Renal tubular and glomerular diseases Flashcards
What percent of the ultra filtrate is reabsorbed in the proximal tubule?
60-65%
What percent of NaCl is absorbed in the loop of Henle?
30%
After passing through the loop of Henle, what is the osmolarity of the ultra filtrate compared to the plasma?
Hypoosmolar
What causes cystinuria?
Inherited proximal tubular defects, in which resorption of particular non-essential amino acids fails. Of the amino acids that are not resorbed, cystine is the most insoluble, resulting in the formation of cystic calculi in acidic urine
What dog breeds develop cystinuria due to an autosomal recessive mutation in the Slc3a1 gene?
Newfoundlands and Labrador Retrievers
What dogs breeds develop cystinuria due to an autosomal dominant mutation in Slc7a9?
Australian Cattle dogs
What is the mean age of calculus formation in dogs with cysteine stones?
Labs and Newfoundlands: can be as early as 4-6 months
All other breeds: 5 years
What other non-essential amino acid can be lost in the urine along with cysteine, and what are the clinical consequences?
Carnitine - chronic, excessive deficiency can lead to cardiomyopathy, especially DCM
What is hyperuricosuria?
Excessive secretion of uric acid, an intermediate product of protein metabolism, in the urine
Describe the normal breakdown of purines
Purine portions of nucleic acids are broken down into hypoxanthine and xanthine => oxidized to uric acid by xanthine oxidase
Uric acid => metabolized to allantoin (more soluble) by hepatic uricase
What breeds are affected with hyperuricosuria?
Dalmatians, English Bulldogs, Black Russian Terriers
Where is uric acid converted to allantoin?
Within the heptatocytes - uricase is stored in hepatic peroxisomes, so uric acid must be transported into hepatocytes before conversion to allantoin can occur
Why are Dalmatians unable to convert uric acid to allantoin?
Have abnormal uric acid transport across hepatic membranes. They express normal amounts of uricase, but can’t transport the uric acid into cells to access the enzyme
Apart from increased serum levels of uric acid, why do Dalmatians secrete more of it in the urine? What gene is responsible and how is it inherited?
Have less proximal tubular resorption that other breeds
Also have active distal tubular secretion of urates as a result of a membrane transport defect - mutation in Slc2a9 (gene that encodes for a transporter of uric acid) - autosomal recessive
What percent of male Dalmatians are clinically affected by Slc2a9 mutations?
25%
What gene mutation is responsible for hyperuricosuria in English Bulldogs and Black Russian Terriers?
Same as Dalmatians - mutations in Slc2a9
Why do dogs with hepatic disease develop hyperuricosuria?
Reduced conversion of uric acid to allantoin
Primary renal glucosuria has been reported in what breeds?
Scottish Terriers, Norwegian Elkhounds
What drug can rarely cause acquired Fanconi’s syndrome in cats?
Chlorambucil
The renal tubules regulate acid-base status through what two processes?
- Resorption of 80-90% of filtered HCO3- in the proximal renal tubule
- Excretion of acids by means of titration of urinary budders and excretion of ammonium in the distal renal tubule
Renal tubular acidosis leads to what form of acidosis?
Hyperchloremic metabolic acidosis
What occurs in type II renal tubular acidosis? What are the clinicopathologic changes and urinalysis changes?
Damage to the proximal tubule results in an inability of the proximal tubule to resorb HCO3-
- Moderate reductions in plasma HCO3-
- Urine pH during acidemia <6.0
- Mild hypokalemia
- Other defects of proximal tubule dysfunction noted
What occurs in type I renal tubular acidosis? What are the clinicopathologic changes and urinalysis changes?
Damage to the distal tubule results in an inability of the distal tubule to excrete H+
- Variable reductions in plasma HCO3-
- Urine pH during acidemia >6.0
- No other proximal tubule defects
- Mild to severe hypokalemia
What occurs in type IV renal tubular acidosis?
A type of distal RTA and hyperkalemia secondary to hypoaldosteronism or aldosterone deficiency
Why is metabolic acidosis less severe with proximal RTAs?
The distal tubule can still excrete acid to compensate
Why does the administration of sodium bicarbonate worsen potassium wasting in proximal RTAs?
The amount of HCO3- presented to the distal tubule increases, resulting in increased H+ secretion (and loss of potassium) - eventually the distal buffering system is overwhelmed, resulting in marked bicarbonaturia (>15% FE)
What is a better way to correct metabolic acidosis in proximal RTAs than using sodium bicarbonate?
Potassium citrate
How does the distal tubule secrete H+ ions?
Through a H+ ATPase pump
Also generates ammonia, which captures H+ ions in the tubule, leading to ammonium excretion
Why does hypoaldosteronism cause a distal RTA?
Aldosterone stimulates the H+ ATPase pump
What test can be used to confirm a distal RTA?
Ammonium chloride challenge test - give oral ammonium chloride and monitor urine pH hourly for 6 hours. Normal dogs should acidify their urine to a pH of 5.0
What is nephrogenic diabetes insipidus?
Any disorder in which the urinary concentrating mechanism is unable to respond to ADH to produce concentrated urine
Where is ADH produced, stored and why is it released?
Produced in the hypothalamus, stored in the posterior pituitary
Released in response to hyperosmolarity or hypovolemia
Name 5 causes of nephrogenic diabetes insipidus
- Toxins: E coli endotoxin
- Drugs: glucocorticoids, chemotherapeutics
- Metabolic conditions: hypokalemia, hypercalcemia
- Tubular injury or loss: renal cystic disease, pyelonephritis
- Alterations in the medullary concentration gradient: medullary washout
What is congenital nephrogenic diabetes insipidus?
Rare, inherited disease caused by a deficiency of ADH receptors in the tubules
What are the 3 layers of the filtration barrier in the glomerulus?
Fenestrated endothelium, glomerular basement membrane, and visceral epithelial cells (podocytes)
What are slit diaphragms?
Specialized cell junctions between podocytes and bridge the filtration slits
What size molecules freely pass through the glomerulus? What is the maximum size that can pass?
<5000 Daltons = freely filtered
Substances are retained with increasing efficiency as they increase in size to ~60,000 to 70,000 Daltons
How does ionic change influence filtration? Why?
- Negatively changed proteins are retained in the blood to a greater extent that would be predicted by size alone
- The podocyte foot processes, basement membrane, and endothelium all contain negative charged glycoproteins - creating a charge barrier
Renal azotemia with an intact concentrating ability in a dog should raise concerns for what disease process?
Glomerular disease - tubules are still intact to concentrate the urine
How are hyaline casts formed and why are they common with glomerular disease?
Proteinuria promotes the precipitation of Tamm-Horsfall mucoprotein, which envelops the protein in the tubular lumen into a hyaline cast. The purpose is to protect the renal tubular epithelium from damage due to protein
What glomerular disease is associated with the most severe clinical abnormalities (highest UPC, lowest albumin, higher incidence of nephrotic syndrome and hypertension)?
Membranoproliferative glomerulonephritis
What dog breed develops a familial form of membranoproliferative glomerulonephritis?
Bernese Mountain Dogs
What infection causes a rapidly progressive form of membranoproliferative glomerulonephritis along with tubular necrosis and interstitial inflammation?
Borrelia burgdorferi
What are the histologic findings with membranoproliferative glomerulonephritis?
- Immune complex deposition on the sub endothelial side of the GBM
- Thickened capillary loops
- Mesangial hypercellularity with interposition of the mesangial cells between the basement membrane, causing a “railroad” appearance of the GBM
What is the pathogenesis of membranoproliferative glomerulonephritis
Deposition of immune complexes leads to cytokine-mediated complement activation, expansion of the mesangium, and inflow of leukocytes
Name 4 other infectious diseases that can cause membranoproliferative glomerulonephritis in dogs
- Leishmaniasis
- Babesiosis
- Dirofilariasis
- Heterobilharzia
What does immunofluorescence of TEM reveal with membranoproliferative glomerulonephritis?
Granular deposits of C3 combined with IgG, IgA, or IgM
How is membranoproliferative glomerulonephritis or membranous nephropathy treated?
- Manage underlying infectious/inflammatory/neoplastic diseases that are causing immune complex formation
- Immunosuppression for severe, persistent, or progressive disease
- Antiplatelet drugs
- Treat proteinuria
What is the most common glomerular disease in cats?
Membranous nephropathy
Describe the pathogenesis of membranous nephropathy
- Immune complexes are deposited on the subepithelial side of the glomerulus
- Causes less complement activation, less cytokines response, and less inflammation (away from circulation)
What are the histopathologic findings with membranous nephropathy?
- Uniform thickening and increased rigidity of the basement membrane
- Immune deposits look like “spikes” or “beads” on the outside of the basement membrane using silver staining
Describe the pathogenesis of proliferative glomerulonephritis
- Endocapillary or mesangial proliferation occurs due to a type III hypersensitivity
- IgG/IgM antibodies bind to antigens and the immune complexes are deposited within the glomerular basement membrane
- Activates the complement system and the membrane attack complex forms, damaging the podocytes and mesangial cells
- Inflammatory cells are then recruited
What are 3 known causes of proliferative glomerulonephritis in dogs?
- Leishmaniasis
- Canine adenovirus type 1
- Systemic lupus erythematosus
What is the pathogenesis of immunoglobulin A nephropathy?
Immune deposits consisting of IgA are trapped in the mesangium, leading to mesangial proliferation
Dogs with what types of diseases had the highest prevalence of IgA deposition?
Enteric or hepatic disease - IgA complexes are thought to be excessively formed in GI disease and not cleared appropriately in hepatic disease
Describe the pathogenesis of minimal change disease
- Increased production of cytokines by dysfunctional T cells leads to effacement of podocyte foot processes
- This leads to a loss of anionic charge in the glomerular capillary wall and increase in permeability
- Small proteins, like albumin, that were prevented from passing through due to their negative charge now are lost in the urine
What are the histopathologic changes with minimal change disease?
- TEM required - no lesions under light microscopy
- Marked podocyte food process effacement on TEM
What is the treatment for minimal change disease?
Responds very well to corticosteroids
What is glomerulosclerosis?
- General term for scarring or hardening of the glomeruli
- Can develop as an end stage lesion in response to glomerular injury
- Can develop after hypertensive renal damage
What is focal segmental glomerulosclerosis (FSGS)?
Glomerulosclerosis where only part of the glomerulus and only some of the glomeruli in that section are affected
What is the pathogenesis of FSGS?
- The foot processes of the podocytes become damaged, leading to increased filtration of plasma proteins and lipids
- Some of these proteins and lipids become trapped in the tissue and build up within the glomeruli
- Leads to hyalinosis and scar tissue formation
What changes can be induced by chronic proteinuria?
Interstitial fibrosis, tubular degeneration and atrophy, peritubular capillary rarefaction
How do ACEi decrease proteinuria?
- Decrease efferent glomerular arteriolar resistance => decreased glomerular hydrostatic pressure => decreased proteinuria
What should the goal of using ACEi to treat proteinuria be?
Ideally decreased UPC <0.5, but a 50% reduction in proteinuria is more realistic
If azotemia worsens by what percent, ACEi should be dose reduced or discontinued?
> 30%
In dogs where renal biopsy is not performed, when should immunosuppressive drugs be considered?
- Proteinuria is clearly glomerular in origin
- Dog breed/age are not consistent with familial nephropathy and amyloidosis is considered unlikely
- Creatinine >3 or albumin <2
If immunosuppressive therapy is used, when should response be monitored?
After 8-12 weeks, check UPC - if no response, consider switching drugs
After 3-4 months, if no response is noted, consider discontinuing therapy (especially if no renal biopsy was done) - monitor for worsening proteinuria or azotemia while tapering drugs
Dogs with stable glomerular disease and IRIS stage I or 2 CKD should be evaluated how many days after changing therapy? Dogs with unstable disease or IRIS stage 3 or 4?
Stable: 3-14 days
Unstable: 3-5 days
If therapy is not changed and the dog is stable, how frequently should UPC, urinalysis, body weight, blood pressure, and a chemistry panel be monitored?
Every 3 months
How can hyperlipidemia lead to glomerular lesions?
- LDL may after mesangial cell function and increase the synthesis of mesangial matrix, thereby accelerating glomerulosclerosis
- Glomerular and tubulointerstitial lipoprotein deposition and lipoprotein induced cytotoxicity may also contribute
In a retrospective study of 209 proteinuric dogs, what percent tested positive for exposure to 1 or more VBD? What was the most common exposure?
34% positive
- 19% Rickettsia exposure
- 12% Ehrlichia exposure
- 9% Lyme exposure
Compared to control dogs, dogs with PLN had what changes in serum amino acids?
Overall decrease in both essential and non-essential amino acids
- Lower tyrosine to phenylalanine ratio
- Lower glycine to serine ratio
- Greater valine to glycine ratio
Compared to healthy dogs, with PLN and minimal to no azotemia had what changes in vitamin D metabolites?
Decreases in all vitamin D metabolites
- Calcidiol and 24,25(OH)2D concentrations were positive correlated with albumin
- Urine calcidiol:creatinine ratio was negative correlated with serum albumin and positive correlated with UPC
What percent of dogs with PLN (UPC >2) were hypercoagulable in the JVECC prospective study?
89%
In the JVECC study, what was hypercoagulability in PLN dogs correlated to?
Nothing - not correlated to albumin, AT activity, BP, UPC
Hypercoagulability cannot be predicted based on degree of proteinuria, hypertension, hypoalbuminemia, or low AT
In the JVECC study, what percent of PLN dogs developed thromboembolism?
6%
So high rate of hypercoagulability, low thrombus rate
In a retrospective review of biopsy samples submitted to the International Renal Pathology Service, FSGS accounted for what percent of cases?
26% of dogs biopsied for proteinuria
In a retrospective review of FSGS, what were the signalment and clinicopathologic findings of the dogs?
- Female (63%) > male
- Median creatinine 1.2
- Median UPC 5.9
- Median albumin 2.8
In a retrospective review of FSGS, what was the MST and what factors were associated with shorter survival?
- MST 258 days
- Creatinine >2.1 and Alb <2 correlated with shorter survival
Renal biopsy samples from Miniature Schnauzers with proteinuria and hypertriglyceridemia revealed what changes?
- Glomerular lipid thromboemboli
- FSGS
In a retrospective study of Miniature Schnauzers with hypertriglyceridemia and proteinuria what other clinicopathologic changes were noted?
None - not hypoalbuminemic, not azotemic, no decrease in AT, not hypertensive and these things did not develop over 18 months of monitoring
May be more similar to other endocrine causes of proteinuria rather than true FSGS
In a retrospective study evaluating renal biopsy specimens submitted to the European Renal Pathology Service, which diagnosis had higher proteinuria and worse hypoalbuminemia?
ICGN, in particular MPGN
What percent of geriatric, “healthy” dogs were proteinuric in a prospective study?
11% had UPC>0.5
14% had UPC >0.2 but <0.5
Of samples repeated one month later, 19% of these dogs were repeatedly proteinuric
No blood work or imaging done to rule out other causes of proteinuria
Are free catch urinalysis as accurate for detecting proteinuria as cystocentesis?
Yes as long as you are ruling out post-renal causes of proteinuria (shown in both dogs and cats)
PLN dogs testing positive for Borrelia had what clinicopathologic changes compared to negative PLN dogs?
More likely to be thrombocytopenic, azotemic, hyperphosphatemic, anemic, and neutrophilic
What were the histopathologic findings in PLN dogs that were positive for Borrelia vs those that were negative?
All dogs with Borrelia had ICGN compared to 30% of negative dogs
In dogs with UPC >4, proteinuria should be measured in what way?
3 samples - either averaged or pooled
More day to day variability exists in these dogs
In dogs with PLN, the fractional excretion of what markers correlated with glomerular damage?
IgM and IgG
In dogs with PLN, what was the sensitivity and specificity for urine IgM/creatinine and NAG/creatinine for detecting ICGN?
Sensitivity 75%
Specificity 78%
In dogs with PLN, what biomarkers correlated with survival time?
FE of IgM, creatinine, and glomerular damaged based on TEM
In a retrospective study, treatment with an ACEi combine with telmisartan reduced BP and UPC by what magnitude?
BP reduced by 13 mmHg
UPC reduced by 2.5
How does two weeks of treatment with Palladia affect BP?
BP increased from 136 to 152 mmHg
- 37% of dogs develop SBP >160 mmHg
In a prospective, randomized study comparing telmisartan vs enalapril, which drug caused a greater change in UPC at day 30, 60 and 90?
Telmisartan: -65% change in UPC
Enalapril: -35% change in UPC
In a prospective, randomized study, combination treatment with enalapril and telmisartan resulted in azotemia in what percent of dogs?
31%
Which receptor subtype does telmisartan inhibit? Why is this beneficial?
Inhibits angiotensin II subtype 1 receptor
What are the clinical effects of angiotensin II subtype 1 receptor?
Vasoconstriction, sodium retention, congestion, and remodeling
Essential the negative cardiovascular and renal effects - block this one
What are the clinical effects of angiotensin II subtype 2 receptor?
Vasodilation, natriuresis, diuresis, anti-remodeling
Good things
In a prospective, randomized study comparing telmisartan vs enalapril, telmisartan was how many times more likely to achieve a decrease of >50% UPC by 30 days?
6.9 times more likely
In a prospective, randomized study comparing telmisartan vs enalapril, which drug led to a greater decrease in systolic BP?
Telmisartan - no animals became hypotensive though
Soft Coated Wheaten Terriers with PLE often have what change on intestinal biopsies?
Lipogranulomatous lymphangitis (35%)
Soft Coated Wheaten Terriers with combined PLE/PLN tend to have what change compared to PLN only dogs?
Higher UPC
What causes PLN in Soft Coated Wheaten Terriers?
Genetic mutation leading to a podocytopathy that then leads to the development of lesions resembling FSGS
What percent of proteinuric cats have ICGN?
74%
What was the MST for cats with PLN? What improved the MST for cats with ICGN?
94 days
ICGN treated with immunosuppressives did better: MST 244 days vs 17 days
What was the average age of cats with proteinuria?
ICGN 3.5 years
Other causes 1.3 years
What is osmotic nephrosis?
Intracytoplasmic vacuolization and swelling of the renal proximal tubular cells that occurs following administration of hyperosmolar agents
Administration of what agent resulted in osmotic nephrosis in critically ill dogs? How did dose correlate with severity?
6% HES - cumulative dose was predictive of severity and for every 1mL/kg increase dose, there was a 1.6% increase change of osmotic nephrosis
What percent of dogs with gallbladder mucoceles displayed proteinuria?
50%
In a retrospective study on the use of telmisartan in PLN dogs, what percent of dogs achieved a UPC <0.5 or a 50% reduction in UPC?
70-80%
CKD results in maladaptive compensatory responses of the surviving nephrons that can induce glomerular changes. What is the magnitude of proteinuria in these cases?
Mild to moderate
How is benazepril eliminated from the body compared to enalapril?
Benazepril - primarily biliary excretion
Enalapril - primarily renal excretion
So for dogs in stage 3 or 4 CKD, may need to dose reduce enalapril
In people treated with maximal doses of an ACEi or ARB, what hormone increases over time?
Aldosterone (aldosterone escape)
In human patients with aldosterone escape, proteinuria and kidney function can improve after treatment with what drug?
Aldosterone receptor blockers (spironolactone)
Treatment with ACEi or ARB should be modified if the potassium concentration is over what?
> 6.5 mmol/L
- Dose reduce drug
- Feed reduced potassium diet
- Use intestinal potassium binders (kayexelate)
In dogs with stage I and II CKD, the dose of an ACEi or ARB should be reduced if creatinine increases by what percent? In stage III and IV dogs?
Stages I and II: >30% increase in creatinine
Stage III and IV: no increase is ok - maintain stable renal function
If the target reduction in UPC is not achieved and there are no adverse effects, the dose of an ACEi can be increased by what amount in what time frame?
Increase by 0.5mg/kg q12 every 4-6 weeks
If a dose of 2mg/kg/day is reached, switch to or add ARB
In dogs with glomerular disease, dietary supplementation with n-3 polyunsaturated fatty acids did what?
Altered the course of renal injury and magnitude of proteinuria
Supplementation with n-3 polyunsaturated fatty acids is recommended for dogs with PLN. What should the n-6/n-3 ratio be?
5:1
When n-3 PUFS supplementation is used for PLN dogs, what is the recommended dose?
0.25-0.5 g/kg containing EHA and DHA
What should the protein and sodium content of food fed to PLN dogs be?
Moderate protein, reduced sodium
What is the mechanisms of action of amlodipine and how does it affect the kidney?
Blocks L-type calcium channels and results in preferential dilation of the afferent arteriole
According to the consensus statement, what is the most compelling evidence on histology for active, immune mediated mechanisms of glomerular injury?
- Electron microscopy: identification of electron-dense deposits in the glomerulus
- IFA: positive immunofluorescent staining for IgG, IgM, IgA, light chains and/or complement in an immune complex or antiglomerular basement membrane pattern
Per the consensus statement, diseases associated with high magnitude proteinuria, hypoalbuminemia, nephrotic syndrome, or rapidly progressive azotemia should be treated with what?
Rapidly acting immunosuppressive drugs (single drug or combination)
What is the mechanism of action of mycophenolate?
Inhibits inosine monophosphate dehydrogenase - the rate limiting enzyme in the de novo synthesis of guanosine nucleotides
Inhibits both T and B cell proliferation, which is dependent on synthesis of purines
What is the mechanism of action of cyclosporine?
Binds to the cytosolic protein cyclophilin. The cyclosporine-cyclophilin complex then inhibits calcineurin, which is essential for the transcription of IL-2 and the IL-2 activation of T lymphocytes
What immunosuppressive agent does the consensus statement recommend as first line for dogs with stable, slowly progressive disease? Which is not recommended?
Mycophenolate - recommended first, but chlorambucil, cyclophosphamide may also be used
Cyclosporine - not recommended - no effectiveness in a controlled clinical trial of patients with GN
What is the mechanism of action of cyclophosphamide and what are side effects?
Alkylating agent that interferes with DNA replication, RNA transcription and replication - affects most mitotically active cells
GI signs, myelosuppression, hemorrhagic cystitis
What is the mechanism of action of azathioprine?
Purine analog that interferes with normal cell DNA and RNA synthesis - affects all lymphocytes
How long does azathioprine take to become fully effective in dogs?
2-5 weeks
Which immunosuppressive drugs does the consensus statement recommend for peracute, rapidly progressive disease?
Mycophenolate +/- prednisone
Cyclophosphamide +/- prednisone
When should dogs be re-assessed after starting treatment with immunosuppressive drugs?
1-2 weeks after initiation of treatment, then every 2 weeks for the first 4-6 weeks
If they are stable, then every 4 weeks for the next 3 months, then quarterly
At low UPC values, a change of what percent is required to demonstrate a significant difference in UPC? At high values?
Low values: 80%
High values: 35%
When evaluating creatinine after immunosuppressive therapy, what is a complete response? A partial response? Therapeutic failure?
- Complete response: reduction in creatinine to <1.4 mg/dL or the patient’s last known creatinine before the onset of GN
- Partial response: sustained reduction in creatinine by >25%
- Failure: reduction <25%
When evaluating albumin after immunosuppressive therapy, what is a complete response? A partial response? Therapeutic failure?
- Complete response: increase in albumin to >2.5 g/dL
- Partial response: increase in albumin to 2.0-2.5 g/dL or an increase of 50% from baseline
- Failure: albumin <2 or less than 50% increase
How long should immunosuppressive therapy be tried, if it is well tolerated?
At least 8 weeks for a rapidly acting agent (mycophenolate) or 8-12 weeks for a slowly acting drug
- If no response consider switching drugs or dosing
- If no response after 3-4 months, consider discontinuing immunosuppression
If dogs respond to immunosuppressive therapy, how long should it be continued prior to tapering the treatment?
12-16 weeks minimum
