUERES
(A) ELECTROLYTE ABNORMALITIES (B) WATER IMBALANCE
Mechanism :
↓GFR

 Lungs

 Cardiovascular System
• Hypertension
 Lower Extremities
• Peripheral Edema

Another mechanism that cause edema

o Albuminuria

• Pulmonary Edema
• Peripheral Edema

Albumin creates osmotic gradient to keep water in

(1) K+ and PO43- the vessels

Kidneys normally excrete two ions

o Potassium K+
o Phosphate PO43-
Hyperkalemia
o ↓GFR → ↓Excretion of K+→ Hyperkalemia
o Tubular damage → ↓Excretion of K+→ Hyperkalemia
Hyperphosphatemia
o ↓GFR →↓Excretion PO43- → Hyperphosphatemia
(2) Ca2+
Proximal Convoluted tubular cells Produce

Hypocalcemia
o ↓Kidney function

(3) Na+
Variable depending on the severity of CKD
Beginning → Stages Water retention → ↓sodium

Very Low GFR → Unable to Excrete Sodium

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 (C) UREMIA (D) HORMONE IMBALANCE
Azotemia= Urea buildup without any organ damage (1) Erythropoietin
Uremia = Urea elevation with organ damage
Proximal Convoluted tubular cells
Clinical Features of Uremia
Encephalopathy
o Asterixis = Flapping Tremor
o Seizure
o Coma
o Fatigue CKD
o Nausea/vomiting o Damage of Proximal convoluted tubular cells
Uremic Pericarditis / Pericardial effusion
o Urea deposition in the pericardium
o Inflammation of the pericardium
o Normocytic and Normochromic Anemia

Uremic Frost
o Urea secreted in the sweat

Coagulopathy
o Uremia

Chronic Kidney Disease (CKD) RENAL PATHOLOGY: NOTE #8. 5 of 15

 (2) Renin (3) PTH
CKD Vitamin D Synthesis:
o Renal Damage
o In skin
 UV exposure
 7 -Dehydrocholesterol → cholecalciferol (D3)
o liver
 25-Hydroxylase

o kidney
 1α-Hydroxylase

Renin-Angiotensin-Aldosterone-ADH System

Components of RAAAS
Renin
o Enzyme produced by the kidneys
Angiotensinogen
o Protein produced by the liver §circulates in the blood
Angiotensin-I Figure 2. Vitamin D Metabolism. [ Brunton et al, 2017]
o precursor molecule ↓Kidney function
Angiotensin Converting Enzyme (ACE)
o Mostly Produced by Capillary endothelial cells of the lungs
Angiotensin-II
o Extremely potent vasoconstrictive agent

Production of ANG-II ↓ Ca2+

↓Systemic BP, ↓ Blood Flow to the kidneys

If the kidney’s function was normal then PTH would

Renin converts Angiotensinogen made by the liver into
Angiotensin-I
Angiotensin-I circulates in the body and goes to lungs
Angiotensin-I in lungs reacts with Angiotensin Converting
enzyme (ACE)
ACE converts Angiotensin-I into Angiotensin
Angiotensin-II Effects:
Vasoconstriction
Angiotensin-II receptors on the vascular smooth muscle
increase the Calcium Reabsorption
PTH cannot increase Ca2+ by reabsorption from
kidneys so it affects the bones → stimulate
Osteoclasts →Bone Resorption → ↑ Ca2+
High Bone turnover may cause various diseases:
o Renal Osteodystrophy
o Osteitis cystica fibrosa
o ↑ Risk of Fracture

Antidiuretic Hormone ADH

Angiotensin-II Stimulates Posterior Pituitary

Aldosterone
o Steroid Hormone produced by Zona Glomerulosa of the
adrenal medulla
o Angiotensin-II Stimulates Aldosterone Production from
Adrenal Cortex

o Aldosterone initiates K+ Excretion in the Urine

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 (E) ACID-BASE IMBALANCE (F) ALBUMIN REGULATION
Mechanism : Mechanism:
↓Kidney function →↑ Albumin Excretion into the
Alpha-Intercalated cells in distal convoluted tubules Urine→↓ Albumin in the blood
and collecting duct
↓ Albumin in the blood
Kidney damage o →3rd spacing of Fluid
o → Stimulate Liver →↑ Protein production
→↑Lipoproteins →↑ TG and ↑LDL →
↓ Kidney function Hyperlipidemia

Third Spacing [UpToDate, 2021]

H+ retention+↑ HCO3- excretion

Third-spacing refers to the process of capillary leak
and extravasation of protein-rich serum into the
interstitial spaces of the soft tissues (e.g., skin, fat,
muscle), organs, deep space cavities (e.g., chest,
abdomen), or retroperitoneum.

Third-spacing into the soft tissue results in edema,

whereas fluid that leaks from the peritoneal or pleural
surfaces generates ascites or pleural effusion.

Hypoalbuminemia contributes to third-spacing; it is

theorized that the resultant intravascular oncotic
pressure, resulting from hypoalbuminemia, contributes
to the fluid shifting.

Chronic Kidney Disease (CKD) RENAL PATHOLOGY: NOTE #8. 7 of 15

 IV) DIAGNOSIS
History of (B) ALBUMINURIA
o Hypertension
o Diabetes Kidney damage marker
o Drugs Predictor of the severity of the disease
≥ 3 months Evidence of Kidney injury Urine analysis → Urine Albumin/Creatinine ratio
Table 2. Severity of the CKD based on albumin creatinine
o Markers → GFR, Albumin
ratio
(A) GFR Severity ACR (mg/g) Description
Normal GFR= 130 and 120 mL/min/1.73 m2 Normal to mildly
Mild <30
Best index of overall kidney function increased
Methods to Estimate GFR Moderate 30-299 Micro-Albuminuria
o Using Creatinine Severe ≥300 Macro-Albuminuria
o Serum cystatin C
Table 1. CKD staging based on GFR.
CKD GFR Description
Stages (mL/min/1.73 m2)

I >90 Normal or High

II 60-89 Mildly decreased
IIIa 45-59 Mildly to Moderately decreased
IIIb 30-44 Moderately to severely decreased
IV 15-29 Severely decreased
V <15 Kidney failure

Figure 3 Prognosis of CKD by GFR and Albuminuria

Category [KDIGO, 2012].

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 (C) RENAL ULTRASOUND (E) ADDITIONAL LAB TESTS
(1) Findings: Order BMP =Basic Metabolic Panel
o BMP measures: Glucose, Calcium, Sodium,
o Cysts → Diagnosis of polycystic kidney disease
Potassium, Bicarbonate, Chloride, BUN, Creatinine
(i) Small,
(ii) atrophic, Table 3. Additional Lab Tests for the Diagnosis of CKD.
(iii) fibrotic kidneys z
LAB Test Findings
o ↓perfusion, ↓vascularity (using Doppler Ultrasound)
Calcium Hypocalcemia
Sodium Hyponatremia or Hypernatremia

BMP
Potassium Hyperkalemia
Bicarbonate Low due to acidosis
Creatinine Use to estimate GFR
Phosphate Hyperphosphatemia
RBCs
Hb
Hct
Anemia
MCV

CBC
Normocytic= Normal MCV
MCH
MCHC
(D) RENAL BIOPSY + SEROLOGY WBC
Platelets
To Determine cause and types of Glomerulonephritis
(1) Renal Biopsy Serum Iron
May have Iron deficiency

Studies
Ferritin
Iron associated anemia
(2) Serology Transferrin
TIBC
(i) Antinuclear antibodies
ANA
 (screening for Lupus) Bicarbonate
ABG

PaO2 Metabolic Acidosis

(ii) Antineutrophil cytoplasmic autoantibodies SaO2
(ANCA;
 for DX of Vasculitis, Goodpasture)
Lipid Panel

TG
(iii) RF (Rheumatoid factor for rheumatoid arthritis) LDL
(iv) Serology for hepatitis virus, and HIV ↑ TG and ↑LDL
HDL
Cholesterol

↑PTH
If Severe CKD and↑↑↑↑PTH →
PTH
Hypercalcemia

Chronic Kidney Disease (CKD) RENAL PATHOLOGY: NOTE #8. 9 of 15

 V) TREATMENT
(A) SLOWING THE PROGRESSION OF CKD
Treat the underlying causes
Disease-Modifying Antirheumatic Drug (DMARD)
(1) HTN
Goal of Therapy: BP ≤ 130/80 A group of unrelated medications with
Treatment: immunosuppressive and anti-inflammatory properties
that improve symptoms and prevent further disease
(i) RAAAS inhibitors progression. They are commonly used to treat
rheumatoid arthritis but may also be indicated in other
o ACEI diseases (e.g., malignancies, psoriatic arthritis, systemic
o ARBs lupus erythematosus). [AMBOSS, 2021]
o Potassium sparing diuretics

Table 4. Commonly Used DMARDs. [UpToDate, 2021]

(ii) Decrease H2O Retention
Traditional Biologic Other
o Diuretics
DMARDs DMARDs DMARDs
 Loop Diuretics
o Sodium Intake Restriction → Low-Sodium Diet Etanercept Tofacitinib
Adalimumab Baricitinib
Infliximab
Methotrexate Upadacitinib
(2) Diabetes Certolizumab
Sulfasalazine Golimumab
Goal of Therapy: HbA1c < 6.5% Hydroxychloroquine Anakinra
Treatment: Leflunomide Abatacept
o Insulin Cyclosporine Rituximab
o Antidiabetic drugs Azathioprine
 Metformin Tocilizumab
 SGLT2 inhibitors Sarilumab
o Weight loss
o Diet Modification
(4) Polycystic Kidney Disease
(3) Glomerulonephritis
Treatment :
Treatment: o Control the secondary HTN and other complications
o Treat the underlying cause (e.g., Autoimmune
May lead to Renal Transplant
diseases, Inflammatory reactions)
o Steroids
o DMARDs (5) Discontinue Nephrotoxins
NSAIDs
Nephrotoxic Agents

10 of 15 RENAL PATHOLOGY: NOTE #8. Chronic Kidney Disease (CKD)

 (B) MANAGING THE COMPLICATIONS OF CKD – ELECTROLYTES
May need Renal Replacement Therapy
(2) Hyperphosphatemia
(1) Hyperkalemia
Mechanism:
Mechanism: o ↓GFR →↑PO43- retention
o ↓GFR → ↓Excretion of K+→ Hyperkalemia
Treatment:
Treatment: o Dietary Phosphate Restriction
o Insulin o Phosphate binder
o Short-Acting Beta Agonists (SABA)  Sevelamer Hydrochloride
 Albuterol
(3) Hypocalcemia
o HCO3-
o Diuretics
Treatment:
 Loop
 Thiazide o Calcium
o Cation Exchanger o Vitamin D increase the calcium absorption
 Sodium polystyrene sulfonate (SPS) (4) Secondary Hyperparathyroidism
o If all failed → dialysis
Mechanism:
o If Severe CKD and ↑↑↑↑PTH → Hypercalcemia

Treatment:
o ↓ PTH production
 Cinacalcet
o If Medications Fail → Parathyroidectomy

(C) MANAGING THE COMPLICATIONS OF CKD-HORMONES

(1) Anemia
Target : Hgb 8-10

(a) Mechanism:
o ↓EPO → ↓RBCs
Treatment:
o Synthetic Erythropoietin
(2) Secondary Hypertension
Goal of Therapy: BP ≤ 130/80

(a) Mechanism:
o ↓GFR

o Secondary HTN associated with elevated Renin

Treatment:
o ACEI
o ARBs
o Potassium sparing diuretics

Chronic Kidney Disease (CKD) RENAL PATHOLOGY: NOTE #8. 11 of 15

 (D) MANAGING THE COMPLICATIONS OF CKD- (F) MANAGING THE COMPLICATIONS OF CKD-
WATER BALANCE ALBUMINURIA

Mechanism: Mechanism:
o ↑Albumin Excretion
o ↓GFR →↑H2O retention →↑volume overload
 Manifestations:
• Pulmonary Edema
• Peripheral Edema Treatment:
• HTN o Proteinuria
 ACEI (unknown mechanism)
Treatment:  ARBs (unknown mechanism)
o Diuretics
 Loop Diuretics Important ACEI and ARBs Side effects in CKD
 Thiazide Diuretics patients
 Potassium sparing diuretics o ↑ Creatinine
o Sodium Intake Restriction o Hyperkalemia

(G) MANAGING THE COMPLICATIONS OF CKD-

(E) MANAGING THE COMPLICATIONS OF CKD-
DYSLIPIDEMIA
ACIDOSIS
Mechanism: Mechanism:
o ↓ Albumin in the blood
o ↓Ability to excrete H → H retention
+ +

o ↑ HCO3- excretion
o H+ retention+↑ HCO3- excretion → Acidosis
o Acidosis → pH<7.2 → May affect
 Cardiac System →↓Cardiac contractility
 Electrolyte Abnormalities
 Resistance to vasopressors Treatment:
Treatment: o Statins
o Sodium Bicarbonate (H) MANAGING THE COMPLICATIONS OF CKD-
PLATELET DSYFUNCTION
Mechanism:
o Uremia

Treatment:
o DDAVP = Desmopressin
 Increase Platelets Activity

12 of 15 RENAL PATHOLOGY: NOTE #8. Chronic Kidney Disease (CKD)

 (I) DIALYSIS
Need Dialysis if CKD worsening :
o Exacerbation of following conditions that are
refractory to medical therapies
 Acidosis
 Electrolyte abnormalities
 Intoxication due to drug/waste accumulation
 Volume Overload
 Uremia
o Continuous reduction of GFR → Stage IV, V
Dialysis may be the bridge to Kidney Transplant
Different types of Dialysis :
o Peritoneal dialysis
o Hemodialysis

VI) APPENDIX
Table 5. Summary of CKD.
CKD
Decreased Kidney function for three or more months
Definition

Hypertension
Diabetes
Glomerulonephritis
Causes

Polycystic Kidney Disease

NSAID Overuse
Prolonged/ Recurrent AKI

Electrolyte Abnormalities Hyperkalemia

Hyperphosphatemia
Hypocalcemia
Water Imbalance Pulmonary Edema
o ↓H2O filtration Hypertension
o Albuminuria Peripheral Edema
Uremia Nervous System
o Encephalopathy
 Asterixis
Pathophysiology & Clinical Features

 Seizure
 Coma
Cardiovascular System
o Uremic Pericarditis
Skin
o Uremic Frost
Platelets
o ↑ Risk of Bleeding
Hormone Imbalance Anemia
o EPO
o Renin Secondary Hypertension
o PTH
Secondary Hyperparathyroidism → CKD-related Bone Diseases
o Renal Osteodystrophy
o Osteitis cystica fibrosa
o Fractures
Acid-Base Imbalance Metabolic Acidosis

Albumin Imbalance Albuminuria → Hypoalbuminemia

o 3rd Spacing of fluids → Edema
o Hyperlipidemia
Additional Lab Tests
D

GFR
i

Chronic Kidney Disease (CKD) RENAL PATHOLOGY: NOTE #8. 13 of 15

 CKD
Albumin o CBC
Ultrasound o BMP
Biopsy o ABG
Serology o Iron Studies
o Lipid Panel
o PTH

Slowing the progression of CKD HTN ACEI

ARBs
Diuretics
Low Sodium Intake
DM Insulin
Antidiabetic Drugs
Weight Loss
Diet Modification
Glomerulonephritis Steroids
DMARDs
PKD Treat Secondary HTN
Renal Transplant
Discontinue e.g., NSAIDs
Nephrotoxins

Managing the Complications Hyperkalemia

Insulin
Short-Acting Beta Agonists (SABA)
o Albuterol
HCO3-
Diuretics
o Loop
o thiazide
Cation Exchanger
Treatment

o Sodium polystyrene sulfonate (SPS)

If all failed → dialysis
Hyperphosphatemia Dietary Phosphate Restriction
Phosphate binder
o Sevelamer Hydrochloride
Hypocalcemia Calcium
Vitamin D
Secondary Cinacalcet
Hyperparathyroidism Parathyroidectomy
Anemia EPO

Volume Overload Diuretics

Low Sodium Intake
Acidosis Sodium Bicarbonate
Albuminuria ACEI
ARBs
Dyslipidemia Statins
Platelet Dysfunction DDAVP
Dialysis Exacerbation of following conditions that are refractory to medical therapies
o Acidosis
o Electrolyte abnormalities
o Intoxication due to drug/waste accumulation
o Volume Overload
o Uremia
Continuous reduction of GFR → Stage IV, V

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 VII) REVIEW QUESTIONS
1) All the following conditions can cause CKD except:
a) Diabetes
b) Hypertension
c) Acute Kidney Injury less than 40 days
d) Polycystic kidney disease
2) The use of angiotensin-converting enzyme (ACE)
inhibitors is beneficial in patients with
a) Hypertension
b) Albuminuria
c) Hyperkalemia
d) A and B
3) The most common cause of CKD is
a) Diabetes
b) Hypertension
c) Glomerulonephritis
d) Polycystic Kidney Disease
4) A common marker of CKD is
a) Rash
b) Hematuria
c) Proteinuria
d) Bacteremia
5) Which statement is not true about the managing of
CKD complications:
a) Cation exchangers can be used to treat
Hyperkalemia.
b) Anemia in CKD patients is treated with Iron
Supplements only.
c) ARBs should Use cautiously in CKD patients with
Albuminuria.
d) Calcium and Vitamin D supplements can be used in
CKD patients with Hypocalcemia.

CHECK YOUR ANSWERS

VIII) REFERENCES
● Brunton, L., Knollman, B., & Hilal-Dandan, R. (2017). Goodman
and Gilman’s The Pharmacological Basis of Therapeutics, 13th
Edition. McGraw-Hill Education.
● AMBOSS: medical knowledge platform for doctors and students.
(n.d.). Amboss. Retrieved 2021, from https://www.amboss.com/
● UpToDate: Evidence-based Clinical Decision Support. (n.d.).
UpToDate.Com. Retrieved 2021, from
https://www.wolterskluwer.com/en/solutions/uptodate
● Ross, M. H., & Pawlina, W. (2015). Histology: A Text and Atlas:
With Correlated Cell and Molecular Biology (7th ed.). Lippincott
Williams & Wilkins.
● Klatt, E. C. (n.d.). Renal Pathology. The Internet Pathology
Laboratory for Medical Education. Retrieved November 12, 2021,
from https://webpath.med.utah.edu/RENAHTML/RENAL027.html
● Lab Tests Online. (n.d.). Patient Education on Blood, Urine, and
Other Lab Tests. Retrieved August 22, 2021, from
https://labtestsonline.org/
● Le, T., Bhushan, V., & Sochat, M. (2021). First Aid for the
USMLE Step 1 2021, Thirty First Edition (31st ed.). McGraw-Hill
Education / Medical.
● Gabriel, D. (2019). USMLE Step 2 CK: A Student-to-student
Guide (Clinical Knowledge) (10th ed.). Independently published.
● Papadakis, M., McPhee, S., & Rabow, M. (2019). CURRENT
Medical Diagnosis and Treatment 2020 (59th ed.). McGraw-Hill
Education / Medical.

Chronic Kidney Disease (CKD) RENAL PATHOLOGY: NOTE #8. 15 of 15