64. Acute tubular necrosis (ischaemic and toxic). Drug-induced (hypersensitive) interstitial nephritis, analgetic nephropathy, urate nephropathy. Acute and chronic pyelonephritis (pathogenesis, morphology, consequences and clinical course)

Tubulointerstitial diseases?

Infections and inflammations affecting the interstitium and the tubules

- Not the glomeruli primarily

Can be caused by:

- Infections

- Obstruction

- Drug-related side effects

- Ischemic effects

Tubulointerstitial nephritis?

Caused by:

- bacterial infection

Renal pelvis is usually prominently involved -> therefore pyelonephritis is often used instead

Interstitial nephritis?

Non-bacterial origin q

Acute tubular necrosis? ATN

(Acute tubular injury)

- Damage to tubular epithelial cells

- Acute decline in renal function

What can be observed in urine in ATN?

- Granular casts

- Tubular cells

Most frequent cause of acute renal failure?

Acute tubular necrosis

Two forms of ATN?

Ischemic ATN

Toxic ATN

Causes of ischemic ATN?

- Shock

- Thromboembolism of renal a.

Causes of toxic ATN?

• Iodinated contrast medium

• Aminoglycosides

Pigment nephropathy

- Myoglobin due to rhabdomyolysis

- Hb-uria due to hemolysis

Poisons

- Heavy metal

- Organic solvents

Ischemia of tubules?

Tubules perform a lot of transport

- Needs high load of perfusion

Ischemia -> quickly damage of tubules

What parts of the tubules are most vulnerable to ischemia?

- Proximal tubule (straight segment)

- Distal tubule (straight segment)

What functions does ischemic tubular cells lose?

Polarity is lost

(Membrane proteins move from their normal side to other surfaces of the cell)

- Proximal tubules are unable to reabsorb sodium

= Sodium will reach distal tubules

TGF-system senses it => decreases GFR

Why will there be tubular cells in the urine in ATN?

When they lose their polarity, they also lose their anchors to the BM

- They will detach and shed into the urine

Excessive shedding of tubular cells into the urine?

Can block the outflow of urine

- Increases backward pressure in the tubules => forces filtrate to leak through the damaged tubules & back into the interstitium - "Backleak"

Intrarenal vasoconstriction in ATN?

Ischemia will cause intrarenal vasoconstriction & activate RAAS

= Further decreases renal perfusion

Damaged endothelium will produce endothelin => further reduces perfusion

What part of the tubule is most susceptible to toxic ATN?

Convoluted segment of proximal tubule

Otherwise, the pathogenesis is quite similar to that of ischemic ATN

Histology of ischemic ATN?

Lesions in straight part of proximal- and distal tubule

Lesions:

- Focal necrosis

- Focal apoptosis

- "Skip lesions" - sharp border bw. affected and non-affected segments

- Tubules may be obstructed by cell-casts

Interstitium:

- Edamatous

- Mild inflammatory infiltrate

Histology of toxic ATN?

Similar to ischemic type, only proximal convoluted tubule is affected

Three phases of ATN?

Initiation phase:

- Acute decrease in GFR

- Sudden azotemia

Maintenance phase:

- Sustained reduction of GFR

- Creatinine & BUN rise

Recovery phase:

- Polyuria occurs as the tubular function restores

- Creatinine & bun normalize

Prognosis ATN?

Toxic ATN:

- Very good prognosis

Ischemic ATN:

- More than 50% death rate -> as they often lead to acute renal failure

Drug-induced interstitial nephritis?

Occurs as an adverse reaction to many drugs

- "Allergic/hypersensitive" nephritis

What drugs are associated with drug-induced interstitial nephritis?

- NSAIDs

- Synthetic penicillin (ampicillin)

- Thiazides (diuretic)

- Sulphonamide antibiotics

Pathomechanism - drug-induced interstitial nephritis?

Not completely known

- Some cases type I, other involves type IV hypers.re.

- Drugs are most likely haptens that bind to proteins in the tubules, to form immunogenic antigens = causing damage

Morphology of kidney in drug-induced interstitial nephritis?

- Interstitial edema

- Leukocyte infiltration

- Necrosis & regeneration of the tubules

Symptoms - drug-induced interstitial nephritis?

Begin around 15 days after started treatment

- Fever

- Rash

- Hematuria

- Eosinophilia

50% experience rise in serum creatinine,

Prognosis - drug-induced interstitial nephritis?

Usually good

Analgesic nephropathy?

Most common cause of chronic interstitial nephritis

- Associated with heavy use of painkillers like

- NSAIDs

- Paracetamol

- Phenacetin (not used today)

Pathomechanism analgesic nephropathy?

Reduction of renal blood flow, due to decreased prostaglandin synthesis

= Causes necrosis of the papilla -> later: interstitial nephritis

Paracetamol:

- Damages kidney by oxidative damage

Symptoms of affected patients with nephropathy?

- Pyuria

- Tubular acidosis

- Hematuria

May be asymptomatic also

What does analgesic nephropathy increase the risk of?

- Urothelial carcinoma of the renal cell pelvis

Acute urate nephropathy?

A complication of hyperuricemia and gout

Causes chronic interstitial nephritis with uric acid crystals deposition in the stroma of the kidney

= Initiating inflammatory processes

What other causes of acute urate nephropathy are there?

It can occur due to tumor lysis syndrome

- In patients who receive chemotherapy or radiation against tumor

As the tumor cells lyse, they die and release (among others): uric acid

= Causing hyperuricemia

Pyelonephritis?

Bacterial infection of the renal pelvis

Usually due to ascending bacterial infection from the bladder

- Gram-neg. bacteria from GI tract (most often) -> E.coli

Pyelonephritis - acute or chronic?

Is mostly acute, but can be chronic in two cases

Clinical symptoms of pyelonephritis?

- Bacteria in urine

- Pyuria

- Proteinuria

- WBC casts (of collecting duct) -> cylindrical, can also contain RBCs & bacteria

Acute pyelonephritis?

Mostly develop when UTI ascends into the ureter and kidney

Risk factors are therefore similar to that of UTIs

Risk factors acute pyelonephritis (& UTIs)?

- Female gender

- Sexual intercourse (if you do not attend the bathroom afterwards)

- Catheter

- Diabetes mellitus (bacteria likes glucosuria)

- Immunosuppression

- Urinary stasis (i.e. obstruction)

- Vesicoureteral reflux (urine is refluxed into ureter from bladder)

Hematological cause of acute pyelonephritis?

Septicaemia and infective endocarditis can cause acute pyelonephritis

Pathomechanism of pyelonephritis?

Bacteria attach to the renal tubules -> initiating inflammation => tubular necrosis

Infection is purulent -> there is pus formation

Complications of acute pyelonephritis?

• Pyonephrosis -> infection spreads to collecting system

• Perinephric abscess

• Necrosis of the renal papilla

• Urosepsis - sepsis originates from urinary tract

Acute pyelonephritis symptoms?

- High fever

- Pain at flanks

- Dysuria

- Increased frequency of urination

Chronic pyelonephritis?

Recurrent/persistent acute pyelonephritis

Due to:

- Obstruction of UT (BPH, kidney stone)

- Vesicoureteral reflux

What can chronic pyelonephritis lead to?

Chronic renal failure

Xanthogranulomatous pyelonephritis?

Benign lipidic neoplasm in the kidney that occurs due to inappropriate inflammatory response to a bacterial infection

- Is chronic