Chronic Kidney Disease

Etiologies of CKD

Diabetes (40% of new cases in the US) - Type 2 have 50% lifetime risk of developing CKD

Hypertension (25% of new cases)

Glomerulonephritis (10%)

Others - Urinary tract disease, polycystic kidney disease, lupus, analgesic nephropathy, idiopathic

Pathophysiology of CKD

Loss of Nephron Mass —> Intraglomerular Hypertension —> Proteinuria

Chronic Kidney Disease

Kidney damage for > 3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifested by either: Pathological abnormalities, or Markers of kidney disease: abnormalities in the composition of blood or urine, or abnormalities in imaging tests

Glomerular filtration rate (GFR) < 60 ml/min/1.73m2 for > 3 months with or without kidney damage

GFR Ranges

90 - G1, normal

60-89 - G2, mildly decreased

45-59 - G3a, mildly to moderately decreased

30-44 - G3b, moderately to severely decreased

15-29 - G4, severely decreased

<15 - G5, kidney failure

Albuminuria Categories (excretion and alb-creatinine ratio)

<30 - A1, normal to mildly decreased

30-300 - A2, moderately increased

>300 - A3, severely increased

Albumin excretion ratio of over 30 mg/24hr sustained for 3 months = CKD

Susceptibility Risk Factors

increased risk for the development of kidney disease

Low income or education, Advanced age, Family History, Dyslipidemia, Reduced kidney mass and low birth weight

Racial/ethnic minority - African American, Hispanic, Native American, Asian

Initiation Factors

(conditions that directly result in kidney failure)

Diabetes mellitus, Hypertension, Glomerulonephritis, Autoimmune disease, Polycystic kidney disease, Drug toxicity, Kidney stones

Progression Factors

(Cause worsening kidney function & faster decline)

Uncontrolled diabetes, Elevated blood pressure, High levels of proteinuria, Smoking, Obesity

Interventions to Slow Progression of CKD

Optimize glycemic control in diabetes (type I and 2) - Goal A1c < 7%

Optimize blood pressure control

Medications – ACE inhibitors/ARBs, SGLT2 inhibitors, finerenone, GLP-1 agonists

Treat hyperlipidemia

Smoking cessation

Plant dominant, low-protein diet- consider if GFR < 30 mL/min

Weight loss if BMI > 25 kg/m2

Exercise

Avoiding acute kidney injury

RAAS Antagonists: ACE Inhibitors/Angiotensin II Receptor Blockers

Vasodilation of arteries and efferent and afferent glomerular arterioles (particularly efferent)

Reduction in adrenal secretion of aldosterone

Reduce urine albumin levels

May reduce cardiovascular risk (e.g. HOPE study)

First line therapy for: Those with albuminuria > 30 mg/g

Reasonable to consider in any CKD patient

Second Line: Sodium glucose transport-2 inhibitors (SGLT-2 inhibitors)

Second Line

Indications: Treatment of diabetes type 2, Heart failure, CKD (eGFR > 20 ml/min) with or without diabetes and persistently elevated urinary album

Decrease glomerular hyperfiltration and reduce glomerular hypertension - Reduces proteinuria

Limitations for use of SGLT2 Inhibitors in CKD

Very few patients with eGFR < 20 ml/min included in studies (though data emerging)

Cost

Adverse effects: Urinary tract infections (typically fungal), Necrotizing fasciitis, Diabetic ketoacidosis (in patients with diabetes), Genital mycotic infections, Bone fractures?, Hypotension/Volume depletion

Non-Steroidal Mineralocorticoid Receptor Antagonists (MRAs)

Last line

Finerenone (Kerendia)

Indication: Those with both CKD and diabetes with persistently elevated urinary albumin excretion (urine albumin to creatinine ration > 30 mg/g) while on max ACEi/ARB therapy

Renal and CV benefits: reduces risk of kidney function decline, kidney failure, CV death, nonfatal heart attack, and hospitalization for heart failure in adults with CKD and DM2

Not recommended with eGFR < 25 ml/min

Do NOT initiate if serum potassium > 5 mEq/L

GLP-1 Receptor Agonists

Last Line

Indication per KDIGO: In adults with type 2 diabetes and CKD who need more blood sugar control, may initiate GLP-1 agonist AFTER initiating a SGLT2 inhibitor

Options: liraglutide, semaglutide, dulaglutide

For Cardiovascular Benefit

Diagnosis of Anemia

Hemoglobin (Hb) concentration < 13 g/dL in males and < 12 g/dL in females

Treatment Strategies for Anemia

Iron

Erythropoietin-stimulating agent (ESA) therapy

Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors (HIF-PHI)

Red blood cell transfusions

Iron Replacement in Anemia

To provide the elemental iron required for production of hemoglobin with the end goal of increasing oxygen transport to tissues

Those receiving ESA/HIF-PHI treatment: Prevent development of iron deficiency, Enhance responsiveness to ESA/HIF-PHI therapy, Reduce ESA/HIF-PHI doses

Avoids transfusions, Minimize anemia-related symptoms, Minimize ESA/HIF-PHI usage

When to Replace Iron in CKD 5 on Hemodialysis

TSAT is < 30% and ferritin < 500 ng /mL

Available Routes of Iron Repletion

Oral or IV; IM not recommended

Oral - About 10% is absorbed; absorption decreased by food and achlorhydria; one tablet every other day: better absorption by allowing time for hepcidin levels to lower

IV preparations - Products: iron dextran, sodium ferric gluconate, iron sucrose, ferric carboxymaltose, and ferumoxytol

Iron AdverseEffects and Monitoring

Oral: GI (constipation, nausea, abdominal cramping, dark stools)

IV : anaphylactic reactions (iron dextran- test dose needed), hypotension, dizziness, dyspnea, headaches, syncope, iron overload

Drug Interactions (PO iron) - Drugs that increase gastric pH (proton pump inhibitors, H2 antagonists), calcium-based products reduce absorption, some antibiotics

Monitoring iron status - Check Hgb, TSAT and ferritin at least every 3 months

Iron dextran

INFeD

25 mg test dose required due to higher risk for anaphylaxis

Sodium ferric gluconate

Ferrlecit, Nulecit

Iron sucrose

Venofer

Considered to be least likely to cause anaphylaxis

Ferric carboxymaltose

Injectafer

Ferumoxytol

Feraheme

Good number of anaphylaxis cases reported, some fatal

Ferric Pyrophosphate Citrate

Triferic

May be continued for as long as the patient is receiving maintenance hemodialysis

Also can be added to dialysate (intradialytic route)

Erythropoietin-Stimulating Agent (ESA) Therapy

Epoetin alfa - Recombinant erythropoietin; same amino acid sequence as endogenous form

Darbepoetin alfa - Has 2 additional N-linked carbohydrate chains that decrease affinity for the erythropoietin receptor, but prolong duration of activity

Methoxy PEG-epoetin beta - Amide bond between the N-terminal or ε-amino group of epoetin beta and methoxy polyethylene glycol butanoic acid; much longer half-life than the other agents

Pharmacokinetics of ESAs

Route : IV or SQ

Less bioavailability with SQ, however, prolonged absorption increases the half-life compared to IV

Benefits of ESA Treatment

Reduces need for red blood cell transfusions and associated risks of transfusions

Can improve quality of life and anemia-related symptoms

ESA Warnings and Effects

Use with caution: Active or previous malignancy, History of stroke

ADEs - Hypertension (do not initiate if uncontrolled), MI/stroke, Vascular access thrombosis/VTE, Seizures (within first 90 days)

Antibody-associated pure red cell aplasia (PRCA) - development of antibodies that neutralize both the ESA and endogenous erythropoietin

Unresponsiveness to ESA Therapy

Should be evaluated after about 2 months of therapy

Common causes: iron deficiency, deficient vitamin B12 and folate, acute illness, chronic bleeding, malnutrition, hyperparathyroidism, cancer and chemotherapy, inflammation, and infection

Unresponsive after 12 weeks: Further increases of ESA dose will likely not improve response but may increase risk of adverse effects

Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitors (HIF-PHI)

Vadadustat (Vafseo) – only agent on the market in US

Indication: Anemia due to CKD in adults receiving dialysis

Dosing: 300 mg PO once daily (range 150-600 mg daily)

HIF PHI inhibitors ADEs and warnings

Black Box: increased risk of death, MI, CVA, VTE, and thrombosis of vascular access

Malignancy - may promote tumor progression due to effects on vascular endothelial growth factor and angiogenesis

Avoid use in: patients with recent cardiovascular event, recent thrombosis, or active cancer

GI erosions/ulcers

Hepatotoxicity, Hypertension, Seizures,Thrombosis

When to Initiate ESA or HIF-PHI Therapy

Step 1: First, rule out other causes and replace iron

Step 2: Evaluate the patient to determine approach

CKD on dialysis: Initiate if hemoglobin level < 9-10 g/dL; Once hemoglobin level reaches 11.5 g/dL, reduce or interrupt the dose of ESA/HIF-PHIs

CKD not on dialysis (CKD ND): Shared decision making based on symptoms and risk/benefit analysis (often between 8.5-10 g/dL)

When to change dose of ESA or HIF-PIH

Hb <1 g/dL in 4 wks - Increase dose 25%

Hb > 1 g/dL in 2 wks - Decrease dose 25-50%

ESAs recommended as first line over HIF-PHIs

Reduce or interrupt dose if Hb > 11.5 g/dL

Non-Pharmacologic Therapy of CKD-Related Hyperparathyroidism

Dietary phosphorous restriction (800-1000 mg/day)

Dialysis

Parathyroidectomy if unresponsive to other therapies

Hyperparathyroidism Pharmacologic Therapy: Calcium Carbonate

Tums, Os-Cal, Caltrate 600

Inexpensive, More soluble in acidic environments, Can be used to correct hypocalcemia

No > 2000 mg elemental calcium/day (from meds and diet)

Calcium-Based

(40% elemental)

(Phosphate Binder)

Hyperthyroidism Pharmacologic Therapy: Calcium acetate

Calcium-Based

Phos-Lo, Phoslyra

Contains less calcium than carbonate form

No > 2000 mg elemental calcium/day (from meds and diet)

(25% elemental)

(Phosphate Binder)

Hyperthyroidism Pharmacologic Therapy: Ferric citrate

Iron-Based

Auryxia

May increase serum iron, ferritin, and TSat, Also approved to treat anemia in non-dialysis CKD patients

May cause discolored (dark) stools

Evaluate for drug interactions with iron

(Phosphate Binder)

Hyperthyroidism Pharmacologic Therapy: Sucroferric oxyhydroxide

Iron-Based

Velphoro

May cause discolored (dark) stools

Evaluate for drug interactions with iron

(Phosphate Binder)

Hyperthyroidism Pharmacologic Therapy: Sevelamer Carbonate

Resin Phosphate Binders

Renvela

Lowers LDL and increases HDL

More expensive, consider in patients with extra skeletal calcification or hypercalcemia

(Phosphate Binder)

Hyperthyroidism Pharmacologic Therapy: Sevelamer HCL

Resin Phosphate Binders

Renagel

Metabolic acidosis due to HCl

(Phosphate Binder)

Hyperthyroidism Pharmacologic Therapy: Lanthanum Carbonate

Fosrenol

More expensive, consider in patients with extra skeletal calcification or hypercalcemia.

(Phosphate Binder)

Hyperthyroidism Pharmacologic Therapy: Aluminum Hydroxide

Altema GEL

LAST line agent; risk of aluminum toxicity

Short term treatment only (4 weeks) in patients not responding to other binders)

(Phosphate Binder)

Drug Interactions and Adverse Effects of Phosphate Binders

May interfere with absorption of several drugs (e.g. iron, zinc, antacids, fluoroquinolones)

Separate interacting medications by at least 1 hour before or 3 hours after phosphate binder

ADEs: GI (constipation, diarrhea, nausea, vomiting, abdominal pain), Hypercalcemia with calcium-containing products, CNS toxicity and worsening anemia with aluminum binders

Hyperthyroidism Pharmacologic Therapy: Calcimimetics

“Mimic” an increase in levels of serum calcium by increasing sensitivity of the calcium-sensing receptors on the parathyroid gland to extracellular calcium

Results in reduction of PTH secretion

When to Treat with Vitamin D/Calcimimetic and Agent Selection

Use vitamin D products for low vitamin D levels

Progressively rising PTH above normal range despite correction of modifiable factors

In cases of hypercalcemia or hyperphosphatemia, calcitriol and other vitamin D sterols not recommended

In those with hypocalcemia, reduce dose or stop calcimimetic

Adverse Effects and Monitoring of Vitamin D Agents and Calcimimetics

ADEs: Vitamin D- Hypercalcemia and hyperphosphatemia (most likely with calcitriol)

Calcimimetics- nausea, vomiting, diarrhea and hypocalcemia

Maintain serum calcium within normal range

Lower phosphate toward normal range

No known optimal level of PTH (possibly 130 to 600 pg/mL)

25(OH)D levels > 30 mg/dL (for vitamin D products)

Hyperthyroidism Pharmacologic Therapy: Nutritional/Inactive Vitamin D Products

Ergocalciferol D2 - Vitamin D2

Cholecalciferol D3 - Vitamin D3

Calcifediol D3 - Rayaldee

Must be converted to active form in the kidney

Indicated in stages 3-4

All PO medications

Pharmacologic Therapy: Active Vitamin D and Analogs

Calcitriol D3 (Calcijex IV, Rocaltrol PO) - High incidence of hypercalcemia

Paricalcitol D2 (Zemplar PO, IV) - Does not require hepatic or renal activation, Lower incidence of hypercalcemia than calcitriol

Doxercalciferol D2 (Hectoral PO) - Also IV, Prodrug: requires hepatic activation, Lower incidence of hypercalcemia than calcitriol

Cinacalcet

Sensipar (PO), Calcimimetics

Risk of hypocalcemia

Do not initiate if serum calcium is <8.4 mg/dL

Inhibits CYP 2D6 and is metabolized by CYP 3A4

Titrate every 2-4 weeks

Etelcalcetide

Parsabiv (IV)

Specifically indicated for patients on hemodialysis

Greater reduction in serum calcium and phosphorus than cinacalcet

Hypertension: Goal Blood Pressure in CKD

KDIGO (2021): < 120 mm Hg systolic target in those who can tolerate it

Treatment of Hypertension: Lifestyle Modifications

Exercise (at least 30 minutes 5 times per week)

Sodium restriction to < 2 g per day

Limit alcohol intake to <2 standard drinks per day for men and <1 per day for women

Caution with potassium-containing salt substitutes due to risk for hyperkalemia (especially with higher CKD stages)

Treatment of Hypertension: Diuretics

THIAZIDE DIURETICS - As GFR falls below 30-50 ml/min, ability to promote fluid diuresis declines; however, anti-hypertensive effect may be preserved

LOOP DIURETICS - Effective for blood pressure lowering in the short-term, but not as effective as thiazides in the long-term

Often used in CKD stages 4 and 5 for edema

Calcium Channel Blockers

Dihydropyridines (amlodipine, nifedipine) - More selective for vascular smooth muscle causing vasodilation; Fluid retention and ankle edema may occur

Non-dihydropyridines (diltiazem, verapamil - Reduce heart rate and cardiac-muscle contraction, Beneficial effect on proteinuria, though not as profound as ACE inhibitors or ARBs

Beta-Blockers

carvedilol, metoprolol, propranolol, etc.

May select as add-on therapy based on compelling indications (e.g.HFrEF)

Accumulation may occur with atenolol and bisoprolol

Steroidal Mineralocorticoid Receptor Antagonists (MRAs)

Spironolactone - Non-selective MRA, Adjunct therapy for resistant hypertension, Monitor for hyperkalemia and gynecomastia

Eplerenone - Selective MRA, Adjunct therapy for resistant hypertension, Less concern for gynecomastia; monitor for, hyperkalemia

Treatment of Volume Overload: Loop Diuretics

Furosemide, Torsemide, Bumex

→ 50% —> 80% —> 90% bioavailability

Potassium-Binding Resins in Hyperkalemia

Sodium Polystyrene Sulfonate (Kayexalate) - Risk of intestinal necrosis

Patiromer (Veltassa) - Constipation

Sodium zirconium cyclosilicate (Lokelma) - Edema

Potassium-Binding Resin Clinical Pearls

Drug-drug interactions: Can reduce absorption of other medications, so administer 3 hours before or after other medications (2 hours for Lokelma)

Delayed onset so should not be used alone for life-threatening hyperkalemia

All non-absorbable

Treatment of Metabolic Acidosis

Sodium bicarbonate or sodium citrate

Consider when serum bicarbonate < 18 mEq/L (or lower)

Monitor: fluid retention due to sodium component, blood pressure, potassium, serum bicarbonate concentrations