Kidney Stones
Gaurang M. Shah, MD, FACP, FASN
Chief, Nephrology Section
Long Beach VA HCS
Health Sciences Professor of
Medicine
University of California, Irvine
Objectives

Pathogenesis
 Metabolic disorder
 Natural inhibitors



Management of renal colic
Shock wave lithotripsy
Prevention of recurrence:
 Role of diet and fluids
 Pharmacotherapy
Case Presentation

35 year old male developed left flank pain and hematuria. He had
been passing kidney stones for 5 years, 3 times spontaneously and
had lithotripsy on last two occasions.

Lab: UA pH 5.0, 300 RBC, CaOx and Uric Acid crystals
Stone analysis: CaOx.2H2O and traces of uric acid
24 hour urine:
Ca 380 mg/d, Uric acid 900 mg/d, Oxalate 50 mg/d, Citrate 200 mg/d,
Sodium 200 mEq/d, magnesium 119 mg/d, Volume 1800 ml/d

Patient was placed on sodium restricted, low oxalate diet.
Hydrochlorthiazide 12.5 mg/d and allopurinol 200 mg/d were
prescribed.

Over the next 2 years, he did not have recurrence of kidney stone .
History
 First known stone:
Calcium Oxalate Monohydrate
(Mummy Stone – 800 AD)
herringlab.com
– 6.5 cm bladder stone consisted of
Calcium Phosphate and Uric acid.
– Carbon-dated 4800 B.C., it was
found in 1901 in a child’s mummy
at a grave site in El Amrah, Upper
Egypt.
– Preserved in Royal Museum in
London until destroyed by
bombardment in 1941.
Stone surgery: Vedic times in
India:
Sushruta Samhita (सश्र
ु ुतसंहिता) is a
surgery textbook written in 800 BCE,
describes 300 surgical procedure, 120
surgical instruments, and 8 types of
surgery.




First record of stone surgery
Described varieties of stones, and signs
and symptoms
Detailed anatomy and extraction of
urinary bladder stones and operative
complications
Wine was used as an anesthetic
Sushruta (1500
BCE) Statue in
Haridwar
http://en.wikipedia.org/wiki/Sushurata
The Nephrocentric Art of Michelangelo
"fevers, flanks, aches, diseases, eyes and teeth“(1544)
Detail from the panel of the Separation of Earth and Waters in the Sistine Chapel (1511)
"As regards my malady, I'm much better. We are now certain that I'm suffering from the
stone, but it's a small one and thanks to God and to the virtues of the water I'm drinking,
it's being dissolved little by little, so that I'm hopeful of being free of it" (Letter 326, 1549)
Eknoyan (Kidney International 2000) 57, 1190–1201
Risk Factors

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Prevalence: 2-3% in the U.S., geographic
variations
Gender: Male/Female ratio 4:1
Life-time risk: Males: 12 % Females: 7 %, incident
is rising
Peak age 20-50 years
Family History
Genetic factors
– Medullary sponge kidney
– CaSR or FGF 23 polymorphism


Caucasians more than blacks or hispanics
Recurrence 30%- 40% at 5 years, 50%- 60% at
10 years
Types of kidney stones
Calcium Oxalate
Stone
types
Calcium Phosphate
(60-70%)
Uric Acid (10-15%)
Struvite (10-15%)
Uncommon
types of Stones
Calcium Carbonate
Calcium Citrate
Ammonium Urate
(laxative abuse)
Hereditary
Disorders
Xanthine
• Polycystic kidney Disease
• Medullary Sponge Kidney
• Horseshoe kidney
2,8-dihydroxyadenine
adenine phosphoribosyltransferase (APRT)
Alcaptonuria
homogentisate 1,2-dioxygenase
Cystine (1%)
dibasic AA transporter
Drugs & Metabolites
(<1%)
Ciprofloxacin
Aminophylline
Traimeterene
Phenazopyridine
Sulfamethoxazole
Phenytoin
Indinavir
Oxypurinol
Amoxicillin
herringlab.com
Drugs & Metabolites
(<1%)
Amorphous silica
(magnesium trisilicate)
Guaifenesin
Metabolite
Methylglucamine
Iothalamate
herringlab.com
• Infection?
Physico-chemical process
Physics of Crystallization
Formation product (FP)
Solubility product (SP)
Supersaturated
•Agglutination
Sodium Acid Urate
Metastable •Aggregation
•Nucleation
Undersaturated
Uric Acid Dihydrate
herringlab.com
Uric Acid Dihydrate
Crystal-cell interaction
2h
3h
6h
BSC-1 cell line from
green monkey
exposed to oxalic
acid vapor
Crystal growth
Kidney Int (1998) 54: 796-803
A and B Crystal
nucleation and
binding to anionic
sites
Internalization
C Internalization and
cytokine activation
D Dissolution or
peritubular exit
Current Opinion in Nephrology & Hypertension. 2000; 9(4):349-355
Pathophysiology:
Plaque hypothesis
Site of stone formation
CaOX stones: Randell’s plaque
(Randall,1940)
Randall’s plaque
Calcium apatite
in BBM of thin
limbs of Henle’s
loop
Laminated
microspherules
of white apatite
crystals and
black organic
matrix
Islands of
crystals in the
interstitium
Osteopontin
Alpha trypsin
inhibitor
Pathobiology of stone
formation
Brushite stones: CaHPO4·2H2O
 Increasing
in incidence
 Conversion from CaOX to
brushite
 High recurrent rates
 Higher urinary calcium and
pH
 Hard to fragment by SWL
or ultrasound
 Greater tubular and
interstitial damage – CKD?
Urol Res. 2010 Jun;38(3):147-60
Micro-molecular inhibitors:
 Citrate
 Magnesium, a weak inhibitor of CaOx
crystallization. Hypomagnesemia may
occur in enteric disorders, malnutrition
or low dietary intake.
 Pyrophosphates and phosphocitrate
are inhibitors of CaP crystallization.
Citrate
 Citrate, by complexing iCa, is a
powerful inhibitor of CaOx and CaP
crystal growth and aggregation.
 Formation of a pH dependant Cacitrate-phosphate species,
independent of urinary citrate
concentration. NDT 2006 Feb;21(2):361-9
 Higher excretion in women than
men.
Causes of hypocitrituria

Disorders of acid-base and electrolytes
– Metabolic acidosis (Systemic or RTA)
– Hypokalemia, hypocalciuria and hypomagnesuria

Diet
– High protein and sodium intake
– Low intake of fruit and vegetables

Drugs
– Acetazolamide and topiramide (Carbonic anhydrase inhibitors)
– ACE inhibitors (intracellular acidosis)
– Thiazides

Genetic factors
– VDR polymorphisms
– NaDC-1 gene polymorphism
Macro-molecular inhibitors
Inhibitory Action
Name










Tamm-Horsfall protein*
Nephrocalcin
Osteopontin*
Prothrombin fragment-1
Bikunin
Alfa-1 microglobulin
Calgranulin
Heparan sulfate
Fibronectin
Matrix Gla protein





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
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
Aggregation
Nucleation, growth, aggregation, attachment
Nucleation, growth, aggregation
Growth, aggregation
Nucleation, growth, aggregation, attachment
Crystallization
Growth, aggregation
Aggregation, attachment
Aggregation, attachment, endocytosis
Crystal deposition
Modified from Urol Res 2009 Aug;37(4):169-80
Metabolic and dietary factors
Ca intake and Hypercalciuria:
 Dietary calcium intake and relative risk
(RR) of stone disease in 45,619 men (age
40-75 years):
Ca intake (mg)
< 600
> 1000
Multivariate RR
1.0
0.66
 Water hardness inversely correlated with
incidence of stone disease
Ann Int Med 1978; 88: 513-514
Protein intake and calciuria
Sodium intake and calciuria
“MILD” Hyperoxaluria Syndrome
 Urinary oxalate excretion 40-100 mg/day,
correlates well with no. of stone episodes per year.
 Incidence in stone formers 20 to 60%.
 Post-prandial CaOx supersaturation may occur.
Enteric hyperoxaluria

GI disorders
– Malabsorption syndrome
– Surgical procedures, such as gastro-jejunal
bypass, bowel resection
– Bariatric surgery (7.6%)
– Inflammatory bowel diseases

Mechanism
– Diarrhea: acidic pH, low urine volume
– Hyperabsorption: mucosal hypertrophy, bile salts
– Inhibitors: low urinary citrate, magnesium

Treatment:
– Fluids, calcium carbonate, cholestyramine,
Potassium citrate, magnesium oxide
Colonic microbiome:
Oxalobactor formigenes
Association between the
number of stone episodes
and O. formigenes
colonization rate (n=37).
Kidney International (2013) 83, 1144–1149
Hyperuricosuria:
 20-40% of stone formers.
 Elevated RBC urate transport.
 Uric acid may interact with glutamic acid
and act as a promoter.
 Reduces inhibitory activity of urinary
macromolecular inhibitors.
 “Salting out” phenomenon.
 Solubility enhanced by urine pH > 6.5.
 Dietary purine intake is the major source.
Newer concepts in stone disease
 Stone
and diabetes mellitus
 Stone and morbid obesity
 Stone and bariatric surgery
 Stone and CKD
 Stone and bone disease
Diabetes and incidence
of kidney stones
Person- years
Kidney stones
Age-adjusted RR Multivariate RR
NHS I
Diabetes –
1,371,080
1578
1.00 (reference) 1.00 (reference)
Diabetes +
65,566
109
1.45 (1.20, 1.77) 1.29 (1.05, 1.58)
NHS II
Diabetes –
824,076
1491
1.00 (reference) 1.00 (reference)
Diabetes +
12,291
40
1.86 (1.36, 2.56) 1.60 (1.16, 2.21)
HPFS
Diabetes –
450,984
1426
1.00 (reference) 1.00 (reference)
Diabetes +
21,676
44
0.76 (0.56, 1.03) 0.81 (0.59, 1.09)
Relative risk of incident symptomatic kidney stones according to diabetes history in
older women (NHS I), younger women (NHS II), and men (HPFS)
Kidney International (2005) 68, 1230–1235
Metabolic syndrome and uric acid
stone
Distribution of calcium and UA stones with respect to body mass index (in kg/m 2 )
and diabetes mellitus status. BMI, body mass index; DM, diabetes mellitus.
Calcium stones UA stones.
Seminars in Nephrology Volume 28, Issue 2 2008 174 - 180
Metabolic changes after bariatric
surgery
 4639
RYGB patients
 3 year follow-up
 7.65% in bypass
patients
 4.63% in control (p
< 0.0001)
Percentage of abnormal laboratory and 24-hour
urine values before and after surgery
Journal of Urology. 182(5):2334-2339, November 2009
J Urol 2009; 181:2573–2577
Stone and CKD
Risk for a clinical diagnosis of CKD between stone
formers and control subjects in Olmsted County.
Initial creatinine clearance in 1,856 stone formers and
153 normal individuals
Brushite (Br), calcium oxalate (CaOx), apatite (Apa), struvite
(Str), uric acid (Ua), and cystine (Cys).
Rule A D et al. CJASN 2011;6 (8) 2069-2075
Worcester EM J Urol. 2006 Aug;176(2):600-3
Bone disease in nephrolithiasis
Cumulative incidence of vertebral
fracture among Rochester,
Minnesota, residents following an
initial episode of symptomatic
nephrolithiasis
Kidney Int. 1998;53:459–464
Prevalence
Skeletal sites
Total number of
patients
Number of
patients with
low BMD
Percentage (%)
Vertebral spine
975
388
40
Hip
450
141
31
Radius
627
410
65
Kidney International (2011) 79, 393–403
Stone disease in pregnancy
 1:200
– 1:1500 pregnancies
– 2nd and 3rd trimester
 Mechanisms:
– CaP ( Octacalcium phosphate pentahydrate,
a transitional molecule) Ca8H2(PO4)6*5H2O
– Hydroureter
– Supra-normal GFR
– Increase urine pH
– Hypercalciuria
» Diet
» Placental production of calcitriol
herringlab.com
Stone disease in pregnancy:
Complications
 Colic,
obstruction, pyelonephritis,
sepsis
 Premature membrane rupture, pre-term
labor, preeclampsia
 Recurrent abortions, hypertension,
gestational diabetes, Cesarean section
Stone disease in pregnancy:
Diagnosis and Management
 Ultrasound,
low dose non-contrast CT,
HASTE MRI
 Conservative approach
– Stone passage rate is double the nonpregnant women
 Urologic
interventions
– Ureteroscopy vs. drainage procedure
Acute Colic: Pain management

Adequate Analgesia
–
NSAIDs, e.g. ketorolac, highly effective in renal colic
»
–
NSAID compared with Opioids
» Equal to or more effective than Opioids
» Less Vomiting than with Opioids
»

Holdgate (2004) BMJ 328:1401-4
Local warming of abdomen and lower back to 42o c with
heating blanket
»

Cordell (1996) Ann Emerg Med 28:151-8
Kober A J (2003) Urol 170: 741-4
IV or oral fluid >2.5 Liters per day
Medical Stone Expulsion Therapy
Alpha-blockers
Control
Risk ratio
(95% C.I.)
Events
Total
Events
Total
1074
1335
590
1086
Ca-Channel blockers
Control
1.45 (1.34, 1.57)
Risk ratio
(95% C.I.)
Events
Total
Events
Total
269
342
182
344
1.49 (1.33, 1.66)
Adapted from EUROPEAN UROLOGY (2009 56: 455 – 471)
Comprehensive Metabolic
Evaluation

Two 24 hour urine baseline collections for:
– Volume
– pH (by electrode)
0.2 N HCL Boric acid
» < 5.5 = uric acid, RTA > 5.5
A study of
» > 7.5 = infection stones
28,836
– Calcium, Oxalate, Magnesium (HCl preservative)
patients
– Citrate, Uric acid (Boric acid preservative)
showed only
– Urea nitrogen, Creatinine, Sodium
7.4 percent
 Serum PTH, calcitriol and calcidiol as clinically had a
indicated.
metabolic
 Use of commercially available labs or special evaluation

collection containers such as pee-splitter
Stone analysis: composition
J Urol. 2014
Feb;191(2):376-80
Metabolic abnormalities: Urinary
excretion values
 Hypercalciuria
 > 4 mg/kg/d or
140 mg/gm Cr
 Hyperoxaluria
 Hyperuricosuria
 > 40 mg/d
 Hypocitrituria
 Hypomagnesuria
 < 320 mg/d
>
 800 mg/d (M), 750
mg/d (F) or 300 mg/L
 < 60 mg/d
Role of Shock Wave Lithotripsy (SWL)
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Non-lower pole < 2 cm in diameter Lower pole < 1 cm in diameter
Cystine and brushite most resistant to shock-wave, followed by
cancium oxalate monohydrate, struvite, calcium oxalate dihydreate,
and uric acid
CT attenuation coefficient < 900 Hounsfield units
Skin-to-stone distance < 10 cm
Peri-operative antibiotics
Post-procedure tamsulosin with or without methyprednisolone, or
potassium citrate to facilitate stone passage
Stone passage may last up to three months
Contraindicated in active UTI, pregnancy, distal obstruction, aortic or
renal artery aneurisms, and bleeding diathesis
Large staghorn type, massive obesity and body deformities may
pose limitations
N Engl J Med. 2012 Jul 5;367(1):50-7.
doi: 10.1056/NEJMct1103074
SWL: Complications
 Local:

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
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Pain and bleeding, gross hematuria
Obstruction of urinary flow (6 to 25%)
Steinstrasse (6-20%)
Perirenal/intrarenal hematoma (CT or MRI)
 Renal:
 Tubular enzymuria,
 Acute reduction in RBF and GFR
 Stone recurrence
 Systemic:
 New onset hypertension (8%)
 Urosepsis (< 5%)
 Pulmonary embolism, Acute MI, Ileus (< 1%)
 Mortality rate (< 0.02%)
Long-term follow-up of SWL




630 patients treated by HM-3 lithotriptor at Mayo clinic in 1985.
340 responded to questionnaire.
Nineteen year follow-up in a case-controlled study.
Development of new onset hypertension and diabetes mellitus
(damage to pancreas by shock-waves).
Krambeck: J. urol., Volume 175(5).May 2006.1742–1747
Calcium Phosphate stones
after SWL
Urol Res 2010, Volume 38,3, pp 147-160
Medical Therapy : Fluids

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

2.5 to 3 L/day. Important in hot climate.
Weight based regimen (2 to 4 liters)
50% water.
Regular schedule, e.g. 8 fluid oz. every hour during
day and 2 to 3 times at night.
Induce nocturia to prevent supersaturation.
Cranberry (1 L/d) and grapefruit (8 oz.) juice increase
oxaluria by 18 and 44% respectively.
Lemonade and orange increase citrate excretion.
Sugary drinks increase oxalate excretion.
Fructose increases uric acid excretion.
Types of drinks





194,095 participants in three health surveys
Median 8 years follow-up
4462 incidents of stones
Compared highest category (> 1 drink/d) to lowest (<
1 drink/d) category of drinks
Findings: Drink
Percent
p
Sugar-sweetened cola
Sugar-sweetened noncola
Punch
Coffee
Decaffeinated coffee
Tea
Orange juice
Wine/beer
23
33
18
26
16
11
12
31/41
0.02
0.003
0.04
<0.001
0.01
0.02
0.004
<0.005
Clin J Am Soc Nephrol. 2013 Aug;8(8):1389-95
Urine volume and relative saturation
Primary prevention of stones
Secondary prevention
Therapy: Diet
• Calcium
• Oxalate
• Protein
• Sodium
• Caloric
restriction
• 1.0 gm/day
• Restricted in
oxalate foods
• 1.0 gm/kg/day or less
Low purine content
• 100 mEq/day
• Metabolic syndrome
Diet & Calcium Stones
p=0.04
From Borghi et al N EngJMed 2002
Therapy: Drugs
•
•
•
•
•
•
•
•
Hydrochlorothiazide
Allopurinol
Potassium Citrate
Sodium Cellulose
Phosphate *#
Cholestyramine ##
Orthophosphate *#
Magnesium Citrate *
Pyridoxine*
•
•
•
•
12.5 to 50 mg/day
100 to 300 mg/day
30 to 60 mEq/day
10 to 15 gm/day
•
•
•
•
10 to 16 gm/day
1.5 gm/day
20 to 40 mEq/day
50 to 200 mg/day
* No control study, # High relapse rate,
## Enteric hyperoxaluria
Thiazides
Citrate and Allopurinol
Treatment of other types of
Stones:
 Uric acid: Fluid, potassium citrate,
allopurinol.
 Struvite: Fluid, urine acidification,
acetohydroxamic acid.
 Cystine: Fluids, urine alkalinization,
d-penicillinamine, tiopronin, ? Vaptans.