autosomal dominant tubulo- insterstitial kidney...

Autosomal Dominant Tubulo-

Insterstitial Kidney Disease

(ADTKD)

Anthony J. Bleyer, M.D.

Wake Forest School of Medicine

Winston-Salem, NC

Autosomal Dominant Tubulo-

Insterstitial Kidney Disease• Medullary cystic kidney disease

• Medullary cystic kidney

disease/nephronophthisis

• Familial juvenile hyperuricemic

nephropathy

• Uromodulin kidney disease

Medullary Cystic Kidney

Disease• Forget about this term

• Medullary cysts are occasionally found in

individuals with these conditions

– Only seen in very advanced disease.

– Usually not seen on ultrasound/MRI/CT

– Sometimes seen in kidney biopsy

Tubulo-Interstitial Kidney

Disease• Not a glomerular disease

• No proteinuria

• No hematuria

• Renal ultrasound: unremarkable or small kidneys if late in the disease

• Kidney biopsy

– Secondary glomerular changes

– Tubular atrophy

– No tubulointerstitial inflammaiton

Inherited Tubulo-Interstitial Kidney Disease

Autosomal Dominant

Nephronophthisis

Autosomal Recessive

Childhood with

ESRD < 20

CKD

Ciliopathies

Salt wasting,

anemia

MCKD2

Gout (women, teens)

CKD in 3rd to 7th decade

UMOD

RENIN Anemia, hyperkalemia,

mild hypotension in

childhood

CKD in 3rd to 7th decade

Other

MUC1 MCKD1

CKD in 3rd to 9th decade

No other symptoms

• A 15 year old presents with anemia and

decreased vision

• Serum creatinine 400 mmol/l

• Urine: dipstick negative for blood, trace

protein.

• Renal ultrasound small kidneys

• Neither parent with kidney disease

• A brother with kidney disease

Family 11 Pedigree

I

II

III

88 85

31

15

Note characteristics of autosomal

dominant inheritance

Inherited Interstitial Kidney Disease

Autosomal Dominant

Nephronophthisis

Autosomal Recessive

Childhood

CKD

Ciliopathies

Salt wasting,

anemia

MCKD2

Gout (women, teens)

CKD in 3rd to 7th decade

UMOD

RENIN Anemia, hyperkalemia,

mild hypotension in

childhood

CKD in 3rd to 7th decade

Other

MUC1 MCKD1

CKD in 3rd to 9th decade

No other symptoms

Inherited Interstitial Kidney Disease

Autosomal Dominant

Nephronophthisis

Autosomal Recessive

Childhood

CKD

Ciliopathies

Salt wasting,

anemia

MCKD2

Gout (women, teens)

CKD in 3rd to 7th decade

UMOD

RENIN Anemia, hyperkalemia,

mild hypotension in

childhood

CKD in 3rd to 7th decade

Other

MUC1 MCKD1

CKD in 3rd to 9th decade

No other symptoms

Nephronophthisis

• Caused by mutations in genes expressed

in the renal tubular cilia

• Slowly progressive kidney disease

• Associated with: blindness, situs inversus

Friedhelm Hlidebrandt, MD

Corinne Antignac, MD

First Case 4/18/96

• 41 year old white male

– Serum Creatinine 300 mmol/l

• Urinalysis:

– Dipstick negative for blood

– Dipstick negative for protein

• Renal ultrasound unremarkable

Family Tree

Inherited Interstitial Kidney Disease

Autosomal Dominant

Nephronophthisis

Autosomal Recessive

Childhood

CKD

Ciliopathies

Salt wasting,

anemia

MCKD2

Gout (women, teens)

CKD in 3rd to 7th decade

UMOD

RENIN Anemia, hyperkalemia,

mild hypotension in

childhood

CKD in 3rd to 7th decade

Other

MUC1 MCKD1

CKD in 3rd to 9th decade

No other symptoms

Inherited Interstitial Kidney Disease

Autosomal Dominant

Nephronophthisis

Autosomal Recessive

Childhood

CKD

Ciliopathies

Salt wasting,

anemia

MCKD2

Gout (women, teens)

CKD in 3rd to 7th decade

UMOD

RENIN Anemia, hyperkalemia,

mild hypotension in

childhood

CKD in 3rd to 7th decade

Other

MUC1 MCKD1

CKD in 3rd to 9th decade

No other symptoms

First Case 4/18/96

• 41 year old white male

– Gout in late teens

– Noncompliant with allopurinol

– Development of tophi

– Many, but not all, family members had suffered from gout

• Women in their 30’s and 40’s

• Young men in their teens

– Gout occurred prior to onset of kidney dysfunction.

• Parents watched closely for the presence

of gout, which determined the fate of their

child.

• Working with Thomas Hart, DDS, over the

next six years we collected numerous

samples and were able to identify

mutations in the UMOD gene encoding

uromodulin as the cause of this condition.

What is Uromodulin?

• “Tamm Horsfall Glycoprotein”

• The most common urinary protein

• Synthesized only in the thick ascending

limb of Henle’s loop

Uromodulin

• The most cysteine residues of any known

human protein

• Extensive cross-linking in the endoplasmic

reticulum

Possible Uromodulin Functions

• Prevents urinary tract infection

• Prevents kidney stone formation

• Prevents inflammation in the kidney

• New data suggests that these are not the

current functions of uromodulin in humans.

Uromodulin

• Regulates movement of bumetanide –

sensitive Na K 2 Cl (NKCC2) transporter

• Patients who produce less uromodulin

excrete more sodium, have lower blood

pressures, and have less interstitial

fibrosis.

Renigunta A et al., J Biol Chem 2011

Mutig K et al. J biol Chem 2011

THP Production

• Uromodulin has more cysteines than any

other proteins in the body.

• These cysteines allow uromodulin to

cross-link.

• It is critical that the correct cysteines cross

linke for the function of the molecule.

• About 75% of mutations in UKD involve a cysteine.

• Almost all are predicted to affect structure

• No mutations resulting in truncation of the protein

• The abnormal uromodulin cannot form its normal structure. It precipiates in the cell and builds up.

L

H2

N-

EGF 1

EGF 2

M G Q P S L T WM

L

M

V

V

V

A

S

W

I

F

T

T

A

ATDTSEARWSE

C

H

S

N

TC

T

A

E

D

E

A

T

T

V

T

Q

E

G

T

F

G

D

G

LT

V

D

L D

A E

I P G

H A

S A N S

N V C S

P G S

V S F

P E

F G

R L

S

P

L

G

T

D V

D

A

E

EPG

L

H

C H S

A L A

T

V

N V

V G S

Y

C

V L

P A G

YRGD

G W H

E

EGF 3

SP

G S C G P G L D C V P E G D A L V A P Q

A

H

R

T

L

D

E

Y

W

S

T

E

Y

G

E

G

A

T

D

L

R

G

Y

F

V

G

Q

G

A R

M

A

E

T

V

P

V

L

N

A

A

P

M

L

N

G

T

H

P

S

S

D

E

G

I

V

S

R

K

AH

W

S

G

H

C

L

W

D

A

S

V

Q

V

K

A

A

G

Y

Y

V

Y

N

L

T

A

P

P

E

H

LA

Y CT

D

P

S

S

V

E

G

T

E

E

S

I

D

E

D

C

K

S

N

N

G

W

H

Q

K

Q

D

F

NI T

D

I

S

L

L

E

H

R

L

E C G A N D M K V S

LGKQLKSLG

F D K V F M Y L S D

SRCSGFNDRD

N D W V S V V T P

ARDGPCGTVL

T R N E T H A T Y S

NTLYLADEII

I R D L N I K I N F

ACSYPLDMKV

35

100

108

150

200

250

300

334

S L K434

T A L Q P M V

SALNIRVGGT

G M F T R M L F

QTPSYQPYQ

G S S V T L S T E A

FLYVTMLDG

G D L S R F A L L M

TNCYAP TSSN

A T D P L K Y F I I

QDRCPHTRDS

TC

C

C

C

C

C C

C

C

C

C

C

C

C

C

I Q V V E N G E S

SQ

Signal Peptide

GRFSVQMF

R F A G N Y D L V Y

DCEVYLCDT CC

M N E K C K P T C S

G

T

R

F

R

S

GS

V ID

Q

S

R

V

L

N

L

G

P

I

R

K

G

V

Q

A

TV

SR

A

F

S

S

L

G

L

L

K

V

L

W

P

L

L

LS

A

TL

TF

Q

534

600

Zona Pellucida

-COOH

614

TransmembraneDomain

Extracellular Matrix

Cell Membrane24

35

65

37

40

43

47

51

556

2

70

73

77

81

85

89

94 96

98

110

113

117

121

125

129

133

137

141

145

148

344

354

364

374

384

394

404

414

424

444

464

484

504

524

544

564

454

474

494

514

554

574

E

G

170

103

106

3234

63

50

112

122

D

172

173

174

178

184

R185

195

D196

W202

R204

G

210

217

R222

223

T225

229

W230

236

237

248

255

257

267

269

G270

273274

282

284

285

297

307

R

312

315

316

317

R

V A

T

G

T 605

177

188

Y

221

246

A

252

N

Cysteine-Rich 1

(149-199)

Domain of 8 Cysteines (199-287)

Cysteine-Rich 2 (287-334)

UMOD Mutations that Cause Uromodulin Kidney Disease

C

C

C

C CysteineCysteine mutation -substitution

Cysteine mutation - substitution & deletionCysteine mutation - substitution & inversion

Mutation - substitution

Mutation – substitution & deletion

Mutation – deletion

Mutation – inversion

Color-coding key:

C

C

C

C

C

C

C

C

C

C

C

C

C

C C

C

C

C

C

C

C

C

C

C

C

C

C

C

T

306

C

T Likely clinically silent mutation

Deletion 177-185

Deletion 188-221

Deletion 246-252

Estimated GFR (ml/min) vs. Age (years)

0

20

40

60

80

100

120

140

0 10 20 30 40 50 60 70

Age (years)

Es

tim

ate

d G

FR

(m

l/m

in)

Female

Male

How does the uromodulin mutation

cause gout?

Reabsorption

Reabsorption

depends on

volume status,

diuretics

Sodium Reabsorption

Reabsorption

Reabsorption

depends on

volume status,

diuretics

Sodium Reabsorption in UMOD

mutationDecreased UMOD

decreases NKCC2.

More sodium in the

urine.

Increased urine sodium causes

volume depletion and increased

proximal sodium uptake.

Reabsorption

depends on

volume status,

diuretics

Sodium Reabsorption

Na

Urate follows proximal Na

reabsorption. As more Na is

reabsorbed, more urate is

reabsorbed.

Reabsorption

depends on

volume status,

diuretics

Urate Reabsorption

Na

Na Urate

• Hyperuricemia and gout.

• More sodium is reabsorbed proximally.

• More urate is reabsorbed proximally.

• Hypouricosuric hyperuricemia

Diagnosis

• Suspect disease based on cardinal

manifestations

• Send sample for UMOD genetic analysis

• We can aid in the diagnosis of new cases.

Treatment

• Allopurinol is effective in the treatment of

gout and MAY slow progression of kidney

disease.

• Otherwise treatment is supportive.

• Patient should undergo pre-emptive

kidney transplantation.

Mutation UMOD REN MUC-1

Loss of normal

gene function

Urate

Gout

Tx of loss of fxn Allopurinol

Knockout mouse No effect

Gene deletion or

truncation

No effect

Abnormal

production

Intracellular

deposition,

Kidney failure

• 8 year old girl

• Anemia at 1 year testing

• Mild hypotension

• Serum potassium mildly elevated

• Acute kidney injury when given a non-steroidal

medication for a febrile illness.

• Father and granfather also with anemia in

childhood and kidney failure

Inherited Interstitial Kidney Disease

Autosomal Dominant

Nephronophthisis

Autosomal Recessive

Childhood

CKD

Ciliopathies

Salt wasting,

anemia

MCKD2

Gout (women, teens)

CKD in 3rd to 7th decade

UMOD

RENIN Anemia, hyperkalemia,

mild hypotension in

childhood

CKD in 3rd to 7th decade

Other

MUC1 MCKD1

CKD in 3rd to 9th decade

No other symptoms

Inherited Interstitial Kidney Disease

Autosomal Dominant

Nephronophthisis

Autosomal Recessive

Childhood

CKD

Ciliopathies

Salt wasting,

anemia

MCKD2

Gout (women, teens)

CKD in 3rd to 7th decade

UMOD

RENIN Anemia, hyperkalemia,

mild hypotension in

childhood

CKD in 3rd to 7th decade

Other

MUC1 MCKD1

CKD in 3rd to 9th decade

No other symptoms

• Decreased production of normal renin

• Deposition of abnormal renin intracellularly

Effects of Low Renin

• Low BP

• High normal potassium

• Anemia

• Predisposition to acute kidney injury

Anemia

• Low erythropoietin levels

• Due to decreased renin production– Similar to ACE inhibitor in ESRD

– Polycythemia in kidney transplantation

• Present by 1 year of age

• Found in all affected individuals

• Hgb from 8 to 10 g/dl.

• Responds to erythropoietin

• Resolves by adolescence due to sex steroid production

Normal BP Low

BP

Renin

causes

vasoconstric

tion

Low

ReninLow

Renin +

low BP

P

8 year old child with fever, nausea, headache – given ibuprofen

This constellation will lead to AKI

NormalNormal

AbnormalNormal

GenePromoter

We want to decrease production via the

promoter, but this will result in decreased

production of both alleles.

ReninNormal

Abnormal ReninNormal

Fludrocortisone

Negative feedback

Negative feedback

Fludrocortisone

Fludrocortisone Treatment

• Treats aldosterone deficiency

– Corrects mild hyperkalemia

– Decreases risk from volume depletion

• Removes “bad” renin

– Prevents tubulo-interstitial fibrosis

Fludrocortisone Treatment

Time BP Wt K Cr Uvol

-11wk 87/50 5.0 114 1825

-1wk 39.8 5.6 140 2275

1wk 106/69 40.9 4.2 96 2450

6wks 112/67 4.3 88 2675

Figure 2. Estimated Glomerular Filtration Rate vs. Age(Years)

20

30

40

50

60

70

80

90

0 10 20 30 40

Age (years)

Esti

mate

d G

FR

(m

l/m

in/1

.73m

2)

Patient AII6

Patient AIII2

Fludrocortisone

started.

Mutation UMOD REN MUC 1

Loss of normal

gene function

Urate

Gout

BP, Hgb

K, Urate

Tx of loss of fxn Allopurinol Fludrocortisone

Knockout mouse No effect Death in utero

Gene deletion or

truncation

No effect No effect for one

gene

Abnormal

production

Intracellular

deposition,

Kidney failure

Intracellular

deposition,

Kidney failure

Case Description

• 35 year old white female presents for evaluation of

serum creatinine 200 mmol/l

• The patient developed HTN (140/90) at age 34 which

has been easily treated with enalapril, 20 mg po q d.

• There is no history of anemia, hyperkalemia, or gout

• PE: Unremarkable

Case Description

• Urinalysis: Bland without blood or protein

• Renal ultrasound: Normal sized kidneys, no cysts

Family L1

I

II

III

IV

V

VI

VII

42.5*

35*

60

63*

42.5*32 34

41 39 29

42.5*

40 40*

25 38*

* *

Affected with ESRD age

Affected without ESRD age

Unknown genotype

Unaffected

* Historically Affected

Inherited Interstitial Kidney Disease

Autosomal Dominant

Nephronophthisis

Autosomal Recessive

Childhood

CKD

Ciliopathies

Salt wasting,

anemia

MCKD2

Gout (women, teens)

CKD in 3rd to 7th decade

UMOD

RENIN Anemia, hyperkalemia,

mild hypotension in

childhood

CKD in 3rd to 7th decade

Other

MUC1 MCKD1

CKD in 3rd to 9th decade

No other symptoms

Pathology

Medullary Cystic Kidney

Disease Type 1

• Autosomal dominant

• Slowly progressive chronic kidney disease

Linkage

• First performed by Otto, Hildebrandt in

2001

• Subsequently performed by other groups

• Consistent linkage to Chromosome 1

• 37 genes evaluated with mutational

analysis

SLIM INITIATIVE FOR

GENOMIC MEDICINE

2nd SAB MEETING

May 2-3 2011

MCKD1 genetics team

Linkage, sequence analysis

Andrew KirbyChristine StevensKiran GarimellaMark dePristoJim Robinson

Bioinformatics AnalysisJimmie YeNathalie PochetAviv RegevLizzy Rossin

MUC1, targeted sequence& assembly

Andi GnirkeDave JaffeChad Nusbaum

DNA sequencingJen BaldwinJane WilkinsonLauren AmbrogioSnaevar SigurdssonKerstin Lindblad-Toh

Clinical Phenotyping &Functional Insights

Tony BleyerSuzanne Hart

MUC1

• MUC1 is a membrane-

anchored mucoprotein

• Expressed in secretory

epithelium of the lungs,

kidneys, breasts, GI tract.

• Contains a VNTR unit for

glycosylation

Amino terminus

Extra C in Patient OK #563 Causes Frameshift

GTCACCTCGGCCCCGGACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCCcAGCCCACGGT

GTCACCTCGGCCCCGGACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCaAGCCCACGGT

GTCACCTCGGCCCCGGACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCCAGCCCACGGT

GTCACCTCGGCCCCGGACACCAGGCCcGCCCCGGGCTCCACCGCCCCCCCAGCCCACGGT

GTCACCTCGGCCCCGGACACCAGGCCGGCCCCGGGCTCCACCGCCCCCCCAGCCCACGGT

GTCACCTCGGCCCCGGAgAgCAGGCCGGCCCCGGGCTCCACCGCgCCCgCAGCCCACGGT

GTCACCTCGGCCCCGGAgAgCAGGCCGGCCCCGGGCTCCACCGCgCCCgCAGCCCACGGT

GTCACCTCGGCCCCGGAgAgCAGGCCGGCCCCGGGCTCCACCGCgCCCgCAGCCCACGGT

GTCACCTCGGCCCCGGAgAgCAGGCCGGCCCCGGGCTCCACCGCgCCCgCAGCCCACGGT

GTCACCTCGGCCCCGGAgAgCAGGCCGGCCCCGGGCTCCACCGCCCCCCCAGCCCACGGT

V T S A P D T R P A P G S T A P P S P R

C H L G P G H Q A G P G L H R P P S P R

C H L G P G H Q A G P G L H R P P S P R

C H L G P G H Q A R P G L H R P P S P R

C H L G P G H Q A G P G L H R P P S P R

C H L G P G E Q A G P G L H R A R S P R

C H L G P G E Q A G P G L H R A R S P R

C H L G P G E Q A G P G L H R A R S P R

C H L G P G E Q A G P G L H R A R S P R

C H L G P G E Q A G P G L H R P P S P R

MUC1 Mutation

• Results in addition of a cytosine to 7

cytosines

• Creation of a new repetitive unit that

repeats a unique number of times for each

family

• Self termination

• Cytosolic unit is not created

Mutant MUC1

protein

Theoretical Affect of MUC1

insertion• Mutation is in the VNTR

unit

• Causes a frameshift, resulting in VNTR truncation and creation of a neopeptide

• Neopeptide appears to be improperly processed in the cytoplasm

• Leads to apoptosis and slow, progressive tubular cell death

+

+

+

+

+

++

+

+

+

+

++

++

Dr. Stan Kmoch, Charles Medical School,

Prague

Normal and Mutant MUC1

Immunostaining

Mutant MUC1 and Breast Tissue

Skin Tissue

MUC1 Knockout Mouse

• No clinical disease

• Many mucoproteins

– Some functions may be interchangeable

MUC1

• Mutant seen in many tissues

• Only causes kidney disease

• In the knockout mouse, MUC1 does not

have an essential function.

• All patients have a mutation producing the

same mutant peptide.

Hypothesis

• There are many mucoproteins, and their

function overlaps.

• The absence of MUC1 is not important.

• There is some property of renal tubular

cells that make them very sensitive to the

abnormal MUC1, leading to slowly

progressive cell death.

Clinical Characterization

• 35 imaging studies (70 kidneys)

– Normal or small kidneys

– 49/70 kidneys no cysts

– 13/70 had one cyst

– No medullary cysts

– MCKD not suspected on any ultrasound

– CKD was most common diagnosis

Clinical Characterization

• 34 renal biopsies reviewed:

– All showed tubulo-interstitial kidney disease

– 4 microcystic dilation of the tubules

• 2 suggested medullary cystic kidney disease

• 1 suggested polycystic kidney disease

• 1 suggested tubular toxic injury

ESRD According to Family

0

10

20

30

40

50

60

70

80

90

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Ag

e E

SR

D

Families

Individuals

Median

24 1 5 12 11 8 4 7 L5 9 L6 L1 23 3 13 L3 6 L2 L4 2

Development of Genotyping

Assay• 21 additional potential families identified

– 18 families had the insertion

• All 24 families to date have the same type

of mutation

• We have subsequently identified another

20 families with the same type of mutation

Mutation UMOD REN MUC 1

Loss of normal

gene function

Urate

Gout

BP, Hgb

K, Urate

No other

symptoms

Tx of loss of fxn Allopurinol Fludrocortisone Supportive

Knockout mouse No effect Death in utero No effect

Gene deletion or

truncation

No effect No effect No effect

Abnormal

production

Intracellular

deposition,

Kidney failure

Intracellular

deposition,

Kidney failure

Intracelular

deposition,

Kidney failure

eGFR of MCKD1 Affected and

Unaffected Individuals

0

20

40

60

80

100

120

140

160

180

200

0,00 10,00 20,00 30,00 40,00 50,00 60,00 70,00 80,00 90,00

eG

FR

age

Affected

Unaffected

eGFR Decline in 12

MCKD1Individuals

0

10

20

30

40

50

60

70

80

90

100

20,00 30,00 40,00 50,00 60,00 70,00 80,00

eG

FR

Age

eGFR change ≥ 50 ml/min .99 ± 6 ml/in/year

eGFR change < 50 ml/min -6.7 ± 4 ml/in/year

p<0.001

Treatment

• Supportive

• Follow eGFR closely when <50 ml/min

• Do not allow kidney donation without

genetic testing for the mutation

Issues to Reconcile

• How does mutant MUC1 contribute to

pathology

• Why is pathology found only in the kidney?

• Why is there a variable rate of expression?

Identifying Families

• 450 families to date have contacted us

• 90 are positive for UMOD mutation

• 6 are positive for REN mutation

• 24 families with MUC1 mutation

Challenges

• Uncommon disorders

• Confusing terminology

• Predominant interest in glomerular

disease

• Kidney biopsies are not diagnostic

Genetic Testing

• Available in a research setting

• Remains extremely difficult to do

• Contact me (ableyer@wakehealth.edu) for

information

Inherited Tubulo-Interstitial Kidney Disease

Autosomal Dominant

Nephronophthisis

Autosomal Recessive

Childhood with

ESRD < 20

CKD

Ciliopathies

Salt wasting,

anemia

MCKD2

Gout (women, teens)

CKD in 3rd to 7th decade

UMOD

RENIN Anemia, hyperkalemia,

mild hypotension in

childhood

CKD in 3rd to 7th decade

Other

MUC1 MCKD1

CKD in 3rd to 9th decade

No other symptoms

Mutation UMOD REN MUC 1

Loss of normal

gene function

Urate

Gout

BP, Hgb

K, Urate

No other

symptoms

Tx of loss of fxn Allopurinol Fludrocortisone Supportive

Knockout mouse No effect Death in utero No effect

Gene deletion or

truncation

No effect No effect No effect

Abnormal

production

Intracellular

deposition,

Kidney failure

Intracellular

deposition,

Kidney failure

Intracelular

deposition,

Kidney failure

Research Team

Katerinacell biology

Helenapathology

Lenkamolecular biology

Janaimmunohistochemistry

Hátamolecular biology

Viktorbioinformatics

Stanislavgroup leader

Petrprotein analysis

MirekDNA sequencing

MCKD group Prague

Wake Forest

Medical

School

Uromodulin

• A ZP domain protein

• Carboxy terminal membrane domain

• Filaments are cross linked

• Heavily glycosylated

MOVE

Uromodulin

• 75,000 kD protein

• Monomers come together to form polymer

that is heavily glycated

• VERY insoluble

MOVE

THP Production

• Conversion of precursor (84 kD) to mature

form (97kD) depends on processing of

glycans in the Golgi apparatus

Serafini-Cessi F, et al.

Biochem Biophys Res

Comm 1993

MOVE

Figure 2. Tamm Horsfall Protein Excretion According to Creatinine Clearance

0

5

10

15

20

25

30

35

40

0 5 10 15 20 25 30

Creatinine clearance (ml/min)

Tam

m H

ors

fall p

rote

in 2

4 h

ou

r u

rin

ary

excre

tio

n (

mg

/d)

unaffected

mutation

Clinical Presentation

Nephronophthisis ADTKD (UMOD and MUC1)

Rare Rare

Autosomal recessive Autosomal dominant

Salt-wasting, fatigue

Anemia

Gout in teen years (UMOD)

Median ESRD 13 years Median ESRD 40

Bland urinary sediment Bland urinary sediment

Bx: tubulo-interstitial scarring Bx: tubulo-interstitial scarring

Conditions would not be difficult to distinguish, except for

confusing terminology, early misunderstanding, and their rarity.