4 Renal Disease

Compare the Essential and HTN crisis.

What is Essential Hypertension defined as?

HTN requiring immediate tx when:

• SBP ≥140 mm Hg

• DBP ≥90 mm Hg

How common is hypertensive crisis?

 1% to 2%

What % of HTN is idiopathy?

90% - HTN is 1er

10% - HTN is altering function of organs related to BP (e.g. kidney/heart)

What is Hypertensive urgency?

BP greater than 180/120 mmHg WITHOUT acute end-organ damage

What is hypertensive emergency?

BP greater than 180/120 mmHg WITH acute end-organ damage, such as:

• Renal damage

• Brain damage

• Heart damage

What is the classification of High BP?

How does BP exhibit seasonal variation?

↑ temp = ↓ BP

↓ temp = ↑ BP

What is the new term “ELEVATED” BP mean?

SBP = 120-130

DBP = no elevation

How does renal arteriolosclerosis contribute to worsening hypertension?

1. Renal arteriolosclerosis causes narrowing of the renal blood vessel lumen

2. Kidneys interpret the reduced blood flow as ↓BP

3. Kidneys release renin, activating the RAAS pathway →

4. This causes ↑BP even though BP is already elevated

5. The cycle repeats, causing progressively worsening HTN

List 3 major Renal Changes that occur in HTN. What do these changes do?

1. Glomerulosclerosis

2. Tubular atrophy

3. Scarring (benign nephrosclerosis)

→ these destroy individual nephrons one by one

• when enough nephrons are non-functional through ischemia, the pt slowly develops progressive chronic renal failure (benign hypertensive nephroscerlosis)

  

What effect does HTN have on the heart?

• HTN induced arteriolosclerosis ↑ peripheral resistance → ↑ workload of left side of heart → LVH

  • if workload becomes greater, LHF can occur → pulmonary complications → affect right side of heart

What does Acute pulmonary edema occur due to?

occurs due to HTN causing LVF → right sided hypertrophy & failure

What do changes in coronary arteries (pro- atherogenic) lead to?

MI

What are the Aortic Complications in HTN?

• Cystic medial necrosis → aortic dissection

• atherosclerotic plaques in the aorta can ulcerate with consequent aneurysm formation or embolization of atheromatous material

What is the triple A?

1. Abdominal

2. Aortic

3. Aneurysm

Why might someone with aortic issue have a CC of “back pain”?

aorta is retroperitoneal

What are the Brain Complications in HTN?

• System HTN = risk factor for stroke and transient ischemic attacks caused by extracranial atherosclerosis

  • also risk factor for Alzheimers in later life

• 1er hemorrhage may occur into the cerebral hemispheres, brainstem or cerebellum due to rupture of microaneurysms

• Congenital aneurysms of the Circle of Willis → rupture → subarachnoid hemorrhage

What is the role of the RAAS in essential hypertension?

• circulating RAS is not considered the main direct cause of ↑ BP in essential HTN

  • many hypertensive patients have low renin and Ang 2 levels

    • esp older and Black pt

    • drugs directly blocking renin aren’t effective in many of these patients

• ACE inhibitors and Ang II receptor blockers (ARBs) are effective in treating HTN

What are the characteristics of young hypertensive patients related to sympathetic activity?

1. ↑ circulating catecholamines

2. ↑ HR

3. ↑ vascular reactivity to NE

How does sympathetic stimulation of the kidneys increase BP?

β-adrenergic stimulation of the kidneys ↑ renin secretion, activating RAAS pathway and ↑BP

How do psychological and repetitive stress increase blood pressure chronically?

• Cortical inhibition of depressor reflexes

• Direct stimulation of sympathetic centers

List what ↑ SNS activity lead to.

• Arteriolar and venous vasoconstriction

• Stimulates Renin release from the kidney

• ↑ CO

• Catcholamine and mineralocorticoid release

• Pre-hypertensives have an elevated resting pulse rate

How can Na⁺ retention lead to ↑BP?

1. ↓ Filtration SA due to a congenital or acquired deficiency in the # or functions of nephrons

2. ↑ Renin secretion due to afferent arteriolar narrowing in some nephrons (“Nephron Heterogeneity”)

3. Acquired inhibitor of Na⁺ pump

4. ↓ responsiveness to atrial natriuretic hormone

What’s responsible for the ↑ vascular resistance of HTN in the absence of arteriolosclerosis?

↑ intracellular Na⁺ in vascular smooth muscle

• this leads to ↑Ca²⁺ → ↑ resting tone of the vascular smooth muscle by 50% → ↑ vascular resistance

What is the main salt active steroid?

Aldosterone

Where is aldosterone made? What controls it?

• Synthesized in the zona glomerulosa of adrenal cortex

• Controlled by Ang 2

• ↑ Na⁺ reabsorption → K⁺ excretion by the distal nephron

What is endothelin?

→ powerful, vascular, endothelial vasoconstrictor

• may produce a salt sensitive ↑ BP

• activates local RAAS

What is Nitric Oxide (NO)?

→ Endothelial derived relaxant factor produced by arterial and venous endothelium

• causes vasodilatation

What is Atrial natriuretic peptide?

→ hormone secreted from the atria in response to ↑ BV

• ↑ Na⁺ & H₂O from the kidney

• defect → fluid retention & HTN

List 3 major mechanisms of essential HTN.

1. ↑ CO (from ↓ PR) via adrenergic hyperactivity or altered Ca²⁺ homeostasis

2. ↑ PR (but normal CO) due to ↑ vasoreactivity/arteriolosclerosis

3. ↑ Salt and water retention → ↑ Blood volume

What lifestyle changes help reduce blood pressure in essential hypertension?

• Low-sodium diet

• High-vegetable diet

• Regular exercise

• Weight loss

List 4 physiological mechanisms through which HTN treatments lower BP.

1. ↓ Fluid volume - excrete excess Na⁺ and the H₂O that follows it

2. ↓ PR - inhibit ACE-mediated and SNS vasoconstriction

3. ↓ HR - inhibit SNS stimulation of the heart

4. ↓ SV - ↓ SNS stimulation of ventricular contraction (negative inotropic effect)

What is the 1er apporach to meds for tx HTN?

A – ACE inhibitors and ARBs

• ✅ kidney disease

• ✅ diabetics

• ✅ CHF

• ✅ post-MI

• ✅ white + young ppl

B – β-blockers

• ✅ CHF

• ✅ post-MI

• ✅ white + young ppl

C – Ca²⁺ channel blockers

• ✅ African Americans + elderly

D – Diuretics

• ✅ African Americans + elderly

How do thiazide diuretics lower blood pressure?

1. Block Na⁺/Cl⁻ symporter in the DCT

2. ↓ Na⁺ and Cl^- reabsorption

3. ↓ Water reabsorption → ↑ fluid loss

4. ↓ Blood volume → ↓ Cardiac output → ↓ BP

What electrolyte changes can thiazide diuretics cause?

↓ K⁺: ↑ K⁺ loss → hypokalemia risk

↑ Ca²⁺: ↑ Ca²⁺ reabsorption in DCT → risk of hypercalcemia

Who should thiazide diuretics be avoided or used cautiously in?

• Hypercalcemia

• Kidney stones

• Gout

List and describe 3 ways to ↓ Peripheral Resistance.

1. Inhibit ACE-induced vasoconstriction

   • ACE inhibitors

   • ARBs

   • ↓ Renin production

2. Inhibit sympathetic stimulated vasoconstriction

   • α-blockers

3. Direct Vasodilators

List and describe 2 ways to ↓ HR/SV.

1. Inhibit sympathetic inputs that would ↑ HR

   • B- blockers - decreases HR & SV

2. Inhibit heart contractility and vascular smooth muscle contraction

   • Ca²⁺ channel blockers

Who are Beta-blockers contraindicated in?

• Bradycardia (e.g. heart block) conditions

• Breathing problems (e.g. COPD)

How does injury to the glomerular basement membrane and podocytes affect kidney function?

Glomerular Basement Membrane (GBM)

• made of type 4 collagen + other matrix proteins

• attacked by antibodies in certain types of glomerulonephritis

• Genetic abnormalities in proteins → hereditary nephritis

Podocytes (visceral epithelial cells)

• make up glomerular filtration barrier

• injury damages the filtration barrier → allow proteins to leak into the urinary space → proteinuria

What are acute glomerular response to injury?

• hypercellularity with proliferation of mesangial and/or endothelial cells

• leukocyte influx

• formation of crescents in severe injuries

What are chronic glomerular response to injury?

• BM thickening

• hyalinosis

• sclerosis

What causes pyelonephritis, and how can bacteria reach the kidneys?

• Ascending infection: reflux of infected urine from a UTI (bladder) back toward the kidneys

• Bloodstream spread: Bacteria travel through the blood to infect the kidneys

Note: 3 antireflux mechanisms (pseudovalves) b/w the kidney and bladder help prevent backward flow of urine

What is the main sx of painful urination?

Urethritis

List the 3 main causes of Urethritis.

1. E. coli - bacteria transferred from stool

   • can produce cystitis and pyelonephritis

2. Neisseria gonorrhoeae - sexually transmitted (causes gonorrhea) confined to urethra

3. Chlamydia trachomatis - sexually transmitted (causes chlamydia) confined to urethra

What is Reiters Syndrome?

1. Arthritis

2. “Sterile” urethritis

3. Conjunctivitis/anterior uveitis

What does sterile urethiris mean?

→ urine sample you ordered was put onto nutrient agar and nothing grew out (not gonorrhea or E-coli)

• chlamydia WON’T grow on standard agar

• it’s an obligate intracellular parasite so it must be grown on any of these treated with cycloheximide: McCoy, HEp-2, HeLa, or buffalo green monkey cells

List 6 common mechanisms by which medications cause nephrotoxicity (kidney injury).

1. Altered intraglomerular hemodynamics

2. Tubular cell toxicity

3. Inflammation

4. Crystal nephropathy

5. Rhabdomyolysis

6. Thrombotic microangiopathy

What is the Normal GFR?

120 mL/ min - kidney autoregulates intraglomerular pressure by modulating the afferent and efferent arterial tone to preserve GFR and urine output

In patients with volume depletion, renal perfusion depends on circulating __________ to _____________, allowing more blood flow through the glomerulus.

In patients with volume depletion, renal perfusion depends on circulating prostaglandins to vasodilate the afferent arterioles, allowing more blood flow through the glomerulus.

What is Intraglomerular pressure sustained by?

via Ang 2 mediated vasoconstriction of the efferent arteriole

What drugs can interfere with the kidneys' ability to autoregulate glomerular pressure and ↓ GFR?

Drugs with:

• antiprostaglandin activity (NSAIDs)

• anti-Ang-II activity (ACE inhibitors, ARBs)

How can drugs cause tubular cell toxicity?

• interfering with tubular transport

• impairing mit function

• ↑ oxidative stress

• forming free radicals

What is Glomerulonephritis?

→ inflammatory condition caused primarily by immune mechanisms

• associated with proteinuria

• causes by gold therapy, IFN-a, lithium, NSAIDs

What is Acute interstitial nephritis caused by?

→ results from an allergic response to a suspected drug

• develops in an idiosyncratic, non–dose-dependent fashion

What is Crystal nephropathy?

→ Renal impairment that results from the use of drugs that produce crystals that are insoluble in human urine

• crystals precipitate in the DCT lumen → obstruct urine flow

  • likelihood of developing crystal precipitation depends on [drug] in the urine & urinary pH

• At risk: volume depletion & underlying renal insufficiency

What are commonly prescribed drugs associated with production of crystals?

• antibiotics

• antivirals

• methotrexate

What is Rhabdomyolysis?

→ syndrome where skeletal muscle injury

• myocyte lysis releases intracellular contents (myoglobin and creatine kinase) into plasma

  • Myoglobin - induces renal injury 2er to direct toxicity, tubular obstruction, and GFR alterations

• weakness, myalgia & tea-colored urine

• Causes: Statins, drug abuse, alcohol

• 50% subsequently develop acute renal failure

What is Thrombotic microangiopathy?

→ organ damage is caused by platelet thrombi in the microcirculation

• caused by renal injury 2er to drug-induced thrombotic microangiopathy (e.g., immune-mediated reaction or direct endothelial toxicity)

What is Tubular interstitial nephritis and Uveitis Syndrome (TINU)?

Demographics: young females, 15 years

Sx:

• Renal: Fever, malaise, fatigue, flank pain

• Ocular: Acute anterior uveitis (eye inflammation)

Risk factors: Certain HLA genetic variants (HLA-DQA1 and DRB1) and meds (antibiotics & NSAIDs)

Prognosis:

• Nephritis usually resolves before uveitis

• Nephritis rarely recurs

• Uveitis recurs in approximately 40% of cases

Diagnostic markers:

• ↑ urinary β2-microglobulin (β2M)

• ↑ urinary protein

• ↑ serum creatinine

What is Creatinine?

→ waste product of creatine metabolism

• produced muscle when creatine is metabolized to generate energy so it’s produced constantly.

• directly filtered through the kidneys (shows how efficient kidneys are)

What is Cystatin-C?

→ made by ALL nucleated cells

• may replace creatinine

What is BUN?

→ measure of renal health

• normal range is 1.8-7.1 mmol/L or 6–20 mg/dL

List the main causes of ↑ BUN.

• High protein diet

• ↓ GFR (suggests renal failure)

• ↓ BV

• Congestive HF

• Gastrointestinal hemorrhage

What is Proteinuria a sign of? What is it commonly caused by?

renal capillary endothelial damage

• commonly caused by diabetes

How do creatinine and BUN reflect kidney function, and why are both measured?

Creatinine

• Produced by muscle breakdown of creatine at a relatively constant rate

• Filtered by the glomerulus

• A small amount is also secreted by the renal tubules

• slightly overestimates GFR

• ↓ GFR → ↓ creatinine clearance → ↑ blood creatinine

BUN (Blood Urea Nitrogen)

• Urea is produced in the liver from protein (amino acid) breakdown

• Filtered by the glomerulus

• Unlike creatinine, some urea is reabsorbed by the kidneys

BUN-to-creatinine ratio helps distinguish causes of kidney dysfunction:

• Prerenal: ↓ blood volume/perfusion (e.g., dehydration)

• Renal: Intrinsic kidney damage

Define Azotemia.

→ increases in nitrogen-containing compounds (urea, creatinine)

• related to insufficient or dysfunctional filtering of blood by the kidneys

What are the 3 types of azotemia, their causes?

Prerenal Azotemia

• Caused by decreased blood flow/perfusion to the kidneys (e.g., dehydration)

• No intrinsic kidney damage initially

• BUN:Creatinine ratio is typically greater than 20:1

Renal (Intrinsic) Azotemia

• Caused by damage to the kidney tissue (renal parenchyma)

• e.g., Renal failure, glomerulonephritis, acute tubular necrosis

• Decreased GFR → increased BUN and creatinine

• BUN:Creatinine ratio is typically less than 15:1

Postrenal Azotemia

• Caused by obstruction of urine flow below the kidneys

• Causes:

  • Kidney or bladder stones

  • Enlarged prostate (BPH)

  • Tumors compressing the ureters

  • Congenital abnormalities or pregnancy

• Urine backs up into the kidneys → hydronephrosis

• No initial intrinsic kidney disease

What is the BUN:Cr postrenal azotemia initially?

>15

How does prolonged urinary obstruction affect BUN and creatinine levels in postrenal azotemia?

Initially:

• Urine backs up → ↑ tubular pressure

• ↑ urea reabsorption → ↑ BUN relative to creatinine

• ↑ BUN:Cr ratio

With prolonged obstruction:

• Tubular epithelial damage develops

• ↓ Kidney function

• ↓ BUN:Cr ratio (resembles intrinsic renal azotemia)