autosomal dominant tubulo- insterstitial kidney...
TRANSCRIPT
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
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ATDTSEARWSE
C
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N
TC
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G S C G P G L D C V P E G D A L V A P Q
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W
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L
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LA
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D
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G
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C
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N
N
G
W
H
Q
K
Q
D
F
NI T
D
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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 ([email protected]) 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.