MD Notes

creation date: 2025-09-22 13:50
tags: Pathologies

Chronic Kidney Disease

Background

Definitions

Chronic kidney disease (CKD) is characterized by the presence of kidney damage that persists for >3 months.

CKD involves progressive kidney function loss, often leading the need for renal replacement therapy such as dialysis or transplantation.

Etiology

There are a number of diseases that leads to CKD and ultimately end-stage renal disease:

  • Type 2 diabetes (30-50%)
  • Type 1 diabetes (4%)
  • Hypertension (27%)
  • Primary glomerulonephritis (8%)
  • Chronic tubulointerstitial nephritis
  • Hereditary or cystic diseases
  • Secondary glomerulonephritis or vasculitis
  • Plasma cell dyscrasias or neoplasm
  • Sickle cell nephropathy

In some cases, damage/inflammation to the kidney can be separated by nephrotic or nephritic.

Prerenal disease can also lead to progressive loss of renal function. These conditions have chronic decreased renal perfusion which increase risk of kidney injury:

  • Chronic heart failure
  • Cirrhosis
    Intrinsic renal diseases such as damage to the blood vessels, glomerulus, and tubules can affect renal function and damage. Postrenal obstructions (eg. with tumour or nephrolithiasis) can have an effect on the ureters.

It should be noted that differentiation to pre- and post-renal processes is not as important with CKD as with acute kidney injury.

Pathogenesis

The pathophysiology of CKD involves chronic and sustained insults from progressive nephropathies which lead to fibrosis and destruction of kidney architecture.

The glomeruli, tubules, interstitium, and vessels are all affected and manifests histologically as glomerulosclerosis, tubulointerstitial fibrosis, and vascular sclerosis. The damage scarring and fibrosis occur in stages which are complex and overlapping:

  • Infiltration of damaged kidneys with extrinsic inflammatory cell
  • Activation, proliferation, and loss of intrinsic renal cells (via apoptosis, necrosis, mesangiolysis, podocytopenia)
  • Activation and proliferation of extracellular matrix producing cells (incl. myofibroblasts and fibroblasts)
  • Deposition of extracellular matrix, replacing normal architecture

Certain mechanisms can accelerate the progression of CKD leading to glomerulosclerosis:

  • Systemic intraglomerular hypertension
  • Glomerular hypertrophy
  • Intrarenal precipitation of calcium phosphate
  • Altered prostanoid metabolism

The progression of kidney disease vary based on the response to insults which differ based on the various comorbid diseases present. In some cases patients can recover fully but in other patients, chronic/recurrent insults result in lasting damage.

In response to damage, the kidney responds by increasing the filtration rate of undamaged nephrons through a process known as adaptive hyperfiltration. As a result, mild kidney insufficiency is often masked and the patient’s serum creatinine appears to be normal or near-normal. Additional homeostatic mechanisms within the tubules also maintain serum levels of electrolytes to remain within normal ranges.

Adaptive hyperfiltration, although initially beneficial, causes damage to the glomeruli of the remaining nephrons due to the increased filtration load. As the function of the kidney deteriorates, manifestations may be observed associated with fluid overload and electrolyte imbalances.

In end-stage kidney disease, the kidney’s inability to excrete urea effectively and the subsequent buildup results in uremia. This results in a constellation of signs and symptoms that require kidney replacement therapy to prevent death.

Clinical Presentation

Signs & Symptoms

Early disease is often asymptomatic, occasionally manifesting with nonspecific symptoms:

  • Mild fatigue
  • Decreased exercise tolerance
  • Nocturia
  • Mild peripheral edema

As the disease progresses, symptom burden increases progressively. However, this is not typically noticeable until stage 4:

  • Fatigue and weakness
  • Muscle soreness
  • Cramps
  • Dry skin
  • Diminished sexual function
  • Oliguria
  • Decrease in cognition
  • Swelling of feet and ankles
  • Shortness of breath due to pulmonary edema (fluid overload)
  • Hypertension

Late stage disease manifest as signs and symptoms of uremia:

  • Persistent pruritus
  • Anorexia and malnutrition
  • Nausea and vomiting
  • Fatigue
  • Platelet dysfunction
  • Chest pain (uremic pericarditis)
  • Neuropathy
  • Seizures and coma
  • Significant fluid overload (anasarca: multiple vascular beds edematous)

History & Physical Exam

History should elucidate risk factors. Physical exam often isn’t helpful but may find:

  • Skin pigmentation
  • Scratch mark from pruritus
  • Pericardial friction rub
  • Uremic frost (fine white powder on skin due to urea in sweat)
  • Hyperreflexia or muscle twitches
  • Hypertensive fundal changes

Risk factors

Risk factors for developing community CKD include:

  • Older age
  • Cardiovascular risk factors and diseases

Risk factors for referred CKD (those in nephrology practices) differ slightly:

  • Hereditary conditions (eg. autosomal-dominant polycystic kidney disease)
  • Acquired nephropathies (eg. glomerulonephritis, diabetic nephropathy)

Risk factors for progression of CKD include:

  • Older age
  • Male and non-white ethnicity
  • Systemic hypertension (modifiable)
  • Proteinuria (modifiable)
  • Metabolic factors such as insulin resistance, dyslipidemia, hyperuricemia (modifiable)

Diagnosis

Criteria

KDOQI/KDIGO guidelines define CKD as:

  • Presence of kidney damage OR decreased kidney function
  • For ≥3 months (to distinguish from AKI)

Kidney damage refers to pathologic abnormalities which can be established via:

  • Kidney biopsy (evidence for glomerular, vascular, tubulointerstitial disease)
  • Imaging studies (eg. polycystic kidneys, hydronephrosis (possible obstruction), small and echogenic kidneys)
  • Inferred from markers such as:
    • Urinary sediment abnormalities (RBC/WBC casts in urine)
    • Increased rates of urinary albumin excretion (ACR ≥3.4 mg/mmol)
  • Patients with history of kidney transplantation are assumed to have kidney damage

Decreased kidney function refers to a decreased glomerular filtration rate (GFR), estimated using eGFR based on serum creatinine:

  • Decreased: GFR <60 mL/min per 1.73 m2
  • Kidney failure: GFR <15 mL/min per 1.73 m2 or treatment by dialysis
  • eGFR is calculated currently using 2021 CKD-EPI equation
  • Note that older adults have lower levels of serum creatinine (decreased in muscle mass / sarcopenia) and thus can have a eGFR that is falsely elevated if calculated from creatinine. This can be mitigated with cystatin C-based eGFR equations.

Chronicity should be confirmed which can be documented or inferred. This is typically in the form of past measurements and imaging. In cases where chronicity cannot be established, repeated testing is needed to rule out acute kidney disease.

Staging of CKD

Staging is used for risk of progression and complications, and to inform treatment and intensity of monitoring. Staging is based on:

Cause of disease

  • Identification of the cause is required to use specific therapy for preventing further injury
    GFR (G stage)
  • G1: GFR >90 mL/min per 1.73 m2
  • G2: GFR 60-89 mL/min per 1.73 m2
  • G3a: GFR 45-59 mL/min per 1.73 m2
  • G3b: GFR 30-44 mL/min per 1.73 m2
  • G4: GFR 15-29 mL/min per 1.73 m2
  • G5: GFR <15 mL/min per 1.73 m2 or treatment by dialysis
    Albuminuria (A stage)
  • A1: ACR <3.0 mg/mmol (normal)
  • A2: ACR 3.0 to 30 mg/mmol (microalbuminuria)
  • A3: ACR >30 mg/mmol (macroalbuminuria)

Work-up

Initial suspicion of chronic kidney disease should start with evaluation of urgency and whether dialysis is needed. The following findings should prompt initiation of dialysis:

  • Refractory pulmonary edema
  • Life-threatening hyperkalemia or metabolic acidosis
  • Encephalopathy
  • Pericardial rub

If there is presence of urgent symptoms, a referral to a nephrologist should be considered even if dialysis is not needed.

The remainder of the workup consist of establishing the criteria for diagnosis and identification of the cause. This will typically include:

  • Creatinine/eGFR
  • Electrolytes
  • Urinalysis or dip stick for albumin
  • CBC with differential

Consider a nephrology referral for patients with low or rapidly declining kidney function.

Differential

Other diagnoses that may present similarly include:

  • Acute kidney injury
  • Alport syndrome
  • Antigiomerular basement membrane disease
  • Diabetic nephropathy
  • Multiple myeloma
  • Nephrolithiasis
  • Rapidly progressive glomerulonephritis
  • Renal artery stenosis

Red Flags / Complications

Systemic complications of CKD include:

  • Salt/fluid balance (corrected by sodium restriction and loop diuretics)
  • Hypertension (manifestation of volume expansion)
  • Hyperkalemia (distal renal tubular dysfunction in conjunction of dietary potassium intake, tissue breakdown, and aldosterone resistance; may be worsened by ACEi and nonselective beta-blockers)
  • Metabolic acidosis (retention of acidic compounds)
  • Hyperphosphatemia (decreased phosphorous filtered leads to secretion of PTH causing secondary hyperparathyroidism to normalize phosphorus and calcium levels → hurts bone health)
  • Normocytic normochromic anemia (due to reduced EPO which is due to decreased renal function, abnormal iron metabolism, and reduced RBC survival)
  • Cardiovascular disease
  • Insulin resistance

Management

General management

The general principles of management are:

  • Treat reversible causes of kidney failure
  • Prevent or slow the progression of kidney disease
  • Treat complications
  • Adjust drug doses when appropriate
  • Identification of need and preparation for kidney replacement therapy

Blood pressure control and albuminuria
Optimization of antihypertensives therapy if patient has cooccuring hypertension (80-85% of patients). In nondiabetic patients, recommended choices are:

  • ACE inhibitor (recommended) or ARB
  • Combination therapy with another antihypertensive (not ACEi + ARB)

Additionally, patients with elevated ACR may benefit from an SGLT2 inhibitor.

Treatment of underlying cause
To slow the progression of kidney disease, treatment of conditions ranging from cardiac, obesity, or diabetic kidney disease. These are discussed in separately.

SGLT2 inhibitors and GLP-1 may improve outcomes with or without diabetes.

Prevention of infection
Due to the increased risk of infection, patients should be vaccinated against:

  • Annual influenza virus
  • Hep B (for those at risk of progression of CKD or CKD stage 4-5)
  • Pneumococcal (for those at risk)

Acute exacerbation of CKD

In CKD patients with a recent decrease in eGFR or increase in proteinuria, identification and correction of a possible reversible process may result in recovery of function. Some possible causes are:

  • Decreased kidney perfusion - hypovolemia (eg. from vomiting), hypotension, infection, or certain eGFR lowering drugs (eg. NSAIDs, ACEi) can result in hypoperfusion and temporarily decreased eGFR
  • Administration of nephrotoxic drugs - common offenders includeaminoglycoside antibiotics, NSAIDs, and radiographic contrast material
  • Urinary tract obstruction - can be ruled out with ultrasound; especially in presence of prostatic disease (less common without)

Treatment of complications

Manifestations of CKD can vary and thus treatment of each will depend on the complications present. Common complications are discussed here:

Volume overload

  • Sodium restriction (<2 g/day in adults, <1 teaspoon)
  • Diuretic therapy (eg. loop diuretic daily)
    Hyperkalemia
  • Low-potassium diet (<1.5-2.7 g/day)
  • Avoid potassium raising drugs such as NSAIDs
  • Also, salt substitutes replace Na with K, which may cause hyperkalemia
    Metabolic acidosis
  • Bicarbonate supplementation with volume status monitoring (due to concurrent administration with sodium)
    Mineral and bone disorders (MBD)
  • Dietary phosphate restriction and oral phosphate binder
  • Monitoring of PTH levels
    Hypertension
  • Discussed above
    Anemia
  • Hb checked yearly for stage 3, q6 months for stage 4-5, and q3 months for dialysis patients
  • Treat underlying cause if present (eg. iron deficiency)
  • Erythropoietin stimulating agents (ESAs) such as erythropoietin and darbepoetin alfa may correct anemia
    Dyslipidemia
  • Assessment of cardiovascular risk should be made
  • Statin therapy
    Sexual dysfunction
  • Erectile dysfunction/decreased libido in males
  • Disturbances in menstruation (including amenorrhea) in females

Treatment of end-stage kidney disease

Nearing ESKD (eGFR <15 mL/min/1.73m2), some uremic symptoms must be monitored and treated:

Malnutrition

  • Monitor using serum albumin (correlates to nutritional status)
  • Low-protein diet - providing 30-35 kcal/kg daily, do not exceed 0.8g/kg/day
    Uremic bleeding
  • Correction of platelet dysfunction via desmopressin, cryoprecipitate, or estrogen
  • Typically not needed if asymptomatic but may be considered prior to invasive procedures
    Pericarditis
  • Uremic pericarditis presents with fever, pleuritic chest pain, and pericardial friction rub w/ typical ventricular strain pattern on ECG
  • Resolves with dialysis
    Uremic neuropathy
  • Dysfunction of CNS and PNS including encephalopathy
  • Resolves with dialysis
    Thyroid dysfunction

In these cases, a nephrology referral is typically recommended. The eligibility of referral is found here. A low eGFR may not necessarily indicate dialysis and choice to initiate is typically based on symptoms.

References

Tools / Guidelines

MDCalc - eGFR
CKD Framework for Nephrology Referral

Additional Reading

Backlinks