Renal Function

Core Roles of the Kidneys

• Urine formation

• Fluid and electrolyte balance

• Acid–base regulation

• Excretion of waste (esp. nitrogenous waste from protein metabolism)

• Drug and toxin elimination

• Hormone secretion:

  • Renin → blood pressure regulation

  • Erythropoietin → RBC production

  • 1,25-dihydroxyvitamin D₃ → calcium regulation

  • Prostaglandins → local vasodilation, perfusion support

Purpose of Kidney Function Testing

• Evaluate renal disease

• Assess hydration status (water balance)

• Detect acid–base imbalances

• Monitor renal impact in:

  • Trauma

  • Head injury

  • Surgery

  • Infectious disease

Glomerular Filtration — Structure & Selectivity

• Site: First part of nephron (glomerulus)

• Function: Filters incoming blood

• Facilitating Factors:

  • High glomerular capillary pressure

  • Semipermeable basement membrane (~66 kDa cutoff ≈ albumin)

  • Negatively charged membrane repels proteins

• Filtered: Water, electrolytes, glucose (partly reabsorbed), amino acids (completely reabsorbed), LMW proteins, urea, creatinine

• Excluded: Albumin, large plasma proteins, cells, lipids, bilirubin

Glomerular Filtration — Rate & Clinical Utility

• Renal blood flow: 1200–1500 mL/min

• Filtrate produced: 125–130 mL/min (protein- & cell-free)

• Key metric: Glomerular Filtration Rate (GFR)

  • Essential for assessing renal function

Renal Tubular Anatomy Summary

• Glomerulus (Bowman's Capsule)
  • Located at the start of the nephron
  • Filters blood plasma into filtrate

• Proximal Convoluted Tubule
  • In the renal cortex
  • Major site of reabsorption of water, electrolytes, nutrients

• Loop of Henle
  • Descends into medulla, then ascends back
  • Establishes medullary concentration gradient (via countercurrent mechanism)
  • Descending limb: permeable to water
  • Ascending limb: permeable to Na⁺/Cl⁻, impermeable to water

• Distal Convoluted Tubule
  • In the cortex
  • Fine-tunes electrolyte and pH balance

• Collecting Duct
  • Formed from multiple distal tubules
  • Final site of water/electrolyte regulation, responsive to ADH/aldosterone

Tubular Physiology Overview

• 3 Core Renal Processes
  • Glomerular filtration: blood → tubule
  • Tubular reabsorption: tubule → blood
  • Tubular secretion: blood → tubule

• Substance Handling
  • NH₃ (Ammonia): filtered & secreted, not reabsorbed
  • Glucose: filtered, partially reabsorbed (reabsorption saturates if threshold exceeded)
  • Amino acids: filtered & completely reabsorbed

PCT – Filtrate Reception & Content

Receives filtrate from glomerulus (cell- and protein-free)
• Filtrate contains both waste and valuable solutes

PCT – Reabsorption Function

Returns valuable solutes (glucose, amino acids, ions) to blood via active transport
• Water follows passively (except for chloride, which also moves passively)
• Renal threshold = concentration beyond which solutes appear in urine

PCT – Secretion Function

Moves substances from peritubular capillaries → tubular lumen
• Also secretes metabolic waste from tubule cells into filtrate

Loop of Henle Role

Hairpin loop between PCT and DCT
• Maintains medullary hyperosmolality via countercurrent multiplier
• Descending limb: water reabsorbed
• Ascending limb: Na⁺ & Cl⁻ reabsorbed (impermeable to water)

Distal Convoluted Tubule Function

• Shorter segment; final adjustments to filtrate

• • Key site for electrolyte balance & acid-base fine-tuning

Hormonal Regulation

Aldosterone

• Source: Adrenal cortex

• Stimulus: Renin–angiotensin mechanism

• Effect:

  • Increases sodium reabsorption

  • Promotes potassium and hydrogen ion secretion

  • Acts primarily on distal tubule

Hormonal Regulation

AVP (ADH)

• Full Name: Arginine Vasopressin (aka ADH)

• Source: Posterior pituitary

• Stimulus: Increased plasma osmolality

• Effect:

  • Increases water reabsorption

  • Makes distal tubule & collecting duct walls permeable to water

Hormonal Response Cascade

• ↓ Blood pressure/volume → Renin release → Angiotensin II → Aldosterone → ↑ Na⁺ reabsorption → ↑ blood volume

• ↑ Osmolality → Hypothalamus → Posterior pituitary → AVP → ↑ water reabsorption → ↓ osmolality

Collecting Duct Function

• Final site for urine concentration/dilution

• Hormonal targets:

  • AVP: ↑ water reabsorption

  • Aldosterone: ↑ sodium reabsorption

• Also reabsorbs: chloride and urea

• Urea: helps maintain medullary hyperosmolality

• Ducts are highly permeable, especially under hormonal influence

NPNs Overview

• Definition: Waste products of protein & nucleic acid metabolism

• Sources: Degradation of nucleic acids, amino acids, proteins

• Key Compounds:

  • Urea

  • Creatinine

  • Uric acid

Urea/BUN

• Major NPN (>75%)

• Synthesized in the liver from ammonia (protein → amino acids → ammonia → urea)

• Prevents toxicity by converting toxic ammonia

• Filtered by glomerulus

• 40–60% reabsorbed in collecting ducts

Creatinine Metabolism

• Derived from muscle creatine phosphate via creatine kinase (first muscle fuel source)

• ~20% of muscle creatine → creatinine daily

• Amount produced correlates with muscle mass

• Filtered by glomerulus, not reabsorbed

Uric Acid Excretion

• End product of purine metabolism

• Freely filtered at glomerulus

• Undergoes both reabsorption and secretion in tubules

• Final excretion: only 6–12% of filtered load

Build up can lead to gout

Water Balance Regulation

• Controlled by AVP (arginine vasopressin) in response to ↑ plasma osmolality

• Dehydration → max H₂O reabsorption in renal tubules (up to 1200 mOsm/L)

• Water excess → excretion of dilute urine (as low as 50 mOsm/L)

• Hypothalamus stimulates thirst and AVP release

• Fine-tunes fluid status between extremes

Sodium Role in Renal Balance

• Primary extracellular cation

• Balance controlled solely by excretion

• Regulated via renin-angiotensin-aldosterone system (RAAS)

• Sodium reabsorption influenced by aldosterone

Potassium Role in Renal Balance

• Primary intracellular cation

• Competes with H⁺ in exchange for Na⁺

• Filtered by the glomerulus and reabsorbed

• Plays a role in acid-base and electrical balance

Chloride Role in Renal Balance

• Principal extracellular anion

• Maintains extracellular fluid volume and osmotic pressure

• Passively reabsorbed with Na⁺

Phosphate Role in Renal Balance

• Predominantly intracellular anion

• Exists in protein-bound and non-protein-bound forms

• Higher concentration inside cells than outside

• Renal handling regulated by parathyroid hormone (PTH)

Calcium Role in Renal Balance

• Second most abundant intracellular cation

• Circulates in protein-bound and non-protein-bound forms

• Non-protein-bound fraction can be ionized or unionized

• Ionized calcium is freely filtered by the glomerulus

Magnesium Role in Renal Balance

• Major intracellular cation

• Acts as enzyme cofactor

• Exists in both protein-bound and ionized forms

• Ionized magnesium is filtered and reabsorbed by the kidney

Renal Role in Acid-Base Balance

• One of 3 pH regulation systems (with respiratory & buffering)

• Conserves HCO₃⁻ and excretes metabolic acids

• Regenerates bicarbonate ions

• Excretes acid via:
  • Binding to ammonia → NH₄⁺
  • Reaction with monohydrogen phosphate (HPO₄²⁻)

Endocrine Function of the Kidney

• Acts as both a hormone producer (primary) and target (secondary)

• Synthesizes key hormones:
  • Renin – blood pressure regulation
  • Erythropoietin – RBC production
  • 1,25-dihydroxyvitamin D – calcium/phosphate metabolism
  • Prostaglandins – local blood flow and inflammation modulation

Renin

• RAAS Initiator

• Initial component of RAAS

• Synthesized by renal medulla

• Catalyzes conversion of angiotensinogen to angiotensin I

Erythropoietin

• RBC Production Hormone

• Acts on erythroid progenitor cells in bone marrow

• Stimulates erythropoiesis

• ↓ in chronic renal insufficiency → anemia

1,25-Dihydroxyvitamin D – Active Vitamin D

• Formed in kidney

• Regulates Ca²⁺ & phosphate homeostasis

• Promotes bone calcification

• Deficiency in renal disease → osteomalacia

Prostaglandins

• Renal Vasodilators

• produced by kidneys (local effect)

• ↑ renal blood flow, Na⁺/H₂O excretion, renin release

• Counteracts vasoconstriction from angiotensin & norepinephrine

• Group of potent cyclic fatty acids

Creatinine Clearance – GFR Estimation Tool

• Ideal for measuring clearance: freely filtered, not reabsorbed

• Produced at constant rate (muscle metabolism)

• Excreted solely by glomerular filtration

• Directly correlates with muscle mass

• Calculation compares 24-hr urine & serum creatinine to estimate GFR

• Know the formula for the test

Estimated GFR – Clinical Use & Advantages

• Recommended with every serum creatinine by NKF

• Uses creatinine + age, sex, body size, race for estimation

• No urine collection required

• More routinely performed than CrCl

• Detects chronic kidney disease (CKD) earlier

Evolution of eGFR Estimation Formulas

• Cockcroft-Gault: Early formula; no BSA correction; assumes ↓CrCl in women

• MDRD: Adds BSA correction; no weight input; uses age, sex, race, serum Cr

  • Underestimates in healthy, overestimates in underweight

• CKD-EPI (2009): Less weight bias, more accurate; still uses race

CKD-EPI 2021 and Modern eGFR Estimation

• Updated CKD-EPI equation (2021)

• Uses creatinine, age, sex

• Optionally includes Cystatin C

• Eliminates race as a variable

Cystatin C in Renal Assessment

• Low molecular weight protein; produced at steady rate by most tissues

• Freely filtered by glomerulus, reabsorbed & catabolized in proximal tubule

• Rises earlier than creatinine in acute kidney injury (AKI)

• Detects ↓GFR before creatinine changes

• Measured via immunoassay methods

Creatinine vs. Cystatin C in Monitoring Renal Function

• Biologic variation: fluctuation around a homeostatic point

• Creatinine:

  • Greater variation between individuals than within a single person

  • Better for long-term renal monitoring

• Cystatin C:

  • Less variation between subjects

  • More sensitive to minor renal impairment

β₂-Microglobulin and Renal Function

• Small, non-glycosylated peptide on most cell surfaces

• Shed into plasma at a constant rate

• Freely filtered by glomerulus; 99.9% reabsorbed by proximal tubules

• Elevated serum: ↑ cell turnover (e.g., myeloproliferative, lymphoproliferative disorders, inflammation, renal failure)

• Used in blood & urine to assess kidney damage, distinguish glomerular vs tubular disorders

• Transplant monitoring: elevated levels may signal renal rejection

Myoglobin and Renal Implications

• Type: Low molecular weight protein

• Role: Binds and transports O₂ from plasma membrane to mitochondria of muscle cells

• Toxicity: Nephrotoxin

• Clinical association:

  • Released during acute skeletal or cardiac muscle injury

  • Rhabdomyolysis: massive myoglobin release → proximal tubule overload → acute renal failure (high Hgb, low RBC on dipstick)

• Diagnostics: Early detection critical; measured by immunoassays

Albuminuria

• Aka microalbuminuria—*presence of albumin in urine*

• Early marker of diabetic nephropathy

• Due to glomerulosclerosis → ↑ glomerular permeability

• 30–300 mg/day in 24-hr collection diagnostic

• Random urine w/ creatinine: ACR >30 mg/g = albuminuria

• Early detection allows for prevention via BP & glucose control

NGAL in AKI Detection

• Neutrophil Gelatinase-Associated Lipocalin (NGAL)

• 25-kDa protein from neutrophils and epithelial cells (esp. proximal tubule)

• Detectable in plasma/urine within 2–6 hrs of AKI onset

• May elevate in systemic stress (non-AKI)

• Research use only

NephroCheck for AKI Risk

• FDA-cleared test

• Identifies risk of moderate–severe AKI in critically ill patients

• Predictive window: next 12 hours

AKI = acute kidney Injury

Specimen Collection (Urinalysis)

• First morning urine preferred — more concentrated (esp. for protein)

• Clean-catch midstream or catheterization

• Stable: 1 hr RT or 8 hrs refrigerated (2–8 °C)

• Improper storage → bacterial overgrowth
    → false + nitrite
    → urease activity → urea → ammonia → ↑ pH
    → CO₂ loss → ↑ pH
    → cast degradation, RBC lysis

Urine Color Findings

• Correlates with concentration

• Yellow/amber = urochromes

• Yellow-brown to green = bile pigment oxidation

• Red/brown after standing = porphyrins

• Red/brown fresh = hemoglobin or RBCs

• Brownish black after standing = alkaptonuria

• Drugs/foods may alter color (beets, asparagus, food dyes)

Urine Odor Characteristics

• Minimal clinical significance

• Foul = UTI

• Sweet/fruity = diabetes mellitus

• Maple syrup odor = maple syrup urine disease

Urine Clarity Parameters

• Cloudiness depends on pH and dissolved solids

• May be affected by particulates

Urine Volume Significance

• Normal range: 750–2000 mL/24 hrs (avg ~1.5 L/day)

• Polyuria: diabetes mellitus or diabetes insipidus

• Oliguria/Anuria (<200 mL/day): nephritis, obstruction, AKI, renal failure

Specific Gravity (SG)

• Measures density of dissolved solids

• Reflects hydration status or kidney concentrating ability

• Method: Refractive index

• Normal range: 1.003–1.035

• Low SG: diabetes insipidus, pyelonephritis, glomerulonephritis

• High SG: diabetes mellitus, CHF, dehydration, liver disease, adrenal insufficiency, nephrosis

Urine pH Overview

• Perform on fresh specimen

• Alkalinizes on standing

• Normal range: 4.7–7.8

• Acidity = phosphates

• Alkalinity = Na⁺/H⁺ exchange (retains Na⁺ → ↑pH)

• Alkaline causes: gastric HCl in duodenum, alkaline foods/meds, UTIs, contamination, Fanconi syndrome

Urine Glucose Testing

• Normal result: Negative

• Glucosuria occurs when renal threshold exceeds 180 mg/dL

Urine Ketone Testing

• Hallmark of diabetes mellitus

• Ketonuria may indicate ketoacidosis

Urine Protein Testing

• Detects primarily albumin

• May show false positives with alkaline or highly buffered urine

• Confirm with more specific assays

• Evaluate for casts as supportive evidence

Urine Nitrite Testing

• Semi-quantitative for urinary nitrate reduction

• Positive: suggests presence of nitrite-reducing bacteria (gram-negatives)

• Negative: doesn’t rule out infection (e.g., gram-positive organisms)

Bilirubin in Urine

• Product of hemoglobin degradation

• Converted to urobilinogen in the gut

• Presence may indicate liver dysfunction or biliary obstruction

Urobilinogen in Urine

• Normally present in trace amounts

• Reported as normal (not negative)

• Elevated in liver disease or hemolysis

Blood in Urine

• Positive with intact or lysed RBCs

• Seen in:

  • Renal trauma

  • Infections

  • Obstruction (e.g. stones, tumors)

• May also detect myoglobin

RBCs in Urine

• 2 RBCs/hpf = abnormal

• Possible causes: trauma, vascular injury, calculi, pyelonephritis, cystitis

• Contamination: menstrual blood, post-exercise

• Hematuria + WBCs suggests infection

WBCs in Urine

• 5 WBCs/hpf = abnormal

• Typically neutrophils

• Seen in: glomerulonephritis, UTI, inflammation

• In dilute urine → can appear enlarged & sparkle (glitter cells), no pathologic significance

Epithelial Cells in Urine

• Types: squamous, renal, transitional

• Squamous: common contaminant

• Renal: associated with tubular injury

• Transitional: from bladder/ureter lining

Miscellaneous Elements in Urine

• Spermatozoa: age/gender dependent

• Yeast: small, oval, budding

• Trichomonas (STI): motile flagellated parasites

Bacteria in Urine

• Normal urine = sterile

• <20 orgs/hpf = possible contamination

• 20 orgs/hpf = clinically significant

• Most are Gram-neg rods

• Asymptomatic bacteriuria in high-risk groups can lead to pyelonephritis if untreated

Hyaline Casts

• Composed of Tamm-Horsfall protein

• Clear, gelatinous matrix

• Often normal in small numbers

• ↑ in glomerular protein leakage

• Phase contrast helps ID

Granular Casts

• Coarse or finely granular texture

• Common in chronic lead toxicity, pyelonephritis

• Occasional presence = not necessarily pathologic

Cellular Casts

• RBC Casts: glomerulonephritis

• WBC Casts: nephron inflammation (e.g., pyelonephritis)

• Epithelial Casts: can be normal occasionally

• Waxy Casts: always pathologic, late stage renal disease

• Fatty Casts: lipiduria (e.g., nephrotic syndrome)

• Broad Casts: severe stasis, end-stage renal failure

Crystals

Acidic Urine

• Calcium oxalate

• Amorphous urates

• Uric acid

• Cholesterol: nephrotic syndrome

• Cystine: pathologic, seen in cystinuria/homocystinuria

Crystals

Alkaline Urine

• Amorphous phosphates

• Calcium carbonate

• Triple phosphate (struvite) pictured

• Ammonium biurate

Pathologic Crystals

• Leucine

• Tyrosine

• Cystine

• Sulfonamides

• Cholesterol

Glomerular Damage Progression

• Glomerular damage may initially preserve normal function

• As disease progresses → tubular involvement ensues

Acute Glomerulonephritis

• Glomerular lesions → ↓ capillary lumen, inflammation

• Rapid onset: hematuria + proteinuria

• Lab: ↓ GFR, anemia, ↑ BUN & creatinine, oliguria, Na⁺/H₂O retention, CHF

• Hyaline, granular, and especially RBC casts

• Commonly post-β-hemolytic strep

• Other causes: drugs, AKI, immune complex disease

Chronic Glomerulonephritis

• Prolonged inflammation → nephron scarring/loss

• Often subclinical early

• Slight ↓ renal function, mild proteinuria & hematuria

Nephrotic Syndrome Overview

• Caused by glomerular basement membrane injury → ↑ permeability

• Key findings:
  • Massive proteinuria → hypoalbuminemia
  • Generalized edema
  • Hyperlipidemia + lipiduria (oval fat bodies)

Nephrotic Syndrome Pathophysiology

• ↑ Glomerular permeability → heavy proteinuria

• Proteinuria results in:
  • Hypoalbuminemia → edema, ↑ lipoprotein synthesis → hyperlipidemia
  • Hypogammaglobulinemia → ↑ infection susceptibility
  • Loss of antithrombin III → hypercoagulability

Tubular Disease Progression

• Tubular defects arise as GFR declines in renal disease

• Tubular dysfunction may become the dominant issue

• Leads to:

  • ↓ Excretion or reabsorption of substances

  • ↓ Urinary concentrating ability

Renal Tubular Acidosis (RTA): Types

• Clinically important tubular disorder affecting acid-base balance

• Distal RTA: tubules can't maintain pH gradient between blood and tubular fluid

• Proximal RTA: ↓ Bicarbonate reabsorption → hyperchloremic acidosis

RTA: General Findings

Rental Tubular Acidosis

• ↓ Serum phosphorus and uric acid

• Glucose and amino acids in urine

• Mild proteinuria possible

• Interstitial nephritis may cause:

  • ↓ GFR, ↓ urine concentration, ↓ acid excretion

  • WBC casts in urine

  • Na⁺ imbalance

Infection

• Pyelonephritis (kidneys) vs Cystitis (bladder)

• Diagnostic if >10⁵ colonies/mL

• Bacteriuria = nitrite+, hematuria, pyuria

• WBC casts = diagnostic for pyelonephritis

Obstruction

• Raises intratubular pressure, causes nephron necrosis

• Predisposes to infections

• Upper: obstructed collecting duct

• Lower: residual urine, slow voiding

• Causes: tumors, congenital/acquired disease

• ↓ GFR, ↓ concentrating ability, ↓ acid excretion

• Dx: urinalysis, culture, BUN/Cr, CBC, imaging

Renal Calculi Overview

• Kidney stones = crystallized substance aggregates

• Calcium oxalate = most common type

• Caused by ↓ urine flow rate + ↑ insoluble substances in urine

• Symptoms:
  • Hematuria
  • UTIs
  • Abdominal pain (characteristic)

Acute Kidney Injury (AKI)

• Sudden drop in renal function from toxic or hypoxic insult

• 50% of Pts admitted to ICU

• Diagnosed using:
  • Serum creatinine
  • Urinary output

Prerenal AKI

• Blood supply defect before reaching kidneys

• Caused by cardiovascular failure → hypovolemia

Intrinsic AKI

• Defect occurs within the kidney

• Most common: acute tubular necrosis

• Also caused by glomerulonephritis or vascular obstruction/inflammation

Postrenal AKI

• Defect in urinary tract after the kidney

• Caused by lower urinary obstruction or bladder ruptureRenal Hypertension

Renal Hypertension

• Caused by decreased renal perfusion (trauma, artery/arteriole narrowing)

• Chronic ischemia → nephron dysfunction & necrosis

• Triggers RAAS activation → vasoconstriction → persistent hypertension

• Lab findings: ↑ aldosterone, ↑ serum Na, ↓ serum K, ↑ urine K

Acute Kidney Injury: Dialysis Therapy

• Indications: uremic symptoms, hyperkalemia, acidosis

• Only options in irreversible failure:
  • Traditional dialysis
  • Peritoneal dialysis

• Monitoring via lab tests required

• Most effective dialysis = 10–12% of normal kidney function

• Associated with physical disability and reduced quality of life

Hemodialysis

• Synthetic membrane outside the body

• Arterial blood pumped through dialysate at high speed

• Blood returned to venous circulation; dialysate discarded

Peritoneal Dialysis (CAPD)

• Peritoneal wall serves as dialysate membrane

• Less efficient: small solutes (e.g. K⁺) cleared slowly

• Steady clearance of larger solutes over time

Hemofiltration

• Continuous venovenous or arteriovenous systems

• Combines hemofiltration + dialysis for slow, sustained clearance

• Used in intensive care (continuous renal replacement therapy)

Kidney Transplantation

• Offers best chance for full recovery

• Limited donor supply → wait times range months to years

• Donor source: 80% cadaver, 20% live (live grafts = better outcomes)

• Requires ABO & HLA matching + lifelong immune suppression

• Grafts can last decades (mean half-life cadaver: 7 yrs)

• 3-yr survival: 65–85% (higher with live donor)

• Survival similar across CAPD, hemodialysis, cadaver transplant

Chronic Renal Failure (CKD)

• Incidence rising due to diabetes, aging, obesity, metabolic syndrome

• Diabetes: leading cause (→ 45% of kidney failure cases)

  • Leads to glucosuria, polyuria, nocturia

  • Diuresis of hyperosmotic urine → strain on nephrons

  • Mild proteinuria, hypertension common

• Metabolic syndrome (≥3: abd. obesity, HTN, low HDL, hypertriglyceridemia, hyperglycemia)
  → 2.6× increased CKD risk

Know the levels of CKD for EXAM

monitor Delta changes. they don’t get better