2 - Chronic Kidney Disease

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Chronic kidney disease epidemiology?

14% of the adult population in the US have CKD

Among those with CKD, only 12.3% report awareness of weak/failing kidneys

Patients with CKD are at higher risk of dying earlier than people of similar age without CKD

Chronic kidney disease definition?

Kidney damage OR GFR <60 ml/min/1.73m2 for at least 3 months

Examples of markers of kidney damage?

Proteinuria

Abnormalities detected by histology

Structural abnormalities detected by imaging

How is CKD staged?

From 1-5 using GFR

G1, G2, G3a, G3b, G4, G5

Stage G1 of CKD?

>90 GFR and markers of kidney damage

Normal or High

Stage G2 of CKD?

60-89 GFR and markers of kidney damage

Mildly decreased

Stage G3a of CKD?

45-59 GFR

Mildy to moderately decreased

Stage G3b of CKD?

30-44 GFR
Moderately to severely decreased

Stage G4 of CKD?

15-29 GFR
Severely decreased

Stage G5 of CKD?

<15 GFR
Kidney failure

If 5D → receiving dialysis

What is albuminuria, and how is it staged?

Is the amount of albumin in the urine

Measured by the urine albumin-to-creatinine ratio

Albumin in the urine → indicates kidney damage

A1 of albuminuria?

<30 mg/g albumin to creatine ratio

Normal to mildly increased

A2 of albuminuria?

30-300 mg/g albumin to creatine ratio

Moderately increased

A3 albuminuria?

>300 mg/g albumin to creatine ratio

Severely increased

GFR?

Glomerular filtration rate

Units → ml/min/1.73m2

Why are the units of GFR standardizedw to ml/min/1.73m2

It is standardized to a body surface area (BSA) of 1.73 m²

This is so kidney function can be compared fairly between people of different body sizes

How is kidney function assessed for CKD staging?

1. Measured GFR (mGFR)

2. Estimated GFR (eGFR)

How is measured GFR determined?

Administer a substance to a patient that is cleared from the body through glomerular filtration → then measure its rate of clearance

Ex →inulin or iothalamate

What are the drawbacks of measured GFR?

Costly → have to pay for drug and its administration

Timely → continuous IV administration with multiple blood / urine collections

How is estimated GFR determined?

Uses → serum creatinine, age, and sex to calculate eGFR

What are the limitations of using creatinine as a filtration marker?

Many non-GFR determinants of creatinine concentration in the blood plasma

Age and sex adjustments only capture some non-GFR factors

Equations reflect average populations and may be inaccurate for outliers

What is cystatin C?

Protein produced by cells and filtered by the kidneys

Less affected by age, body mass, and diet than creatinine

Can still be affected by medications and medical conditions

Why are creatinine and cystatin C used together as markers of kidney function?

Both are used for eGFR

Creatinine can be affected by muscle mass and diet

Cystatin C is less affected by those factors

Using both gives a more accurate estimate of kidney function

What is proteinuria?

Protein in the urine

Is an independent risk factor for progressive decline in renal function / cardiovascular disease

UACR and how is it used for albuminuria?

Urine albumin-to-creatinine ratio

Measured from a spot urine sample

Used to categorize albuminuria

A1 → <30 mg/g → Normal to mildly increased

A2 → 30–300 mg/g → Moderately increased

A3 → >300 mg/g → Severely increased

Is dietary protein restriction useful for proteinuria?

Limited evidence to support protein restriction may delay time to dialysis → likely due to uremic symptoms

Risks of malnutrition must be considered

Generally not recommended

What are the main causes of CKD?

Diabetes Mellitus → 38%

Hypertension → 27%

Other → 35%

What is Cardiovascular-Kidney-Metabolic (CKM) Syndrome?

A framework, not a single disease

Shows how heart, kidney, and metabolic conditions interact

CVD, CKD, type 2 diabetes, and obesity often occur/overlap together and can worsen each other

What are the stages of CKM syndrome?

Stage 0 → Prevent risk factors; promote heart health

Stage 1 → Excess weight/metabolic risk

Stage 2 → Metabolic risk or kidney disease

Stage 3 → Subclinical heart disease

Stage 4 → Clinical heart disease

What are Life’s Essential 8?

8 factors for better cardiovascular health →

Diet

Physical activity

Nicotine exposure

Sleep

Weight

Cholesterol

Blood sugar

Blood pressure

What factors contribute to CKD progression?

Hypertension

Hyperglycemia

To stop progression, use medications that slow → CKD progression

What are some possible complications of CKD?

Cardiovascular disease

Mineral and Bone disorders

Anemia

Acidosis

What are the blood pressure target in CKD?

KDIGO → Systolic BP <120 mmHg if tolerated in patients with CKD and HTN

AHA/ACC → <130/80 mmHg

What therapies are used for hypertension with CKD?

Non-pharm → Salt restricted diet

Pharm → ACEI/ARB or other med

Salt restriction diet in CKD?

Recommended dietary intake of less than 2 grams / day for most patients with CKD

Can use salt substitutes → potassium based, but warn against due to risk of hyperkalemia

What is the first line treatment for hypertension with CKD?

ACEI or ARB

First line for patients with CKD with moderately increased albuminuria → ACR >30mg/g

After that → other agents are okay, no one class is preferred for CKD outcomes

Thiazide diuretics for hypertension?

New evidence → that chlorthalidone can still lower BP in stage 4 CKD (GFR <30)

It was previously thought thiazides stopped working when GFR <30

Monitoring for thiazide diuretics?

Volume depletion → hypotension, AKI

Lab abnormalities → hypokalemia, hypercalcemia, hyperuricemia, hyponatremia

Loop Diuretics for hypertension?

Less effective for BP reduction in CKD stages 1-3

Effective adjunct for blood pressure reduction and fluid management in CKD stages 4-5

Monitoring Loop Diuretics for hypertension?

Volume depletion → hypotension, AKI

Lab abnormalities → hypokalemia, hyperuricemia, hyponatremia

What is the HbA1c target for patients with diabetes and CKD not on dialysis?

Individualize the target between 6.5% - 8.0%

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What medication classes delay the progression of CKD?

• Renin angiotensin system inhibitors (RASi)

• Sodium-glucose cotransporter-2 inhibitors (SGLT2i)

• Nonsteroidal mineralocorticoid receptor antagonists (nsMRA)

• Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RAs)

Why must serum creatinine be monitored when starting ACEIs/ARBs?

Angiotensin II normally constricts the efferent arteriole → helping maintain GFR

ACEIs/ARBs block this effect → efferent arteriole dilates → GFR decreases → serum creatinine may rise

Monitoring checks for an excessive rise in creatinine, which may indicate kidney problems

How do ACEIs/ARBs help manage proteinuria in CKD?

Reduce proteinuria

Slow GFR decline

Benefits occur partly independent of BP lowering

When should an ACEI/ARB be initiated in hypertension?

Initiate in CKD when ACR >30 mg/g

When should an ACEI/ARB be initiated in someone with NO hypertension?

Initiate when ACR >300 mg/g

Initiate when ACR >30 mg/g in patients with diabetes

Dosing of ACEI/ARBs in proteinuria?

Max dose!!!
Ex → Lisinopril 40mg, Losartan 100mg

Dose limiting ADE → Hyperkalemia

Is combination ACEI / ARB therapy recommended for proteinuria ?

NO

Does NOT improve clinical outcomes

What should you try before decreasing or stopping ACEIs/ARBs due to hyperkalemia?

1. Stop other meds that increase K

   1. K supplements, NSAIDs, beta blockers

2. Maximize meds that lower potassium

   1. Diuretics, SGLT2 inhibitors

3. Correct metabolic acidosis

4. Consider utilization of potassium binder therapy

What is Sodium Zirconium Cyclosilicate / Lokelma ?

Potassium binder

Must take 2 hours before or after all other meds

Side effects → GI upset, edema possible

Cost → Expensive !!

What is Patiromer / Valtessa ?

Potassium binder

Must take 3 hours before or after all other meds

Side effects → GI upset, hypomagnesemia possible

Cost → Expensive !!!

How do SGLT2 inhibitors protect the kidneys in CKD?

Decrease tubular workload and oxygen use → less kidney stress

Decrease inflammation and fibrosis → less kidney damage/scarring

Metabolic and systemic effects

Canagliflozin?

SGLT2i

100mg daily

Do not initiate if GFR <30 ml/min1,73m2

Can continue at GFR <30 for renal/CV outcomes if ACR >300 mg/g

Not really used

Empagliflozin?

SGLT2i

10mg daily

Not recommended for glucose lowering if eGFR <30

Dapagliflozin?

SGLT2i

10mg daily

Not recommended for glucose lowering if eGFR <45

Do not initiate at all if GFR <25 ml/min/1.73m2

Can continue at GFR <25 to reduce to reduce the risk of eGFR decline, ESKD, CV death and HF

What is treatment with SGLT2i recommended with T2DM?

Patients with T2DM, CKD, and an eGFR ≥20 ml/min per 1.73m2

What is treatment with SGLT2i recommended without T2DM?

Patients with CKD but without T2DM and one of the following:

• eGFR ≥20 ml/min per 1.73 m2 and UACR ≥200 mg/g

• eGFR 20-45 ml/min per 1.73 m2 with any level of UACR

• Heart failure as a comorbidity with any level of UACR

Prescribing SGLT2i considerations for CKD?

Consider reducing thiazide/loop diuretics before starting

Reversible eGFR decrease may occur, does not indicate to stop therapy

Rarely cause ketoacidosis → hold during prolonged fasting, surgery, or critical illness

May cause genital fungal infections

Finerenone / Kerendia ?

Non-steroidal mineralocorticoid receptor antagonist (ns-MRA)

Indicated for → reduce risk of eGFR decline, ESKD, CV death, MI, and hospitalization for HF in patients with CKD associated with T2DM

What is Finerenone / Kerendia recommended for?

Patients with:

• T2D

• eGFR >25ml/min per 1.73m2

• Normal serum potassium concentration

• Albuminuria >30mg/g, despite max tolerated dose of RAASi

Adverse effects of finerenone / kerendia?

Do not combine with steroidal MRA, will increase AE

Hyperkalemia risks for patients with decreased kidney function/higher baseline potassium levels

Can finerenone slow CKD progression in patients without diabetes?

Yes

Major risk → Hyperkalemia

MOA of GLP-1 receptor agonists?

Mimic the gut hormone GLP-1

Binds / activates the GLP-1 receptor to increase insulin production and cause satiety → leading to lower blood glucose and weight loss

How do GLP-1 RA protect the kidneys?

Decrease in inflammation, oxidative stress, and fibrosis

Intrinsic kidney and immune cells contain the GLP-1 receptor

What did the FLOW trial find for semaglutide in patients with T2DM and CKD?

Key takeaway → Semaglutide slowed CKD progression in patients with type 2 diabetes and CKD

What is semaglutide's kidney indication (updated 1/2025)?

Reduce the risk of:

• Sustained eGFR decline

• End-stage kidney disease (ESKD)

• Cardiovascular death

Pillars of therapy for patients with CKD and T2DM?

ACEi/ARBs

SGLT2i

Ns-MRA
GLP-1 RA

Pillars of therapy for patients with CKD without T2DM?

ACEi/ARB

SGLT2i

Traditional risk factors for cardiovascular disease with CKD?

Dyslipidemia

Hypertension

Diabetes

Smoking

Obesity

Sedentary Lifestyle

Non-traditional risk factors for cardiovascular disease with CKD?

Mineral and bone disorders

Elevated PTH

Elevated serum phosphorus

Elevated serum FGF-23

Low serum 25(OH)-

Vitamin D

Calcification

Treatment for adults >50yrs in GFR categories G3a-5?

Statin therapy or statin/ezetimibe combo therapy

Treatment for adults >50yrs in GFR categories G1-2?

Statin therapy

When is statin therapy recommended in adults 18-49 years with CKD?

In people with one or more of the following:

• Known coronary disease

• Diabetes mellitus

• Prior ischemic stroke

• Estimated 10-year incidence of coronary death or nonfatal myocardial infarction >10%

When is statin therapy not recommended?

In adults with dialysis dependent CKD

IF they are already receiving statins or statin/ezetimibe therapy at the time of dialysis initiation → still continue these agents

Can targeting hypercoagulability prevent CV events in CKD?

No

TRACK Trial Takeaway → Low-dose rivaroxaban did not provide cardiovascular benefit and increased bleeding risk in this trial.

What happens to phosphate, vitamin D, and calcium in CKD?

Serum phosphate increases

Active vitamin D decreases

Serum calcium decreases

How does CKD cause increased PTH and bone resorption?

Decreased calcium stimulate PTH production

Increased PTH causes bone resorption → releasing calcium into the blood and increasing serum calcium

How does CKD cause increased FGF-23?

Phosphate retention from CKD increases FGF-23

FGF-23 causes decreased vitamin D activation

What are FGF-23 and PTH?

They are phosphaturic hormones.

They promote phosphate excretion in urine

How are mineral and bone disorders dealt with in CKD?

Goal is to normalize biochemical parameters

Calcium

Phosphorus

Vitamin D

Parathyroid Hormone

Serum calcium?

A measurement of calcium that includes both bound (inactive) and unbound/free/ionize (active) calcium

Has a test that is → very easy to run, widely available, and cost effective

Ionized calcium?

A measure of calcium that includes only unbound/free (active) calcium

Test is more → technical to run

What percentage of serum calcium is bound to albumin?

About 40% of serum calcium is bound to albumin (inactive)

What is hypoalbuminemia in CKD?

Common in CKD

Low albumin can cause a falsely low total calcium level

Recommendation of calcium measurement?

Use serum calcium

If a precise measurement is needed → use ionized

Hypocalcemia?

Classic feature of untreated CKD

Vitamin D deficiency decreases calcium absorption from the GI tract

Low blood calcium stimulates increased PTH production, causing secondary hyperparathyroidism

How do you treat hypocalcemia?

Replace vitamin D first if needed to improve calcium absorption

Avoid unnecessary calcium supplementation because excess calcium can be harmful

Treatment of moderate hypocalcemia (7.5–8.5 mg/dL)?

Treatment is not needed

Treatment of low levels or symptomatic hypocalcemia?

Treatment needed!

Symptoms include → Tetany, muscle spasms, hypoactive reflexes, anxiety, hallucinations, lethargy, hypotensions, seizures

What happens to phosphate balance in CKD stages 4–5 and dialysis?

Phosphate balance becomes positive

Meaning the body retains more phosphate than it excretes

What poor outcomes are associated with hyperphosphatemia?

Abnormal bone remodeling

Arterial calcification

Mortality

How is hyperphosphatemia managed?

Restriction of dietary phosphate

Phosphate binders

Dietary phosphate restriction?

Limit dietary phosphate intake alone or in combo with other treatments

Recommended intake → 800-1000mg daily

High phosphate foods → dairy, meat, whole grain

Aluminum containing binders for hyperphosphatemia?

Widely used in the past

High capacity to bind phosphorus

Inexpensive

AE → Constipation, neurotoxicity, microcytic anemia, impairment of bone mineralization

Long term use not recommended

Calcium based binders for hyperphosphatemia?

Inexpensive

Calcium citrate not recommended → binds phosphorus poorly

Concern for vascular calcification exists

Examples of calcium based binders?

Calcium acetate → PhosLo → 667mg

Calcium carbonate → Tums → 200-600mg

How do calcium-based and non-calcium-based phosphate binders compare in CKD?

It is recommended to restrict calcium-based binders due to concerns about excess calcium

Non-calcium binders may improve clinical outcomes compared with calcium-based binders

Sevelamer Hydrochloride / Renagel ?

Non-calcium based binder

No calcium / aluminum

Similar structure to resin binders

Secondary benefits of Sevelamer Hydrochloride / Renagel ?

Lowers LDL cholesterol

Avoids excess calcium that can cause blood vessel calcification

Administration of Sevelamer Hydrochloride / Renagel ?

800-1600 mg TID with meals

Separate administration from meds with narrow therapeutic window

AE → dyspepsia, diarrhea, vomiting