Residency · Residency · Internal Medicine

Chronic Kidney Disease: Slowing Progression and Managing Complications

Overview

Chronic kidney disease affects approximately 15% of adults in the United States and is defined as abnormalities in kidney structure or function persisting for more than 3 months. The leading causes are diabetes mellitus (40%), hypertension (25%), glomerulonephritis, and polycystic kidney disease. CKD is an independent risk factor for cardiovascular disease, and patients are more likely to die of CVD than to progress to end-stage renal disease. Management focuses on slowing progression and treating complications including anemia, mineral bone disease, metabolic acidosis, and hyperkalemia.

Classification -- KDIGO Staging

GFR Categories

Stage G1 represents GFR of 90 mL/min or above with evidence of kidney damage (proteinuria, hematuria, or structural abnormality). G2 is mildly decreased (GFR 60-89). G3a is mild-to-moderately decreased (45-59). G3b is moderate-to-severely decreased (30-44). G4 is severely decreased (15-29). G5 represents kidney failure (GFR below 15).

Albuminuria Categories

Category A1 (below 30 mg/g) is normal to mildly increased. A2 (30-300 mg/g) is moderately increased, previously termed microalbuminuria. A3 (above 300 mg/g) is severely increased, previously termed macroalbuminuria.

Estimating GFR

The CKD-EPI 2021 equation (race-free) is currently recommended. Cystatin C-based equations are used when creatinine-based GFR may be inaccurate, such as at extremes of muscle mass or in patients with amputations.

<image>KDIGO heat map showing CKD prognosis by GFR and albuminuria categories with color-coded risk stratification from green (low risk) to red (very high risk)</image>

Slowing Progression

Blood Pressure Control

The target is below 120/80 mmHg for most CKD patients based on the SPRINT CKD subgroup analysis. ACE inhibitors or ARBs are first-line for CKD with albuminuria (A2 or A3) and should be titrated to the maximum tolerated dose. A creatinine rise of up to 30% after initiation reflects a hemodynamic effect rather than injury and is acceptable. ACE inhibitors and ARBs should not be combined (the ONTARGET and VA NEPHRON-D trials demonstrated increased harm without benefit).

SGLT2 Inhibitors -- Paradigm Shift

Dapagliflozin (DAPA-CKD) and empagliflozin (EMPA-KIDNEY) both demonstrated reduction in a composite of sustained GFR decline, ESRD, renal death, and cardiovascular death. Benefits extend to patients with and without diabetes. Empagliflozin is effective down to eGFR 20 mL/min based on the EMPA-KIDNEY expanded range. The mechanism involves restoration of tubuloglomerular feedback, reduced hyperfiltration, and anti-inflammatory and antifibrotic effects. Side effects include genital mycotic infections, euglycemic DKA (rare), and volume depletion. These agents should be started at any qualifying eGFR and continued even as eGFR drops below the initiation threshold, as the "dip and recover" pattern is expected.

Non-Steroidal Mineralocorticoid Receptor Antagonist (ns-MRA)

Finerenone demonstrated reduced kidney and cardiovascular composite endpoints in diabetic kidney disease in the FIDELIO-DKD and FIGARO-DKD trials. It is added to ACE inhibitor/ARB plus SGLT2 inhibitor therapy for diabetic CKD with persistent albuminuria. Potassium must be monitored closely, though the hyperkalemia risk is less than with steroidal MRAs.

GLP-1 Receptor Agonists

The FLOW trial demonstrated that semaglutide is the first GLP-1 receptor agonist to show primary kidney outcome benefit in type 2 diabetes with CKD, providing additional cardiorenal protection beyond glycemic control.

Other Measures

Dietary protein moderation (0.8 g/kg/day for CKD G3-G5) is recommended, while very low protein diets should be avoided without dietitian guidance. Sodium restriction to below 2 g/day, smoking cessation, and avoidance of nephrotoxins (NSAIDs, contrast when possible, aminoglycosides) are important. Metabolic acidosis should be treated with oral sodium bicarbonate to maintain serum bicarbonate at or above 22 mEq/L, which may slow CKD progression.

<image>Pillars of CKD progression prevention showing ACE inhibitor/ARB, SGLT2 inhibitor, finerenone, blood pressure control, and lifestyle modifications with supporting trial evidence</image>

Managing Complications

Anemia of CKD

CKD produces a normocytic, normochromic anemia due to decreased erythropoietin production. The evaluation includes CBC, reticulocyte count, iron studies (ferritin, TSAT), and B12/folate. Iron repletion is the first priority, targeting ferritin above 100 (above 200 for dialysis patients) and TSAT above 20%; IV iron is preferred for dialysis patients, with oral or IV acceptable for non-dialysis CKD. Erythropoiesis-stimulating agents (ESAs) such as epoetin alfa and darbepoetin are initiated when hemoglobin falls below 10 g/dL (after iron repletion) and symptoms are present, targeting hemoglobin of 10-11.5 g/dL. Normalization should not be targeted, as the TREAT and CHOIR trials demonstrated increased cardiovascular events and death with higher targets. HIF-prolyl hydroxylase inhibitors such as daprodustat (oral) represent an FDA-approved alternative to ESAs that is more convenient, though long-term safety data are still accumulating.

CKD-Mineral Bone Disease (CKD-MBD)

Hyperphosphatemia is managed with dietary phosphorus restriction and phosphorus binders (calcium-based, sevelamer, lanthanum). Hypocalcemia typically corrects with phosphorus and vitamin D management. Secondary hyperparathyroidism, driven by low calcitriol and high phosphorus, is treated with active vitamin D (calcitriol) or vitamin D analogs (paricalcitol), with calcimimetics (cinacalcet) reserved for dialysis patients with persistent hyperparathyroidism. Renal osteodystrophy encompasses a spectrum from high-turnover disease (osteitis fibrosa) to low-turnover disease (adynamic bone disease).

Metabolic Acidosis

Common in CKD G4-G5, metabolic acidosis is treated with oral sodium bicarbonate 650-1300 mg three times daily to maintain serum bicarbonate at or above 22 mEq/L. This may slow CKD progression and reduce muscle wasting, but monitoring for volume overload from the sodium load is important.

Volume and Potassium Management

Loop diuretics manage volume overload; thiazides are less effective at GFR below 30, though recent evidence supports chlorthalidone use. Dietary potassium restriction and potassium binders (patiromer, SZC) enable continued RAAS inhibitor use.

Dialysis Planning

Nephrology referral should occur by CKD G4 (GFR below 30) at the latest. Vascular access planning requires AV fistula creation ideally 6 months before anticipated dialysis start. Dialysis initiation should be based on symptoms (uremia, refractory volume overload, refractory hyperkalemia, pericarditis) rather than a GFR threshold alone; the IDEAL trial demonstrated no benefit to early start at GFR 10-14 versus intent to defer to GFR 5-7. Modality education should cover in-center hemodialysis, home hemodialysis, and peritoneal dialysis. Kidney transplant evaluation should begin early because preemptive transplant (before dialysis) offers the best outcomes.

<image>Timeline of CKD management showing stage-appropriate interventions from early RAASi and SGLT2i therapy through mineral bone disease management to dialysis access planning and transplant referral</image>

Clinical Pearls

The "dip and recover" pattern with SGLT2 inhibitor initiation (GFR drops 3-5 mL/min then stabilizes) is expected and is not a reason to discontinue, as it reflects reduced hyperfiltration. Creatinine rise of up to 30% after ACE inhibitor/ARB initiation is acceptable and should not trigger discontinuation unless hyperkalemia develops or the rise exceeds 30%. SGLT2 inhibitors, finerenone, and ACE inhibitors/ARBs are additive, and the goal is to layer these therapies for maximum nephroprotection in diabetic CKD. NSAIDs are a leading preventable cause of CKD progression, and patients should be explicitly counseled. Contrast-associated AKI risk is often overstated in CKD G3, and necessary contrast-enhanced imaging should not be withheld based on eGFR above 30 alone. Bisphosphonates are generally avoided in CKD G4-G5 due to accumulation and risk of adynamic bone disease.

References

• KDIGO 2024 Clinical Practice Guideline for CKD Evaluation and Management. Kidney Int. 2024.
• Heerspink HJL, et al. Dapagliflozin in CKD (DAPA-CKD). N Engl J Med. 2020;383:1436-1446.
• The EMPA-KIDNEY Collaborative Group. Empagliflozin in CKD. N Engl J Med. 2023;388:117-127.
• Bakris GL, et al. Effect of Finerenone on CKD Outcomes in Type 2 Diabetes (FIDELIO-DKD). N Engl J Med. 2020;383:2219-2229.
• Perkovic V, et al. Effects of Semaglutide on CKD in Type 2 Diabetes (FLOW). N Engl J Med. 2024;391:109-121.
• Cooper BA, et al. A Randomized, Controlled Trial of Early vs. Late Initiation of Dialysis (IDEAL). N Engl J Med. 2010;363:609-619.

Read this lecture as Markdown