Azotemia

Etiology

For each classification of azotemia, there are unique etiologies. 

• Prerenal azotemia results from an insult/injury to the kidney. Most commonly, we see this in the form of hypoperfusion, or decreased blood flow, to the kidneys from various etiologies of volume depletion, such as the physiologic state shock, dehydration, hemorrhage, over-diuresis, burns, and even intravascular depletion from low-oncotic pressure states, such as congestive heart failure and liver failure.[1]

• Intrinsic azotemia results from damage to the kidney's structure; the affected structures include the glomeruli, renal tubules, interstitium, and renal vasculature. This can result from inflammatory conditions, such as vasculitis, toxins, drugs, infections, and damage from hypoperfusion.[2]

• Post-renal azotemia comes from issues in the ureters and bladder. Usually, a patient has some diagnosis of obstruction, seen in patients with risk factors such as recurrent urinary tract infections, nephrolithiasis, hydronephrosis, and benign prostatic hyperplasia.

Epidemiology

Interestingly, many aspects of the natural history of azotemia remain unclear to this day. With that said, azotemia is quite common, responsible for 8% to 16% of hospital admissions, and is more strongly associated with a significantly higher risk of mortality.[3] There is a need for studies to help understand new knowledge about the incidence of AKI and its epidemiology. Without this, we cannot improve our understanding and stratification of this disease process. The International Society of Nephrology initiative has an ambitious aim to prevent all avoidable deaths from AKI worldwide by 2025.[4] A global study conducted over 10 weeks in 2014 collected data on the burden of KDIGO-based AKI across 289 centers and 72 countries. Seven-day mortality was 10 to 12% in both high- and low-income countries. Key etiologic risk factors varied between countries but included dehydration, shock, infection, sepsis, cardiac disease, and nephrotoxic medications. The study showcased the potential for global data collection to inform international strategy.

Pathophysiology

The kidney receives about 25% of the body's cardiac output. Therefore, they are quite sensitive to any decrease in perfusion and oxygenation. In the setting of severe/prolonged decreased blood flow or hypoxia to these organs, it impairs cellular integrity and metabolism, and ultimately leads to vascular, glomerular, and tubular dysfunction. The damage is reflected by the glomerular filtration rate (GFR), which falls in the setting of injury. However, the GFR is not always correlated to the underlying condition, demonstrating the complexity of vascular and tubular processes in renal dysfunction.

Some of the most common findings in AKI include ischemia, apoptosis, tubular necrosis, detachment of renal epithelial cells from the basement membranes, effacement of the brush border in proximal tubules, tubular casts resulting from cell sloughing, interstitial edema, and peritubular capillary congestion.[5]

History and Physical

When evaluating a patient for azotemia/AKI, several key questions and physical findings can help guide the appropriate diagnosis and treatment.

1. Evaluate volume status
   • Mucous membranes (dry/wet)
   • Skin tenting
   • Edema (pitting/nonpitting)
   • Hepatojugular reflux
   • Pulmonary crackles
   • Ascites
2. Check for signs of infection (lung, skin, intra-abdominal), fever, chills, diaphoresis, cough, congestion, nausea, vomiting, diarrhea, dysuria, frequency, pyuria, hematuria

Prerenal findings: Sepsis/shock, burn, bleeding, dehydration (history of diarrhea and vomiting), skin tenting, worsening third spacing from intravascular depletion (pitting edema and ascites), hypotension

Intra-renal findings: Nephrotoxic medication history, contrast exposure, poorly controlled hypertension, or diabetes mellitus

Post-renal findings: Flank pain, concerning for pyelonephritis; colicky pain, concerning for nephrolithiasis; boggy prostate, urinary hesitancy, anuria, concerning for benign prostatic hyperplasia (BPH); smoking history, concerning for bladder cancer; spinal cord trauma, concerning for neurogenic bladder.

Evaluation

Laboratory evaluation for azotemia includes a basic metabolic panel (BMP), BUN/Cr, urinary sodium (Na), protein, Cr, urea, urine osmolality (Ur Osmo), and urinalysis (UA). Radiographic evaluation can be performed with a renal ultrasound (US), CT of the abdomen and pelvis with or without contrast, or a renal Doppler examination.

Diagnosis of Azotemia can be made by a BUN greater than 21 mg/dL

Significant findings for prerenal azotemia

• BUN: Cr ratio greater than 20:1
• Fractional excretion of sodium (FeNa) less than 1, fractional excretion of urea (FeUr) less than 35%
• Urine osmolality 500 mOsm/kg
• UA can show hyaline casts [6]

Intra-Renal Azotemia

• BUN: Cr ratio less than 20:1
• FeNa greater than 2, FeUr greater than 50%
• Ur Osmolality is less than 300 mOsm/kg
• UA: Cellular debris, muddy brown casts, red cell casts, eosinophils, + proteinuria

Post-Renal Azotemia

• BUN: Cr ratio less than 20:1
• FeNa greater than 2
• Ur Osmo is less than 300 mOsm/kg
• UA: WBC casts
• Imaging findings: pyelonephritis, nephrolithiasis, bladder mass

Treatment / Management

The goal in managing azotemia is to treat the underlying condition. For prerenal causes, IV fluid hydration and possible vasopressor support are crucial to reestablish adequate perfusion to the kidneys, thereby optimizing and salvaging the integrity of the renal vasculature and tubules. Intrinsic renal diseases are so multifaceted and variable. Cessation of toxic substances, avoidance of further use, and contrast, followed by hydration, can facilitate the recovery of kidney structures. Hypertension and diabetes are 2 of the most common disease processes that can adversely affect renal vascular and tubular epithelium and renal interstitium if poorly managed. Therefore, optimizing blood pressure and hemoglobin A1c is crucial for protecting the kidneys. For porto-renal azotemia, relief of any obstruction followed by hydration is the mainstay of treatment. A urologic evaluation might be necessary, along with catheter placement.

Along with following BUN/Cr for normalization/stabilization, urine output is very important in ensuring adequate renal function. A minimum of 0.5 mL/kg per hour is considered reassured urine output and a sign of stable kidney function.[7][8][9]

Differential Diagnosis

The differential diagnoses for azotemia include the following:

• Gastrointestinal (GI) bleeding
• Corticosteroid use
• Ketoacidosis
• States of protein catabolism
• Congestive heart failure (CHF)
• Hyperalimentation (TPN)

Prognosis

Generally, treating the underlying causes of azotemia yields favorable outcomes. A remarkable feature of the kidneys is their ability to undergo cellular repair, resolving injury and restoring normal perfusion. The GFR stabilizes, allowing cellular repair, migration, and proliferation to begin with the differentiation of renal epithelium.[10] Progression of renal dysfunction includes chronic kidney disease (CKD) and, more so, end-stage renal disease (ESRD), requiring dialysis.

Complications

A complication related to elevated BUN levels is mostly associated with excess nitrogenous waste production from renal failure. The toxic effects of such waste can cause uremia. Uremic complications include platelet dysfunction and bleeding, encephalopathy, peripheral neuropathy, nausea, vomiting, hypothermia, and itching. Uremia is an indication for emergent hemodialysis. Allopurinol and rasburicase are medications that control uric acid levels and are renal-protective.