Kidney disease Flashcards
What is the mechanism behind proximal (type 2) and distal (type 1) renal tubular acidosis
- Proximal: decreased HCO3- reabsorption in proximal convoluted tubule (reduced transport maximum for HCO3-)
- Distal: decreased H+ secretion in late distal convoluted tubule / collecting duct (decreased HCO3- production)
What is the serum bicarbonate, urine pH (without treatment), urine pH after NaHCO3 administration, bicarbonate therapy requirement for proximal / distal RTA
- Proximal RTA:
- HCO3 = 15-18 mmol/L
- Urine pH < 6 (in steady state)
- Urine pH after NaHCO3 = alkaline
- NaHCO3 requirement = > 10 mEq/kg/d - Distal RTA:
- HCO3 = < 10-12 mmol/L
- Urine pH > 6
- Urine pH after NaHCO3 = no change
- NaHCO3 requirement = < 3 mEq/kg/d
Name causes of proximal and distal RTA
- Proximal:
- Aminoglycoside toxicity
- Fanconi syndrome (congenital: Basenjis)
- Acetazolamide treatment
- Cisplatin toxicity
- Ethylene glycol toxicity
- Leptospirosis
- Multiple myeloma
- Heavy metal toxicity - Distal:
- IMHA
- Pyelonephritis
- Multiple myeloma
- Amphotericin B toxicity
- Heavy metal toxicity
What is a consequence of alkali therapy in proximal RTA
Worsening hypokalemia (due to presence of HCO3- in the urine)
What is a possible complication of distal RTA
Urolithiasis due to:
- increased calciuresis due to bone resorption from chronic metabolic acidosis
- alkaline urine reducing the solubility of Ca and P
What is a possible alternative to sodium bicarbonate therapy in dogs with RTA
Potassium citrate
What is the histological finding with NSAID toxicity
Papillary necrosis
Name 5 toxins affecting the renal tubule
- Grapes
- Ethylene glycol
- Aminoglycosides
- Cisplatin
- Contrast agents
What are the 3 staging systems for AKI in humans
- Risk Injury Failure End Stage Kidney Disease (RIFLE)
- Acute Kidney Injury Network (AKIN)
- Kidney Disease: Improving Global Outcomes (KDIGO)
Describe the IRIS AKI grading system
- Grade I: Non-azotemic AKI (creat < 140 umol/L)
- Documented AKI (historical, clinical, lab, imaging) and/or
- Increase in creatinine > 26 umol/L in 48h and/or
- Oliguria < 1 mL/kg/h over 6h - Grade II: Mild AKI (creat 141 - 220 umol/L)
- Documented AKI and static or progressive azotemia and/or
- Increase in creatinine > 26 umol/L within 48h and/or
- Oliguria <1 mL/kg/h over 6h - Grade III: Moderate to severe AKI (creat 221-439 umol/L)
- Documented AKI and increasing severities of azotemia and functional failure - Grade IV: creat 440-880 umol/L
- Grade V: creat > 880 umol/L
Each grade subdivided with non-oliguric or oliguric, and need for RRT or no need
What are the 4 phases of the pathophysiology of AKI and their duration? What model are they based on?
Based on ischemic injury - might not apply to all types of injury
(0. Insult phase)
- Initiation phase (hours to days): cellular damage (decreased GFR but no clinical / biochemical changes)
- Extension phase (1-2 days): cellular death (biochemical and clinical manifestations start)
- Maintenance phase (days-weeks): simultaneous cell death and regeneration (GFR stabilizes, creatinine reaches a plateau)
- Recovery phase (weeks-months): improvement in GFR and tubular function
What is the pathophysiology of ischemic AKI
In initiation phase (hours - day):
1. Ischemia -> increase in intracellular Ca2+ -> ROS -> cellular damage + release of cytokines and chemokines
- Disruption of cytoskeleton and redistribution of Na/K ATPase to apical membrane -> entry of water in cells -> swelling -> tubular obstruction
- Relocation of integrins -> loss of cell anchorage to basal membrane ->cell desquamation, tubular obstruction + back-leakage of filtrate into interstitium
In extension phase (1-2 days):
1. Damaged endothelial cells -> expression of selectins, ICAM-1 responsible for leukocyte activation
- Endothelial glycocalyx shedding -> increased permeability -> edema -> hypoxia
- Sluggish flow in capillaries -> microthrombi -> capillary plugging -> ischemia
Maintenance phase (days-weeks):
- Stabilization of GFR
- Cell death vs regeneration
Recovery phase (weeks-months):
- Restoration of GFR
- reestablished cell polarity + tubular integrity
How is the ultrasonographic architecture of the kidneys in most cases of AKI? What are exceptions?
Normal in most cases (or sometimes enlarged kidneys +/- perirenal fluid).
Exceptions:
- Lymphoma: thickened cortex with hypoechoic perirenal halo
- AKI on CKD
- Ethylene glycol: hyperechoic renal cortices and medulla
- Obstruction
- Pyelonephritis
What are indicators of ethylene glycol toxicosis
- High anion gap metabolic acidosis
- Calcium oxalate crystalluria (especially Ca oxalate monohydrate)
- Hyperechoic renal cortices and medullary rim sign
- Hyperlactatemia in some analyzers
- Hypocalcemia
What are diagnostic criteria for Leptospirosis based on serology? Which serovar is the most at risk of false positive?
- Initial titers of >1:800 with clinical suspicion (L autumnalis most at risk of false positive from cross-reactivity with vaccines)
- OR 4-fold increase in titers after 2-4 weeks
What is the recommended rate of fluid tapering for patients recovering from AKI
Decrease rate by 10-25% per day as long as urine output decreases accordingly and weight and perfusion remain stable
(LOL)
What is the mortality rate from AKI in dogs and cats
- Dogs: 45% mortality (but survival up to 82-86% for lepto)
- Cats: 53% mortality
(Among surviving patients, about 50% will have chronic kidney disease)
What is the most common cause of CKD in cats and dogs
Cats: often unknown
Dogs: glomerular disease
What are the most common histologic lesions in cats and dogs with CKD
Cats: lymphoplasmocytic tubulointerstitial nephritis and fibrosis
Dogs: glomerular lesions and interstitial nephritis with common lipid infiltration
Described the IRIS CKD staging system
- Stage based on creatinine
- Stage I: creat < 125 (dogs) or 140 (cats)
- Stage II: creat 125-250 (dogs) or 140-250 (cats)
- Stage III: creat 251-440
- Stage IV: creat > 440 - Substage based on UPCR
- Nonproteinuric: UPCR<0.2
- Borderline proteinuric: UPCR 0.2-0.5 (dogs) or 0.2-0.4 (cats)
- Proteinuric: UPCR>0.5 (dogs) or 0.4 (cats) - Substage based on BP
- Normotensive: SBP<140
- Prehypertensive: SBP 140-159
- Hypertensive: SBP 160-179
- Severely hypertensive: SBP > 180
True or false: a USG>1.030 rules out CKD
False.
Some dogs and cats will have a CKD despite USG>1.030 (susp secondary to the presence of lipids in the urine)
What UPCR is suggestive of glomerular disease
UPCR >2
Name some congenital nephropathies in dogs and cats (with associated breeds)
- Dogs:
- Renal dysplasia (Lhassa Apso, Shih Tzu, Wheaten Terrier, Standard Poodle)
- Primary glomerulopathy (Cocker Spaniel Springer Spaniel, Bull Terrier)
- Polycystic kidney disease (Bull Terrier, Cairn Terrier, Westie)
- Amyloidosis (Shar Pei)
- Immune mediated glomerulonephritis (Bernese Mountain Dog, Brittany Spaniel)
- Fanconi syndrome (Basenji) - Cats:
- Plolycystic kidney disease (Persian)
- Amyloidosis (Abyssinian, Siamese)
What is the median pelvic width in dogs and cats with ureteral obstruction
Dogs: 15 mm
Cats: 6.8 mm
Name a renal disease potentially identified on renal aspirates (one in dogs, one in cats)
Dogs: renal lymphoma
Cats: FIP (and renal lymphoma)
Are antacids indicated in the treatment of CKD
No - there is no evidence of increased gastric acidity or gastric ulceration ; antacids increase the burden of medications and are associated with AKI in humans
What variables are associated with decompensation / mortality in cats and dogs with CKD
Creatinine, UPC, urine albumin-to-creatinine ratio, leukocytosis, hyperphosphatemia, weight loss
Name a few possible post-op complications of kidney transplantation in cats
- Graft rejection
- Retroperitoneal fibrosis (causing ureteral obstruction)
- Ureteral obstruction
- Infections
- Neoplasia (lymphoma)
- Diabetes mellitus
- Hemolytic uremic syndrome
What are mechanisms of pathogenesis of oligoanuria
- Decreased renal blood flow (hypovolemia, decreased CO, vasodilation, renal artery thrombosis)
- Tubular obstruction from casts or cells (pyelonephritis, acute interstitial nephritis, acute tubular necrosis)
- Backflow of glomerular filtrate in renal interstitium (tubular / pelvic / ureteral / urethral obstruction)
- Intrarenal RAAS activation (high Cl fluids)
- Altered permeability of glomerular capillaries (glomerulonephritis, vasculitis)
What should be the IV fluid plan for a normovolemic oligo-anuric patient
- Challenge with fluids to correct 3-5% dehydration (likely to be missed on physical exam)
- If responds, match INs/OUTs
- If does not respond, give fluids for insensible losses only (about 20 mL/kg/day, usually met with meds and flushes)
Why is furosemide unlikely to be effective in anuric patients
Furosemide needs to reach the tubular fluid to be inhibit the Na-K-2Cl pumps (by active secretion in proximal tubule +/- some glomerular filtration). If there is no urine production furosemide will likely not reach its site of action.
What medications can be given to attempt to convert oligoanuria to polyuria (+ mechanism of action and 1 adverse effect)
- Mannitol: osmotic diuretic, can help wash out tubules from casts etc.
Can worsen pulmonary edema and intracellular dehydration (not recommended in humans with AKI) - Furosemide: Na-K-2Cl transporter inhibitor (thick ascending limb of the loop of Henle).
Can cause ototoxicity. Might increase urine volume but not GFR. - Dopamine: stimulates DA-1, DA-1, and alpha and beta-adrenergic receptors ; leads to afferent arteriole vasodilation (at low doses) + increases natriuresis by inhibition of tubular transporters.
Can cause tachyarrhythmias. - Fenoldopam: selective dopamin receptor (DA-1) agonist leading to renal vasodilation.
Can cause hypotension from systemic vasodilation. - Diltiazem: calcium channel blocker leading to afferent arteriole vasodilation
Can cause hypotension.
Common bacteria responsible for UTIs in dogs
- E Coli
- Staphylococcus spp
- Enterococcus spp
- Proteus spp
- Streptococcus spp
- Klebsiella spp
What breeds are predisposed to Lyme nephritis
Retriever breeds
What are typical physical examination / laboratory findings of Lyme nephritis
- Lyme + status
- Proteinuria
- Hypoalbuminemia
- Thrombocytopenia
- Hypertension
- Mild to moderate azotemia (USG 1.020-1.030 until late stages)
- Hypercholesterolemia
What family of ticks is responsible for transmission of Lyme disease? For how long does it need to be attached to the dog?
Ixodes (I scapularis, I pacificus, I ricinus)
Needs to be attached for 2 days
Describe 5 diagnostic tests for leptospirosis
- Serology with micro-agglutination testing (MAT): Gold standard. Reports serum titer at which 50% of leptospires agglutinate (seen on darkfield microscopy) for 6-7 serovars (but cross-reactivity is frequent). Positive if >1:800 in acute titers (Se 50% only) or 4-fold increase in titers after 7-14 days.
Affected by vaccination. - PCR: Identifies leptospire DNA in blood and/or urine. Positive blood confirms lepto, positive urine can happen in 20% healthy dogs. False negatives are frequent due to short leptospiremic phase (<6 days) and intermittent urinary shedding (+ antibiotic use). Not affected by vaccination.
- Point-of-care serologic tests: SNAP Lepto (Idexx) detects IgG to LipL32. WITNESS Lepto (Zoetis) detects IgM for L Bratislava and Grippotyphosa.
Can have false negative due to delay in antibody production (less for IgM) and false positive from vaccination (LipL32 supposed to be more specific of pathogenic lepto but still).
Se and Sp vary with geographic location - Darkfield microscopy: Direct observation of leptospires. Low sensitivity, requires expertise.
- Culture: Requires prolonged incubation time on special culture medium, difficult, low sensitivity
What are mechanisms of AKI development in sepsis
- Microcirculatory dysfunction: microthrombi, heterogeneous blood flow
- Increased capillary permeability: peritubular interstitial edema, contributes to hypoxia of medulla
- Glomerular shunt capillaries bypassing glomeruli (and medulla)
- Inflammatory response and oxidative stress causing direct epithelial cell injury (ROS)
- Epithelial damage causes decreased Na and Cl reabsorption -> increased delivery to macula dense -> decrease in GFR (tubuloglomerular feedback)
- Epithelial damage also causes disruption of tight junctions with back-leakage of tubular fluid and shedding of epithelial cells (causing tubular obstruction)
- Metabolic reprogramming of tubular cells favouring cell survival over transport functions (sublethal injury)
What are possible mechanisms of nephrotoxicity
- Hemodynamically mediated (NSAIDs, ACEIs): decrease renal blood flow / GFR by vasoconstriction or afferent and efferent arterioles (NSAIDs) or vasodilation of efferent > afferent arteriole (ACEIs)
- Tubular necrosis (aminoglycosides, contrast agents): direct tubular cell injury from contact with toxin
- Interstitial nephritis (beta-lactams, PPIs): act as antigens, attract T cells and lead to inflammation
- Crystalline (ethylene glycol, methotrexate): crystal deposits in tubules causing obstruction + cytotoxic effect
Is short term prognosis worse for cats and dogs with acute on chronic kidney injury vs AKI?
Not worse, even a little better (65% survival in dogs, 58% survival in cats) because more often caused by reversible cause.
Long term survival is not good though (median survival time 105 days in dogs, 66 days in cats)
What is the long term outcome for dogs who survive AKI (in terms of long term survival and creatinine normalization)
Overall good prognosis. Creatinine normalization in 75% of dogs (55% before discharge, 20% after). Long median survival time with most dogs still alive or dead from other causes.
Where is erythropoietin produced? Under what stimulation?
In the peritubular interstitial cells of the inner cortex and outer medulla. Stimulated by hypoxia (sensed by HIF: hypoxia-inducible factor)
What are mechanisms of anemia in CKD
- Decreased EPO production by peritubular interstitial cells (worsened by ACEIs)
- Iron deficiency due to production of hepcidin (inhibits intestinal iron absorption + sequestrates it in macrophages) + chronic GI bleed + urinary iron losses
- GI bleed due to uremic ulcers
- Hemorrhage due to thrombocytopathy
- RBC fragility and hemolysis due to uremic toxins
What are complications of darbepoietin therapy
- Anaphylaxis
- Hypertension (increase in vascular resistance)
- Pure red cell aplasia
- Seizures
Is unilateral or bilateral ureteral obstruction more likely to cause more severe kidney damage
Unilateral obstruction because it causes more afferent vasoconstriction (vs bilateral causes more efferent vasoconstriction)
What are the 3 phases of vascular regulation with ureteral obstruction and their duration
- Phase I (0-1.5h): afferent vasodilation
- Phase II (1.5-5h): efferent vasoconstriction
- Phase III (5-18h): afferent vasoconstriction
What are 2 mechanisms of the loss for concentrating ability of the kidney after ureteral obstruction
- Loss of hypertonicity of the medulla
- Decreased response to ADH, downregulated transporters
What proportion of cats with ureteral obstruction don’t have marked pelvic / ureteral dilation
About 25%
True or false: Creatinine on presentation is a prognostic marker for cats with ureteral obstruction
False.
But marker of duration of hospitalization, and creat after discharge marker of mortality.
What are the different types of casts that can be found in urine? Which can be normal?
- Hyaline casts
- Epithelial casts
- Mixed cellular / granular casts
- Coarse granular casts
- Fine granular casts
- Waxy casts
Hyaline and fine granular casts can be normal if < 2 / LPF in well concentrated urine
What is the pathogenesis of leptospirosis in different organs
Leptospires invade endotheliums and break down endothelial barriers
- Pulmonary hemorrhage: from disruption of endothelium
- Liver dysfunction: from disruption of hepatocyte inter-cellular junctions (causing leakage of bile)
- Direct cytotoxic effect on platelets causing decreased aggregation
- Invasion of interstitium and tubular cells causing direct damage (tubular cell necrosis) and tubulointerstitial nephritis in kidneys
- Vasculitis from endothelial damage
What are common UA findings associated with leptospirosis
- Isosthenuria (or less commonly hyposthenuria)
- Glucosuria
- Proteinuria (typically UPCR<5)
- Bilirubinuria
- Possible hematuria
What are radiographic changes associated with pulmonary hemorrhage in leptospirosis
Bilateral interstitial pattern followed by reticulo-nodular pattern and generalized alveolar infiltrates
What are supportive / confirmatory laboratory criteria of leptospirosis
Supportive:
- MAT titer > 1:800
- Detection of IgM lepto antibodies
- Positive urine PCR
- Visualization of leptospires in blood or urine on darkfield microscopy by reference laboratory
Confirmatory:
- 4-fold or higher increase in MAT titers between acute and convalescent (at same lab)
- Positive blood PCR
- Isolation of Leptospira from a clinical specimen by a reference lab
What is required to diagnose a probable case of lepto vs a confirmed case
Probable case: meets clinical criteria and at least 1 supportive lab criteria
Confirmed case: meets clinical criteria and at least 1 confirmatory lab criteria
What are the clinical criteria for leptospirosis
- Onset of systemic illness (fever, lethargy, PUPD, anorexia) within the past 2 weeks +/- signs suggestive of lepto:
- GI
- Pulmonary (cough, hemoptysis, tachypnea)
- Ocular (uveitis, conjunctivitis, retinal hemorrhage)
- AKI (oliguria)
- Hepatobiliary (icterus)
- Coagulation (hemorrhage) - AND 2 or more clinicopathologic abnormalities:
- Neutrophilic leukocytosis
- Thrombocytopenia
- Increased creat with isosthenuria
- Cholestatic hepatopathy
- Increased lipase
- Increased CK
- Glucosuria (with normal BG)
- Active urine sediment
- Rads consistent with pulmonary hemorrhage
- Abd ultrasound consistent with lepto (pancreatitis, hyperechoic renal cortex, perirenal fluid)
- Arrhythmias or increased cTnI
What are the 4 vaccinal serovars for lepto in the US / Canada
Leptospira canicola, L. grippotyphosa, L. icterohaemorrhagiae, L. pomona
(Australis instead of Pomona in Europe)
How should penicillin dosage be adjusted for dogs with AKI grade 4 and higher
Dosing interval should be doubled
Is ursodeoxycholic acid (Ursodiol) recommended in leptospirosis?
No - not enough data and could worsen bile leakage
When should RRT start being considered in dogs with lepto
When they are AKI grade 4 or higher (creat > 440)
What is the prognosis for dogs with lepto treated with RRT
> 80% recovery
What are negative prognostic factors for lepto in dogs
Hyperbilirubinemia (bilirubin >= 10 umol/L associated with death) and hypocoagulability
Pulmonary hemorrhage associated with 70% mortality
For how long should zoonosis precautions be taken for dogs with leptospirosis
For 48h on antibiotics
(Protection include gloves, gowns, mask, eye protection)
Should other dogs living in the household of a dog with lepto be treated with antimicrobials
Prophylactic treatment with doxycycline for 2 weeks is recommended (ideally with monitoring of MAT)
No evidence for cats at this point
What is the most pathogenic species of Leptospira
Leptospira interrogans
What are the 2 mechanisms which can lead to AKI in tumor lysis syndrome
- Hyperphosphatemia -> precipitation of calcium phosphate in renal tubules
- Hyperuricemia -> precipitation of urate crystals in kidneys
What are the IRIS stages of AKI?
Grade I: Nonazotemic AKI (<140)
- Documented AKI and/or
- Progressive non azotemic increase in serum creat (>26.4 mol/L) with 48h and/or
- Measured oliguria (<1ml/kg/h) or anuria over 6h
Garde II: Mild AKI (141-220)
- Documented AKI and static or progressive azotemia
- Progresive azotemic increase in creat (> 26.4 umol/L) within 48h, serum responsiveness, and/or
- Measured oliguria (<1ml/kg/h) or anuria over 6h
Grade III: Moderate to severe AKI (221-439)
- Documented AKI ad increasing severities of azotemia and functional failure
Grade IV: 440-880
Grade V: > 880x
How is fluid overload defined?
Fluid accumulation more than 10% of baseline body weight
What is the median pelvic width in animals with normal renal function?
2mm
Why is there a higher risk of hemorrhage secondary to renal tissue sampling in renal disease?
Uremic inhibition of platelet function
Define oliguria
Urine production of < 1ml/kg/h after fluid volume restoration
Why is the BUN to creatinine ratio often increased in pre-renal azotemia?
Due to the increased reabsorption of BUN in the nephron as a physiological response to re-establish euvolemic state (in presence of ADH)
How does uraemia lead to oral ulceration?
Conversion of urea by bacterial urease into ammonia which is caustic to the oral mucosa.
What are 5 mechanisms of oliguria?
- Decreased renal blood flow
- Tubular obstruction from casts or cellular debris
- Backflow of glomerular filtrate into renal interstitium
- Inrarenal renine-angiotensis system activation
- Altered permeability of glomerular filtration barrier
What are the most important predictors of outcome for animals with AKI managed medically?
- Etiology (reversibility?)
- Severity (AKI grade)
- Body systems involved
- Comorbidities
- Treatment quality
In a 2022 JVIM paper on longterm outcome of dogs with AKI, what was the outcome?
Creat normalized in 75% of cases
- 55% at discharge and 20% during follow-up period (up to 3 months)
Estimated MST = 3.5 years
In dogs who’s creat did not normalize, median value was 167 mmol/L
** New data suggests good short and long term outcome in animals with AKI
In which species can bilirubinuria be normal?
Dogs - more than 20% have 1+ bilirubinuria
* low renal threshold - expect bilirubinuria before bilirubinemia
What serum calcium phosphorus product has been associated with shorter survival in dogs with CKD?
> 70 mg2/dL2
What differentiates sepsis induced AKI from AKI due to ischemia or nephrotoxins?
Sepsis-induced AKI is characterized by marked reduction in kidney function with only mild histological changes in the kidney
VS diffuse glomerular and tubular damage with extensive necrosis in other forms of AKI
Other than colloids, what fluids should be avoided in patients with AKI and why?
Chloride-rich fluids should be avoided. Has been associated with higher incidence of kidney injury possibly due to activation of macula densa and subsequent renal afferent arteriole vasoconstriction.
True or false: The prophylactic use of furosemide to prevent AKI has been shown to be effective in critical illness.
False - ineffective and even harmful
Why is Dopamine no longer recommended as a vasodilator in AKI?
At low doses in healthy individuals, dopamine causes renal vasodilation, increased GFR and diuresis.
–> These effects are not preserved in patients with AKI
–> In patients with AKI, dopamine increases renal vascular resistance and reduces RBF
–> Risk of tachyarrhythmias, myocardial hypoxia, reduced splanchnic blood flow and suppressed Tcell function
Name 3 biomarkers that can be used to detect AKI before an increase in creatinine
- Urinary neutrophil gelatinase associated lipocalin (NGAL)
- Urinary cystatin C
- Urinary N-acetyl-beta-D-glucosaminidase (NAG)
- Urinary retinol-binding protein
