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Calcium stones:

Hyper -Ca uria
● most common ab-N
in Ca stone formers.

● treatment aimed - ⤵ urinary Ca.
this assoc. with ⤵stone reccurence

● critical role in stone formation:

hyper-Ca uria & subsequent
Ca phosphate supersaturation.

❕: Randall plaques-
potential precursors to Ca stones

🚩 origin of plaque:
basement membrane of thin limbs LOH.

☝ N kidney :
filters ~ 270 mmol Ca/d
reabs . all but 4 mmol

🚩 Definition:

hyperCa-uria > 200 mg/ d
after adherence to
400 mg Ca & 100 mg Na diet for 1 wk

HyperCa - uria :
excretion > 4mg/kg/d
or > 7 mmol/day (M)
> 6 mmol/day (F).


HyperCa -uria:

Absorptive hyperCa -uria
✔ Definition:

⤴ urinary Ca excretion
( > 0.2 mg/mg creatinine) after
oral Ca load.

🔽fasting urinary Ca usually N
( < 0.11 mg/dL glomerular filtr.),
severe forms assoc. with fasting AH.


❕ pathophysiologic ab- N :

⤴intestinal absorption of Ca
occur in ~ 55% of stone formers


Absorptive hyperCa- uria:
classification
● type 1:

urinary Ca remains high despite
low Ca diet
( 400 mg dietsry Ca daily)

● type 2 :

urinary Ca normalized with restricted
Ca intake
Absorptive hyperCa- uria:
pathophysiology
🚩 intestinal Ca hyperabsorption ↪
transient ⤴ serum Ca ↪
suppress serum PTH &
⤴ renal filtration of Ca ↪
hyperCa-uria.

d/t ⤴ intestinal absorption of Ca
is matched by
enhanced renal Ca secretion:
serum Ca - N.

🚩 ⤴ intestinal Ca absorption
ascribe to vit.D - independent &
dependent processes,
also to upregulation of vit D receptor
Absorptive hyperCa- uria:

inherited form
☝: locus in Chr 1q23.3-24q
absorptive hypoCa - uria:

another etiology
✔ Renal phosphate wasting:

↪ ⤴ active vit D.

Hereditary hypophosphatemic rickets with hyperCa-uria:

• ⤵ renal reabsorption of phosphate
• hypOphosphatemia ↪
• compensatory ⤴vit D level ↪
• ⤴absorption of Ca & phosph.
from intestine ↪
• hypercalciuria

☝: Renal phosphate leak -
rare cause of nephrolithiasis:
2% - 4%



Renal hyperCa- uria:
✔ Kidney:
• filtered ~ 270 mmol Ca
• must reabsorb > 98%
○ ~ 70 % Ca reabs. in PCT

❕: in renal hyperCa- uria:

• impaired renal tubular reabsorb.↪
⤴ urinary Ca ↪ second.hyperPTH

• serum Ca remains N :
d/t renal loss Ca compensated by
⤴ intestinal absorp. Ca &
bone resorption as result :
~ ⤴PTH secretion &
~ enhanced synthesis 1,25(OH) D3.

🚩: High fasting urinary Ca
( > 0.11 mg / dL glomerular filtration)
with N serum Ca -
characteristic renal hypetCa- uria.

❔: DD from absorptive :

⤴ fasting urinary Ca & serum PTH.



Renal hyperCa - uria:

evidence of
primary renal Ca leak
Pts :
with fasting hyperCa-uria & ⤴ PTH

1. w/o improvement in urinary Ca
after Na cellulose phosphate
( bind intraluminal cations)
despite ⤵ intestinal Ca absorption.

2. exaggerated response to HCTZ
( hydrochlorthiazide).


Resorptive hyperCa -uria
✔ infrequent ab-N
most commonly assoc. with
primary hyperPTH.

Resorptive hyperCa - uria:

primary hyperPTH
❕: cause nephrolithiasis ~5%

⤴PTH secretion from
parathyroid adenoma ↪
• ⤴bone resorption &
• ⤴ renal synthesis 1,25 (OH)D3 ↪
enhance intestinal absorp.

⚠ Net effect:
○ ⤴serum & urine Ca
&
○ ⤵ serum phosphorus.
Resorptive hyperCa-uria:

\" thiazide chalange\"
❔: most Pr.hyperPTH pts. have
hyperCa - emia & - uria.

but: may be seen
N serum Ca with ⤴serum PTH
DX - more difficult.

☝ thiazide diuretic
enhance renal Ca reabs.↪
exacerbate hyperCa-emia.

⚠: when Dx primary hyperPTH .-
others causes hyperCa-emia r/o
Resorptive hyperCa- uria:

primary hyperPTH
❕: assoc.with nephrolithiasis in
< 5% of pts.

❔: Dx susp.in pts with
nephrolithiasis &
serum Ca > 10.1mg/dL.

☝ Urinary cyclic AMP
use to Dx primary hyperPTH:

• PTH promote release cAMP from kidney ↪ ⤴ urinary cAMP.

☝ PTH also : ⤴ excretion of
bicarbonate & phosphorus from PCT
↪ Phosphaturia &
mild hyperchloremic acidosis:

• serum
chlorid-to-phosphate ratio > 33
along
with phosphate < 2.5 mg/dL

susp. to hyperPTH



Rare causes of
resorptive hyperCa-uria
● hyperCa-emia of malignancy
● sarcoidosis
● thyrotoxicosis
● vit D deficiency
Sarcoid & Granulomatous
disease:

produce hyperCa- emia
● sarcoidosis
● tuberculosis
● histoplasmosis
● leprosy
● silicosis
Sarcoid & Granulomatous:

most common assoc. with
urolithiasis
● Sarcoidosis

🚩 HyperCa - emia d/t:

production 1,25(OH)vitD3 from
1-ą hydroxylase in macrophages of
sarcoid granuloma ↪
⤴ intestinal Ca absorption &
hyperCa -emia , -uria.

● most pts - suppressed PTH
secondary to hyperCa -emia.

❔: DD
sarcoidosis vs other Dx:

rapid resolution of hyperCa- emia
with corticosteroid therapy
Malignancy -Assoc. HyperCa-emia
🚩 Malignancy - main cause
hyperCa-emia in hospitalized pts

whereas Primary hyperPTH -
most common cause hyperCa-emia
in outpatient pts.

❕: Tu produces humoral factor :
PTH -related protein

Lung & breast tu =
60% malignancy assoc.hyperCa-emia

RCC = 10%-15%
Head & neck = 10%
Lymphoma & myeloma = 10%.
Glucocorticoid -Induced
HypetCa-emia
✔ Glucocorticoids alter Ca metabolism through actions on
bone , intestine,parathyroid glands.

● stimulated PTH release
● nephrolithiasis is common in
Cushing syndrome
HYPEROXALURIA :

definition
❕ : urinary Ox > 40 mg/d

● leads to ⤴ urinary saturation CaOx

● promotion CaOx stone
HyperOx-uria:

causes
🚩: ● disorders in biosynthesis
(primary hyperOxuria)

● intestinal malabsorption
( enteric hyperOxuria)

● excessive dietary intake or
high vit.C levels
( dietary hyperOxuria).
Primary hyperOx-uria
✔ rare autosomal recessive
disorder in glyoxalate metabolism.

● N conversion
glyoxlate ↪ glycine is prevented

● preferential oxydative conversion
glyoxalate ↪ oxalate

✔ high level urinary Ox:
> 100 mg/d
↪ ⤴Ca Ox saturation & form
CaOx crystals in renxl tubule.
primary hyperOx - uria:

type I
✔ primary enzyme catalyzing
convertion to GLYCINE :

alanine/glyoxalate aminotransferase

• synthesize in liver

✔ muration gene AGXT ↪
type I

● pts have ⤴level Ox &
frequently glycolate.



primary hyperOx-uria:

type II
✔ assoc. with defect in
glyoxalate reductase /
hydroxypiruvate reductase
in liver

↪ hyperOx-uric nrphrolithiasis

☝ less aggressive with regard to
renal failure than type I
primary hyperOx-uria:

type III
✔ non-I, non-II - 5% pts with PH.

☝clinically indistiguishable from
I & II.
primary hyperOx-uria:

treatment
⚠: end - stage renal failure
15% - 50% pts.

• death rate ~ 30%

● combine liver- kidney transplant
Enteric hyperOx-uria
✔ most common cause of acquired
hyperOx-uria.

✔ assoc. with chr.diarrheal status

🚩fat malabsorp. ↪ saponification
fatty acids with divalent cations:
Ca & Mg
↪ ⤵ Ca Ox complexation ↪
⤴ available Ox for reabsorption.
Enteric hyperOx-uria
✔ in pts chr.diarrheal syndrome
⤴ risk CaOx stone:
● dehydration
● hypoK -emia
● hypoMg -uria
● hypoCit - uria
● low urinary pH.

✔ assoc.with:
• small bowel resection
• IBD (intrinsic disease)
• jeunoieal bypass.
Enteric hyperOx- uria:

main driving force stone form.
● urinary saturation of Ca Ox
Dietary hyperOx- uria:

● dietary Ox in urinary
Ox excretion:
24% - 42 %

● Ca restriction ↪ ⤵intestinal Ox binding ↪ ⤴ Ox absorp.

● vit C supplement.↪
⤴urinary Ox
by in vivo conversion to Ox.
Dietary hyperOx- uria:

Cystic fibrosis
🚩 CF pts - prolonged ATB use ↪
abs O.formigenes ↪ ⤴urinary Ox.
HyperUr-uria:

definition
✔ urinary UA exceeding 600mg/d
HyperUr-uria
✔ up to 10% Ca stone formers have
high urinary UA as only ab-N :

• hyperUruria ↪⤴monoNa urate ↪
promotes CaOx stone.

✔ pH < 5.5 ↪ UA/CaOx stone form.

🚩: at pH > 5.5 Na Ur formation promotes CaOx stone through
heterologous nucleation.
HyperUr -uria
• UA ⤵ effect natural inhibitors:

🚩: UA crystals bind urinary glycosaminoglycans - heparin, that
inhibit crystallization of CaOx.
HyperUr -uria

most common cause
● ⤴ dietary purine intake
HyperUr- uria

urate transporter
❕: URAT 1 :
• urate transporter in PCT
• mutations encoding gene ↪:

●hyperuricosuric hyperuricemia
( renal UA leak )
● exercise- induced ac.renal failure
● high risk of kidney stone
HypoCit- uria
🚩: important & correctable ab-N
• 10% Ca stone pts as isolated ab-N
• 20%-60% assoc.with other ab-N

● Citrate - inhibitor ⤵ Ca stone form.
HypoCit- uria:

Citrate - mechanisms of inhibition
✔ ⤵urinary saturstion of Ca by complexing with Ca.


✔ directly prevents spontaneuos nucleation of CaOx.

✔ inhibits agglomeration &
sedimentation CaOx crystal

✔ N Cit levels ⤴ inhibitory effect
of Tamm -Horsfall glycoprotein.
HypoCit-uria:

definition
✔ urinary citrate < 320 mg/d
HypoCit-uria:

primary determinant of Citrate excretion
🚩 Acid-Base state.

🚩 Metabolic acidodis:

⤵ urinary citrate levels
secondary to
enhanced renal tubular reabsorp.
&
⤵ synthesis of Cit. in peritubular cells.
HypoCit.-uria:

in states asscoc.with acidosis
● Distal RTA:

• high urinary pH ( > 6.8 )
• high serum Cl
• low serum K & bicarbonate

inability to acidify urine in response
to oral acid ( NH4Cl) load = Dx.


● Chr. diarrheal states:

intestinal alkali loss ↪ systemic acidosis & hypoCit - uria.

● Excessive animal protein intake:
also as
high-protein,low-carbohydrate diet
↪ ⤵⤵ urinary citrate & pH.

● Diuretics: Thiazides

• hypoK-emia
• intracellular acidosis

● Enalapril :

cause hypoCit-uria independently
of systemic acidosis / hypoK -emia

perhapse d/t intracellular asodosis.




LOW URINE pH
☝: Low urine pH ( < 5.5 )

↪ uric acid & Ca stone formation.

● CaOx stones form as result
heterologous nucleation with
UA crystals.

❕: any disorder lead to low urine pH
may predispise to stone formation.


✔ chr.metabolic acidosis ↪
low urine pH , hypetCa- uria ,
hypoCit-uria.


✔ Acidosis :

• ⤴ bone resorption
• ↪ renal Ca leak
RENAL TUBULAR ACIDODIS
RTA
🚩 clinical syndrome
metabolic acidosis d/t defect in
renal tubular [ H+] / bicarbonate
reabsorption
RTA
🚩 type I ( distal) RTA :

• most common form
• most frequently assoc.with stone
~ up to 70% of pts

✔ signs assoc. with nephrolithiasis
↪ initial Dx RTA in 50% of cases.
RTA:

acid-base balance
☝ maintain by kidney through
several mechanisms at level both
PROXIMAL & DISTALE nephron.

🚩 : kidney must reabsorb. or regenerate nearly ALL filtered
bicarbonate each day
( ~ 4500 mmol)

🚩: kidney may excrete excess acid

❕: Defect ↪ Metab.acidosis in:

● bicarbonate reabsorption
or
● acid excretion
Filtered HCO3 reabsorbed
❕: almost completely in
PROXIMAL tubule
through indirect mechanism
involving H+ secretion

🚩: Proximal nephron is
high-capacity,low-gradient transport
system - allows reabsorption filtered
HCO3 w/o causing net H+ secretion
or significant changes in urinary pH
RTA:

DISTAL nephron
❕: 5%-10% of filtered HCO3 reabsorp.
similar to proximal nephron.

🚩: H+ binds with urinary buffers as
phosphate & ammonia
allowing net elimination of H+ in form
NH4.
Net H+ excretion occurs through
active secretion from
ą-intercalated cells.

RTA:

ą - intercalated cells
❕: have & use:

● H+ ATPase & H+/K+ ATPase exvhanger

● Cl-/HCO3 anion exchanger
( that transports HCO3).

🚩: these ACTIVE pumps generate a
1000:1 H+ gradient between cell &
tubular lumen ,
allowing ⤵urine pH to 4.5
RTA:

occurs as
🚩: as result of impairement of:

● net excretion of acid into urine
( type I )
or
● reabsorption HCO3 ( type II ).
RTA :

Type I
🚩: syndrome of ab-N
collecting duct function characterized by inability to
acidify urine in presence of
systemic acidosis
RTA : type I

classic findings
● hypo-K,hyper-Cl,
non - AG met.acidosis
● nephrolithiasis
● nephrocalcinosis
● elevated urinary pH ( > 6.0).
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