Flashcards in Renal - Tubulointerstitial diseases Deck (19):
What are tubulointerstitial diseases?
Renal tubules and interstitium are in contact with one another, both affected by range of diseases.
Clinical presentation is determined by effect on tubular function
- tubules become blocked which reduces GFR
- transport functions become impaired, reduces water and solute reabsorption
- acute and chronic interstitial nephritis
- acute tubular necrosis
Interstitial change can also occur in renal transplant and urinary tract obstruction. Certain disease, mainly hereditary, impair tubular function without causing interstitial changes (isolated tubular disorders).
Acute interstitial nephritis
Causes acute diffuse renal inflammation, can be rapid deterioration in renal function.
Usually asymptomatic, but if drug induced may be maculopapular rash, fever or eosinophilia. Lumbar pain can occur due to stretching of the renal capsule.
Causes of acute interstitial nephritis
Infection - renal or systemic
Investigations in acute interstitial nephritis
Mild proteinuria, microscopic haematuria, white blood cell casts, and eosinophils in urine.
USS shows slightly enlarged kidneys.
Diagnosis requires biopsy - infiltration of the interstitium with inflammatory cells, particularly monocytes and T cells. Tubular basement membrane may be disrupted and tubules may be compressed by infiltrating cells
Treatment for AIN
Discontinuation of any drugs/ precipitating causes
Treatment of infection
Immunosuppression with steroids
Prognosis - good
Etiology of AIN
Main cause is allergic reaction to drugs, esp NSAIDs, diuretics and PPIs such as omeprazole and antibiotics.
Systemic or renal infection, typically acute pyelonephritis, can cause AIN. Gout causes excess urate excretion and urate crystals can precipitate in the tubules, causing tubular obstruction and triggering inflammation.
What is chronic interstitial nephritis?
Typically presents as either chronic renal failure or with symptoms of an associated primary disease. Hypertension is common, the GFR is reduced and there is mild proteinuria, microscopic haematuria and inflammatory cells in the urine.
Tubular transport and reabsorption can be impaired, causing features such as glycosuria. Destruction of interstitial EPO producing cells can cause anaemia. Tubular cells are flat and atrophic, the tubules are dilated and there is interstitial fibrosis with a mononuclear cell infiltrate.
Etiology of CIN
Antibody light chains filtered in glomerulus and normally reabsorbed in the proximal tubule by receptor mediated endocytosis. In myeloma, high levels of light chains saturate this absorption leading to light chain excretion (Bence Jones protein). Light chains are toxic to tubules, cause tubular inflammation and damage.
Excess use of analgesia such as aspirin, paracetamol and NSAIDs causes CIN and sometimes papillary necrosis. Ciclosporin and cisplatin also drug causes
- lead or cadmium
- Balkan nephropathy (endemic chronic interstitial disease affecting countries around the Balkan sea)
Medulla receives all of its blood supply from vasa recta, makes papillae vulnerable to ischaemic damage. Counter current system concentrates some toxins, such as analgesics, in the medulla and papillae.
If severe medullary ischaemia or interstitial damage, the function of the loop of Henle and collecting ducts may be impaired. In the worst cases, damaged papillae can slough off and even obstruct ureters.
- analgesic use
- DM (infection and microvascular disease promote ischaemia)
- sickle cell disease (medullary ischaemia promotes red blood cell sickling in the papillae)
What are the three main patterns of tubular damage?
Three main patterns reflect the transport functions of the individual tubule segment affected. These abnormalities can occur alone in specific diseases or as part of acute or more usually chronic tubulinterstitial nephritis.
1) Proximal tubular damage
- impairs proximal tubule reabsorption --> aminoaciduria, glycosuria, phosphaturia, uricosuria, and bicarbonaturia leading to metabolic acidosis (proximal renal tubular acidosis)
- low molecular weight proteinuria can also occur due to disruption of normal endolytic uptake of filtered proteins by the proximal tubules
- myeloma and heavy metal poisoning
2) Medullary damage
- affects loop of Henle and collecting ducts
- reduces concentrating ability
- infection, analgesic use, and sickle cell disease, and in polyuric recovery phase of acute tubular necrosis
3) Distal tubule damage
- impair distal bicarbonate reabsorption and aldosterone regulated sodium reabsorption and related potassium secretion (hyponatraemia, hyperkalaemia)
- bicarbonaturia causes metabolic acidosis (distal renal tubular acidosis
- lots of causes! SLE, Sjogrens, scleroderma, chronic hepatitis, PBC, Balkan nephropathy, nephrocalcinosis, chronic obstruction, PKD
Mutations in Na/K/2Cl co transporter in thick ascending limb of LOH --> excessive urinary sodium, potassium and water loss - similar to effects of furosemide.
Hypokalaemia promotes enhanced hydrogen ion secretion and a metabolic alkalosis.
Hypercalciuria - mutant protein cannot transport ions so transepithelial potential difference falls and fluid in tubular lumen loses its positive charge --> reduced calcium reabsorption
- predipose to renal stones
Renin and aldosterone levels are high to conserve sodium because of volume depletion
Other causes of Bartter's syndrome
3 other mutations (in addition to one affecting Na/K/2Cl co transporter):
- apical ROMK potassium channel
- basolateral CLC-Kb chloride channel
- barttin, subunit of CLC-Kb
Channelopathy blocks exit of Cl and K ions --> inhibits entry of Na, K and Cl by the NKCC2 co transporter. Barttin defects - deafness
What is Gitelman's syndrome?
Mutations in genes encoding the NCC co-transporter in distal tubule.
Produces effects similar to thiazide diuretics - excess loss of sodium, potassium and magnesium in urine
- excess urinary K+ is the result of enhanced tubular flow ---> increase in K+ secretion in cortical collecting duct
Hypocalciuria occurs - inhibition of apical sodium entry into the cell allows intracellular sodium to fall, promoting more basolateral sodium/calcium exchange --> more apical calcium entry and greater calcium reabsorption
2 different mutations affecting ENaC channels
1) Activating mutations - pseudohypoaldosteronism (Liddle's syndrome)
2) Inactivating mutations - pseudohypoaldosteronism
Activating mutation of the ENaC channel
- mutations dominant, leave channel open and unregulated
- causes excess Na retention --> volume expansion and hypertension
- SUPPRESSES renin and aldosterone
- amiloride can be helpful (blocks the channel)
Pseudohypoaldosteronism caused by inactivating mutation
Affects ENaC channel
Recessive mutations - cause excess Na loss and K+ retention
- promote high serum renin and high aldosterone levels
- aldosterone cannot exert its effect because of defective channel --> pseudohypoaldosteronism
- condition mimics aldosterone deficiency
Cause of nephrogenic diabetes insipidus
Defects in aquaporins or the V2 ADH receptors in collecting ducts
Many inherited and acquired forms
Major component - proximal renal tubular acidosis (caused by reduced bicarbonate reabsorption), glucosuria, aminoaciduria, uricosuria (urinary urate loss), hypophosphataemia and osteomalacia or rickets
May also be tubular proteinuria - failure of tubular reabsorption of small proteins
Hypokalaemia - enhanced distal sodium delivery promoting distal K+ secretion
Osmotic load --> osmotic diuresis and polyuria