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 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:
) is a
Sushruta Samhita (
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, 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
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: Randells plaque

(Randall,1940)

Randalls plaque

Calcium apatite
in BBM of thin
limbs of Henles
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: 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 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

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, 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

Percentage of abnormal laboratory and 24-hour

urine values before and after surgery

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

4639 RYGB patients

3 year follow-up
7.65% in bypass
patients
4.63% in control (p
< 0.0001)
J Urol 2009; 181:25732577

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

Prevalence of low BMD at various skeletal sites in kidney stone form

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

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, 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 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

> 7.5 = infection stones

Calcium, Oxalate, Magnesium (HCl preservative)

Citrate, Uric acid (Boric acid preservative)
Urea nitrogen, Creatinine, Sodium

Serum PTH, calcitriol and calcidiol as clinically

indicated.
Use of commercially available labs or special
collection containers such as pee-splitter
Stone analysis: composition

A study of
28,836
patients
showed only
7.4 percent
had a
metabolic
evaluation
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)

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
Sugar-sweetened noncola 33
Punch
18
0.04
Coffee
26
<0.001
Decaffeinated coffee
16
Tea 11
0.02
Orange juice
12
0.004
Wine/beer 31/41
<0.005

0.02
0.003

0.01

Clin J Am Soc Nephrol. 2013 Aug;8(8):138995

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.