Ch.8 Renal and Metabolic Disease

kidneys are vital organs that maintain the internal environment of the body (homeostasis) by regulating fluid, electrolyte, acid-base, and metabolic balance. They act as both _____ and ____ organs

excretory, endocrine

how does the kidney control fluid regulation (controlled parameter) and what is the primary outcome

Through ECF volume, osmolarity

outcome: stable bp

how does the kidney electrolyte balance (controlled parameter) and what is the primary outcome

controls Na+, K+, Ca2+, and PO4 3- balance

outcome is normal neuromuscular and cardiac function

how does the kidney control acid-base regulation (controlled parameter) and what is the primary outcome

controls blood pH

results in enzymatic and metabolic stability

how does the kidney control excretion (controlled parameter) and what is the primary outcome

excretes wastes, toxins

prevents accumulation and toxicity

how does the kidney contribute to endocrine/metabolic roles (controlled parameter) and what is the primary outcome

EPO, vitamin D, glucose

maintains oxygen delivery, bone health, and energy balance

how are kidney diseases classified?

based on duration

• acute kidney injury (AKI)

• chronic kidney disease (CKD)

based on anatomic site of the kidney affected

• glomerular diseases

• tubular disease

• tubulointerstitial disease

• vasculitis (blood vessels)

based on cause/ etiology

• Genetic/ congenital

• metabolic/systemic

• immunologic/ inflammatory

• toxic/ drug-induced

• infectious

Acute Kidney Injury (AKI)

sudden decline in renal function occurring over hours to days, leading to accumulation of nitrogenous waste and fluid/electrolyte imbalance

Oliguria or anuria: <400 mL/day (common in severe forms)

is often reversible, esp. when treated early

-prerenal, renal, and post renal forms

Prerenal (functional) AKI

caused by decreased renal perfusion (e.g. dehydration, hemorrhage, shock, or heart failure)

kidney tissue remains structurally intact but hypoperfused

Typical lab pattern: concentrated urine w/ minimal sediment; renal function improves when perfusion is restored

Renal (intrinsic) AKI

direct injury to glomeruli, tubules, or insterstitium

3 forms:

• Acute Tubular Necrosis (ATN) → most common

• Acute Glomerulonephritis (AGN)

• Acute Interstitial Nephritis (AIN)

Renal (intrinsic) AKI - Acute Tubular Necrosis (ATN)

most common intrinsic cause

causes: Ischemia (post-shock, sepsis) or nephrotoxins (drugs, contrast, myoglobin)

pathology: tubular epithelial injury and necrosis leading to cast formation and obstruction

Key finding: “muddy brown” granular casts in urine

Renal (intrinsic) AKI - Acute Glomerularnephritis (AGN)

Immune-mediated inflammation of glomeruli

Causes: post-infectious (e.g. post-strep), autoimmune (lupus), or vasculitis

Key findings: hematuria w/ RBC casts and mild proteinuria

Ex.: post-streptococcal GN, rapidly progressive GN, lupus nephritis

Renal (intrinsic) AKI - Acute Interstitial Nephritis (AIN)

Inflammation of the interstitium, usually due to drugs (NSAIDs, ß-lactams antibiotics, medications, or autoimmune diseases)

key findings: WBC casts, eosinophils in urine, mild proteinuria and hematuria

postrenal (obstructive) AKI

caused by obstruction of urine outflow (stones, tumors, enlarged prostate)

back pressure reduced GFR

typical pattern: variable urinary sediment; renal function often improves after relief of obstruction

Lab findings in AKI: BUN:Cr ratio, Urine Na+ (mEq/L), urine osmolality

prerenal

BUN:Cr ratio: >20:1

Urine Na+ (mEq/L): <20

urine osmolality: >500

Lab findings in AKI: BUN:Cr ratio, Urine Na+ (mEq/L), urine osmolality

renal

BUN:Cr ratio: 10-15:1

Urine Na+ (mEq/L): >40

urine osmolality: <350

Lab findings in AKI: BUN:Cr ratio, Urine Na+ (mEq/L), urine osmolality

postrenal

BUN:Cr ratio: variable

Urine Na+ (mEq/L): variable

urine osmolality: variable

Chronic Kidney Disease (CKD)

progressive, irreversible decline in renal function lasting ≥3 months

major causes:

• diabetes mellitus (diabetic nephropathy)

• hypertension (hypertensive nephrosclerosis)

• chronic glomerulonephritis (CGN) → may evolve from unresolved acute GN or occur as primary chronic process (IgA nephropathy, lupus nephritis, FSGS (Focal segmental glomerulosclerosis), membranoproliferative GN)

Progression:

• advances thru 5 stages, based on the glomerular filtration rate (GFR)

• ESRD represents the terminal phase where kidney function is insufficient to sustain life w/o dialysis or transplant

stage 1 of CKD

kidney damage w/ normal or increased GFR

GFR ≥90 mL/min/1.73 m²

stage 2 of CKD

mild decrease in GFR

GFR 60-80 mL/min/1.73 m²

stage 3a-b of CKD

moderate decrease in GFR

GFR 30-59 mL/min/1.73 m²

stage 4 of CKD

severe decrease in GFR

GFR 15-29 mL/min/1.73 m²

stage 5 of CKD

kidney failure/ ESRD

GFR <15 mL/min/1.73 m²

laboratory and clinical features of CKD

persistent proteinuria ± hematuria

progressive azotemia (rising BUN and creatinine)

anemia of CKD (decreased erythropoietin)

CKD-Mineral Bone Disorder (abnormal Ca2+, phosphate, and PTH)

glomerular diseases

group of conditions that affect the glomeruli

can cause inflammation and damage to the glomeruli, leading to various symptoms and potential complications

glomerular diseases that are best understood by recognizing nephritic vs. nephrotic patterns

ex. nephrotic syndrome, nephritic syndrome

Nephrotic Syndrome (leaky to protein)

heavy proteinuria (>3.5 g/day)

hypoalbuminemia, generalized edema, hyperlipidemia, lipiduria, oval fat bodies

Mechanism:

• damage is primarily non-inflammatory and affects the podocytes

• causes the foot processes to become flattened (effacement)

• the loss of the normal filtration barrier’s charge and size selectivity results in massive loss of protein into the urine (proteinuria)

ex. Minimal change disease; membranous GN, focal segmental GN

Nephrotic Syndrome - minimal change disease (MCD)

mechanism, pathology, lab/urinalysis clues

common in children and has good prognosis with steroid response

mechanism:

• non-inflammatory podocyte injury

pathology:

• foot process effacement, normal glomeruli on light microscopy

lab clues:

• abrupt nephrotic-range proteinuria

• bland urine

• usually normal complement

Nephrotic Syndrome - membranous GN

mechanism, pathology, lab/urinalysis clues

is associated w/ various infections, autoimmune diseases, and certain drugs

mechanism:

• immune-complex mediated GBM thickening

pathology:

• subepithelial IgG and C3 deposits → GMB “spike and dome”

lab clues:

• gradual nephrotic-range proteinuria

• may have mild hematuria

• normal complement in primary disease

Nephrotic Syndrome - focal segmental GN (FSGS)

mechanism, pathology, lab/urinalysis clues

more common in adults than children, involves scarring (sclerosis) with a poorer prognosis and less response to steroids than minimal change disease

Mechanism:

• segmental podocyte injury and sclerosis

pathology:

• some glomeruli show sclerosis

• foot process effacement in affected area

lab clues:

• proteinuria (may be sub-nephrotic initially

• microscopic hematuria

• risk of CKD progression

Nephritic Syndrome (leaky to RBC)

Hematuria (cola-colored urine)

RBC casts, mild-moderate proteinuria ( >3 g/day)

hypertension, oliguria, azotemia

examples: post-strep GN, IgA nephropathy, lupus nephritis

mechanism:

• damage is due to inflammation and affects the entire glomerulus, including the endothelial cells, glomerular basement membrane, and the mesangial cells that support the capillary loops

• inflammation causes capillary walls to swell, and the resulting injury creates breaks in the filtration barrier

tubular and tubulointerstitial diseases

disorders the primarily affect the renal tubules and interstitium, leading to impaired reabsorption, secretion, or concentration of urine

ex. acute tubular necrosis (ATN), tubulointerstitial nephritis (TIN), Fanconi syndrme, renal tubular acidosis, nephrogenic diabetes insipidus (NDI), etc.

tubulointerstitial nephritis (TIN) - chronic

progressive fibrosis due to long-term drug exposure, reflux nephropathy, or metabolic causes (hypercalcemia, urate nephropathy)

Fanconi syndrome

proximal tubular dysfunction → loss of glucose, amino acids, phosphate, bicarbonate in urine

causes: cystinosis, Wilson disease, drugs

renal tubular acidosis (RTA)

defect in acid-base handling

nephrogenic diabetes insipidus (NDI)

tubular unresponsiveness to ADH → polyuria, dilute urine, hypernatremia

causes: genetic or drug-induced, e.g. lithium

polycystic kidney disease (PKD)

a genetic disorder characterized by the development of numerous fluid-filled cysts in the kidneys, leading to progressive enlargement and loss of renal function

lab and imaging findings:

• unltrasound/CT/MRI: multiple bilateral cysts

• BUN/creatinine: may rise w. progression

• urinalysis: hematuria, mild proteinuria

complications:

• hypertension, CKD→ ESRD

• UTIs, kidney stones

metabolic disorders linked to kidney disease

diabetes mellitus and diabetic nephropathy

hypertension and renovascular effects

electrolyte/endocrine disorders contributing to renal injury (hypercalcemia)

metabolic acidosis (primary) → kidney stress

obesity and metabolic syndrome → obesity-related glomerulopathy

diabetes mellitus and diabetic nephropathy - mechanism, pathophysiology, lab findings

mechanism: chronic hyperglycemia → non-enzymatic glycation of proteins → damage to glomerular basement membrane (GBM) and mesangial expansion

pathophysiology:

• thickened GBM and mesangial expansion → glomerulosclerosis (scarring of the glomerulus)

• loss of filtration selectivity → albumin leakage

lab findings:

• earliest marker: microalbuminuria (30-300 mg/day; detectable by urine albumin-to-creatinine ratio)

• progression: persistent proteinuria → declining eGFR

• elevated BUN and creatinine in advanced disease

• dyslipidemia (increased trigylcerides, decreased HDL)

clinical importance: diabetic nephropathy is the leading cause of CKD and ESRD worldwide

hypertension and renovascular effects - mechanism, pathophysiology, lab findings

mechanism: chronic high blood pressure damages renal microvasculature → ischemic injury and scarring

pathophysiology:

• arteriolar thickening and narrowing → glomerularsclerosis

• reduced renal blood flow triggers RAAS activation, worsening hypertension (“vicious cycle”)

laboratory findings:

• slowly progressive rise in creatinine and BUN

• mild proteinuria (<1g/day, unless secondary disease)

• urinalysis is often bland compared to GN

electrolyte/endocrine disorders contributing to renal injury - hypercalcemia (e.g. hyperparathyroidism, malignancy, vitamin D intoxication)

pathophysiology: elevated serum calcium leads to calcium deposition in renal tubules and interstitium → nephrocalcinosis

renal consequences: formulation of kidney stones, tubular obstruction, and chronic tubulointerstitial injury → progressive CKD

lab clues: hypercalcemia, hypercalciuria, elevated PTH (if primary hyperparathyroidism), possible crystalluria on urinalysis

Metabolic acidosis (primary) → kidney stress

disorder, pathophysiology, consequences, lab clues

disorder: chronic lactic acidosis (liver disease, inborn errors of metabolism, chronic hypoxia), ketoacidosis (diabetes mellitus, alcoholism)

pathophysiology: high acid load → increased ammoniagenesis, tubular stress, and chronic tubular injury

renal consequences: recurrent or severe acidosis may cause acute tubular necrosis, interstitial fibrosis, and accelrate CKD progression

lab clues: low serum bicarbonate, low blood pH, elevated anion gap (depending on etiology), ketones in urine (if ketoacidosis)

obesity and metabolic syndrome → obesity-related glomerulopathy

disorder, pathophysiology, consequences, lab clues

disorder: insulin resistance, visceral obesity, dyslipidemia, systemic inflammation

pathophysiology: glomerular hyperfiltration, podocyte hypertrophy, mesangial expansion → focal segmental glomerulosclerosis (FSGS)

consequences: progressive proteinuria (usually sub-nephrotic), hypertension, declining GFR, and eventual CKD

lab clues: persistent proteinuria, elevated serum creatinine with declining eGFR, dyslipidemia (high triglycerides, low HDL), occasionally mild hematuria

Inborn errors of metabolism (IEMs)

genetic disorders that disrupt normal metabolic pathways, leading to accumulation or abnormal excretion of metabolites detectable in urine

ex. phenylkentonuria (PKU), maple syrup urine disease (MSUD), cystinuria, alkaptonuria

phenylkentonuria (PKU) - defect and urinary clue

phenylalanine hydroxylase deficiency

clue: increased phenylalanine metabolites (e.g. phenylpyruvate)→ musty/mousy odor

maple syrup urine disease (MSUD) - defect and urinary clue

defect: branched chain a-ketoacid dehydrogenase deficiency

urinary clue: branched-chain ketoacids → sweet, maple syrup-like odor

cystinuria - defect and urinary clue

defect: impaired renal tubular reabsorption of cystine and dibasic amino acids

urinary clue: excess cystine → hexagonal crystals, prone to kidney stones

alkaptonuria

defect: homogentisate 1,2-dioxygenase deficiency - needed to break down homogentistic acid

urinary clue: homogentisic acid → darkening of urine on standing