HISTORY OF THE UNDERSTANDING

AND TREATMENT OF

CYSTINURIA

Matthew Lewis

Imperial

College London

International

Cystinuria

Foundation

A p o l l o P h y s i c i a n a n d A s c l e p i u s a n d H y g i e i a a n d P a n a c e a a n d a l l t h e g o d s a n d g o d d e s s e s , m a k i n g t h e m m y w i t n e s s e s , t h a t I w i l l f u l f i l l a c c o r d i n g t o m y a b i l i t y a n d j u d g m e n t t h i s o a t h a n d t h i s c o v e n a n t :

T o h o l d h i m w h o h a s t a u g h t m e t h i s a r t a s e q u a l t o m y p a r e n t s a n d t o l i v e m y l i f e i n p a r t n e r s h i p w i t h h i m , a n d i f h e i s i n n e e d o f m o n e y t o g i v e h i m a s h a r e o f m i n e , a n d t o r e g a r d h i s o f f s p r i n g a s e q u a l t o m y b r o t h e r s i n m a l e l i n e a g e a n d t o t e a c h t h e m t h i s a r t — i f t h e y d e s i r e t o l e a r n i t — w i t h o u t f e e a n d c o v e n a n t ; t o g i v e a s h a r e o f p r e c e p t s a n d o r a l i n s t r u c t i o n a n d a l l t h e o t h e r l e a r n i n g t o m y s o n s a n d t o t h e s o n s o f h i m w h o h a s i n s t r u c t e d m e a n d t o p u p i l s w h o h a v e s i g n e d t h e c o v e n a n t a n d h a v e t a k e n a n o a t h a c c o r d i n g t o t h e m e d i c a l l a w , b u t t o n o o n e e l s e .

I w i l l a p p l y d i e t e t i c m e a s u r e s f o r t h e b e n e f i t o f t h e s i c k a c c o r d i n g t o m y a b i l i t y a n d j u d g m e n t ; I w i l l k e e p t h e m f r o m h a r m a n d i n j u s t i c e .

I w i l l n e i t h e r g i v e a d e a d l y d r u g t o a n y b o d y i f a s k e d f o r i t , n o r w i l l I m a k e a s u g g e s t i o n t o t h i s e f f e c t . S i m i l a r l y I w i l l n o t g i v e t o a w o m a n a n a b o r t i v e r e m e d y . I n p u r i t y a n d h o l i n e s s I w i l l g u a r d m y l i f e a n d m y a r t .

I wi l l not use the knife, not even on suf ferers from stone, but wil l withdraw in favor of such men as are engaged in this work.

W h a t e v e r h o u s e s I m a y v i s i t , I w i l l c o m e f o r t h e b e n e f i t o f t h e s i c k , r e m a i n i n g f r e e o f a l l i n t e n t i o n a l i n j u s t i c e , o f a l l m i s c h i e f a n d i n p a r t i c u l a r o f s e x u a l r e l a t i o n s w i t h b o t h f e m a l e a n d m a l e p e r s o n s , b e t h e y f r e e o r s l a v e s .

W h a t I m a y s e e o r h e a r i n t h e c o u r s e o f t h e t r e a t m e n t o r e v e n o u t s i d e o f t h e t r e a t m e n t i n r e g a r d t o t h e l i f e o f m e n , w h i c h o n n o a c c o u n t o n e m u s t s p r e a d a b r o a d , I w i l l k e e p t o m y s e l f h o l d i n g s u c h t h i n g s s h a m e f u l t o b e s p o k e n a b o u t .

I f I f u l f i l l t h i s p a t h a n d d o n o t v i o l a t e i t , m a y i t b e g r a n t e d t o m e t o e n j o y l i f e a n d a r t , b e i n g h o n o r e d w i t h f a m e a m o n g a l l m e n f o r a l l t i m e t o c o m e ; i f I t r a n s g r e s s i t a n d s w e a r f a l s e l y , m a y t h e o p p o s i t e o f a l l t h i s b e m y l o t .

THE HIPPOCRATIC OATH

http://en.wikipedia.org/wiki/Hippocratic_Oath

ca. 460-370 BC

WILLIAM HYDE WOLLASTON

Chemist, physicist, and (briefly) physician

Notable contributions to science:

Developed the first physico-

chemical method for processing

platinum ore

Discoverer of two elements:

Palladium

Rhodium

Development of an improved electric battery

Inventor of the camera lucida

WILLIAM HYDE WOLLASTON

WILLIAM HYDE WOLLASTON

Wollaston crater

THE FIRST REPORTED CYSTINE STONES

First Published Report

July 5 th, 1810

William Hyde Wollaston presents his observation and analysis of two cystine stones to the Royal Society of London

Extracted from William Small, age 36

Observed by Wollaston sometime between 1805

and 1810

Originally part of a collection belonging to Guy’s

Hospital in London, formed by William Lucas Sr.

and Jr., successive surgeons to Guy’s from 1773

to 1824, during the course of their practice.

THE FIRST REPORTED CYSTINE STONES

THE FIRST REPORTED CYSTINE STONES

Alexander Marcet’s “An Essay on the Chemical History and

Medical Treatment of Calculus Disorders”, 2nd edition, 1819.

Courtesy of Will iam G.J. Edwards,

Curator, Gordon Museum

at

Guy’s Hospital

WILLIAM

SMALL

STONE

Names the substance “Cystic Oxide”

Taken from the bladder: cystic

Chemical observations: oxide

THE FIRST REPORTED CYSTINE STONES

+

“probably very rare”

“…one mass confusedly

crystallized throughout its

substance… yellowish

semi-transparency [and]

peculiar glistening

lustre…”

THE FIRST REPORTED CYSTINE STONES

Unable to describe the unique smell upon

burning, distinguishing it from other stone

types

RENAL ORIGIN

1817 - Stones reported in kidney

Alexander Marcet ’s Essay on the Chemical History and Medical Treatment of Calculus Disorders

Cystine staghorn used as evidence to conclusively state that kidney stones may form in the kidney lumen

“And as I am possessed of a calculus composed of cystic

oxyd… actually taken out of the kidney after death, there

can be no doubt… that all the varieties of calculi are liable

to originate in the kidneys…” (2nd edition, 1819)

(Guys Hospital physician from 1804 to 1819)

RENAL ORIGIN

Realization that “Cystic” is a misnomer

“The name renal or nephritic oxyd would

therefore be more appropriate. But unless

some great systematic object can be at stake,

there is so much less inconvenience incurred,

in chemical science, by retaining a name which

is not strictly accurate, than by changing

appellations which have been once established,

that I do not feel inclined to propose any new

name for the cystic oxyd.”

1817 – Marcet - observes for the first time a possible familial connection in cystine stone formation

Two brothers with cystine stones, possibly a third.

As more sibling (and one parent/child siblings) cases are recorded, the condition is often assumed to be inherited

FAMILIAL INHERITANCE

Chemist and London Physician

Notable contributions to science: Coined the term “convection” to

describe the heat transfer effect of currents

HCL in stomach juices

Classification of foods into carbohydrates, proteins, and fats

Hypothesized the existence of the proton (named after Prout by Ernest Rutherford in 1920) as the building block for atoms

WILLIAM PROUT

DISEASE PHYSIOLOGY

1823 – cystinuria due to a functional

disturbance in the kidneys

Cited by A. D. Stephens, Cystinuria

and its Treatment: 25 years

Experience at St. Bartholomew's

Hospital,

1820 – crystalluria and stone formation a consequence of excessive cystine excretion

130 years ahead of his time!

DISEASE PHYSIOLOGY

1823 – cystinuria due to a functional

disturbance in the kidneys

Cited by A. D. Stephens, Cystinuria

and its Treatment: 25 years

Experience at St. Bartholomew's

Hospital,

1820 – crystalluria and stone formation a consequence of excessive cystine excretion

130 years ahead of his time!

C3H7NO3

1833, Jöns Jacob Berzelius (a founder of modern chemistry)

not an oxide!

proposes “cystin(e)”

1837, Baudrimont and Malaguti

Cystine contains sulphur

1838, Thaulow

Agrees with early Prout analysis, but replaces oxygen with sulphur to yield correct molecular formula

ADVANCEMENTS IN CHEMICAL

CHARACTERIZATION 1 830’S TO 1903

C3H7NO2S

1899, Morner

Discovers cystine in protein (amino acid!)

Finds hydrolized hair to be rich in cystine

1901, Embden

Cystine isolated from serum and egg albumins

1902 & 1903, Neuberg & Friedmann

Correct structural formula

1903, Erlenmeyer

Cystine synthesized

confirms proper structure

ADVANCEMENTS IN CHEMICAL

CHARACTERIZATION 1 830’S TO 1903

1876 – A. Niemann.

Review of previous cases, comments on familial disposition

1897, Pfeiffer

4 cystinuric children, parents were 1st cousins

1899, Cohn

Cystinuric mother,

normal father

6 of 10 children cystinuric (1 set of twins)

FAMILIAL INHERITANCE LATE 1800’S

1889 – Von Udranszky &

Baumann

Presence of diamines in cystinuric urine

ADDITIONAL AMINO ACIDS

Ornithine Putrescine

Cadaverine

Lysine

1905 – Alsberg & Folin Abnormally large “undetermined nitrogen”

content in cystinuric urine during starvation

1908 – Wolf & Shaffer Confirmed high undetermined nitrogen

attributed in part to presence of additional amino acids

Generalized aminoaciduria?

ADDITIONAL AMINO ACIDS

1911 – Ackermann & Kutscher Presence of crystaline lysine derivatives in cystinuric urine

Equivalent of ~ 0.1g lysine /L urine

1947 – Yeh et al. Found arginine and lysine to be ~10x normal in cystinuric urine

Specific additional aminoacidurias!

1951 - Confirmed by Dent and Rose added to definition of cystinuric condition

1951– Stein Ornithine found in excess

MORE ON ADDITIONAL AMINO ACIDS

PAPER CHROMATOGRAPHY OF AMINO

ACIDS IN URINE

Cys

Arg

Lys

Normal urine Cystinuric urine

Fanconi

Syndrome

Advanced

Cirrhosis of

the Liver

Dent and Rose, 1951

1908 – Archibald Garrod

(London Physician)

Inborn Errors of Metabolism

Cystinuria due to an “arrest” in cystine metabolism

Defective metabolic enzyme inherited

INBORN ERRORS OF METABOLISM

PAPER CHROMATOGRAPHY OF AMINO

ACIDS IN BLOOD PLASMA

Dent and Rose – 1949/1951

When paper chromatographic analysis is applied to blood plasma of cystinuric subjects, no gross overabundance of cystine could be observed

Rejection of Garrod’s Inborn Error Hypothesis

X

Subsequent studies demonstrating significantly reduced cystine in cystinuric plasma. Dent, Senior, Walshe, 1954

Arrow & Westall, 1958

Brigham, Stein, Moore, 1960

Frimpter, Horwith et al 1962

Rosenberg, 1965

Morin, Thompson, Jackson and Sass-Kortsak, 1971

Martensson et al 1990

No studies supporting normal plasma cystine since 1954

ADDITIONAL REPORTS OF PLASMA CYSTINE

IN CYSTINURIA

Bro

wn

an

d L

ewis

19

37

Den

t an

d R

ose

, 19

51

Stei

n 1

95

1

Fow

ler

et a

l 19

52

Den

t H

eath

cote

an

d J

oro

n 1

95

4

Den

t, S

enio

r, a

nd

Wal

she

19

54

Arr

ow

an

d W

esta

ll 1

95

8

Bri

gham

, Ste

in, M

oo

re 1

96

0

Frim

pte

r H

orw

ith

et.

al 1

96

2

Wes

tall

19

62

Frim

pte

r 1

96

3

Lon

do

n a

nd

Fo

ley,

19

65

, p

.12

9

Ro

sen

ber

g 1

96

5

Frim

pte

r, V

ann

ucc

i, Sh

ibu

ya 1

96

8

Mo

rin

, Tet

al

Thei

r an

d S

egal

19

78

Mar

ten

sso

n e

t al

19

90

Sega

l an

d T

hei

r 1

99

5

Palacin, Goodyer, Nunes, Gasparini OMMBID

Scriver 2008

Chillaron, Bertran, Palacin: MTD, 2003

Segal and Their 1995

Martensson et al 1990

Stephens 1989

Morin, Thompson, Jackson and Sass-Kortsak 1971

Frimpter, Vannucci, Shibuya 1968

Pruzanski 1966

Rosenberg 1965

London and Foley, 1965, p.129

Frimpter 1963

Westall 1962

Frimpter Horwith et. al 1962

Brigham, Stein, Moore 1960

Arrow and Westall 1958

Dent, Senior, and Walshe 1954

Dent Heathcote and Joron 1954

Fowler et al 1952 *

Stein 1951

Dent and Rose, 1951

normal normal / slightly low

abnormal

Plasma [cystine]

Data reporting

publications

Citing

Publications

1965 – London and Foley

1966 – Rosenberg, Downing,

Durant, and Segal

Three phenotypes of cystinuria based

on urinary excretion of cystine and

dibasic (lysine, arginine and ornithine)

amino acids of the obligate

heterozygous parent—type I, type II,

and type III.

“CLASSICAL” CLASSIFICATION

“CLASSICAL” CLASSIFICATION

“CLASSICAL” CLASSIFICATION

1999 - Feliubadaló, L. et al.

Type I (including patients formerly also classified as ‘type I’)

Nontype I (including former type II and type III)

Mixed type cystinuria (also known as type I/nontype I)

2002 - Dello Strologo, L. et al.

Enhansed genetic understanding...

Type A (if mutations are found in both SLC3A1 alleles)

Type B (if mutations are found in both SLC7A9 alleles)

Putative type AB (if one mutation is found in each gene)

MODERN CLASSIFICATION(S)

1994 - . Pras, E. et al. and

Calonge, M. J. et al.

Genetic and mutational analysis

studies show that mutations in

SLC3A1 cause cystinuria.

(SLC3A1 is a gene which codes for the

neutral and basic amino acid transport

protein rBAT)

1999 - Feliubadaló, L. et al.

Mutations in another gene - SLC7A9

can also cause cystinuria

(SLC7A9 is a gene which codes for a

subunit of rBAT named (b0, +AT)

ADVANCEMENT OF GENETIC AND

BIOCHEMICAL UNDERSTANDING

Pathophysiology and treatment of cystinuria

Josep Chillarón, Mariona Font-Llitjós, Joana

Fort, Antonio Zorzano, David S. Goldfarb,

Virginia Nunes

and Manuel Palacín

Two mouse models for study:

Mutation in Slc3a1 (rBAT)

Slc7a9 knockout (b0, +AT)

“Both mouse models produce cystine stones at high

rates and have morphological changes in kidney

architecture that result from obstruction and

inflammation .”

MODEL ORGANISMS FOR STUDY

TREATMENT

Water

Use for stone treatment predates cystinuria

Diuretics

Recommended by Prout in 1821, maybe earlier

Home remedies for pain and stone passage, warm bath, etc.

Prout, 1821, maybe earlier

Alkaline therapy

Henry, 1819; Prout, 1825

Concern with encouraging phosphate stones was known

Potassium citrate & bicarbonate used as early as 1880, Cantani

Successful dissolution of stones with K-Cit and K-bicarb 1914, Klemperer & Jacoby

Successful dissolution of stones, verified by x-ray

Protein restriction

As long as cys known to be in protein!

D-Pennicillamine, Thiola

Time for something new???