N14 - Tubulointerstitial and cystic kidney diseases Flashcards
Causes of acute tubular necrosis
- prolonged ischemia, nephrotoxins, sepsis
- radio-contrast materials
- drugs: aminoglycosides, vancomycin, cisplatin, mTOR-inhibitors, amphotericin B
- toxins: ethylene-glycol, heavy metals
- heme pigment (hemoglobin, myoglobin)
Site of injury for acute tubular necrosis
- proximal tubule S3 segment
- medullary thick ascending limb
cellular properties:
- low pO2
- high cellular demand
- small glycolytic capacity
Etiology of acute tubular necrosis
- Hemodynamic factors: impaired renal autoregulation; intrarenal vasoconstriction
- Endothelial injury: impaired vasodilation; cellular swelling
- Tubular epithelial injury: cell death (apoptosis); disruption of actin cytoskeleton; loss of cell polarity; cast obstruction; backleak
- Inflammatory factors
Differential diagnosis of pre-renal AKI vs. ATN
urine Na+: low (<20mmol/L) in pre-renal AKI; high (>40-50mmol/L) in ATN
urine Osm: high (>500mOsm/L) in pre-renal AKI; low (<350mOsm/L) in ATN
BUN/creatinine: > 20:1 in pre-renal AKI; 10-15:1 in ATN
FeNa: low (<1%) in pre-renal AKI, and high (>2%) in ATN
urine sediment: hyaline casts in pre-renal AKI; granular, muddy brown casts in ATN
Prevention and Treatment of ATN
- avoid prolonged ischemia/nephrotoxic agents
- monitor volume status!
- diuretics:
- in case of volume overload
- augment urine output
- no effect on renal/patient survival - dopamine - no longer recommended
- initiate renal replacement therapy if necessary
Prognosis of ATN
- spontaneous recovery of renal function between 1-3 weeks
- chance of not returning to baseline kidney function
Overview of radiocontrast-induced nephropathy
- risk factors: previous renal impairment, advanced age, diabetic nephropathy, volume depletion, congestive heart failure (NOT metformin)
- mechanism: prolonged vasoconstriction - medullary hypoxia direct tubular epithelial cell toxicity
- clinical picture: non-oliguric ATN; 2-3 days after contrast administration
- prevention: cautious use if GFR <30mL/min; adequate hydration (+ loop diuretics); N-acetylcysteine and “preventative” dialysis is NOT recommended
- management: as for ATN
- prognosis: mild and transient renal impairment; recovery within 3-5 days
What causes nephrotoxin-induced ATN?
- aminoglycosides
- ethylene glycol
Overview of aminoglycoside-induced ATN
- risk factors: high doses, longer duration of therapy, preexisting renal disease, older age, hypotension, concurrent liver disease
-
mechanism:
1. drug accumulates in proximal tubular cell lysosomes
2. interferes with cellular energetics
3. induces oxidative stress - clinical picture: non-oliguric ATN
- prevention: administer once daily if possible and monitor serum level
- management: discontinuation of the drug
- prognosis: normalization of renal function within 21 days
Overview of ethylene glycol induced ATN
-
mechanism:
1. metabolized to toxic glycoaldehyde and glyoxylate
2. further metabolized to oxalic acid leading to tubular precipitation the obstruction - clinical picture: ATN with severe anion gap metabolic acidosis; calcium oxalate crystals in urine
- management: intravenous ethanol; alcohol dehydrogenase inhibitor (fomepizole); hemodialysis
- prognosis: early therapy for good or fully recovery; delayed therapy has a poor outcome
Overview of heme pigment nephropathy
- risk factors: rhabdomyolysis (muscle trauma, seizures, statin use, McArdle disease); massive hemolysis
-
mechanism:
1. muscle injury
2. severe hemolysis - clinical picture: oliguric ATN with elevated plasma creatine kinase and LDH
- prevention: early and aggressive intravenous hydration; maintain urine output between 200-300 mL/h; in case of muscle trauma, maintain urine output above 300 mL/h
- management: correct metabolic abnormalities (hyperkalaemia, hypericaemia); maintain fluid balance; initiate renal replacement therapy if needed
- prognosis: favorable – almost normal kidney function or sufficient kidney function to be dialysis-independent
What is the etiology of acute tubulo-interstitial nephritis?
- drugs (>75%)
- infection-related (5-10%)
- AIN (acute interstitial nephritis) with systemic diseases (10-15%)
- idiopathic (5%)
What drugs lead to acute tubulo-interstitial nephritis?
- NSAIDs (ASA, ibuprofen, naproxen)
- antibiotics (ciprofloxacin, methicilin)
- PPIs (omeprazole)
- immune checkpoint inhibitors (ipilumumab, nivolumab)
idiosyncratic reaction: 3 days to several weeks after starting therapy
What infections can lead to acute tubulo-interstitial nephritis?
- viral: hantavirus, CMV, EBV, polyomavirus
- bacterial: legionella, leptospira, streptococcus
What systemic diseases are associated with AIN and can lead to acute tubulo-interstitial nephritis?
- Sjögren’s syndrome
- sarcoidosis
- TINU syndrome (tubulointerstitial nephritis + uveitis)
What is the clinical picture for acute tubulo-interstitial nephritis?
- acute kidney injury
- oliguria, leukocyturia/eosinophiluria, hematuria, proteinuria (~ 1g/day)
- joint pain
- lumbar pain
- weakness, malaise, weight loss
in drug induced forms: fever, eosinophilia, skin rash (10-40%)
How is acute tubulo-interstitial nephritis diagnosed?
- mostly based on clinical picture
- renal biopsy in case:
- no response to treatment
- atypical presentation
- severe kidney injury
What is the treatment and prognosis for acute tubulo-interstitial nephritis?
Drug-induced:
- discontinuation of the drug
- corticosteroids
Infection-related: treat infection
autoimmune: corticosteroids
idiopathic: corticosteroids
prognosis: usually favorable
Overview of myeloma cast nephropathy
the most common renal injury in multiple myeloma
clinical picture:
- acute kidney injury
- mild proteinuria (< 2-3g/day)
- monoclonal light chains in urine
- hypercalcemia, anemia
diagnosis: mostly based on clinical picture
treatment:
- hydration (~3L/day urine output)
- treatment of hypercalcemia
- urine alkalization (pH>7)
- avoidance of NSAIDs, RAAS-inhibitors, furosemide!
- plasma exchange/hemodialysis
- hematologic treatment of multiple myeloma
prognosis: poor (1-year survival on hemodialysis treatment: 50-66%)
Overview of chronic interstitial nephritis - isolated tubulopathies
etiology:
- metabolic (hypercalcemia, hypokalemia, urate nephropathy)
- drugs (CNIs, lithium, tenofovir, phenacetin)
- toxins (heavy metals, aristolochic acid)
- systemic diseases (Sjögren’s syndrom, sarcoidosis, amyloidosis)
- chronic urinary tract obstruction or vesico-ureteral reflux
- chronic infection
- irradiation
- hereditary diseases
clinical picture: mild symptoms and signs, slowly progressing renal failure with insidious onset
- proteinuria <1g/day
- inactive urinary sediment - leukocyturia, WBC casts
- renal anemia at relatively early stage
- hypertension
- various electrolyte and acid-base disturbances
When to consider proximal tubular dysfunction?
it is a rare disease
signs and symptoms:
- tiredness, muscle weaknes, bone pain
- in hereditary forms: excessive thirst, polydipsia, polyuria
*laboratory findings:**
- renal glucosuria, aminoaciduria, uricosuria (–> hypouricaemia), phosphaturia (–> osteomalacia), hypokalaemia, type 2 renal tubular acidosis (RTA)
What are the types of proximal tubular dysfunction?
- Fanconi syndrome
- Type 2, proximal renal tubular acidosis (RTA)
- hypokalaemic nephropathy
What is Fanconi syndrome and how is it treated?
types: hereditary, idiopathic or acquired
hereditary: storage diseases (cystinosis - build up of cysteine in cells)
causes of acquired Fanconi syndrome
- drugs: aminoglycosides, cisplatin, tenofovir
- paraproteinemias: multiple myeloma, amyloidosis
- Wilson disease, chronic heavy metal poisoning
treatment: bicarbonate, phosphate, potassium, and vitamin D3 supplementation
What is type 2 renal tubular acidosis and how is it treated?
Type 2 proximal RTA: decreased HCO3- reabsorption in the proximal tubules
typical ion disturbances:
- hypokalaemia, hyperchloraemia, acidosis
- normal anion gap (12±4 mmol/L)
- variable urine pH (could be <5.3 after acid load)
- elevated HCO3- fractional excretion (>15%)
treatment:
- bicarbonate supplementation – higher dose than in distal RTA to accomplish almost normal HCO3-
- thiazide diuretics: decrease bicarbonate loss
- K-supplementation or K-sparing diuretics
Overview of Hypokalaemic nephropathy
symptoms: polyuria, polydipsia
laboratory: decreased renal concentrating capacity, hypocloraemia, metabolic alkalosis
histology: vacuolar degeneration in proximal tubular epithelial cells
treatment: reversible with potassium replacement
When to consider disorders of the loop of Henle or distal tubules?
- young patient
- symptoms: tiredness, muscle cramps, excessive thirst, polydipsia, polyuria, low-to-normal blood pressure, arrhythmias
- laboratory: hypokalaemia, hypochloraemia, metabolic acidosis
What are some inherited hypokalemic salt-losing tubulopathies?
Bartter syndrome
- transport of Na/K/Cl is disturbed in the loop of Henle (ie. chronic furosemide ingestion)
- autosomal recessive hereditary disorder
- presents mostly in childhood
- hypercalciuria, nephrocalcinosis
Gitelman syndrome
- distal tubular dysfunction (ie. chronic thiazide ingestion)
- AR hereditary disorder
- mostly in adulthood
- hypomagnaesemia, hypocalciuria
When should you consider collecting duct dysfunction?
Signs and symptoms:
- excessive thirst, polydipsia, polyuria, symptoms of kidney stones
Laboratory
- decreased urine concentrating capacity
- hypercalciuria/hypercalcemia (–> nephrocalcinosis)
- type 1 renal tubular acidosis (RTA)
What are the collecting duct dysfunction diseases?
hereditary: Wilson disease, medullary sponge kidney
acquired: diseases associated with hypercalcaemia, Sjögren’s syndrome, sarcoidosis, amyloidosis
drugs/toxins: amphotericin B, lithium
Treatment for collecting duct dysfunction
adequate volume replacement
- thiazide diuretics decrease symptoms of nephrogenic diabetes insipidus
- treatment of hypercalcemia
- bicarbonate and potassium replacement
Treatment for Type 1, distal RTA
Type 1 distal renal tubular acidosis is the decreased H+ excretion in collecting ducts
Therapy
- bicarbonate supplementation (goal: HCO3- 22-24mEg/L)
- start with 80-120mEq/day
- maintenance: 60-100mEq/day
- baking soda: 27mEq = 1/2 tsp
- potassium-citrate (tbl. trikalii-citrici: 10mEq citrate/HCO3-)
in cases of severe hypokalemia, iv. K-supplementation (NOT in glucose solutions)
When to consider chronic tubulo-interstitial nephritis caused by vascular damage?
- gradual decrease in eGFR
- sterile pyuria
- mild proteinuria
- hypertension, renal anemia
- CT: renal scarring with medullary calcification
What are some cystic kidney diseases?
- autosomal recessive polycystic kidney disease (ARPKD)
- autosomal dominant polycystic kidney disease (ADPKD)
- multicystic renal dysplasia
- simple/complex renal cysts
- juvenile nephronophtisis - medullary cystic kidney complex
- medullary sponge kidney
What are the causes and consequences of autosomal dominant polycystic kidney disease?
Causes
- PKD1 mutation: 16p13.3 (~80%)
- PKD2 mutation: 4q21 (no difference in phenotype)
prevalence is relatively common (1:200 - 1:1000)
Consequences:
- cysts along the entire length of the nephron leading to renal failure
- multiple liver, pancreatic and ovarian cysts
- intracerebral aneurysms leading to risk of subarachnoid hemorrhage
Overview of Autosomal dominant polycystic kidney disease
Clinical picture:
- symptom-free or minimal symptoms for a long time
- loin pain, macroscopic hematuria, hypertension, kidney stones, frequent UTIs, polyuria/polydipsia
Diagnosis:
- family history, US, screening for intracerebral aneurysms (MRI)
- genetic testing (rarely)
Treatment
- increases fluid intake (>3 L/day)
- optimal blood pressure control (ACEi/ARB)
- V2R antagonists in case of rapid progression
- cyst puncture is NOT recommended
- in case of renal failure: renal replacement therapy; pre-transplant nephrectomy in case of XL kidneys
Overview of simple renal cysts
- ~10% of the population
- more common in males and elderly
- tends to increase its size
- symptom free until rupture/infection (rare)
- US: round, echo-free structure with sharp border
- usually no treatment required
Bosniak categories for Complex renal cyst
I. simple benign cyst
II. few hairline thin septa
IIF. thickening of septa or multiple septa calcification w/o contrast enhancement
III. thickened irregular septa and contrast enhancement
IV. III. + enhancing soft-tissue
III. and IV. have high risk of malignancy
