US

URINARY TRACT INFECTION

This patient is diagnosed with BPH and UTI / Patient (female) comes with complaint of painful urination.

Anatomical feature that makes female more susceptible to UTI
- Short urethra and close proximity of urethral opening to vagina and anus

Anatomy of external urethral orifice
- In the vestibule of the vagina
- Between the clitoris and the vaginal opening

Nerve supply of urethra that provide pain sensation
- Proximal urethra - visceral innervation via pelvic splanchnic nerve (S2-S4)
- Terminal urethra - somatic innervation via pudendal nerve (S2-S4)

Anatomical reasoning for frequent micturition
- d/t prostate enlargement, mainly in the transitional zone, which surround the prostatic urethra.
- as the gland enlarges, it compresses the urethra leading to bladder outlet obstruction, incomplete emptying of the bladder, reduced urine flow
- because urine is not fully emptied, the bladder fills up more quickly, resulting in frequent urination and nocturia.

Clinical zones of the prostate for BPH (Adenoma) and Prostate CA
- BPH → Transitional zone
- Prostate CA → Peripheral zone

PR Examination
- also known as Digital Rectal Examination.
- It involves inserting a gloved, lubricated finger into the rectum to palpate for prostate gland.
- Indicated for evaluation of prostate enlargement (in suspected BPH or Prostate CA)

Causative agents that caused UTI and its virulence factor
- E.coli - P fimbriae (Pili) that helps E.coli to adhere to uroepithelial cells, resisting flushing by urine
- Pseudomonas aeruginosa
- Proteus sp. - Urease that convert urea to ammonia and make the urine alkaline and forming renal calculi.
- Staphylococcus saprophyticus
- Klebsiella - Capsule that inhibits phagocytosis

How BPH caused UTI
- BPH leads to urinary stasis d/t incomplete bladder emptying.
- This stagnant urine provides a favorable environment for bacterial growth and reduce the natural flushing action of urine.
- As a result, bacteria can multiply and cause UTI.

Risk factors of UTI
- Frequent or recent sexual intercourse - may introduce bacteria into the urinary tract
- Female sex - short urethra
- Recurrent UTI - indicates possible predisposition or colonization of microbes in the urinary tract

Interpretation of Urinalysis
- Urine dipstick test
→ Leukocyte esterase (+ve) - indicates presence of neutrophils, suggesting inflammation or infection. (PYURIA)
→ Nitrite (+ve) - indicates presence of nitrate-reducing bacteria which convert nitrate → nitrite (BACTERIURIA)

Therapeutic interventions (TMP/SMX or CIPROFLOXACIN)
- Acute Uncomplicated Cystitis
→ TMP/SMX - MoA: blocking folate synthesis - not used in pregnancy
→ Ciprofloxacin (Floroquinolones) - MoA: inhibit DNA gyrase and topoisomerase IV
→ Cefuroxime (2nd Gen Cephalosporins) - MoA: same as penicillin
→ Amoxicillin + Clavulanic acid
→ Nitrofurantoin - MoA: undergo rapid enzymatic reduction that cause damage to bacterial DNA

OBSTRUCTIVE NEPHROPATHY (RENAL STONES)

Definition - Obstruction to urine flow can occur at any level from renal pelvis to urethral meatus

Causes of Obstructive Nephropathy
- Intraluminal - Renal calculi, renal tumors
- Extramural - Colon tumors, pregnant uterus
- Intramural - Urethral strictures

Definition of Nephrolithiasis - formation of urinary calculi at any level of urinary tract.

Etiology
- Dietary factors
→ Dehydration, low urine volume, altered urinary pH
- Medical conditions
→ Hypercalcemia, UTI (esp. urease-producing bacteria)

Types of Renal Stones
- Calcium stones - can be d/t hypercalcemia, hyperoxalouria, radio opaque, ovoid
- Mixed/Struvite/Staghorn stones - Mg-NH4+-PO43- stone
- Uric Acid stones - radiolucent
- Cystine stones - radiolucent

Pathophysiology of development of renal calculi
- Supersaturation of urine
→ Urine becomes supersaturated with one or more calculogenic substances (calcium, oxalate, uric acid).
→ Crystal begin to form thru the process nucleation.
→ Crystal starts to grow and aggregate
→ Stones enlarge over time → retention in renal tubule
- Inhibitors of stone formation
→ Normal urine contains chelating agents (citrate) that inhibit the nucleation and growth of the crystals.
→ When these substances fall below their normal proportions, stones can form.

S&S
- Severe intermittent pain (from flank to groin to inner thigh) - RENAL COLIC
- Hematuria
- Recurrent UTI
- Hydronephrosis
- Renal failure

Pathogenesis of renal calculi leading to hydronephrosis
- A staghorn calculus occupies the renal pelvis and calyces → obstruction of urine flow → back pressure → dilation of renal pelvis and calyces → hydronephrosis.
- Progressive pressure causes → compression or renal parenchyma → reduce in renal blood flow → gradual loss of kidney function.
- If prolonged → renal atrophy

Morphology
- Gross - large calculus occupying the renal pelvis and calyces
- Microscopic - tubular atrophy and dilation, chronic inflammatory cell infiltration

Complications
- UTI
- Hydronephrosis
- Pyelonephritis
- Hematuria

Diagnosis
- Hx, PE, Urinalysis, Radiographic studies (Abd. X-ray, CT, Ultrasound, Intravenous Pyelography (IVP))
- Blood studies, Urine culture and sensitivity, Renal function test, 24hrs urine collection, collection of stones

Definition of Hematuria - presence of RBC in the urine

Pigments causes RED URINE
- Hemoglobin
- Myoglobin
- Porphyrins
- Betanin
- Drugs (Rifampicin, Phenazopyridine)

Causes of Hematuria
- UTI
- Kidney stones
- BPH
- Polycystic kidney
- Schistosomiasis

ACUTE RENAL FAILURE

Hx of ureteric obstruction. Pt. is hypotensive and dehydrated.

Definition - Acute and potentially reversible irritability of the kidneys to perform their normal function to maintain homeostasis

Causes
- Pre renal failure
→ cardiogenic shock
→ heart failure
→ dehydration
→ eclampsia
- Intra renal failure
→ nephrotoxins
→ acute glomerulonephritis
→ acute pyelonephritis
→ SLE
- Post renal failure
→ Bladder, ureteral and urethral obstruction

Core pathophysiology
- Low GFR → retention of urea, creatinine and toxins → electrolyte imbalances

Phases of ARF
- Oliguric phase → Diuretic phase → Recovery phase

S&S
- Oliguric
- Hypotension
- Lethargy
- Edema
- Hematuria
- GI symptoms
- Flank pain

Complications
→ Hypertensive crisis
→ CRF
→ Electrolyte imbalance
→ Metabolic acidosis
→ Pulm. edema
→ Infection

Diagnosis
- Blood studies → High BUN, Creatinine, Potassium
- Urine studies → Low urine specific gravity
- Creatinine clearance
- ECG - Tall, peaked T waves, widening QRS complex, disappearing P waves if hyperkalemia is present
- Ultrasonography

Findings that affects the fluid and electrolyte balance
- Oliguria (reduced urine output) → d/t fluid retention → increase water reabsorption
- Hyponatremia → d/t dilution and impaired renal handling
- Fluid overload or dehydration
- Increased urea and creatinine → impaired renal excretion
- This occurs d/t ureteric obstruction → low glomerular filtration and disrupting electrolytes regulation

How does hypotension affect urine production
- Hypotension (low BP) → reduced renal perfusion → low GFR
- Less filtrate is formed
- Urine output reduced

Renal compensatory mechanism to fix hypotension
- Kidney activates RAAS
- Renin release → Angiotensinogen → Angiotensin I → Angiotensin II → Vasoconstriction → increase BP
- Aldosterone release will promote Na+ and water reabsorption → increase blood volume
- ADH release also enhances water reabsorption

Pathophysiology
- High urea and creatinine ratio
→ decreased renal perfusion → increase urea reabsorption
→ creatinine less reabsorbed → ratio rises
→ seen in pre renal states like hypotension or dehydration
- Low iron and sodium
→ d/t CKD → less erythropoietin → anemia
→ dilutional effect from water retention via ADH
→ impaired renal Na+ handling
- Postural hypotension
→ severe fluid loss → low intravascular volume
→ low venous return → decrease cardiac output
→ on standing, inadequate cerebral perfusion → dizziness + hypotension
- Oliguria
→ decreased renal perfusion → low GFR → RAAS activation → Na+ and water retention → decreased urine output
- Low urine sodium
→ Kidney attempts to conserve Na+ d/t hypovolemia
→ Aldosterone → Na+ reabsorption in distal nephron → low urinary Na+

ABG Interpretation
- pH - decide whether it is acidic or basic
- HCO3- - if low, maybe d/t lactic acidosis from hyperperfusion + renal failure
- PCO2 - if low, maybe hyperventilation (tachypnea) to raise pH
- Decide whether it is metabolic/respiratory acidosis/alkalosis with renal/respiratory compensation

Management
- Relieve obstruction (catheter, stent, surgery)
- Restore BP and perfusion by giving IV fluids
- Correct electrolyte imbalance
- Monitor renal function
- In severe cases, dialysis may be required

NEPHROTIC SYNDROME

Basic renal processes
- Glomerular filtration (primarily affected in Nephrotic Syndrome)
- Tubular reabsorption
- Tubular secretion
- Excretion

Causes of proteinuria
- d/t damage to glomerular filtration barrier especially the podocytes and basement membrane
- loss of negative charge and size selectivity
- increase permeability → leakage of albumin into urine
- most commonly d/t Minimal Change Disease, where podocyte foot processes are effaced

Link between hypoalbuminemia and periorbital edema
- d/t proteinuria which albumin leaks into urine → low plasma albumin
- low plasma oncotic pressure → fluid shifts from intravascular space into interstitial spaces
- the fluid go to loose CT around the eyes and cause periorbital edema
- worsened by Na+ and water retention

Causes of Nephrotic and Nephritic Syndrome
- Minimal Change Disease//Lipoid Nephrosis//Minimal Change Glomerulonephritis//Nil Disease
- Focal Segmental Glomerulosclerosis (FSGS)
- Membranous Nephropathy - most common cause of nephrotic syndrome in adults
- Diabetic Nephropathy

Pathogenesis
- Glomerular injury (podocyte damage)
- Increase permeability of filtration barrier
- Massive proteinuria
- Hypoalbuminemia develops
- Low plasma oncotic pressure → edema
- RAAS activation → Na+ and water retention → worsens edema
- Liver increase lipoprotein synthesis → hyperlipidemia

Nephrotic VS Nephritic
- Marked proteinuria - Moderate proteinuria
- Absent hematuria - Hematuria
- Significant swelling - Less pronounce
- Severe hypoalbuminemia - Mild to moderate hypoalbuminemia
- Normal or Low BP - High BP
- Frothy urine - Dark or tea-colored urine
- Hyperlipidemia - Mild or absent

CHRONIC KIDNEY DISEASE SECONDARY TO DIABETIC NEPHROPATHY

Anatomy of Filtration Barrier
- Fenestrated endothelium
- GBM
- Podocyte slit diaphragm

Key anatomical changes
- Thickened GBM
- Mesangial expansion
- Damaged podocytes
- Nodular sclerosis of glomerulus
- Proteinuria
- Tubular atrophy
- Blood vessels hyaline thickening

Explain why facial puffiness is obvious in the morning
- When lying down during sleep, fluid redistributes to the face, making swelling more obvious in the morning.
- Children have relatively softer CT, so even small fluid shifts becomes visible early around the eyes.

Pathophysiology
1. Bilateral ankle edema
→ d/t low plasma oncotic pressure → fluid shifts from intravascular space into interstitial space → edema
→ fluid accumulates in gravity-dependent areas

2. Nausea & vomiting
→ d/t low GFR → accumulation of uraemic toxins → stimulation of CTZ + GI irritation

3. Loss of appetite
→ uraemic toxin accumulation → altered taste + central appetite suppression

4. Frothy urine
→ glomerular damage → increase permeability of filtration barrier → proteinuria → reduced surface tension of urine → foam formation

5. Pallor/Anemia
→ CKD → low erythropoietin production → less RBC production in bone marrow → normocytic, normochromic anemia → pallor

6.Lethargy
→ anemia + uremia + metabolic acidosis → less oxygen delivery + toxin effects

7. Hypocalcemia
→ Diseased kidneys cannot convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol) d/t reduced 1a-hydroxylase activity.
→ Low calcitriol → low intestinal calcium absorption.
→ Phosphate retention causes hyperphosphatemia, which binds calcium, further lowering serum calcium → hypocalcemia which contributes to secondary hyperparathyroidism.

8. Proteinuria
- Hyperglycemia damages the glomerular filtration barrier.
- GBM thickening and podocytes injury increase permeability → albumin leaks into urine.

9. Hypertension
- Reduced nephron number → sodium and water retention.
- Decreased renal perfusion activates the RAAS.
- Ang II causes vasoconstriction, aldosterone increases sodium and water reabsorption.
- Increased BV and peripheral resistance → HTN.

10. Hyperkalemia
- Reduced GFR decreases potassium filtration.
- Fewer functioning nephrons reduce potassium secretion in the distal nephron.
- Potassium accumulates in blood.

Why serum sodium (Na+) is normal?
- Sodium balance is regulated by RAAS, ADH and natriuretic peptides.
- Although total body sodium may increase d/t fluid retention, water is retained proportionally.
- Therefore, the serum sodium concentration often remains within the normal range, especially in early to moderate CKD.
- The problem is increased total body sodium, not necessarily an increased serum sodium concentration.

Pathogenesis of CKD
- Chronic hyperglycemia → formation of AGEs + glomerular hyperfiltration → GBM thickening and mesangial expansion →
Podocyte injury → loss of filtration barrier → proteinuria →
Tubulointerstitial fibrosis and nodular glomerulosclerosis →
Progressive nephron loss → reduced GFR → CKD

Management
- Anti hypertensive - ACEi
→ MoA: inhibit ACE
- Diuretics - Furosemide
→ MoA: inhibit Na+-K+-2Cl- cotransporters at thick ascending limb of loop of Henle
- Subcutaneous insulin - enhances peripheral glucose uptake
- Referred to dietician for dietary advice
- Planned for renal dialysis
- Planned for renal transplantation

Creatinine Clearance
Creatinine Clearance = Ucr x V / Pcr
- If Serum Creatinine high = Low GFR
→ Creatinine must be filtered out of the blood.
→ When there’s creatinine in blood, kidney f(x) is impaired → low GFR.
- Why creatinine clearance used to estimate GFR?
→ Creatinine is freely filtered by the glomerulus.
→ It is not reabsorbed by the renal tubules.
→ Only a small amount is secreted by the tubules, so Ccr slightly overestimates true GFR.
→ It is practical and widely used estimate of kidney f(x).

Why the patient is not prescribed with diuretics?
- diuretics act on renal tubules but there is markedly reduced GFR and loss of functional nephrons
- very little drug reaches the site of action
- may reduce intravascular volume → decreased renal perfusion → worsen kidney injury
- may cause electrolyte disturbances

Treatment for Diabetes and HTN
- Metformin (Biguanides) - decrease hepatic glucose production and increase peripheral insulin sensitivity
- Empagliflozin (SGLT2i) - blocks glucose reabsorption in kidneys
- Semaglutide (GLP-1RAg) - mimics incretin hormones to stimulate insulin release
- Losartan (ARB) - block AngII rec directly, preventing blood constriction
- Metoprolol (B-blockers) - blocks adrenaline effects on the heart → low HR and FOC

MEMBRANOUS GLOMERULONEPHRITIS

Membranous Glomerulonephritis = Membranous Nephropathy
→ cause of nephrotic syndrome in adults
→ d/t histopathologic changes in light microscope, immunofluoroscence, and electron microscope.
Minimal Change Disease = Lipoid nephrosis = Minimal change glomerulonephritis = Nil Disease = Foot process disease
Membranous Glomerulonephritis =/ MCD
Membranoproliferative Glomerulonephritis (stand alone)
- All of the above can cause Nephrotic and Nephritic Syndrome

Main criteria to dx Nephrotic Syndrome
1. Massive proteinuria
2. Hypoalbuminemia
3. Generalized edema

Components of Glomerular Filtration Barrier
1. Fenestrated glomerular capillary endothelium
2. Glomerular basement membrane (GBM)
3. Podocytes with slit diaphragm

Factors affecting protein filtration
1. Molecular size of the protein.
2. Electrical charge of the protein and GBM. (Albumin is negatively charged)

Pathophysiology of:
1. Edema
- Damage to filtration barrier especially podocytes and GBM.
- Loss of -ve charge and size selectivity.
- Increase permeability → leakage of albumin into urine (Massive proteinuria).
- Hypoalbuminemia → low plasma oncotic pressure.
- Fluid shifts from intravascular space into interstitial space → generalized edema.
- Reduced effective circulating volume activates RAAS → Na+ and H2O retention → worsening edema.

2. Hyperlipidemia
- Hypoalbuminemia stimulates the liver to increase synthesis of albumin.
- The liver simultaneously increase synthesis of lipoproteins (VLDL, LDL, cholesterol).
- Reduced lipid catabolism also contributes → hypercholesterolemia and hypertriglyceridemia.

Microscopic features of Membranous Nephropathy
1. Light micrscope
- Diffuse thickening of GBM
- No significant hypercellularity
2. Immunofluorescence
- Deposits of IgG and complement along the GBM
3. Electron microscope
- Electron-dense immune deposits in the GBM
- ‘Spike” appearance d/t GBM projection between deposits.

Pathophysiology of Complications:
1. Thrombosis
- Loss of ATIII in urine causes a hypercoagulable state.
- Increased hepatic production of clotting factor (fibrinogen) further promotes thrombosis.
- Common complication: Renal vein thrombosis (especially in membranous nephropathy)

2. Infection
- Urinary loss of immunoglobulins (IgG) reduces humoral immunity.
- Loss of complement factors impairs opsonization.
- Edema fluid can serve as a medium for bacteria growth.
- Pt become more susceptible to bacterial infxn (cellulitis, spontaneous bacterial peritonitis, pneumonia).

SALICYLATE (ASPIRIN) POISONING

Anion Gap = -ve charge of unmeasured ions
Anion Gap = [Na+] + [K+] - ([Cl-] + [HCO3-])
→ if lactic acidosis, we use HCO3- to neutralize the acid from lactic acid dissociation. So in this case, HCO3- is utilized and not replaced with anything → Increase anion gap.
→ if diarrhea, we totally lost HCO3- from the intestinal fluid. But our body retained Cl- to neutralize the electrical charge. No total net lost → Anion gap normal.

Acid-base status in Salicylate Poisoning
- Mixed acid-base disorder
→ Early - Primary respiratory alkalosis (Hyperventilating)
→ Late - Metabolic acidosis (HAGMA)

Henderson-Hasselbalch equation
pH = 6.1 + log [HCO3-]/0.03 x pCO2

Reaction of Hyperventilating
CO2 + H2O ←> H2CO3 ←> H+ + HCO3-
- CO2 combines with water (catalyzed by carbonic anhydrase) to form carbonic acid (H2CO3).
- Carbonic acid dissociates into H+ and HCO3-
- This rxn is reversible and helps maintain acid-base balance.
- In hyperventilation, CO2 is lost, shifting the reaction to the left, decreasing H+ concentration and increasing pH (respiratory alkalosis)

Why HCO3- is low?
1. Early phase
- Hyperventilation lowers PCO2 (respiratory alkalosis)
- The kidneys compensate by excreting bicarbonate, reducing plasma HCO3-.

2. Late phase
- Salicylates uncouple oxidative phosphorylation, causing increased production of lactic acid and ketoacids.
- Bicarbonate is consumed while buffering these excess acids.
- This leads to high anion gap metabolic acidosis.

Renal compensation
- In response to respiratory alkalosis (high pH, low H+), the kidneys:
→ Decrease H+ secretion - don’t want further losses in urine.
→ Decrease HCO3- reabsorption in the PCT.
→ Increase bicarbonate excretion in urine.
→ Retain H+.

How does acetylsalicylic acid cause hyperventilation?
- Salicylate directly stimulates the respiratory centre in the medulla oblongata.
- This increases the rate and depth of breathing (hyperventilation).
- Excessive exhalation of CO2 lowers PCO2.
- The fall in CO2 reduces H+ concentration, producing primary respiratory alkalosis.