Renal physiology TBL

From Iusmphysiology

Contents 1 Acute kidney injury 1.1 Definition 1.2 Epidemiology 1.3 Pathophysiology 1.3.1 Prerenal AKI 1.3.2 Intrinsic AKI 1.3.2.1 Tubular intrinsic AKI 1.3.2.2 Interstitium intrinsic AKI 1.3.2.3 Vascular intrinsic AK 1.3.3 Postrenal AKI 1.4 Clinical findings 1.5 Diagnosis 1.5.1 CBC and FE (fractional excretion) 1.5.2 Prerenal azotemia 1.5.3 Intrinsic AKI 1.5.4 Postrenal AKI 1.6 Treatment 1.7 Prognosis

Acute kidney injury

Definition

• We have renamed acute renal failure (AFR) to acute kidney injury (AKI).
  • We renamed it because of an historic inability to sufficiently define ARF.
• Now we define acute kidney injury (AKI) as "a functional or structural abnormality of the kidney as determined by blood, urine, or tissue tests or imagine studies that manifests with 48 hours".
• We use diagnostics like serum creatinine (normally cleared by the kidney) and urine production to determine the occurrance of AKI (acute kidney injury).
  • Serum creatinine increase by 50% or over 0.3 mg / dL is considered diagnostic for AKI.
  • Reduced urine production resulting in less than 0.5 ml / kg / hr for 6 hours is diagnostic for AKI.
    • Oliguria: "production of an abnormally small amount of urine" per wornet

Epidemiology

• The incidence of AKI (acute kidney injury) depends on the setting:
  • hospital population: 5-7%
  • ICU: 15-40%
  • community: 1%
• The mortality of AKI (acute kidney injury) ranges from 36-86% and depends on:
  • setting ICU > hospital > community
  • age
  • illness acuity
  • severity of injury
• Elevated serum creatinine levels, even with only mild increases, can result in large increases in mortality.

Pathophysiology

• There are many ways that the kidney can be injured:
  • decreased perfusion
  • toxins
  • ischemic or obstructive injury to the tubule
  • inflammation and / or edema of the tubulointerstitium,
  • primary glomerular disease
• We divide the pathophysiology into three, broad, anatomical divisions: prerenal, intrinsic / intrarenal, and post-renal.
  • Prerenal makes up 40-70% of AKI pathophys
  • Intrinsic makes up 25-40% of AKI pathophys
  • Postrenal makes up 5-10% of AKI pathophys
• Intrinsic pathophysiology will be the focus of our inquiries and includes several types of injury:
  • acute glomerulonephritis
  • acute interstitial nephritis
  • tubular cell injury
    • Ischemia and inflammation (sepsis, surgery, hypoperfusion)
    • Toxins (direct or indirect)

Prerenal AKI

• Azotemia: "Azotemia is a medical condition characterized by abnormally high levels of nitrogen-containing compounds, such as urea, creatinine, various body waste compounds, and other nitrogen-rich compounds in the blood." per wikipedia
• Azotemia is the most common etiology of prerenal AKI.
• Azotemia can occur when the extracellular compartment undergoes a severe decrease in volume.
• We categorize azotemia into volume-responsive or not depending on whether expanding the extracellular compartment resolves the azotemia.
  • For example, adding saline will expand the extracellular compartment.
• Another major cause of prerenal AKI is medications that work upstream of renal function: angiotensin converting enzyme inhibitors (ACEI’s), angiotensin receptor blockers (ARB’s) and NSAIDs (reduce glomerular

capillary perfusion by reducing prostaglandins such that vasodilation is reduced).

• Prerenal AKI timeline:
  • autoregulatory mechanisms of the kidney attempt to maintain blood flow and GFR (think myogenic and tubuloglomerular feedback),
    • Recall that these serve to change the blood flow in the afferent and efferent glomerular arterioles
  • renal hypoperfusion triggers the hormonal response (think renin, aldosterone, and AVP) which mostly maintains the GFR
  • without interventsion, the pt progressive to significant tubular cell injury due to ischemia (which is then intrinsic AKI).

Intrinsic AKI

• There are many causes of intrinsic AKI, so we classify them by their histological location: tubules, interstitium, vasculature, or glomerulus.

Tubular intrinsic AKI

• Tubular injury often occurs by way of inschemia but may also occur because of specific renal toxins that target tubular cells.
• Tubular injury from ischemia is an extension of prerenal injury and occurs in four distinct stages: initiation, extension, maintenance, and recovery.
• Initiation: tubular cells demonstrate a severe depletion of ATP.
• Extension: microvascular congestion and inflammation occur.
• Maintenance: cells continue to repair, migrate, and proliferate to maintain tubular integrity.
• Recovery: GFR improves as cellular differentiation continues and normal cellular and organ function continues

• Tubular injury causes bleb formation on the apical membrane, loss of brush border, loss of surface membrane proteins, reduced polarity, loss of tight junctions, cell detachment, cast formation in the distal tubule (causing obstruction), and leakage of filtrate back into the interstitium.

• Renal toxins can act directly or indireclty.
  • Direct damage to tubular epithelial cells: aminoglycocides, radiocontrast, and cisplatin (a cancer drug)
  • Indirect damage via decreased blood flow: NSAIDs, cyclosporine, radiocontrast.
    • Cocaine and HGM-CoA reductase inhibitors can cause skeletal muscle damage, releasing heme which acts as a sort of endogenous toxin to tubular cells.
  • Precipitatory injury can occur when solutes or metabolites precipitate becasue of pharma: acyclovir, sulfonamides, ethylene glycol (calcium oxalate metabolite), methotrexate, and multiple myeloma light chains.
    • Patients with comorbidities like diabetes mellitus are far more likely to come down with pharam-induced precipitatory toxin damage.

Interstitium intrinsic AKI

• Injury to the interstitium of the kidney is sometimes called acute interstitial nephritis (AIN).
• Acute interstitial nephritis is characterized by invasion of T cells, monocytes, and macrophages.
  • These patches of inflammation can be diffuse or patchy.
• When chronic, AIN leads to interstitial scarring.
• AIN can be induced by drugs, infections, and auto-immune responses:
  • Drugs: penecillins, cephalosporins, sulfonamides, and NSAIDs.
  • Infections: bacterial and viral infections
  • Autoimmune responses: systemic or localized to the kidneys

Vascular intrinsic AK

• Vascular injury to the renal tissue occurs at the micro or macro vascular level.
• Microvascular damage is usually due to thrombocytic purpura, sepsis, hemolytic uremia syndrome, and HELLP (hemolysis, elevated liver enzymes, and low platelets).
• Macrovascular damage can occur due to atherosclerosis, especially when plaque is dislodged during surgeries.

Postrenal AKI

• Postrenal AKI is generally caused by some sort of blockage, either within the tract, pressing on the tract, or a functional blockaged like denervation of the bladder.
• Intraluminal obstruction can be caused by "renal calculi", papillary necrosis, or blood clots in addition to drug precipitation.
  • 'Calculus - a hard lump produced by the concretion of mineral salts; found in hollow organs or ducts of the body; "renal calculi can be very painful"'
  • Drugs that precipitate or cause precipitation of solutes: uric acid, calcium oxalate, acyclovir, sulfonamide and methotrexate, as well as myeloma light chains.
• Postrenal AKIs initially are able to maintain the GFR (by way of afferent arteriole dilation ) in spite of the backpressure at the Bowman's space. However, at some point the back pressure overwhelms the ability of the afferent arterioles to compensate and the cortex begins to lose blood flow. Eventually, glomeruli are not well perfused and the tissue becomes injured by ischemia.

Clinical findings

• Clinical findings in AKI (acute kidney injury) are "protean" and are often not apparent until late in the course of kidney injury.
  • Protean: "Exceedingly variable; readily assuming different shapes or forms; Of or pertaining to Proteus; characteristic of Proteus" per wiktionary
  • Often, AKI is diagnosed by lab as the patient could be asymptomatic or have non-specific symptoms.
• Symptoms of AKI can include:
  • anorexia
  • fatigue
  • nausea and vomiting
  • pruritus: itching
  • decline in urine output or dark-colored urine
  • asterixis: "Asterixis (also called the flapping tremor, or liver flap) is a tremor of the wrist when the wrist is extended (dorsiflexion), sometimes said to resemble a bird flapping its wings." per wikipedia
  • myoclonus
  • pericardial rub
  • volume overload leadning to:
    • shortness of breath and dyspnea on exertion
    • peripheral edema,
    • pulmonary crackles and
    • jugular venous distension

Diagnosis

• A thorough history and physical can be very useful in diagnosing and treating AKI.
• To achieve the optimal therapeutic plan, one should systematically evaluate all three categories of AKI: prerenal, intrinsic, and postrenal.
• Generally, one rules out pre and postrenal injury before evaluating intrinsic renal state.
• Laboratory values are especially important in diagnosis and treatment of AKI.
  • Laboratory values can help determine how rapidly therapy should be commenced because kidney injury is usually clinically silent as it progresses.
• There are a series of tests that should be run for AKI assessment and diagnosis:
  • a renal panel
  • a CBC
  • urine dipstick
  • urine microscopy
    • Urine microscopy should be performed on a fresh urine sample as etiology-indicating cellular elements can degrade quickly.
  • a renal ultrasound
    • To reveal blockages like stones.

CBC and FE (fractional excretion)

• One should pay particular attention to the Na, K, Cl, and creatinine values of the CBC and calculate the FE_Na (the fractional excretion of Na).
  • FE_Na = (Urine Na * Urine creatinine / Plasma Na * Plasma creatinine) * 100

Why does it make sense that we multiply the concentrations?  Won't this augment the change in FENa given a change in either Na or creatinine concentration?

• The value of FE_Na can guide the etiology of the AKI:
  • Recall that in a healthy state, urine Na will be low and urine creatinine will be high. Also, plasma Na will be high and plasma creatinine will be high.
  • Note that FE_Cl is sometimes used when the patient is alkalotic because FE_Na will be elevated due to HCO3- secretion at the kidney coupled with Na secretion.

I expect that Na in the urine will increase when the kidney is injured in a way that damages the tubule and anything having to do with reabsorption.
I expect that Na in the urine will decrease when the kidney is injured in a way that damages the vasculature or glomerulus and thus decreases the GFR.

• Let's examine the change in FE_Na for each type of AKI:
  • Prerenal: FE_Na is decreased because the GFR will decrease and thus Na in the urine will decrease as there is less flow and more time to reabsorb the Na.
  • Intrinsic:
    • Vasculogenic intrinsic AKI: FE_Na will be decreased because the GFR will be depressed and thus Na in the urine will decrease as there is less flow and more time to reabsorb the Na.
    • Glomerulogenic intrinsic AKI: FE_Na will be decreased because the GFR will be depressed and thus Na in the urine will decrease as there is less flow and more time to reabsorb the Na.
    • Tubulogenic intrinsic AKI: FE_Na will be elevated because the tubule cells are less able to reabsorb Na from the filtrate.
    • Interstitial intrinsic AKI: FE_Na will be elevated because the interstitial fluid is infiltrated with lymphocytes and all sorts of signals such that the expected gradient that helps tubule cells reabsorb Na is disrupted and urine Na is increased.

**Postrenal AKI: FENa is elevated because ....

• Decreased FE_Na occurs when AKI is due to prerenal issues or issues with vasculature or the glomerulus.
• Increased FE_Na occurs when AKI is due to postrenal issues or issues with the tubule or interstitium.
• So, the dividing point as to when AKI will result in increased or decreased AKI is at the glomerulus / vasculature.

Prerenal azotemia

• Prerenal azotemia (high levels of nitrogen containing compounds) is one of the most common etiologies of renal dysfunction.
• Common patient histories for prerenal azotemia include:
  • vomiting, diarrhea, poor oral intake, and congestive heart failure
  • CHF and other drugs can inhibit renal blood flow and thus cause azotemia.
• Common patient signs for prerenal azotemia include:
  • tachycardia, systemic and / or orthostatic hypotension, and dry membranes.
• The FE_urea is the measure of interest in assessing prerenal azotemia:
  • Like FE_Na, FE_urea = (Urine urea * urine creatinine / plasma urea * plasma creatinine) * 100

Do we use the creatinine terms as some sort of standard?  Does creatinine excretion not change much during AKI?
Why not consider only Na or only urea?

• • FE_urea less than 35 is inicative of AKI.
  • Recall that FE_urea will increase when there is excess BUN in the urine.
• We can also use plasma BUN to plasma creatinine ratio as an indicator of prerenal azotemia.
  • A plasma BUN : plasma creatinine > 20 : 1 indicates prerenal azotemia.

Intrinsic AKI

Postrenal AKI

Treatment

• Stabilize extracellular comparment.
• Increase cardiac function to optimum.
• Give Na-Bicarb
• Identify and arrest drugs causing nephrotoxicity.
• Use preventative measures to reduce AKI:
  • Educate patient about NSAIDs and other easy to get nephrotoxins.
  • Monitor serum and urine Na, BUN, and creatinine.

Prognosis

• Prognosis is pretty good for prerenal AKI patients.
• Prognosis is worse for intrinsic AKI patients.