Kidney Stones

1
Kidney Stones
Gaurang M. Shah, MD, FACP, FASN Chief, Nephrology
Section Long Beach VA HCS Health Sciences
Professor of Medicine University of California,
Irvine
2
Objectives

• Pathogenesis
• Metabolic disorder
• Natural inhibitors
• Management of renal colic
• Shock wave lithotripsy
• Prevention of recurrence
• Role of diet and fluids
• Pharmacotherapy

3
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 .

4
History

• First known stone
• 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.

Calcium Oxalate Monohydrate (Mummy Stone 800 AD)
herringlab.com
5
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 urinary
  bladder stones and operative complications
• Wine was used as an anesthetic

Sushruta (1500 BCE) Statue in Haridwar
http//en.wikipedia.org/wiki/Sushurata
6
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
7
Risk Factors

• Prevalence 2-3 in the U.S., geographic
  variations
• Gender Male/Female ratio 41
• 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

8
Types of kidney stones
9
Stone types
Calcium Oxalate
Calcium Phosphate
(60-70)
Struvite (10-15)
Uric Acid (10-15)
10
Uncommon types of Stones
Calcium Carbonate
Calcium Citrate
Ammonium Urate (laxative abuse)
11
Hereditary Disorders
Xanthine

• Polycystic kidney Disease
• Medullary Sponge Kidney
• Horseshoe kidney

2,8-dihydroxyadenine adenine phosphoribosyltransfe
rase (APRT)
Alcaptonuria homogentisate 1,2-dioxygenase
Cystine (1) dibasic AA transporter
12
Drugs Metabolites (lt1)
Ciprofloxacin
Aminophylline
Traimeterene
Phenytoin
Phenazopyridine
Sulfamethoxazole
Oxypurinol
Amoxicillin
Indinavir
herringlab.com
13
Drugs Metabolites (lt1)
Amorphous silica
(magnesium trisilicate)
Guaifenesin Metabolite
Methylglucamine  Iothalamate
herringlab.com
14

• Infection?

15
Physico-chemical process
16
Physics of Crystallization
Formation product (FP)
Solubility product (SP)
Supersaturated

• Agglutination
• Aggregation
• Nucleation

Sodium Acid Urate
Metastable
Undersaturated
Uric Acid Dihydrate
Uric Acid Dihydrate
herringlab.com
17
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
Internalization
A and B Crystal 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
18
PathophysiologyPlaque hypothesis
19
Site of stone formation
20
CaOX stones Randells plaque (Randall,1940)
Calcium apatite in BBM of thin limbs of Henles
loop
Randalls plaque
Laminated microspherules of white apatite
crystals and black organic matrix
Islands of crystals in the interstitium
Alpha trypsin inhibitor
Osteopontin
21
Pathobiology of stone formation
22
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 Jun38(3)147-60
23
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24
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.

25
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.
• Higher excretion in women than men.

NDT 2006 Feb21(2)361-9
26
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

27
Macro-molecular inhibitors

• Name

• Inhibitory Action

• 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 Aug37(4)169-80
28
Metabolic and dietary factors
29
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
• lt 600 1.0
• gt 1000 0.66
• Water hardness inversely correlated with
  incidence of stone disease

Ann Int Med 1978 88 513-514
30
Protein intake and calciuria
31
Sodium intake and calciuria
32
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.

33
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

34
Colonic microbiomeOxalobactor formigenes
Association between the number of stone episodes
and O. formigenes colonization rate (n37).
Kidney International (2013) 83, 11441149
35
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 gt 6.5.
• Dietary purine intake is the major source.

36
Newer concepts in stone disease

• Stone and diabetes mellitus
• Stone and morbid obesity
• Stone and bariatric surgery
• Stone and CKD
• Stone and bone disease

37
Relative risk of incident symptomatic kidney
stones according to diabetes history in older
women (NHS I), younger women (NHS II), and men
(HPFS)
Diabetes and incidence of kidney stones
  Person- years Kidney stones Age-adjusted RR Multivariate RR
NHS I NHS I NHS I NHS I 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 NHS II NHS II NHS II 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 HPFS HPFS HPFS 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)
Kidney International (2005) 68, 12301235
38
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
39
Metabolic changes after bariatric surgery

• 4639 RYGB patients
• 3 year follow-up
• 7.65 in bypass patients
• 4.63 in control (p lt 0.0001)

Percentage of abnormal laboratory and 24-hour
urine values before and after surgery
J Urol 2009 18125732577
Journal of Urology. 182(5)2334-2339, November
2009
40
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).
Worcester EM J Urol. 2006 Aug176(2)600-3
Rule A D et al. CJASN 20116 (8) 2069-2075
41
Bone disease in nephrolithiasis
Prevalence of low BMD at various skeletal sites
in kidney stone formers (cumulative data from
Table 1)
Prevalence of low BMD at various skeletal sites
in kidney stone formers (cumulative data from
Table 1)
Cumulative incidence of vertebral fracture among
Rochester, Minnesota, residents following an
initial episode of symptomatic nephrolithiasis
Kidney Int. 199853459464
Skeletal sites Prevalence Prevalence Percentage ()
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
42
Stone disease in pregnancy

• 1200 11500 pregnancies
• 2nd and 3rd trimester
• Mechanisms
• CaP ( Octacalcium phosphate pentahydrate, a
  transitional molecule) Ca8H2(PO4)65H2O
• Hydroureter
• Supra-normal GFR
• Increase urine pH
• Hypercalciuria
• Diet
• Placental production of calcitriol

herringlab.com
43
Stone disease in pregnancy Complications

• Colic, obstruction, pyelonephritis, sepsis
• Premature membrane rupture, pre-term labor,
  preeclampsia
• Recurrent abortions, hypertension, gestational
  diabetes, Cesarean section

44
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

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46
Acute Colic Pain management

• Adequate Analgesia
• NSAIDs, e.g. ketorolac, highly effective in renal
  colic
• Cordell (1996) Ann Emerg Med 28151-8
• NSAID compared with Opioids
• Equal to or more effective than Opioids
• Less Vomiting than with Opioids
• Holdgate (2004) BMJ 3281401-4
• 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 gt2.5 Liters per day

47
Medical Stone Expulsion Therapy
Alpha-blockers Alpha-blockers Control Control Risk ratio (95 C.I.)
Events Total Events Total
1074 1335 590 1086 1.45 (1.34, 1.57)
Ca-Channel blockers Ca-Channel blockers Control 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)
48
Comprehensive Metabolic Evaluation

• Two 24 hour urine baseline collections for
• Volume
• pH (by electrode)
• lt 5.5 uric acid, RTA gt 5.5
• gt 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

0.2 N HCL Boric acid
A study of 28,836 patients showed only 7.4
percent had a metabolic evaluation J Urol. 2014
Feb191(2)376-80
49
Metabolic abnormalities Urinary excretion values

• gt 4 mg/kg/d or gt 140 mg/gm Cr
• gt 40 mg/d
• 800 mg/d (M), 750 mg/d (F) or 300 mg/L
• lt 320 mg/d
• lt 60 mg/d

• Hypercalciuria
• Hyperoxaluria
• Hyperuricosuria
• Hypocitrituria
• Hypomagnesuria

50
Role of Shock Wave Lithotripsy (SWL)

• Non-lower pole lt 2 cm in diameter Lower pole lt 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 lt 900 Hounsfield units
• Skin-to-stone distance lt 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 5367(1)50-7. doi
10.1056/NEJMct1103074
51
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 (lt 5)
• Pulmonary embolism, Acute MI, Ileus (lt 1)
• Mortality rate (lt 0.02)

52
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
53
Calcium Phosphate stones after SWL
Urol Res 2010, Volume 38,3, pp 147-160
54
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.

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Types of drinks

• 194,095 participants in three health surveys
• Median 8 years follow-up
• 4462 incidents of stones
• Compared highest category (gt 1 drink/d) to lowest
  (lt 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 lt0.001
• Decaffeinated coffee 16 0.01
• Tea 11 0.02
• Orange juice 12 0.004
• Wine/beer 31/41 lt0.005

Clin J Am Soc Nephrol. 2013 Aug8(8)1389-95
56
Urine volume and relative saturation
57
Primary prevention of stones
58
Secondary prevention
59
Therapy Diet

• Calcium
• Oxalate
• Protein
• Sodium
• Caloric restriction

• 1.0 gm/day
• Restricted inoxalate foods
• 1.0 gm/kg/day or less
• Low purine content
• 100 mEq/day
• Metabolic syndrome

60
Diet Calcium Stones
p0.04
From Borghi et al N EngJMed 2002
61
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
62
Thiazides
63
Citrate and Allopurinol
64
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.

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66
SWL
(a) Electro-hydraulic source. A spark produces
the shock wave, which is focused via an
ellipsoidal reflector. (b) Electromagnetic
source. The magnetic field of the coil moves a
metallic plate. The produced shock wave is
focused with an acoustic lens. (c) Piezoelectric
source. Combined small piezo-ceramic elements,
placed on the surface of a sphere, produce a
shock wave which is focused in the centre of the
sphere
J Med Eng Technol. 2012 Apr36(3)147-55. doi
10.3109/03091902.2012.660797
67
Thiazide effects on bone disease
The effect of thiazide/indapamide and K-Cit on
BMD of the L2L4 spine, femoral neck, and radial
shaft of hypercalciuric kidney stone formers
J Urol. 2003169465469
68
Stone Formation and Pregnancy Stone Analysis
CaOx and CaP stones (numbers above bars) formed
in pregnant women by gestation trimesters 1
(light green bars), 2 (red bars) and 3 (dark
green bars).
The Journal of Urology Volume 183, Issue 4 2010
1412 - 1416