AKI and Tubular Disease Flashcards
What is Fanconi syndrome, pathogenesis and what are some causes
Impairment of renal tubular resorption of: amino acids, glucose, Na, K, Ca, Pi, HCO3 and uric acid
Acquired: any nephrotoxin causing acute tubular necrosis (gentamicin, streptozoscin, hypocalcaemia (hypoPTH); chicken jerky treats/food associated (possibly high inorganic Pi), tetracyclines, Bence jones proteinuria, Leptospirosis
→ acute tubular necrosis → abnormal FE of solutes and reduced resorption of glucose → glucosuria and osmotic diuresis (often cystine or uric acid resorption also affected but this varies)
Disease progression → metabolic acidosis → hyperchloraemia and hypokalaemia
Basenji - inherited proximal tubular defect causes loss of glucose, amino acids, uric acid and Pi. Combined with isosthenuria. Breed prevalence of up to 30% reported
Diagnosis of fanconi syndrome
Glucosuria in absence of hyperglycemia
Clinical Signs: polyuria, polydipsia, weight loss, poor hair coat, weakness, and dehydration
Fructosamine - if normal/low then primary hyperglycemia very unlikely
URine Biomarkers for tubular injury: glucosuria, albuminuria, uCysB, uNGAL, uL-FABP, uKIM-1
The latter 3 are not filtered from urne or if they are are then completely reabsorbed. It is measurement of the locally produced substances (ie in the urine) that are indicative of tubular damage.
Other Inherited tubular disorders
PRIMARY RENAL GLUCOSURIA - Scottish terriers and Basenji
HYPERURICOSURIA - Dalmatian, Bulldog, Black Russian Terrier
–> defect in uric acid transporter (missense mutation) responsible for uptake into hepatocytes and reabsorption by proximal tubular cells AND active excretion in distal tubule
→ Urate stone formation
DDx portal vascular anomalies
CYSTINURIA
Defect in resorption of non-essential amino acids (cysteine among others)
→ Cystine calculi in presence of acidic urine
Can also develop carnitinuria - non-essential sulphur containing amino acid. More common if consuming high fat diets → chronic excessive loss can cause deficiency and is associated with development of cardiomyopathy
Type 1 - labrador autosomal recessive
Type 3 Bulldogs, Mastiff, incomplete penetrance autosomal dominant
Pathogenesis of Proximal tubule RTA (type 2)
Can be congenital or acquired due to toxic injury: Amphotericin B, Pyelonephritis, SLE, MM, heavy metal toxicity, hypocalcaemia
→ proximal tubule is responsible for resorption of HCO3 via combining with H+ then carbonic anhydrase generates CO2 which diffuses into cells and H2O is lost
→ Defect in the basolateral tubular cell membrane Na/HCO3 transporter causing leakage of HCO3 into tubular lumen
→ Ongoing loss results in HCO3 decrease in blood, metabolic acidosis is mitigated by distal tubule excretion of H+
→ K wasting may occur due to HCO3 excess in tubule creating electrochemical gradient drag
Concurrent Fanconi syndrome is reported and helps to confirm PROXIMAL tubule origin
Clinicopathological findings of PROXIMAL RTA (type 2) and response to alkali challenge
normal Ca,
Urine pH <5.5 appropriate for presence of acidosis
low plasma HCO3 hyperchloraemic metabolic acidosis
As long as distal tubule function is normal HCO3 production and resorption are sufficient and urine is acidic
→ administration of HCO3 → overwhelming the distal tubule resorption and marked bicarbonaturia and K+ wasting
Pathogenesis of DISTAL tubule RTA (type I)
→ responsible for production of HCO3 replacing what is used in buffering the daily acid load. Requires Na reabsorption to occur generating gradient for H+ excretion (then binds NH3 in lumen preventing back diffusion)
→ impaired urine H+ excretion (Na reabsorption impairment or impaired excretion of H+ ATPase or increased backflow of H+) → unable to acidify urine in response to acidosis
→ chronic acidosis → muscle weakness, hypokalaemia, nausea, reduced appetite, neurological signs, osteomalacia or Ricketts.
→ urine is ALWAYS Alkaline
Clinicopathological findings in Distal RTA
low K (more severe),
HIGH Ca,
urine pH>5.5 (alkaline always) with plasma acidosis
Can cause nephroliths/nephrocalcinosis as well as bone demineralisation
→ can perform ammonia-Cl challenge and urine will not acidify
Tx options for RTA
Prognosis in patients with distal RTA is not as good as proximal RTA because patients with distal RTA are predisposed to urolithiasis
Distal - requires much higher NaHCO3 dose to correct acidosis and K+ supplementation much more often required.
→ dose titrated based on urine and plasma pH and HCO3
New biomarkers for AKI
uCysB - intracellular protein, limited in circulation, released with tubular damage. JVIm paper looked more at use in identifying progression of CKD but not at use in identification of AKI - 2024 study has shown is higher in AKI (helsinki) and another demonstrated elevation following adder envenomation where SDMA and sCr did not increase.
NGAL - released from neutrophils and normally reabsorbed so little in urine. with tubular injury can increase. Impacted specificity due to effects of systemic inflammation, presence of LUT neoplasia or infection.
LFABP - produced by hepatocytes and proximal tubular cells, circulating LAFBP is filtered but reabsorbed. If tubular injury then released directly into urine
Utility in AKi not evaluated, increased in hyperTH cats and in cats with CKD (but overlap with healthy older cats)
uKIM-1: protein that scavenges oxidised lipoproteins and is upregulated with proximal tubular damage.
Increased in AKI but is variable, less significant in CKD.
ISCAID (and JFMS Tx guidelines) Recommendations for Pyelonephritis Abx
→ Efficacy against G- (Enterobacteriaceae)
IV Fluoroquinolone or amoxicillin in severe illness (dehydration, anorexic)
PO fluoroquinolone if systemically well and good appetite.
ABx with penetration into tissues are likely to be more effective.
→ Therapy is adjusted based on clinical response and sensitivity data: if responding but report resistance then continue.
INI and appropriate ABx chose based on sensitivity then consider alternate diagnosis.
Duration: previously 4-6 weeks was recommended. ISCAID recommends 10-14days for acute bacterial pyelonephritis based on evidence from human medicine where microbiological cures were not inferior compared to longer treatments
ISCAID recommend follow-up culture 1-2 weeks after discontinuation this differs to LUTI where follow up culture is not recommended
Tests to perform for investigation of pyelonphritis suspicion
Positive bacterial culture in conjunction with suggestive clinical findings: fever PUPD, azotaemia, renal pain
Definitive Dx is positive culture from pyelocentesis
Blood cultures recommended by ISCAID if febrile
Leptospirosis testing: blood/urine PCR, cage side ELISA, MAT (acute and convalescent)
Ultrasound: pyelectasia, renal papilla blunting
→ do not overinterpret as not specific for infectious disease
Causes of AKI
HAEMODYNAMIC: reduced blood flow to kidney due to any cause. Reduces ATP production → altered solute handling, tubuloglomerular feedback causing afferent constriction and reduced GFR. Also Tubular apoptosis or necrosis and inflammation
→ reversible with early intervention to underlying cause
INTRINSIC: Vasculitis, acute glomerulonephritis (infectious or autoimmune); acute interstitial nephritis; acute tubular necrosis (ischaemia progression, nephrotoxins (exogenous or endogenous).
POSTRENAL: obstruction resulting in creased pressure in bowmans capsule → altered filtration pressure and reduced GFR. Or leakage of urine → reabsorption and caustic/inflammatory damage
Causes of RTA
Can be congenital or acquired due to toxic injury: Amphotericin B, Pyelonephritis, SLE, MM, heavy metal toxicity, hypocalcaemia
How to differentiate haemodynamic from intrinsic AKI
Urine FE of Na
–> low in haemodynamic due to conservation of water –> inappropriately high in intrinsic damage due to tubular dysfunction
IRIS AKI Grades and subcategories
1) NONAZOTEMIC, 1.5-2x increase in sCr from baseline, measured oliguria, imaging changes supporting AKI, oliguria that is readily volume responsive and sCr reduces to baseline within 48h
2) Mild - documented AKI based on hx/lab/imaging with static or progressive sCr 140-220. Also animals with CKD that have progressive increase in sCr within 48h
3) Moderate - 220-439 sCr
4) 440-880 sCr
5) >880 sCr
Subcategories
→ Non-oliguric, Oliguric, Anuric
→ requirement for RRT (severe azotemia, hyperkalaemia, acid-base disturbance, overhydration, nephrotoxins)
Indications for RRT
Different types
anuria/oliguria, inability to regulate water homeostasis (volume overload), hyperkalaemia, acidosis
Peritoneal dialysis uses dialysate to absorb solutes via peritoneum. Risk of infection introduction (strict asepsis), need specialised solutions for infusion.
→ Haemodialysis: intermittent (most often used), continuous or TPE (separates plasma from cellular blood components).
NB requires systemic heparinization, central line
Pathogenesis of tubular injury in ischaemic AKI
Reduction in RBF –> reduced ATP –> alterations in Na/K ATPase pump (functions and cytoskeletal changes resulting in loss of microvilli
–> ALTERED TUBULAR SOLUTE HANDLING
–> tubuloglomerular feedback which constricts afferent arteriole –> reduced GFR
Loss of cell adhesion molecules and anchorage –> desquamation and either apoptosis or necrosis (more severe injury) of tubular epithelium
Production of DAMPs –> neutrophil infiltration of interstitium and further inflammation
–> altered vascular permeability which can cause proteinuria and further tubular damage.
How does obstructive AKI cause damage to renal functional unit
increased tubule back pressure –> increased pressure in Bowmans capsule –> altered net filtration rate and reduced GFR
Phases of AKI
1 - ischaemic or nephrotoxic insult that is subclinical and causes eventual reduction in GFR
2 - progression (if there is no intervention) due to continued renal hypoxia and inflammation resulting in altered solute handling and tubular cell apoptosis or necrosis (greater risk of nephrotxic damage to cortical cells due to higher proportion of renal blood flow here)
3 - After removal of injury cause –> maintenance phase where UOP is altered and urine is isosthenuric (little tubular processing can occur)
4 recovery –> tubular regeneration and compensatory hypertrophy/hyperfiltration
Increase in UOP can be marked polyuria due to partial restoration.
Compensatory processes can become maladaptive.
Types of renal neoplasia and their prognosis
Canine Renal Carcinoma - usually arise from epithelial cells of nephron, prognosis dependent on tumour subtype, MI and COX expression. Moderate risk of metastatic disease (16-34% at diagnosis)
MST dependent on MI:
<10 = >3y; >30 = <6 months
Renal Cystadenocarcinoma - unique to GSD, see bilateral multifocal lesions and nodular dermatofibrosis.
Autosomal dominant inheritance.
Renal Sarcoma - HSA, leiomyosarcoma, sarcoma, histiocytoma, spindle cell.
Very rare, metastasis reported in up to 88%
Renal
Nephroblastoma - neoplastic transformation during nephrogenesis. Can occur at any age. Can arise as primary renal tumour or a tumour within the thoracolumbar spinal cord.
→ paraneoplastic hypertrophic osteopathy is reported, metastasis in up to 75%.
Feline Renal Lymphoma - most common cause of renal neoplasia in cats. Median 9y, no longer associated with FeLV infection. 80% have bilateral disease.
Response to chemo thought to occur in ~66%
Care with Doxo as nephrotoxic in cats
DDx: adenoma, adenocarcinoma, TCC, HSA, nephroblastoma
CNS involvement is common for feline renal lymphoma
JFMS 27 case series: MST longer for cats treated with LCHOP 203d; compared to pred alone 50d
14/27 had multicentric lymphoma
AKI Tx goals and recommendations from IRIS
Management of common complications
GOALS:limit further damage, improve renal oxygen delivery, reduce metabolic demand, maintain UOP, limit inflammation
- IVFT: 5% rehydration, allows rapid correction of any deficit and reversal of haemodynamic change and can aid in assessing UOP.
→ avoid volume overload (ie no forced diuresis) as this can cause tissue oedema and worsen perfusion.
→ matching of ins and outs+22ml/kg/d insensible. AFTER correction of dehydration
If anuric replace insensible losses only
- Bicarbonate only indicated if pH <7.2 and then correct over 12 hours.
- Mannitol has theoretical beneficial effects but lack of studies to demonstrate its superiority to conventional crystalloids. JVIM 2019 Mannitol had minimal effect on GFR but did increase FE of NA for short duration or time.
Hyperkalemia: Ca-gluconate if bradycardic, insulin/dextrose, correct acidosis
Hypokalemia: excessive losses need to be replaced
Metabolic Acidosis - inability to excrete H+ (distal RTA
Hypertension: CCB preferred over ACEi due to risk of alternating renal perfusion (ensure no evidence of volume overload before treating)
GI bleeding: altered plt function due to uraemia, ulceration from altered perfusion, gastroenteritis from uraemia
