1
Q
What is Fabry disease?
A
X-linked (disease mainly in males), little/no functional alpha-galactosidase A enzyme actvity causing glycolipid accumulation (globotriaosylceramide ie. G3b) -> disease
2
Q
What are the clinical manifestations of Fabry’s?
A
- Corneal opacities
- Infiltrative cardiac disease, concentric LVH, aortic and mitral valve abN, conduction abN, CAD
- Cerebrovascular/stroke
- Acroparesthesias (neuropathic, limb pain)
- Telangiectasis and angiokeratomas, thickening of the lips and bulbous nose
- Heat/cold/exercise intolerance, hypo or hyperhidrosis
- GI sx
- Renal disease
3
Q
What are the specific renal manifestations of Fabry’s and renal pathologic findings?
A
- Renal manifestations:
- Earliest: Distal tubules affected → decreased urinary concentrating ability -> polyuria
- Proximal tubules affected → Fanconi
- Mild-moderate proteinuria
- +/- microscopic hematuria (early adulthood)
- Gradual decline in GFR to ESRD in 4 th and 5 th decade (in affected males, less common in women)
- Renal sinus and parapelvic cysts
- Renal biopsy:
- LM: vacuolization of podocytes + distal tubular epithelial cells (AKA glycolipid accummulation), renal arteries/arterioles show smooth muscle cell Gb3 accummulation and degenerative changes, IFTA
- EM: Gb3 deposits within lysosomes as lamellated membrane structures called myeloid or zebra bodies
4
Q
How do you diagnose Fabry’s?
A
- In all males: leukocyte alpha-galactosidase A (alpha-Gal A) activity
- <3% - diagnostic -> procedwith genetic
- 3-35% - genetic test
- >35% - cannot establish dx
- In females: genetic mutational analysis of the GLA gene as the initial diagnostic assay is required
- alpha-Gal A activity level is unreliable in heterozygotes
5
Q
What are the mechanisms of increased Cr without affecting GFR?
What drugs can do this?
A
- Mechanisms
- Decreased creatinine secretion
- Septra, Cimetidine, Salicylates, Dronedarone
- Interference with assay
- Flucytosine, Cefoxitin
- Increased production of creatinine
- Fenofibrates
- Decreased creatinine secretion
6
Q
5 NON-renal/PD related causes of elevated urea?
A
GI bleeding
High protein intake
Hyperthyroidism
Steroids
Loss of residual renal function
7
Q
cysts required for PKD in those with FHx
A
- Age 15-39: 3 uni or bilat (1.5 each)
- Age 40-59: 2 bilat
- Age >60: >=4 bilat
8
Q
Intracranial aneurysms in ADPKD incidence?
Who to screen?
A
- ~10%
- Screen those with:
- FHx intracranial aneurysm
- High risk occupation (eg. bus drivers)
- Before major surgery
- Require anticoagulation
- Symptoms
- Screen with MRA
9
Q
How can someone have ADPKD without family history?
A
- De novo mutation (5%)
- Undiagnosed family (died or living without detection)
- Misdiagnosed family
- Paternity issue
10
Q
Frequency of PKD1 and PKD2 and differences
A
PKD1 about 80%, PKD2 15%
PKD1 earlier age onset of HTN and renal disease/failure (FHx ESKD age <55 highly predictive)
PKD2 later age onset of HTN and renal disease (FHx no ESKD age >70 highly predictive)
11
Q
Extra-renal manifestations of ADPKD?
A
- Polycystic liver disease
- Intracranial aneurysms
- Cardiac disease - valvular lesions, MV prolapse
- Pancreatic cysts, seminal vesicles and ovarian cysts
- Hernias, GI diverticuli
12
Q
ADPKD vs. simple cysts?
A
- +FHx with cyst # criteria
- No FHx and >10 cysts in each kidney
- Extrarenal cysts
- Impaired GFR
- HTN
- Impaired urinary concentrating ability
13
Q
What is medullary sponge kidney?
A
Congenital disorder characterized by malformation of the terminal collecting ducts in the pericalyceal region of the renal pyramids -> develop medullary “cysts” that are often diffuse but do not involve the cortex.
Can be autosomal dominant but not always, can be variable.
14
Q
Clinical manifestations of medullary sponge kidney?
A
- Cystic kidney disease
- Recurrent stones (calcium oxalate, calcium phosphate)
- Due to stasis in ectatic collecing ducts and “cysts”
- ?Impaired calcium reabsorption in the damaged collecting tubules
- dRTA -> hypocitraturia
- Decreased concentrating ability - polyuria
- Hematuria - gross or microscopic
- UTIs
- dRTA
- Decreased bone mineral density
15
Q
What do you see on 24 hr urine studies for medually sponge kidney?
A
Low urine citrate and high urine calcium excretion rate
16
Q
fHow is medullary sponge kidney diagnosed?
A
- IV pyelography or CT urography shows pooling of radiocontrast leading to calyceal “brush”-like appearance, with either nephrocalcinosis or stones
17
Q
Management of medullary sponge kidney
A
- Non-pharm general stone management
- Pharm: K citrate, thiazides
- Monitor kidney function annually in those with kidney stones
18
Q
3 urinary or structural abnormalities of medullary sponge kidney?
A
Cystic kidney disease (involving medulla only)
Nephrocalcinosis, recurrent kidney stones (ca oxalate, ca phosphate)
dRTA
24 hr urine: low citrate and high urine calcium excretion rate
19
Q
What is cystinuria and how do cystine stones form?
A
- Cystinuria is an autosomal disorder (dominant or recessive; incomplete penetrance) that causes a tubular defect in dibasic amino acid transport, resulting in increased cystine excretion.
- Impaired renal cystine transport -> decreased proximal tubular reabsorption of filtered cystine -> increased urinary cystine excretion and cystine stones.
- Cystine is poorly soluble -> stones
20
Q
What do cystine stones look like under microscopy?
A
Hexagonal
21
Q
How do you investigate and diagnose cystinuria?
A
- Cyanide nitroprusside screen (purple=positive)
- If positive screen, 24-hour urinary excretion of cystine (also check for other stones calcium, oxalate, phosphate, citrate, magnesium, uric acid)
- Normal excretion = 30mg/day (0.13 mmol/day)
- Cystinuria = >400 mg/day (1.7 mcol/day)
22
Q
Management of cystine stones?
A
- High fluid intake to maintain urine cystine concentration < 1mmol/L (<250 mg/L) at pH 7
- Need 24-hr urine cystine excretion information to determine how much volume of urine. Eg. if cystine excretion 3.1 mmol/day, need urine volume >3L/day.
- Low Na diet (reduce urine cystine excretion)
- Urine alkalinization (increase solubility of cystine) - target urine pH >7
- Higher alkali diet (fruits, vegetables)
- Potassium citrate
- ?Low animal protein intake (little evidence but reducing animal protein intake may help by increasing urine pH)
- Thiol-containing drug if conservative measures fail (tiopronin, penicillamine)
23
Q
Meds that can cause kidney stones?
A
- Calcium stones (hypercalciuria)
- Loop diuretics (calciuric)
- Calcium supplements
- Vitamin D
- Uric acid stones (hyperuricosuria/proximal)
- Salicylates
- Probenacid
- Acetazolamide
- Meds that precipitate into stones
- Acyclovir (rapid infusion)
- Indinavir
- Methotrexate
- Triamterene
24
Q
Loin pain hematuria syndrome - what is it and how does it happen?
A
Benign condition, presents in young and middle-aged women with loin pain and microscopic glomerular hematuria
Thought to be due to rupture of GBM leading to bleeding into renal tubules -> tubular obstruction -> renal parenchyma edema -> renal capsule stretch and pain
25
Diagnosis of loin pain hematuria syndrome
Diagnosis of exclusion
Primary vs. secondary made by kidney biopsy (primary - NORMAL GBM with some RBCs in tubules or casts, vs. secondary may be IgA, thin basement membrane, etc.)
26
Treatment of loin pain hematuria syndrome
1. Rule out kidney stone disease, UTIs
2. Reassurance
3. ACE inhibition (may reduce intraglomerular pressure and pain)
4. Assess for risk of kidney stones - 24-hour urine collection for calcium, uric acid, oxalate, citrate, sodium, and creatinine (to estimate the completeness of the urine collection)
5. Pain control (avoid opioids)
27
Stones and crystal findings on urine microscopy:
Calcium oxalate
Calcium phosphate
Urate
Cysteine
Struvite
* Calcium oxalate:
* envelope (dihydate) or dumbbell (monohydrate)
* Calcium phosphate:
* Flat shaped or wedge-shaped prisms; prisms often in **rosette/star-like**
* Urate:
* Needle shaped or Rhomboid
* Cysteine:
* Hexagonal
* Struvite:
* Coffin-lid
28
Crystal shape for ethylene glycol
Cigar-shaped
29
Ways to lower hypercalciuria in stone-former
1. Low sodium diet (enhance Na reabsorption, passive Ca reabsorption in prox tubule)
2. Normal Ca diet (bind oxalate in bowel; 1200 mg/day)
3. Thiazide diuretic – induces mild volume depletion, leading to increase in proximal reabsorption of sodium and thus passive calcium reabsorption
4. Increase urinary volume, target u/o \>2L/day
5. Potassium citrate (decrease stone formation via Ca-binding citrate in urine)
30
Causes of false positive microalbuminuria
1. UTI
2. Gross hematuria
3. Low Cr / cachexia
4. Volume depletion
5. Alkaline urine pH \>8
6. (true but transient/benign: fever, exercise, trauma)
31
4 mechanisms why Crohn's causes kidney stones and most common types of stone (two)?
* Mechanisms:
* Volume depletion
* Increased oxalate reabsorption (due to fat malabsorption)-\> hyperoxaluria
* NAGMA (GI bicarb loss) -\> hypocitraturia
* NAGMA -\> low urine pH -\> H+ binds uric acid
* Most common stone is **Ca oxalate and uric acid**
32
3 metabolic changes with hyperglycemia
1. Hyperkalemia (if lack of insulin)
2. Hyponatremia
3. Acidosis (if no insulin and cannot take up glucose)
33
Incidental hydronephrosis with UPJ obstruction - 4 reasons to intervene?
1. Progressive kidney dysfunction
2. Recurrent UTIs
3. Recurent stones
4. Solitary kidney
34
Causes of nephrocalcinosis
Anything that causes hypercalciuria
* Primary hyperparathyroidism
* Sarcoidosis
* Distal RTA
* Medullary sponge kidney
* Vitamin D therapy
35
Nephrogenic systemic fibrosis risk factors
* Dose and repeated exposure to gadolinium based contrast
* ESKD
* AKI
* CKD GFR \<30
36
What is juvenile nephronopthisis
Group of autosmoal recessive cystic kidney diseases, mutation of NPHP genes (encodes ciliary apparatus), progress to ESKD
37
Renal manifestations of juvenile nephronopthisis?
Polyuria, polydispa (impaired urinary concentrating ability and Na reabsorption)
Bland urinalysis, no proteinuria
Chronic tubulointerstitial nephropathy, tubular basement membrane disruption
Normal BP
38
Extrarenal manifestations of juvenile nephronopthisis
* Skeletal defects
* Retinitis pigmentosa
* Situs inversus, cardiac septal and valve defects
* Liver fibrosis
* Neurologic - ataxis, hypotonia, developmental delay
39
Mechanism of enteric hyperoxaluria
Under normal conditions, dietary calcium binds dietary oxalate to form insoluble CaOx that is excreted in the stool. **In EH, non-absorbed fatty acids instead bind calcium in the small intestine rendering it unavailable to precipitate oxalate**. Soluble oxalate is consequently present in relatively high concentration in the lumen and can diffuse passively out of the colon into the blood, from where it can be excreted by the kidneys
40
Common side effects with tolvaptan?
* Gastrointestinal: Nausea (21%)
* xerostomia (7% to 13%)
* Renal: Pollakiuria (4% to 11%), polyuria (4% to 11%)
* Miscellaneous: Thirst (12% to 16%)
* LIVER INJURY
41
What is von Hippel-Lindau disease and manifestations?
Diagnosis?
* Autosomal dominant, problem with VHL gene
* Causes benign and malignant tumors
* **Clear cell RCC**
* **Pheochromocytoma (HTN)**
* Hemagioblastoma (cerebellum and spine)
* Retinal angiomas
* Middle ear tumors
* Pancreas neuroendocrine tumors
* Papillary cystadenomas of epididymis and broad ligament
* Diagnosis via genetic testing
42
Extra-renal manifestations of Alport's
1. Bilateral sensorineural hearing loss
2. Ocular defects (anterior lenticonus, retinal/corneal changes)
3. Leiomyomatosis (benign tumors found in respiratory/GI/female reproductive tract)
4. Aneurysms of thoracic and abdominal aorta
43
Alport's vs. TBMD?
* Alport's is X-linked whereas TBMD is Autosomal dominant (so no father-to-son transmission in Alport's)
* Alport's: hearing loss, anterior lenticonus, leiomyomas, kidney failure (and FHx kidney failure)
* Alport's kidney bx: thin GBM, splitting of the lamina dense of GBM, ab's against type IV collagen (normal GBM in TBMD).
44
Renal pathology of Alport's
May look normal in early
Abnormal GBM - thinning or thickening, longitudinal splitting of the lamina densa of GBM
Immunostaining for type 4 collagen: absence or an abnormal distribution of the alpha-3, alpha-4 and/or alpha-5(IV) chains of the GBM
45
How to diagnose Alport's syndrome
Kidney biopsy
Skin biopsy (monoclonal Ab against alpha-5 type 4 collagens - absent in male, mosaic in female)
Molecular genetic testing
46
Causes of hyperoxaluria
Primary oxalosis
Enteric oxaluria (malabsorptive syndromes eg. IBD)
Ethylene glycol toxicity
Ascorbic acid toxicity
High oxalate diet (spinach, rhubarb, peanuts, cashews, almonds)
Low dietary Ca (less able to bind)
47
Side effects of kayexalate
Intestional necrosis
Volume overload (sodium)
Hypokalemia
Hypocalcemia
Hypomagnesemia
48
DDx radiolucent mass obstructing ureter?
Uric acid stone
Indinavir stone
Malignancy
Abscess
49
DDx red urine with negative dipstick
1. Red supernatant without RBC present, Red supernatant **positive for heme**
1. Myoglobinuria (plasma clear)
2. Hemoglobinuria (plasma red)
3. Other contaminants: **semen, alkaline urine (\>9.0), cleaning agents**
2. Red supernatant **negative for heme**
1. Food dyes - Beets, food coloring
2. Porphyria
3. Drugs: phenytoin, rifampin
4. Phenanzopyridine (bladder analgesic)
50
Causes of hypercalciuria
* Increased renal loss of Ca
* high Na diet
* hyperparathyroidism
* sarcoidosis
* vitamin D toxicity
* medullary sponge kidney
* idiopathic hypercalciuria
* Increased bone loss
* acidosis?
* Increased intestinal absorption
* excessive dietary Ca diet
51
Causes of hypocitraturia
* High calcium diet (binds up citrate)
* Acidosis (increase intestinal absorption)
* Low fruits/veg diet (low intake of high citrate foods)
* High protein diet (increase H+ generation)
* Hypokalemia
52
Causes of hyperuricosuria
* High uric acid levels
* High animal protein intake -\> more breakdown of uric acid
* High uric acid production eg. gout, TLS, glycogen storage disorder
* Proximal dysfunction eg. Fanconi, glucosuria
* Acidic urine (eg. chronic diarrhea -\> bicarb loss) increases urate stones
53
Management of hypercalciuria and decrease stone risk?
Other strategies for Ca phosphate stones?
Uric acid stones?
* Management of hypercalciuria/stones:
* Low Na diet (increase proximal Ca reabs)
* Normal Ca diet (1200 mg/day; enough to bind oxalate in gut but not cause hypercalciuria)
* Low oxalate diet
* High citrate diet (fruits/veg)
* Increase urine volume \>2L/day
* Thiazide diuretic (increase proximal Ca reabs)
* Alkalinize urine - K citrate
* Ca phosphate stones:
* Don't alkalinize
* Uric acid stones:
* Low animal protein diet
* Allopurinol
54
Causes for papillary necrosis?
POSTCARDS
Pyelonephritis
Obstruction
Sickle cell
TB
Cirrhosis
Analgesia/alcohol abuse
Renal vein thrombosis
Diabetic
Systemic vasculitis
55
A Sjogren's patient gets recurrent ca phosphate stones - why?
* Distal RTA
* Ca and phosphate buffering from bone
* Increased proximal absorption of citrate to convert to bicarb -\> hypocitraturia
* High urine pH -\> more Ca phos precipitation
56
Characteristics of the best molecule to measure renal function?
What are the limitations of using Cr to measure renal function?
* Characteristics:
* Freely filtered
* Not reabsorbed in tbule
* Not secreted in tubule
* Non-toxic
* Not changed during excretion by the kidneys
* Practical and affordable
* Limitations of using Cr:
* Secreted in prox tubule - CrCl overestimates GFR, esp at lower GFR
* Production dependent on muscle mass
* Extra-renal clearance of Cr advanced CKD (intestinal bacterial overgrowth and bacterial creatininase activity)
57
Risks of renal biopsy
* Gross hematuria ~10% (1 in 10)
* Perinephric hematoma ~11% (1 in 10)
* **Transfusion 1.6% (1 in 100)**
* **Requirement for intervention to control bleeding 0.3% (1 in 500)**
* **Requirement for nephrectomy 0.01% (1 in 10,000)**
* Mortality ~0.06%
* Pain at biopsy site 4%
* Localized infection
* Renal AV fistula and potential for high output failure
58
Indications for treatment for tolvaptan with ADPKD?
1. Age 18-55 years
2. CKD stage 1-4 (eGFR \>25)
3. High risk:
1. **TKV \>750 mL**, or
2. PROPKD score \>6, or
3. (?US kidney length of \>16.5 cm)
4. Rapid eGFR decline:
1. **\>=5 mL/min/1.73 m2 in 1-year,** or
2. \>2.5/year x 5-years
59
Indications for nephrectomy in ADPKD
1. Severe bleeding
2. Recurrent and severe cyst infection
3. Infected stones
4. Intractable pain
5. Suspicion of renal cancer
6. Space limitations before transplantation, keeping in mind total kidney volume naturally decreases after transplantation, ~20% over first year.
(Note: ++morbidity and mortality, increased risk for transfusions and allosensitization, deprives residual kidney function)
60
Target UOsm for ADPKD
UOsm \<300
61
What is primary oxalosis?
Clinical manifestations and diagnosis?
Treatment?
* Autosomal recessive, inborn eror of glycoxylate metaboism --\> overpdn of oxalate
* Clinical manifestations:
* Renal stones, nephrocalcinosis --\> obstruction, infection --\> IFTA, ESKD
* Retinal and macular deposition --\> decreased vision
* Cardiac conduction defects, arrest
* Peripheral vascular disease
* Neuropathy
* Bony pain, EPO-resistant anemia, fractures
* Synovitis
* Treatment:
* Liver transplant to replace the missing enzyme
* Stone management
N
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