Acute Tubular Injury (ATI) / Acute Tubular Necrosis

• Tubular and Interstitial Diseases of the Kidney are discussed

Acute Tubular Injury (ATI) / Acute Tubular Necrosis (ATN)

• This is a clinicopathologic condition with decreased renal function and tubular injury evidence
• Potentially reversible cause of acute renal failure
• Signifies rapid reduction of renal function and urine flow, falling within 24 hours to less than 400 mL per day

Causes of ATI / ATN

• Ischemia is a cause
  • This can result from massive hemorrhage, septic shock, severe burns, dehydration, prolonged diarrhea, congestive heart failure, volume redistribution due to pancreatitis or peritonitis and vasculitis
• Direct Toxic injury (direct injury to the tubules) may be caused by exogenous agents like
  • Antibiotics like aminoglycosides and amphotericin B
  • Radiographic contrast agents
  • Heavy metals like mercury and lead
  • Organic solvents like ethylene glycol and CCL4
• Endogenous agents can cause it
  • Including heme proteins like myoglobin from rhabdomyolysis
  • Hemoglobin from hemolysis
  • Bile and bilirubin
• Urinary obstruction by tumors, prostatic hypertrophy, or blood clots can cause postrenal acute renal failure

Pathogenesis of ATI/ATN

• Critical events include tubular injury and persistent, severe vascular disturbances

Tubular Cell Injury

• Tubular epithelial cells, especially proximal convoluted tubule cells, are sensitive to ischemia and prone to toxic damage
  • Due to reabsorption surface area, active ion transportation, high metabolism rate and capability for resorption and concentration of toxins

Blood Flow Disturbances

• These can be caused major hemodynamic alteration, intrarenal vasoconstriction, reduced glomerular blood flow, and reduced oxygen delivery to the tubules
  • Especially in the thick ascending limb and straight segment of the proximal tubule
• Ischemia or toxins can directly affect the glomerulus, reducing the GFR coefficient

Events in ATI

• Reversible loss of cell polarity occurs
  • Na-K-ATPase Redistribution leads to abnormal ion transport
• Increased Na delivery to distal tubules results in intrarenal vasoconstriction
  • Through tubuloglomerular feedback
  • Activation of the Renin-Angiotensin System (RAS)
  • Endothelial dysfunction
• Glomerular capillary permeability decreases
• Tubular obstruction caused by cellular debris with increased hydrostatic pressure
• Back leak of glomerular filtrate into the interstitium
  • This is due to damaged tubular epithelium
  • Which leads to interstitial edema
  • Which leads to increased interstitial pressure
  • and further tubular damage

Morphology of Ischemic ATI

• Swollen kidneys are tense and pale
• On cross section, the renal parenchyma is swollen and bulges from the capsule
• No pathological changes in the glomeruli or blood vessels

Histology of Ischemic ATI

• Patchy tubular necrosis exists, alternating with areas of less tubular cell injury
• Straight segments of the PCT and thick ascending loop of Henle are most affected
• Attenuation or loss of proximal tubule brush borders occur
• Cell structure is simplified
• Swelling and vacuolization of the cell occur Sloughing of non-necrotic tubular cells into the tubular lumina happens
• The severity of these morphologic findings does not correlate well with the severity of clinical manifestations
• Interstitial edema and leukocyte accumulation within dilated vasa recta can occur
• Evidence of epithelial regeneration is present

Morphology of Toxic ATI/ATN

• More extensive necrosis of tubular epithelium occurs
• Changes are mostly seen in the PCT
• Distinctive changes depend on the toxic agent
  • Numerous red-brown tubular casts, colored by heme pigments from hemoglobin or myoglobin occur
  • Mercuric chloride results in acidophilic inclusions
  • Ethylene glycol leads to ballooning/hydropic degeneration of PCT cells

Regeneration / Recovery

• Tubular epithelium regenerates
• Mitoses appear, with increased cell and nuclei size with cell crowding
• Survivors display complete restoration of normal renal architecture

Clinical Features of ATI/ATN

• Highly variable but proceeds in 3 phases
  • Initiation
  • Maintenance
  • Recovery stages

Initiation Phase

• Lasts for approximately 36 hours
• It is dominated by the inciting medical, surgical, or obstetric event in the ischemic form of ATI
• The only indication of renal involvement is a slight decline in urine output with a rise in Blood Urea Nitrogen (BUN)

Maintenance Phase

• Characterized by
  • Decreased urine output between 40 and 400 mL/day (oliguria)
  • Salt and water overload
  • Rising BUN concentrations
  • Hyperkalemia
  • Metabolic acidosis and other uremia manifestations
• With appropriate attention to the balance of water and blood electrolytes, treatment can support the patient

Recovery Phase

• Increased urine volume occurs, which may reach up to 3 liters per day The tubules sustains damage, leading to large amounts of water, sodium, and potassium being lost in the urine flow
• Vulnerability increases to infection at this stage
• Renal tubular function is eventually restored, as well as concentrating ability

Prognosis

• Depends on the clinical setting
• Expected recovery with nephrotoxic ATI if the toxin has not caused serious damage to other organs
• Current supportive care allows 95% of those who do not succumb to the precipitating cause to recover
• In shock related to sepsis, extensive burns, or other causes of multi-organ failure, the mortality rate can rise to more than 50%

Pyelonephritis

• It is a renal disorder affecting tubules, interstitium, and renal pelvis
• Pyelonephritis is one of the most common diseases of the kidney
• Acute pyelonephritis is a bacterial infection often associated with a UTI
• Chronic pyelonephritis is more complex, also caused by bacterial infection
  • Other factors like vesicoureteral reflux and obstruction are involved in the pathogenesis (repeat acute pyelonephritis)

Aetiology & Pathogenesis of Pyelonephritis

• Gram-negative bacteria from enteric origin (faeces), most commonly E. coli, cause 80% of UTIs
• Bacilli is a normal inhabitant of the intestinal tract
• Other causal organisms include Proteus, Klebsiella, Enterobacter, Streptococcus faecalis, Staphylococci, bacterial & fungal agents
• Immunocompromised patients with transplanted organs can contract viruses like polyoma virus, CMV & adenovirus which can cause renal infection
• Most patients with UTIs, the infecting organisms are derived from the patient’s own, fecal flora or endogenous infection

Routes of Bacterial Kidney Infection

• Haematogenous infection occurs
• Ascending infection (from lower urinary tract) occurs

Hematogenous Infection

• less common than ascending infection
• More likely to occur in the presence of ureteral obstruction, in debilitated patients, in those receiving immunosuppressive therapy, and with non-enteric organisms

Ascending Infection

• It is preceded by bladder infection

Steps Involved in Renal Infection

• Colonization of the distal urethra and introitus in females by E. coli, influenced by the ability of the bacteria to adhere to urethral mucosal cells
• Organisms gain entrance to the urethra from urethral catheterization, instrumentation or sexual activity
• Stasis multiplies bacteria in the bladder, and bacteria are normally continuously flushed out by voiding

Vesico-ureteral Reflux

• Incompetent vesicoureteral valve allows bacteria to ascend the ureter into the renal pelvis
• Normal ureteral insertion into the bladder is a competent one-way valve that prevents urine retrograde flow, especially when intravesical pressure rises during micturition

Vesicoureteral Reflux

• An incompetent vesicoureteral orifice allows reflux of the bladder urine into the ureters
• It is mostly due to congenital absence or shortening of the intravesical ureter portion, such that the ureter is not compressed during micturition
• Bladder infection itself can cause or accentuate vesicoureteral reflux, particularly in children
• Vesicoureteral reflux results in retrograde urination that favors bacterial growth

Intrarenal Reflux

• Bacteria are not necessarily carried into the renal parenchyma, even when present in the calyces
• Peripheral compound papillae allow easier access to the collecting system
• Obstructive uropathy with prolonged pressure renders even the papillae vulnerable to retrograde entry
• Bacteria gains access to the interstitial tissue & kidney tubules from the collecting tubules

In the Absence of Vesicoureteral Reflux

• Infection usually remains localized in the bladder Thus, most patients with repeated bacterial colonization of the urinary tract suffer from cystitis & urethritis (lower UTI) rather than pyelonephritis

Acute Pyelonephritis

• It is an acute suppurative inflammation of the kidney caused by bacteria, sometimes viral infection
• Could be acquired through
  • hematogenous route (septicemic spread)
  • ascending infection (vesicoureteral reflux)

Gross Morphology of Acute Infection

• The kidneys contain small white abscesses on the subcapsular surface and cut surfaces
• The urothelium of the pelvis & calyces may be hyperemic & covered by purulent exudates
• Acute pyelonephritis is often a focal disease, so much of the kidney may appear normal
• Infections mostly involve a few papillary systems

Microscopic Morphology of Acute Pyelonephritis

• The parenchyma shows extensive focal destruction by the acute inflammatory process
• Vessels and glomeruli are preferentially preserved
• The inflammatory infiltrates contain predominantly neutrophils
• Tubules, particularly collecting tubules, are filled with neutrophils
• Severe cases cause necrosis of the papillary tips or the infection may extend beyond the renal capsule
  • This results in perinephric abscess formation
• Predisposing factors include
  • Congenital or acquired urinary tract obstruction
  • Vesicoureteral reflux
  • Pregnancy
  • Sex and age
  • Diabetes Mellitus (DM)
  • Immunosuppression
  • Preexisting renal lesions

Common Presentations Include

• Sudden onset
• Pain at the flanks
• Systemic infection evidence: fever and malaise
• Dysuria, frequency, urgency indications of bladder and urethral infections
• Pyuria is seen in both upper and lower UTI patients
• Leukocyte casts in the urine indicating upper UTI

Complications

• Papillary necrosis
• Pyonephrosis
• Perinephric abscess

Chronic Pyelonephritis / Reflux Nephropathy

• Chronic tubulointerstitial renal disorder
  • Tubulointerstitial inflammation & renal scarring are associated with pathologic involvement of the calyces & pelvis
• Pelvicalyceal damage is an important diagnostic clue
  • Several diseases produce chronic tubulointerstitial alterations
  • Chronic pyelonephritis and analgesic nephropathy affect the calyces
• It is an important cause of end-stage kidney disease
  • Accounted for 10 - 20% of transplant or dialysis patients being treated
  • Before predisposing conditions like reflux were better known and diligently evaluated
• Remains an important cause of kidney destruction in children with severe lower urinary tract abnormalities
• Divided into 2 main forms:
  • Reflux Nephropathy
  • Chronic Obstructive pyelonephritis

Reflux Nephropathy

• A more common form of chronic pyelonephritic scarring
• Renal involvement occurs early in childhood
  • Superimposition of a urinary infection on congenital vesicoureteral reflux & intrarenal reflux
• Reflux may be unilateral or bilateral and results in scarring and atrophy of one or both kidneys, and to chronic renal insufficiency
• Vesicoureteral reflux rarely causes damage in the absence of infection (sterile reflux) but is severe obstructing

Chronic Obstructive Pyelonephritis

• Obstruction predisposes the kidney to infection
• Infections superimposed on diffuse or localized obstructive lesions lead to recurrent bouts of renal inflammation & scarring

Regarding the effects of obstruction

• Contribute to the parenchymal atrophy
• May be difficult to differentiate from the effect of the bacterial infection alone
• It can be bilateral (posterior urethral valve) and lead to renal insufficiency unless corrected
• It can be unilateral (calculi and obstructive ureter anomalies)

Gross Morphology of Chronic Pyelonephritis / Reflux Nephropathy

• Kidneys irregularly scarred if bilateral, involvement asymmetric
• A coarse, discrete, corticomedullary scar overlying a dilated, blunted or deformed calyx is present
• The number of scars vary and can affect one or both kidneys
• Scars mostly appear in the upper and lower poles because that is where reflux occurs

Microscopic Morphology of Chronic Pyelonephritis / Reflux Nephropathy

• Microscopic changes are predominant in the tubules & interstitium
• Tubules show atrophy in some areas & hypertrophy or dilation in others
• Dilated tubules with flattened epithelium may be filled with colloid casts (thyroidization)
• Varying degrees of chronic interstitial inflammation & fibrosis in the cortex and medulla can be seen
• Active infection shows neutrophils in the interstitium & pus casts in the tubules
• Glomeruli remain normal aside from ischemic changes and secondary changes due to hypertension
• Fibrosis of the walls of the arteries & arterioles is common

Episodes

• Most patients with chronic pyelonephritis suffer episodic UTI manifestations or acute pyelonephritis
• Patients exhibit recurrent fever and flank pain
• Occasional patients have a silent course until End-Stage Renal Disease (ESRD) develops
• Urinalysis demonstrates leukocytes in the urine
  • Imaging reveals caliectasis (calyceal deformity & dilation) and cortical scarring