Renal CVT Flashcards
Define PU/PD
urine output > 50 ml/kg/day or water consumption > 100 ml/kg/day
Where is ADH synthesized and stored?
ADH synthesized in supraoptic and paraventircular nuclei of hypothalamus, stored in pituitary
What is another name for ADH?
Anti-diuretic hormone = Vasopressin
What stimulates ADH release?
ADH releases when decrease in plasma osmolality, arterial hypotension, fever, pain, nausea, hypoglycemia, exercise, certain drugs
How does ADH work?
○ In distal convoluted tubule and collecting duct ADH stimulates passive resorption of solute-free water (without ADH these areas are impermeable to water)
○ ADH binds to V2 receptors leading to insertion of aquaporin-2
○ Channels allow water to flow along osmotic gradient between distal convoluted tubule/collecting duct and the hypertonic renal medulla
What are 3 physiologic processes that allow for concentration of urine?
○ Concentration of urine in the presence of ADH
§ PROBLEM: Reduced production of ADH
○ Ability of renal tubules to respond to ADH
§ PROBLEM: Inability to respond to ADH
○ Presence of osmotic gradient btwn hypertonic renal medulla and fluid in distal convoluted tubule and collecting duct
§ PROBLEM: Osmotically active substances in urine filtrate or decreased medullary hypertonicity
Name 6 conditions that can result in primary polydipsia.
- Behavioral Problem (pyshcogenic)
- Hyperthyroidism (cats)
- Primary GI disease (dogs)
- Hepatic encphalopathy
- Hyperadrenocorticism
- Fever
- Pain
How can serum [Na+] help in determingin primary PU vs primary PD?
○ Sometimes can tell from Na+ or measured osmolality
§ [Na+] at or below RR → Primary polydipsia
□ Can also be related to hypovolemia
§ [Na+] above RR → Primary polyuria
□ NOT helpful it normal Na+
What is the percentage of functional renal mass results in loss of concentrating ability?
66%
What is the percentage of functional renal mass results in azotemia?
75%
What is central diabetes insipidus?
§ Deficiency in ADH (may be partial or complete)
□ Trauma, neoplasia, congenital defects, idiopathic
§ Patient cannot produce concentrated urine in response to water deprivation but responds to exogenous ADH
What is primary nephrogenic diabetes insipidus?
§ Rare congenital → Renal tubules are unable to respond to ADH
§ Animals cannot concentrate urine in response to water deprivation or administration of exogenous ADH
What is secondary nephrogenic diabetes insipidus?
§ Main cause in dogs and cats, usually primary polyuria and secondary polydipsia
§ Acquired inability of renal tubules to respond to ADH (related to loss of medullary gradient or interference of action of ADH)
§ No use for water deprivation test
What are the 4 major mechanisms of secondary nephrogenic diabetes insipidus?
- Osmotic diuresis
- Loss of medullary hypertonicity (medullary washout)
- Impaired tubular response to ADH
- Downregulation of aquaporin-2
What is renal medulally solute washout?
§ Fluid therapy, diuretics, and chronic PU/PD can all lead to this → Lead to impair renal response to ADH
What are the most common causes of PU/PD in dogs?
CKD, Hyperadrenocorticism and diabetes mellitus
What are the most common causes of PU/PD in cats?
CKD, diabetes mellitus, hyperthyroidism
What are the ranges for minimally concentrated urine?
1.013-1.030 (dog) and 1.013-1.040 (cat)
Name 3 methods to assess GFR?
iohexol clearance, exogenous creatinine clearance, and nuclear scintigraphy
What is DDAVP?
§ Desmopressin (synthetic analog of ADH)
§ When to consider it: All other steps complete and ruled out all causes of secondary NDI, historical information and [Na+] more consistent with CDI, close monitoring and free access to water
□ Look for either drop in water intake or increased USG → CDI
® NOTE: Animals with HAC will also have a positive response!!!
What diseases can result in a positive response to a DDAVP?
CDI, and hyperadrenocorticism
What is the mechanism of PU/PD in diabetes mellitus?
Secondary NDI
Osmotic diuresis
What is the mechanism of PU/PD in primary renal glucosuria?
Secondary NDI
Osmotic diuresis
What is the mechanism of PU/PD in Fanconi syndrome and other tubulopathies?
Secondary NDI
Osmotic diuresis
What is the mechanism of PU/PD in Chronic renal failure?
Secondary NDI
Osmotic diuresis
What is the mechanism of PU/PD in polyuric acute renal failure?
Secondary NDI
Osmotic diuresis
What is the mechanism of PU/PD in postobstructive diuersis?
Secondary NDI
Osmotic diuresis
Downregulation of aquaporin-2
What is the mechanism of PU/PD in chronic partial ureteral obstruction?
Secondary NDI
Downregulation of aquaporin-2
What is the mechanism of PU/PD in renal medullary solute washout?
Secondary NDI
Decreased renal medullary tonicity with loss of osmotic gradient
What is the mechanism of PU/PD in pyelonephritis?
Secondary NDI
Bacterial endotoxin reduced tubular sensitivity to ADH
Damaged countercurrent mechanism
What is the mechanism of PU/PD in pyometra?
Secondary NDI
Bacterial endotoxin reduced tubular sensitivity to ADH
What is the mechanism of PU/PD in liver failure?
Secondary NDI
Loss of medullary hypertonicity (medullary washout)
Impaired hormone metabolism
+/- psychogenic component
What is the mechanism of PU/PD in PSS?
Secondary NDI
Loss of medullary hypertonicity (medullary washout)
Impaired GFR
+/- psychogenic component
What is the mechanism of PU/PD in hyperadrenocorticism?
Secondary NDI
Impaired tubular response to ADH
Central = Impaired release of ADH
Psychogenic polydipsia
What is the mechanism of PU/PD in hypoadrenocorticism?
Secondary NDI
Loss of medullary hypertonicity (medullary washout)
What is the mechanism of PU/PD in hyperthyroidism?
Secondary NDI
Loss of medullary hypertonicity (medullary washout)
+/- Psychogenic component
What is the mechanism of PU/PD in acromegaly?
Secondary NDI
Osmotic diuresis due to diabetes mellitus
Interference with action of ADH?
Partial CDI (some patients)
What is the mechanism of PU/PD in pheochromocytoma?
Secondary NDI
Excessive catecholamines
What is the mechanism of PU/PD in primary hyperaldosteronism?
Secondary NDI
Imapired tubular response to ADH
+/- impaired release of ADH = CDI
What is the mechanism of PU/PD in hypercalemia?
Secondary NDI
Interferes with action of ADH on renal tubule
What is the mechanism of PU/PD in hypokalemia?
Secondary NDI
Downregulation of aquaporin-2
Loss of medullary hyperonicity (medullary washout)
What is the mechanism of PU/PD in hyponatremia?
Secondary NDI
Loss of medullary hyperonicity (medullary washout)
What is the mechanism of PU/PD in leiomyosarcoma?
Secondary NDI
Impaired tubular response to ADH
What is the mechanism of PU/PD in polycythemia?
Secondary NDI
Action of atrial natriuretic peptide
Impaired release of ADH = CDI
What is the mechanism of PU/PD in Leptospirosis?
Secondary NDI
Unknown!! But renal failure is not the cause in all cases!!
What are factors that an influence formation of crystalluria?
- Ion overstauration in urine
- Urine volume
- Urine pH
- Temperature
- Inhibitors or promotors of crystal formation
What are 2 crystal inhibitors in the urine?
Tamm-Horsfall proteins and nephrocalcin
Does crystalluria mean that uroliths will form?
NO!
What are 2 bacteria that are common in struvite formation in dogs?
Staph and Proteus (urease producing bacteria)
Can patients have uroliths without crystals?
Yes, examples with 50% of patients with CaOx uroliths
What occurs with bilirubin crystals in dogs and cats?
Can be normal in concentrated dog urine
ALWAYS abnormal in cats!
What type of crystal is seen with ethylene glycol toxicity?
Calcium oxalte monohydrate
Name 3 tx options for CaOx crystalluria.
- Diet
- Potassium cirtate (alkalizing urine and citrate inhibits CaOx formation)
- Thiazide diuretics (humans)
How is cysteine handled by the kidneys?
○ Cysteine is usually filtered at the glomerulus and resorbed at the proximal tubule, so cysteine crystalluria can occur with defects in resorption at proximal renal tubule
Name 2 ways to treat cysteine crystals?
- Alkalize urine
2. Break disulfide bond with d-penicillamine or 2-MPG (2-mercaptopropionylglycine)
Name 2 breeds that get uric acid crystals.
Dalmatians and English Bulldogs
Name 3 tx options for uric acid crystals.
- Alkaline urine
- Feeding diet low in protein
- Allopurinol (xanthine oxidase inhibitor)
What is the MOA of allopurinol?
xanthine oxidase inhibitor: Competitively inhibits the conversion of xanthine to uric acid
What breed and treatment in dogs can result in xanthine crystal formation in dogs?
Cavalier King Charles Spaniel
Adminstration of allopurinol for uric acid crystals (Dalmatians/English Bulldogs)
What does the urine dipstick detect?
Albumin: >30 mg/dl
What does the SSA test detect?
sulfasalicylic acid test
Detects albumin, globulins, and Bence Jones proteins
> 5 mg/dl
What is the definition of persistent renal proteinuria?
• Proteinuria = positive test results on three or more occasions 2 weeks or more apart
What are the UPC values for albumin of 30 mg/dl in cats and dogs?
• UPC of 0.4 (cats) and 0.5 (dogs) correspond with albumin of 30 mg/dl
What is a normal UPC in dogs and cats?
• Normal UPC: < 0.2-0.3 (cats/dogs)
What are the most common causes of proteinuria in dogs?
• Dogs: neoplasia, infection, polyarthritis, hepatitis, HAC, IMHA, systemic hypertension
What are the most common causes of proteinuria in cats?
• Cats: Viral infections, neoplasia, IM disease, polyarthritis, systemic hypertension
At what UPC is treatment for proteinuria recommended in nonazotemic animals?
• Treatment when UPC >1.0
○ Low protein diet, n-3 fatty acid supplementation (in renal diets), low dose aspirin, ACEi (Enalapril 0.5-1.0 mg/kg/day PO)
At what UPC is treatment for proteinuria recommended in azotemic animals?
• In azotemic animals: treatment when UPC > 0.5
○ Renal diet (n-3 fatty acids), ACEi
What are the NINs?
NINs (neoplastic, infectious, noninfectious inflammatory) causes of glomerular disease
What is mebranoproliferative GN?
• Immune-mediate disease that if associated with deposition of immune complexes within glomerulus
○ Subendothelial, subepithelial, and/or mesangial
○ Complexes may be circulating and passively get trapped OR may form ““in situ”” when antibody binds to normal glomerular antigen or soluble antigen is localized here
What is the most common GN in dogs?
Membranoproliferative GN = 20-60%
What type of Ig is present in membranoproliferative GN?
IgG mainly
What is the tx for membranoproliferative GN?
Treat NINs and antiplatlet drug
What is the prognosis for membranoproliferative GN?
Unknown - studies lacking
What is membranous nephropathy?
(Membranous GN) • Results form IgG deposits on the subepithelial aspect of GBM
Result in complement-mediated injury to podocytes and diffuse foot process effacement
What is most common GN in cats?
Membranous Nephropathy
In dogs, accounts for 10-45%
What is the tx for membranous nephropathy?
Possible immunosuppression, depends on stage of dz (1-4)
What is the prognosis for membranous nephropathy?
Progresses slowly, animals can liver out normal lives
What is mesangioprolifetaive GN?
• Accounted for 2-16% of dog lesions, expect proteinuria and renal failure, mediated by immune-complex deposition
Characterized by mesangial cell hyperplasia and increased mesangial matrix
What Ig is found in mesangioprolifeative GN?
IgA (IgA Nephropathy)
Which disease in dogs have been associated with mesangioproliferative GN?
Excessive IgA complexes can be formed by enteric disease or decreased clearance of IgA complexes in association with liver disease
What is different about Shar Peis and Abyssinians with amyloidosis compared to others?
§ Familial form = Glomerular (only 64%) and medullary amyloid deposition (ischemia, chronic interstitial fibrosis, papillary necrosis, and nephron loss)
□ Shar Peis as few as 25-43% had proteinuria noted!
More likely to present azotemic than proteinuria
Name the common breeds that get reactive amyloidosis in the glomerulus.
• Breeds: Beagles, English foxhounds, collies, and walker hounds
What is glomerulosclerosis?
• Nonspecific, End-stage response to glomerular injury or decreased functional renal mass
• Seen on light microscopy as mesangial cell hyperplasia and mesangial expansions of the glomerulus
○ Hyalinosis, adhesions in tuft of Bowman’s capsule
What is minimal change disease?
GN with no lesions on LM, but on EM Diffuse foot process effacement
Severe proteinuria and nephrotic syndrome
Uncommon in dogs
Humans respond to steroids
What collagen is affected in hereditary nephritis?
- Inherited defects in structure of type IV (basement membrane) collagen
- EM: Irregular GBM splitting (Unique to this disease)
How much day to day variation is noted in UPCs in dogs and cats?
○ Dogs: Up to 50%
○ Cats: Up to 90%
Why is BUN inferior to creatinine for estimating GRF?
BUN is highly influenced by tubular reabsoprtion
Why is there a Nonlinear relationship between GFR and creatinine?
early in CKD large drops in GRF produce small increases in creatinine, and the reverse later in disease; occurs because initially when there is a loss of nephrons there is a compensatory hypertrophy of residual nephrons so single nepron GFR may more than double
What is the gold standard for plasma clearance testing to estimate GFR?
Inulin Clearance
What is a reliable measure of GFR in dogs and cats currently?
Iohexol Clearance (Ominpaque)
What are the 3 core characteristics of CKD?
- Reduction in kidney function
- Proteinuria
- Hypertension
What are the 4 parts of conservative management for CKD?
- Provide adequate nutritional support
- Correct deficits and excesses in fluids, acid-base, and electrolytes
- Amerliorate CS of CDK
- Provide renoprotective therapy to slow the progression of CKD
What are the 3 guidelines for providing adequate nutrition in CKD?
- Feeding a renal diet (best evidence)
- Ensure adrequet nutrition (feeding tube maybe needed)
- Provide omega-3 polyunsaturated fatty acids (most in renal diets)
What are the 4 guidelines to correct deficits and excess fluids, acid-base and electrolyte changes in CKD?
- Maintain Phosphorus
- Maintain potassium
- Correct metabolic acidosis (bicarbonate)
- Maintain hydration
What are the targets for phosphorus levels in CKD?
○ Want below 4.5 mg/dl in Stage II, below 5 mg/dl in Stage III, and below 6 mg/dl in Stage IV
Controlled with renal diet and intestinal phosphate binders
Why does metabolic acidosis occur in CKD?
○ Metabolic acidosis in CKD primarily from impaired renal ammmoniagenesis, impaired excretion of acid and impaired resorption of bicarbonate may also occur
§ Metabolic acidosis in RTA from impaired bicarbonate resorption (proximal RTA) or impaired urine acidification (distal RTA)
What 2 major clinical effects need to be addressed with CKD?
- Anemia (Epo supplementation)
2. GI upset (acid blockers, antiemetics, and sucralfate)
What are the 3 renoprotective therapies that are shown to slow the progression of CKD?
- Reduce proteinuria (ACEi and renal diet)
- Control hypertension (cats - amlodipine, dogs - ACEi + amlodipine)
- Provide calcitriol (to prevent secondary renal hyperparathyroidism and improve appetite/energy)
What is RIFLE?
Description of AKI • Risk • Injury • Failure • Loss • End Stage Renal Failure
What are 3 phases of AKI?
○ Initiation Phase: This is when injury is occurring
§ Extension phase – during this ischemia, hypoxia, inflammation, and cellular injury continue leading to cellular apoptosis and necrosis
§ This phase is usually < 48 hours
§ May not see any abnormalities
○ Maintenance Phase: characterized by azotemia and may last days to weeks, oliguria (< 1 ml urine/kg/hr) or anuria may occur here
○ Recovery Phase: azotemia improves and renal tubules repair, marked polyuria may occur here (from osmotic diuresis from accumulated solutes
Name 3 drugs that can be used to manage oliguria or anuria in patients.
- Furosemide
- Osmotic diuretic - Mannitol or 20% dextrose
- Dopamine CRI
What has proven to work synergistically with dopamine CRI in dog models of AKI?
Furosemide
What are the 2 categories of substaging in IRIS CKD?
- Proteinuria (proteinuria, nonproteinuria, borderline)
2. Hypertension
What has been proven in dogs and cats to lower severity of proteinuria?
o Evidence of dietary therapy (n-3 polyunstaurated fatty acids (PUFA)) (Brown et al 1998), and ACE-I in dogs and cats to lower UPC, glomerular filtration pressures, and limiting structural changes in kidneys, and/or slow the decline in GFR
§ Benefit of diet (n-3 PUFA supplementation, and Protein, Na, Phos restrictions): Jacob et al 2002 for dogs and Elliott et al 2000 and Plantinga et al 2005 for cats = Unable to determine precise factors that improved outcome (ie used commercial diets)
§ Benefit of ACE-I (Grauer et al 2000 and King et al 2006)
Name 4 organs that are most prone to end-organ damage from hypertension?
Organs most prone to damage from systemic hypertension: 1. Heart, 2. Kidney, 3. Brain, and 4. Eyes
What is the treatment goal for hypertension in CKD?
Goal: Reduce systolic BP < 160 mmHg to minimize risk of extrarenal end organ damage
Name the 4 stages of IRIS CKD in dogs.
Stage 1: < 1.4 mg/dl
Stage 2: 1.4-2 mg/dl
Stage 3: 2.1-5 mg/dl
Stage 4: >5 mg/dl
Name the 4 stages of IRIS CKD in cats.
Stage 1: < 1.6 mg/dl
Stage 2: 1.6-2.8 mg/dl
Stage 3: 2.9-5 mg/dl
Stage 4: >5 mg/dl
Name the ranges of proteinuria for IRIS CKD
Based on UPC Nonproteinuria (NP) = < 0.2 (dogs and cats) Borderline proteinuria (BP): 0.2-0.4 (cats), 0.2-0.5 (dogs) Proteinuria (P): > 0.4 (cats), > 0.5 (dogs)
Name the ranges of hypertension for IRIS CKD.
Based on systolic BP Minimal Risk: < 150 mmHg Low Risk: 150-159 mmHg Moderate Risk: 160-170 mmHg High Risk: > 180 mmHg
What RBC parameter may indicate aluminum toxicity?
Microcytosis
What molecule is releases when iCa is low?
Hypocalcemia = ↑ PTH by posttranscriptional mechanism (parathyroid gland membrane Ca-sensing receptor to stabilize PTH ribonucleic acid)
What are the 3 main roles of PTH?
↑ PTH →
- ↑ Renal Ca reabsorption from ascending Loop of Henle, distal tubule, and collecting tubule
- ↑ Ca reabsorption from bone
- Enhancing formation of calcitriol (1,25-dihydroxycholecalciferol) from 25-hydroxycholecalciferol by kidneys
What are the main roles of calcitriol?
Calcitriol promotes ↑ Ca by:
1. Enhancing absorption of Ca from intestine
2. Facilitating PTH effects on bone (resulting ↑ Ca → ↓ PTH)
® Independent of Ca: Calcitriol inhibits synthesis and storage of PTH by activating Vitamin D receptors (VDR) → ↓ PTH gene transcription
How does calcitriol affect PTH?
Independent of Ca: Calcitriol inhibits synthesis and storage of PTH by activating Vitamin D receptors (VDR) → ↓ PTH gene transcription
How do levels of phosphorus influence intestinal Ca and Phos absorption via renal calcitriol production?
® Levels of phos influence intestinal Ca and Phos absorption via renal calcitriol production
® ↑ Phosphorus (hyperphosphatemia) inhibits renal 1-a hydroxylase activity (renal conversion of 25-hydroxycholecalciferol to calcitriol (active form of Vit D))
® ↓ Calcitriol → Phos retention and hyperphosphatemia which ↓ phos intestinal absorption
® If ↓ Phos = ↑ Calcitriol → ↑ Intestinal absorption of phosphate
What is the effect of PTH in the proximal tubules in relation to phosphorus?
PTH blocks proximal tubule from resorbing phos = phosphaturia
What is the inciting event in renal secondary hyperparathyroidism?
Inciting Event = Retention of Phosphorus dt ↓ renal excretion
What are the effects of hyperphosphatemia in development of renal secondayr hyperparathyroidism?
o Hyperphosphatemia → ↑ PTH (direct effects of phos on parathyroid gland and ↓ renal production of calcitriol by inhibiting renal 1-a hydroxylase activity
o Hyperphosphatemia may also complex with iCa (thus ↓ iCa) = leading to further ↑ PTH
§ ↑ PTH → phosphaturia (phosphate in serum to normal range)
· Secondary hyperparathyroidism long term is the “trade off” for short term serum control of Phos levels
o As renal dz progresses, capacity to prevent hyperphosphatemia is insufficient and loss of nephrons means less calcitriol produced
What is the “trade - off” hypothesis of renal secondary hyperparathyroidism?
Secondary hyperparathyroidism long term is the “trade off” for short term serum control of Phos levels
o As renal dz progresses, capacity to prevent hyperphosphatemia is insufficient and loss of nephrons means less calcitriol produced
§ Persistent calcitriol deficiency may cause parathyroid gland hyperplasia and hypertrophy with sustained automonous PTH secretion (tertiary hyperparathyroidism) = Resistant to conventional medical interventions (may need surgical reduction in renal mass to normalize PTH levels)
§ Thus need to maintain calcitriol in CKD to prevent tertiary hyperparathyroidism, since calcitriol is antiproliferative effects, ↓ PTH gene transcription, and represses parathyroid cell proliferation
What are the 3 main goals of managing divalent ion disorders in CKD?
- ↓ Hyperphosphatemia and mechanisms underlying phosphate rentention
- Restore adequate levels of active Vitamin D (calcitriol)
- Normalize serum Ca
What are 3 treatment options for managing divalent ion disorders in CKD?
- ↓ Dietary Phosphorus (serum phos < 6 mg/dl; ideal 4.5-5.5 mg/dl)
§ CKD diet have 75% less phos = helps to ↓ or normalize PTH levels in most patients with CKD Stage II and many patients with CKD Stage III (diet alone is not sufficient for Stage IV)- Intestinal phosphate binders (Aluminum, Ca, lanthanum): Bind irreversibly to phosphate in intestinal lumen, bound phosphate nonabsorbale, cations are released and may be absorbed
§ Sevelamer hydrochloride (Renagel): Polymer that does not release cations, very expensive and not more effective - Calcitriol (once serum phos < 6 mg/dl)
§ Since Calcitriol ↑ intestinal absorption of BOTH Ca and phos, failure to correct hyperphosphatemia prior can result in an ↑ Ca x Phos product = soft tissue mineralization
- Intestinal phosphate binders (Aluminum, Ca, lanthanum): Bind irreversibly to phosphate in intestinal lumen, bound phosphate nonabsorbale, cations are released and may be absorbed
Why is it important to ensure that phosphorus is normal (<6 mg/dl) prior to calcitriol treatment?
Since Calcitriol ↑ intestinal absorption of BOTH Ca and phos, failure to correct hyperphosphatemia prior can result in an ↑ Ca x Phos product = soft tissue mineralization
What are the main benefits of calcitriol treatment in CKD?
· Enhanced survival, appetite, activity, alertness, and interactivity with owners
o Improved survival in dogs with Stage III and IV (Polzin et al 2005); unknown in cats
o Failed to confirm benefit of reducing CS of CKD (hard since studies performed in animals with stable disease that were not showing overt CS and phos aggressively managed thus less hyperparathyroidism)
· ↓ PTH secretion
· Systemic Role in direct activation of VDR (humans, Vit D promotes longer survival independent of Ca, Phos, or PTH)
o Dog studies showed little effect of calcitriol on survival and differences in Serum Phos, Ca, PTH levels
o Humans: Paricalcitol (selective activator of VDR), more efficacy to side-effect profile, less morbidity, and better survival
When is calcitriol indicated in dogs and cats with CKD?
· Randomized controlled clinical trial – Calcitriol prolonged survival and forestall development of uremic crises with Stage III and early Stage IV
o Rate of progression of CKD was slower in animals getting calcitriol = renoprotective effect (same effects seen in humans)
· Calcitriol INDICATED in dogs with Stage III and early Stage IV
o Should be started even if PTH is not high (hard to manage hyperparathyroidism thus early intervention or prophylaxis)
o Unknown values in dogs with Stage I and II
Cats with CKD
· Insufficient data (1 yr randomized, controlled study for Stage II, III, IV failed to show clinical benefit of calcitriol in cats with CKD
What is the problem long-term with calcitriol and hyperparathyroidism?
o Long term hyperparathyroidism with parathyroid hyperplasia = deficiency of VDR on hyperplasic parathyroid cells = hyperparathyroidism that is refractory to calcitriol
· Calcitriol can induce formation of VDR on parathyroid cells, thus if long standing deficiency consider a prolonged calcitriol course or “pulse” therapy
What are the effects of calcitriol on the parathyroid gland and GIT during supplementation?
May induce formation of greater numbers of VDR on parathyroid cells, making gland more responsive to action of calcitriol, may also minimize likelihood of inducing hypercalcemia (promoting intestinal Ca absorption) o Actions on newly formed intestinal cells leaving Crypts of Lieberkuhn (ability of cells to absorb Ca dependent on exposure to calcitriol during development)
o Calcitriol has short T1/2 (4-6 hrs), thus less frequency administration means that less cells are exposed to calcitriol and thus less are primed to enhance Ca absorption
What is a potential complication of calcitriol supplementation?
Hypercalcemia
What are contraindications for calcitriol suppplementation?
hyperphosphatemia, hypercalcemia, ↑ Ca x Phos product
What type of product is used in humans in substitute of calcitriol?
Selective VDR activators: paricalcitol (Zemplar) and doxercalciferol = less changes in Ca and phos levels with adequate control of hyperparathyroidism (No reports in dogs or cats)
What monitoring is required during calciltriol treatment and what are the main goals of treatment?
· Serum Ca, iCa, phos, and PTH levels MUST be monitored (check q2-4 weeks until dose is stable), then recheck q3-6 months
· Goal of Therapy: Maintain serum phos, Ca, and PTH levels within normal limits
Describe the mechanism of development of renal secondary hyperparathyroidism in CKD?
Reduced in GFR initiates development of hyperparathryoidism by promoting phosphorus retenion and hyperphosphatemia
Phosphorus retention suppressess the renal enzyme (1-alpha hydroxylase) - conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (calcitriol) = Most active form of Vitamin D
Calcitriol deficiency, hypocalcemia, and hyperphosphatemia = contribute to development of hyperparathyroidism and parathyroid gland hyperplasia
What are the 2 types of hemodialysis?
Intermittent hemodialysis (IHD) and Continuous Renal Replacement Therapy (CRRT)
What is the general principle behind dialysis?
· Removes uremic toxins from blood by diffusion
· Blood from patient carried in disposable tubing (extracorporeal circuit) → Dialyzer (artificial kidney) with porous membrane (Size and charge are major determinants of which particles are filtered) → Blood returned to patient
o Small to middle sized molecules (urea and Crt) diffuse through pores into dialysate solution on other side
o Large molecules (albumin and cells) remain in blood
Why do you need to monitor for hypocalcemia during dialysis?
· Citrate via CRI into extracorporeal circuit to bind calcium to prevent coagulation in circuit (thus need to give CaCl centrally in patient to avoid hypocalcemia, also need to check blood Ca to adjust both doses)
o Citrate CONTRAINDICATED with hepatic dysfunction
What are the main indications for dialysis?
· Most common = ARF (Goal of ACUTE dialysis: Resolve life threatening disorders (hyperkalemia, pulmonary edema), control uremia (↓ uremic complications), allowing time for renal repair
o Leptosporsis, bacterial pyelonephritis, toxic nephropathy (ethylene glycol, lily ingestion, grapes/raisins, aminoglycosides), renal ischemia, ureteral obstruction (to tx acute uremia syndrome prior to sx; 1-3tx before sx or 2-4 tx prior to renal transplantation)
· CHRONIC Dialysis: Control CS associated with CKD for the rest of patient’s life
What is the indication for dialysis with certain drugs/toxins?
· Certain drugs and toxins can be removed (low MW with little protein binding are readily removed)
o IDH with charcoal perfusion cartridge in series with dialyzer (filters blood across microencapsulated charcoal beads to absorb toxic compound)
o Consider that doses of medications may need to be adjusted since they will also be lowered
What is therapeutic plasmaphersis?
Therapeutic plasmapheresis (plasmapheresis cartridge = large pores to allow removal of albumin and globulins to separate plasma from cellular components)
Name 4 events that would initiate dialysis?
· Anuria or oliguria that does NOT respond to volume expansion and diuretics
o Volume overload (pulmonary edema or pleural effusion dt inappropriate urine output relative to IVF rate)
· Hyperkalemia (start medical management with insulin, dextrose, bicarb, Ca) – Rapid removal of K with IHD
· Severe uremia (BUN> 100 mg/dl, Crt <> 10 mg/dl) or uremia that does not respond to medical management in the first 24 hours
o Humans: Earlier dialysis started in renal failure improves outcome and likelihood of return of renal function
· For CKD: Failure of medical management to control CS of uremia (anorexia, lethargic, vomiting) – Need to place feeding tube
· For toxins: Start ASAP (ex: Antifreeze, get dose of 4-methylpyrazole (dogs) and ethanol (Cats) to slow the metabolism of ethylene glycol
Compared and contrast the different treatment protocols for dialysis?
· IHD: Efficient method of solute removal = Good for ARF, CKD, acute toxicities, and fluid removal
o Severe uremia (rapid ↓ urea can lead to untoward effects, first few IHD tx are short, 3-7 short daily tx to gain gradual control, followed by 4-5 hr duration tx 3 times/week, performed until patient regains renal function)
o If severe uremia in unstable patient (first tx long 6-> 24hrs with slow blood flow to gradually control uremia to reduce complications = slow low-efficiency dialysis)
· CRRT: Good for ARF and fluid removal (applied for short duration)
o Blood flow 2-3 ml/kg/min compared to IHD 5-20 mk/kg/min and slow dialysate flow rate (8-34 ml/min compared to 500 ml/min in IHD): Net fluid removal rate based on patient’s hydration (solute cleranace, 0-35ml/kg/min)
o Clinical improvement (increased urine putput, etc) may prompt decreased blood or dialystae flow rate to wean patient off of CRRT
What is dialysis disequilibrium syndrome?
Rapid decline in blood osmolality caused by removal of solutes (esp urea) by dialysis · Results in the osmoles are removed from the blood faster than diffuse from the intracellular compartment = intracellular hyperosmolaity = cellular swelling (leading to CNS signs like seizures and mentation changes)
· Higher Risk with: Severe Azotemia, Smaller Blood Volume, preexisiting neurologic signs
· Thus use: Slow, low-efficiency dialysis or CRRT to lower the likelihood of this complication
What is the outcome with Dialysis in AKI?
· 40-60% patients with ARF treated with dialysis survive (depending on the etiology)
o Infectious causes of ARF: 60-70% survival rate
o Hemodynamic and metabolic causes: 40-56% survival rate
o Toxic Causes (ethylene glycol): 20-30% survival rate
· Extends time to allow for renal repair and recovery
o Can take 4 weeks to 3-6 months after renal injury
What at the 3 major infectious dz that you should be concerned about in cats undergoing renal transplantation screening?
- FeLV
- FIV
- Toxoplasmosis
Concern since patient will need to undergo immunosupression
When a patient with CKD has a creat < 6 mg/dl is renal transplanation recommended?
If moderate azotemia (Crt < 6 mg/dl) consider medial management (G-tube, fluids, dietary, EPO) – survival times parallel renal transplant survival times in these patients
Is tissue typing performed in feline renal transplantation?
No!
Screening (FeLV, FIV, IgG/IgM Toxo titers, imaging of kidneys, blood type)
What would need to be be screened to prevent allograft rejection in canine renal transplanations?
Dog Lymphocyte Antigen (DLA)
What post-op problem is seen commonly in dogs after renal transplanatation?
Enteroplication in DOGS: High incidence in dogs of intussuspection follow allograft implantation, also helps to administer opioids pre-op and intra-op (NOT needed in cats)
What is the mainstay drug for immunosupression to prevent allograft rejection in renal transplanation?
Cyclosporine: Calcineurin inhibitor with specific anti-T cell activity
Ketoconazole can be added to dose reduce the cyclosporine
What is the overall outcome of feline renal transplantation?
· 80% cats survive perioperative period and discharged; 60% survive to 6 months after sx (Adin et al 2001)
· 42% cats remaining alive at 3 yrs
· Overall median survival 22 months (Matthews and Gregory, 1997)
o Median Crt 8 mg/dl and medical options exhausted
o Improves QOL and duration but not to normal cats lifespan
· Harder to predict in dogs, small number of transplants performed and variation in drugs used
o Survival in experimental dogs exceeds those with naturally occurring renal dz
§ Only about 50% dogs survive first 2 months after kidney transplantation, high rate of opportunistic infections may occur in patients with long term survival (Gregory et al 2006)
What percentage of patients with CKD will have feeding tube stoma site complications?
stoma site complications in 46% dogs (may be dt impaired immune function, increased susceptibility to infection, delayed wound healing dt malnutrition and/or uremia)
What percentage of patients will remove their own G-tube?
20% dogs will remove their own G-tubes (Elliott et al 2000) = ER situation, peritonitis, new tube needs to be placed ASAP
If tube in for < 7 days, check with radiographic contrast leakage, may need laparotomy
How many dogs and cats get hypertension related to CKD and what is the mechanism?
Hypertension in 19.4% felines and 61% canine with renal dz (exact cause unknown – interactions btwn heart, kidney, endothelial signaling, and autonomic NS)
How are the eyes, kidneys, heart, and brain affected by hypertension?
o Hypertensive retinopathy/choroidopathy: Retinal edema, tortuous vessels, hemorrhage, retinal detachment (cats come in for acute blindness)
o Some cats, hypertension will precede azotemia with early CKD
o Murmur, arrhythmia, gallop rhythm secondary to hypertension = cardiac muscle hypertrophy
o Hypertensive encephalopathy: Head tilt, ataxia, depression, seizures (hypertension overwhelms cerebral vasculature autoregulatory mechanisms)
What is the initial drug of choice for hypertension in dogs?
ACEi
As long as there is no end-organ damage
What is the MOA of angiotensin-converting enzyme (ACE) inhibitor?
o Blocks conversion of Ang I to Ang II (powerful vasoconstrictor), systemic vasodilation when blocked
o Ang II directly promotes Na absorption in proximal tubules → IV Expansion
o Ang II stimulates aldosterone release = Na and water reabsoprtion
o Can worsen azotemia therefore check renal values (start at lowest possible dose)
What is the initial drug of choice for hypertension in cats?
Since 50% of cats failure to respond to ACEi = Calcium channel blockers (amlodipine)
What is the MOA of calcium channel blockers such as amlodipine?
o Blocking influx of Ca needed to cause smooth muscle contraction and thus ↓ systemic vascular resistance (amlodipine: long acting, q24 hr dosing, and gradual effect)
Why should calcium channel blockers such as amlodipine not be used as monotherapy in dogs?
§ Humans and dogs: Ca channel blockers may worsen renal dz (paradoxic effect that Ca Channel blockers preferentially dilate the afferent arteriole of glomerulus = glomerular hypertension)
· Therefore DO NOT use in dogs as monotherapy! (Same effect is NOT seen in cats)
§ Cats treated with amlodipine live longer and with fewer hypertensive complications (safe as monotherapy in cats)
What is a potential complication in cats with spironolactone?
Horrible facial excoriations
What are potential effects of spironolactone during hypertension?
May protect the heart, brain, and kidneys from effects of hypertension, may also help to reduce hypertensive-induced fibrosis of target organ Spironolactone: ↓ Na resorption and K excretion
How does the kidney result in increased preload that can contribute to hypertension?
By activating RAAS - Na resorption (water follows)
Name the mechanism of anemia in renal failure.
- Blood Loss, 2. RBC destruction, 3. Failure of bone marrow to produce RBCs
o Can have > 1 etiology in CKD (Normally = blood loss and lack of RBC production)