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 .

First known stone:
Calcium Oxalate Monohydrate
(Mummy Stone 800 AD)
herringlab.com
History
6.5 cm bladder stone consisted of
Calcium Phosphate and Uric acid.
Carbon-dated 4800 B.C., it was
found in 1901 in a childs 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 () 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 Sushruta (1500
urinary bladder stones and operative
BCE) Statue in
complications
Haridwar
Wine was used as an anesthetic
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, 11901201

Risk Factors
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 Calcium Phosphate
types
(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 Cystine (1%)

dibasic AA transporter
homogentisate 1,2-dioxygenase
 Drugs & Metabolites
(<1%)

Ciprofloxacin
Aminophylline Traimeterene

Phenazopyridine Phenytoin
Sulfamethoxazole

Amoxicillin Indinavir Oxypurinol

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

Uric Acid Dihydrate

herringlab.com
 Crystal-cell interaction
2h 3h 6h

BSC-1 cell line from

green monkey
exposed to oxalic
acid vapor

Kidney Int (1998) 54: 796-803

Crystal growth
A and B Crystal Internalization
nucleation and
binding to anionic
sites

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: Randells plaque
(Randall,1940)

Calcium apatite
in BBM of thin
Randalls plaque
limbs of Henles
loop

Laminated
microspherules
Islands of
of white apatite
crystals in the
crystals and
interstitium
black organic
matrix

Alpha trypsin
Osteopontin
inhibitor
Pathobiology of stone
formation
Brushite stones: CaHPO42H2O
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 Ca-
citrate-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
Name Inhibitory Action
Tamm-Horsfall protein* Aggregation
Nephrocalcin Nucleation, growth, aggregation, attachment
Osteopontin* Nucleation, growth, aggregation
Prothrombin fragment-1 Growth, aggregation
Bikunin Nucleation, growth, aggregation, attachment
Alfa-1 microglobulin Crystallization
Calgranulin Growth, aggregation
Heparan sulfate Aggregation, attachment
Fibronectin Aggregation, attachment, endocytosis
Matrix Gla protein 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) Multivariate RR
< 600 1.0
> 1000 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, 11441149
 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, 12301235
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

J Urol 2009; 181:25732577
urine values before and after surgery

Journal of Urology. 182(5):2334-2339, November 2009

 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;53:459464

Prevalence
Number of
Total number of patients with
Skeletal sites patients low BMD Percentage (%)
Vertebral spine 975 388 40
Hip 450 141 31
Radius 627 410 65

Kidney International (2011) 79, 393403

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 non-
pregnant women
Urologic interventions
Ureteroscopy vs. drainage procedure
Acute Colic: Pain management

Adequate Analgesia
NSAIDs, e.g. ketorolac, highly effective in renal colic
Cordell (1996) Ann Emerg Med 28:151-8
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
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 1.45 (1.34, 1.57)

Ca-Channel blockers Control 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:

0.2 N HCL Boric acid
Volume
pH (by electrode)
< 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
J Urol. 2014
Stone analysis: composition Feb;191(2):376-80
Metabolic abnormalities: Urinary
excretion values

Hypercalciuria > 4 mg/kg/d or >

140 mg/gm Cr
Hyperoxaluria > 40 mg/d
Hyperuricosuria 800 mg/d (M), 750
mg/d (F) or 300 mg/L
Hypocitrituria < 320 mg/d
Hypomagnesuria < 60 mg/d
Role of Shock Wave Lithotripsy (SWL)
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:
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 2006.17421747

Calcium Phosphate stones
after SWL

Urol Res 2010, Volume 38,3, pp 147-160

 Medical Therapy : Fluids
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 23 0.02
Sugar-sweetened noncola 33 0.003
Punch 18 0.04
Coffee 26 <0.001
Decaffeinated coffee 16 0.01
Tea 11 0.02
Orange juice 12 0.004
Wine/beer 31/41 <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 1.0 gm/day
Oxalate Restricted in
oxalate foods
Protein 1.0 gm/kg/day or less
Low purine content
Sodium 100 mEq/day
Caloric Metabolic syndrome
restriction
Diet & Calcium Stones

p=0.04

From Borghi et al N EngJMed 2002

 Therapy: Drugs
Hydrochlorothiazide 12.5 to 50 mg/day
Allopurinol 100 to 300 mg/day
Potassium Citrate 30 to 60 mEq/day
Sodium Cellulose 10 to 15 gm/day
Phosphate *#
Cholestyramine ## 10 to 16 gm/day
Orthophosphate *# 1.5 gm/day
Magnesium Citrate * 20 to 40 mEq/day
Pyridoxine* 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.