A 74-year-old man with chronic kidney disease and an increase in serum creatinine from baseline

A 74-year-old man with chronic kidney disease (CKD) and type 2 diabetes presented to our nephrology clinic for follow-up of diabetic kidney disease with a serum creatinine of 180 (reference range 59 to 104) μmol/L and a urine albumin-to-creatinine ratio (ACR) of 95 (reference range < 3) mg/mmol. Two years earlier, his serum creatinine level was 125 μmol/L. He had a history of type 2 diabetes, hypertension, and hypercholesterolemia. His medications included perindopril 2 mg daily, amlodipine 5 mg daily, atorvastatin 40 mg daily, metformin 500 mg twice daily, dapagliflozin 10 mg daily, and semaglutide 1 mg subcutaneous weekly. He did not smoke or consume alcohol. On examination, he appeared well, his blood pressure was 140/85 mm Hg, and he had mild peripheral edema.

How can a potentially reversible acute kidney injury be distinguished from CKD progression?

In patients with CKD, a rise in serum creatinine may indicate either disease progression or acute kidney injury (AKI). Acute kidney injury is a rapid decline in kidney function, while CKD progresses slowly and typically without acute symptoms. In our patient, distinguishing between AKI and CKD based on serum creatinine was not possible unless more recent testing was available. Distinguishing between them is critical because AKI is expected to be reversible depending on the duration and severity of AKI and baseline kidney function. A mild increase in serum creatinine (as much as 25%) after initiation of cardiovascular and kidney-protective or nonsteroidal anti-inflammatory medications does not necessarily reflect true kidney function decline.¹ Evaluation should take into account factors such as recent illness, fluid volume changes, infections, urinary symptoms, and medications including angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and sodium–glucose cotransporter 2 inhibitors (Box 1). Assessment of blood pressure and volume status is key; orthostatic vitals may be helpful. Hypotension or other signs of hypovolemia may suggest prerenal AKI, while fluid overload can suggest decreased cardiac output as a cause of AKI.

Box 1: Potential causes of acute kidney injury (AKI) .

Prerenal

• Decreased effective circulating volume

  • Vomiting, diarrhea

  • Decreased cardiac output (renal venous congestion is another potential contributor to AKI in patients with congestive heart failure)

  • Excessive diuresis (e.g., owing to diuretics such as furosemide or metolazone)

  • Cirrhosis

• Renal artery stenosis

Renal

• Acute tubular necrosis

  • Ischemic from a prolonged or severe prerenal insult (see above)

  • Nephrotoxic (e.g., myoglobin from rhabdomyolysis, aminoglycosides such as gentamicin), nonsteroidal anti-inflammatories (NSAIDs), cisplatin

• Acute interstitial nephritis

  • Medications are the most common cause (e.g., fluroquinolones, sulfonamides, proton pump inhibitors, NSAIDs, allopurinol, and ranitidine)

• Glomerulonephritis

  • Presentation with hematuria or proteinuria, and possibly systemic symptoms (e.g., fatigue, elevated blood pressure, peripheral or periorbital edema, flu-like symptoms)

Postrenal

• Any impediment to urine flow due to structural or functional change occurring anywhere from the renal pelvis to the tip of the urethra

What investigations should be ordered?

Repeat testing for serum creatinine and electrolytes is essential, including sodium, potassium, chloride, bicarbonate, and calcium (hypercalcemia can reduce the glomerular filtration rate via vasoconstriction). Urinalysis and ACR assess proteinuria and glomerular injury. Ultrasound should be ordered for persistent, unexplained kidney function decline, especially with urinary symptoms or urologic history.

What is the impact of acute kidney injury on the progression of CKD?

Acute kidney injury accelerates CKD progression, with even a single episode raising the risk of kidney failure or death by 30% in patients with CKD.² This occurs because of residual nephron damage, inflammation, and fibrosis, reducing kidney reserve. Recurrent AKI compounds the effect, and CKD itself predisposes to AKI. A history of AKI can be elicited by asking about hospital admissions, severe illness, medication holds, or temporary dialysis.

What is the role of baseline proteinuria in predicting the progression of CKD?

Persistent albuminuria predicts CKD progression and cardiovascular risk; one guideline classifies CKD by both estimated glomerular filtration rate (eGFR) and ACR.¹ Rising proteinuria may indicate glomerular disease, while stable proteinuria with worsening serum creatinine may suggest hemodynamic or prerenal causes. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers reduce proteinuria and slow progression.³ Because ACR varies with hydration, exercise, and assay factors, repeat testing is needed. Proteinuria rarely causes edema unless it is in the nephrotic range, defined as severe albuminuria (≤ 3 g/d in a 24-hour urine collection or ACR ≥ 300 mg/mmol). At this level, hypoalbuminemia can develop, leading to edema and hyperlipidemia, together causing a nephrotic syndrome.

What is the significance of intra-individual variability in serum creatinine and urine ACR?

Intra-individual variation in serum creatinine of as much as 25% is common. Serum creatinine fluctuates with hydration, diet, and medications (e.g., trimethoprim); increased muscle mass will also cause levels to rise.¹ Isolated elevations may not indicate a true decline in function, so repeat testing is often appropriate, as two-thirds of AKI episodes resolve within a week.²

When should patients be referred to a nephrologist?

Patients should be referred when eGFR is less than 30 mL/min/1.73 m² or ACR is greater than 60 mg/mmol, particularly in the presence of hypertension, diabetes, autoimmune disease, family history, hematuria, or anatomic abnormalities.¹ Younger patients, those with genetic disease (e.g., polycystic kidney disease), evidence of glomerulonephritis, obesity, or structural abnormalities, such as vesicoureteral reflux, should be referred. These patients may benefit from early specialist input with respect to diagnosis and management, including management of complications (e.g., anemia, bone disease, cardiovascular risk) and plan for potential dialysis or transplantation. The Kidney Failure Risk Equation (KFRE) score, based on eGFR and ACR, estimates an individual patient’s risk of kidney failure. Easy-to-use online calculators and provincial toolkits (e.g., Ontario Renal Network, bcguidelines.ca) can translate risk into practical thresholds guiding clinicians on which patients require referral to a nephrologist (e.g., eGFR < 30 mL/min/1.73 m², ACR > 60 mg/mmol, 5-year KFRE risk ≥ 5%, or rapid decline in eGFR in absence of self-limited illness).^4,5

Case revisited

The patient had stable oral intake with no recent illness, urinary symptoms, or medication changes. His mild edema was likely related to his calcium channel blocker, as his proteinuria was not severe. His glycated hemoglobin level was beneath target at 6.9%. One week later, a repeat serum creatinine of 178 μmol/L and ACR of 100 mg/mmol were consistent with CKD progression. The patient’s blood pressure was 140/85 mm Hg and his potassium level was normal. Sodium restriction (2 g/d) was advised. Perindopril was increased to 4 mg daily for blood pressure and proteinuria control. Because his edema was mild and not bothersome, the calcium channel blocker was continued. Two weeks later, his potassium was normal and serum creatinine rose to 200 μmol/L. At 4 months, his blood pressure was 129/77 mm Hg, serum creatinine 190 μmol/L, and ACR 55 mg/mmol, indicating stabilization and a hemodynamic angiotensin-converting enzyme inhibitor effect.