CKD and its complications

define chronic kidney disease (CKD):

a progressive decline in renal function over months to years or sustained kidney dysfunction for > 3 months

what happens to the normal renal tissue in CKD?

it is replaced by scarred/fibrotic tissue

how does the National Kidney Foundation (NFK) define CKD?

a glomerular filtration rate of < 60 mL/min/1.73m² for > 3 months

what is the intact nephron hypothesis?

as diseased nephrons become non-functional, the remaining nephrons will adapt to increase excretion of water/toxins/solutes with increased GFR through adaptations to blood flow

T/F: there can be appearance of normal renal function even if there is loss in nephron mass

true

when do clinical manifestations of CKD begin?

once a critical threshold of nephron loss occurs and the remaining nephrons can no longer compensate

CLrenal =

f_up(GFR) + CL_secretion - CL_reabsorption

T/F: as nephrons are lost, the remaining nephrons must decrease Fr to maintain excretion

false

what should be looked at for CKD classification?

cause, GFR, and albuminuria category

what things are looked at for the cause of CKD?

past medical history and kidney biopsy

how is GFR estimated?

through SCr or serum creatinine and cystatin C based equation (CKD EPI 2021)

how to determine albuminuria category for CKD?

24-hour urine collection and albumin-to-creatinine ratio (ACR)

normal range (A1) of albumin in the urine

< 30 mg/day (< 30 mg / g creatinine)

what is the range for microalbuminuria (A2)?

30-299 mg/day (30-299 mg/ g creatinine)

what is the range for macroalbuminuria (A3)?

≥ 300 mg/day (≥ 300mg/g creatinine)

What are the GFR categories from KDIGO 2012?

G1, G2, G3a, G3b, G4, G5

what are the categories of persistent albuminuria from KDIGO 2012?

A1, A2, and A3

what is G1?

normal or high GFR (>= 90)

what is G2?

mildly decreased GFR (60-89)

what is G3a?

mildly to moderately decreased GFR (45-59)

what is G3b?

moderately to severely decreased GFR (30-44)

what is G4?

severely decreased GFR (15-29)

what is G5?

kidney failure (GFR < 15)

What does A1 mean?

normal to mildly increased albuminuria

What does A2 mean?

moderately increased albuminuria

What does A3 mean?

Severely increased albuminuria

signs and symptoms of CKD Stage 1

GFR > 90 mL/min/1.73m2 and asymptomatic

signs and symptoms of CKD Stage 2

GFR 50-89 mL/min/1.73m2, HTN, and asymptomatic

signs and symptoms of CKD stage 3

GFR 30-60, edema, loss of appetite, proteinuria, and azotemia

signs and symptoms of CKD stage 4

GFR 15-30 mL/min/1.73m2, fatigue, anemia, hyperkalemia, and acidosis

signs and symptoms of CKD stage 5

GFR < 15, nausea, pruritis, SOB, volume overload, hyperphosphatemia, and hypermagnesemia

CKD stage 1 clinical presentation

‘normal renal function’ with underlying kidney damage

CKD stage 2 clinical presentation

decreased renal reserve, GFR declines but SCr and BUN are relatively normal, typically asymptomatic

CKD stage 3 clinical presentation

extensive loss of renal function, increased SCr and BUN, volume expansion (HTN, edema), mild anemia may develop, and MUST determine etiology (renal biopsy) to slow progression

CKD stage 4 clinical presentation

extensive symptoms develop (fatigue, anorexia, cold intolerance), lab abnormalities (azotemia, hyperkalemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, progressive anemia)

CKD stage 5 clinical presentation

uremia (azotemia + pruritis, intractable N/V, encephalopathy), co-morbid conditions worsen (anemia, hyperkalemia, mineral bone disease), renal replacement therapy needed to maintain life (dialysis)

what are 4 common causes of CKD

diabetes mellitus, hypertension, glomerulonephritis, and polycystic kidney disease

what are some other causes of CKD?

HIV nephropathy, drug nephrotoxicity, Alport’s syndrome, Wegner’s granulomatosis, nephrolithiasis, reflux/chronic pyelonephritis, recurrent episodes of AKI

what is the renal function decline over time for CKD?

0.5-1 mL/min/year

CKD pathophysiology overview:

loss of nephron mass, glomerular capillary hypertension, glomerulo-sclerosis, proteinuria, normal renal tissue is replaced by fibrotic tissue, and irreversible damage

what are the major mediators of CKD (i.e. drug targets)?

Angiotensin II, Proteinuria, and advanced glycation end-products (AGE)

how does angiotensin II cause CKD

vasoconstriction leads to increased glomerular capillary pressure (and HTN) which leads to mesangial cell hyperplasia which then causes glomerular damage and proteinuria

how does proteinuria cause CKD

immune activation, worsening vasoconstriction, direct cellular damage, complement activation

what is AGE a major mechanism in?

diabetic nephropathy

what is critical in preventing AGE formation?

control of blood glucose

what are the downstream effects of AG II?

vasoconstriction, aldosterone production, Na/H20 reabsorption in kidney, K secretion in the kidney, ADH release which leads to free water reabsorption at collecting duct, and sympathetic nervous system activation

T/F: the juxtaglomerular apparatus senses perfusion pressure and distal sodium delivery

true

when is renin released?

when there is low perfusion/low sodium delivery

how does the tubuloglomerular feedback system work?

The juxtaglomerular apparatus macula densa cells sense distal Na+ delivery in the nephron and relay the information to the afferent arteriole

what happens when the macula densa cells sense increased [Na+]

afferent arteriole constriction and decreased intraglomerular hydrostatic pressure (decreased GFR) - may be protective via reduction in albuminuria

modifiable CKD progression risk factors

diabetes, HTN, proteinuria, hyperlipidemia, tobacco use, systemic inflammation, and environmental exposures (heavy metals)

Non-modifiable CKD progression risk factors

older age, African-American or Native American ethnicity, genetics (family hx)

what is the most important predictor of CKD progression

management of the underlying cause

what functional changes occur in Pre-diabetic nephropathy

hyperfiltration - increased GFR (25-50%)

why does GFR increase in pre-diabetic nephropathy?

intact nephron hypothesis and hyperglycemia which causes water to be pulled into the intravascular space (more blood to filter)

what functional changes occur in incipient DN

microalbuminuria and HTN

T/F: there are large changes in GFR in incipient DN

false

what is the only way to identify a patient with incipient DN?

look at albumin levels microalbuminuria)

what structural changes occur in incipient DN?

mesangial expansion (hyperplasia), GBM thickening, and arteriolar hyalinosis

when does a diabetic patient officially have (overt) diabetic nephropathy

when GFR starts to decline

functional changes that occur in (overt) diabetic nephropathy

proteinuria, nephrotic syndrome, and decreased GFR

what structural changes occur in (overt) diabetic nephropathy?

mesangial nodules (Kimmelstiel-Wilson lesions) and tubulointerstitial fibrosis

how is diabetic nephropathy diagnosed?

persistent microalbuminuria with diabetes mellitus

define microalbuminuria:

30-300 mg of albumin in the urine per 24-hour period

what can be used as a good surrogate for a 24-hour urine collection when diagnosing microalbuminuria?

a spot urine albumin-to-creatinine ratio of 30-300 mg/g

T/F: a spot urine test must be repeated to confirm DN diagnosis

true

when should diabetic patients have their urine protein assessed?

annually

what is a normal urine protein?

<300 mg/day

what is a normal urine albumin?

<30 mg/day

what is the other name for Kimmelstiel-wilson-nodules?

glomerulosclerosis

which medication is able to address/inhibit inflammation and fibrosis at low MR overactivation?

finerenone