Genetic based renal transport disorder dr rani shal

1. ‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬

2. Genetically Based Renal Transport
Disorders
Dr. Rania Elshal
MNGH

3. 1. X-linked hypophosphatemic rickets (XLHR):
• Impaired proximal phosphate reabsorption.
• There are fewer units of the sodium-dependent
phosphate transporter type 2 (NaPi2) in the apical
membrane of proximal tubular cells, in which the
maximal transport capacity for phosphate is reduced.
• Mutations in a phosphate-regulating gene.
• It is the most common form of hereditary rickets.
Disorders of proximal tubular transport function:

4. • Excess fibroblast growth factor (FGF23).
• FGF23 inhibits renal phosphate reabsorption also
inhibits the 1-hydroxylation of 25-hydroxyvitamin D.
• Normal levels of 1,25-dihydroxyvitamin D
• Absence of hypercalciuria.
2. Autosomal dominant hypophosphatemic
rickets (ADHR):

5. • Defective protein: Dentin matrix protein 1 (a bone
matrix
protein that appears to play a role in regulating bone
mineralization and FGF23 production)
• Renal phosphate wasting.
• Normal levels of 1,25-dihydroxyvitamin D,
• Absence of hypercalciuria,
• Elevated serum levels of FGF23
3. Autosomal recessive hypophosphatemic
rickets:

6. • Primary defect in Sodium-phosphate cotransporter
Npt2c.
• An autosomal recessive disorder.
• Elevations of 1,25-dihydroxyvitamin D levels.
• FGF23 levels are normal or reduced.
4. Hereditary hypophosphatemic rickets with
hypercalciuria (HHRH):

7. • FGF23 (deficiency)
• Mirror image of ADHR and XLHR, with
• Excessive renal phosphate reabsorption,
hyperphosphatemia,
• Normal levels of 1,25-dihydroxyvitamin D,
• Low levels of FGF23.
5. Familial hyperostosis hyperphosphatemia

8. • An autosomal recessive.
• Mutations that inactivate the basolateral sodium
bicarbonate cotransporter NBC1.
• Ocular abnormalities, including blindness, band
keratopathy, cataracts, and glaucoma; these ocular
manifestations probably are a consequence of
impaired bicarbonate transport in the eye.
6. Proximal renal tubular acidosis (RTA):

9.  Generalized impairment in reabsorptive function of
the proximal tubule and comprises proximal RTA with
aminoaciduria, renal glycosuria, hypouricemia, and
hypophosphatemia.
 Some or all of these abnormalities are present in
patients with Fanconi syndrome.
 Inherited causes of partial or complete Fanconi
syndrome include hereditary fructose intolerance,
Lowe syndrome, and Dent disease.
7.Inherited fanconi syndrome:

10. Hereditary fructose intolerance:
• Deficiency of the aldolase B enzyme, which cleaves
fructose-1-phosphate.
• Symptoms are precipitated by intake of sweets.
• Hypoglycemic shock, severe abdominal symptoms,
metabolic acidosis.
• Rickets and stunted growth, Hyperuricemia,
hypermagnesemia
• Avoiding dietary sources of fructose can minimize acute
symptoms and chronic consequences such as liver disease.

11. Lowe syndrome
• Mutations in OCRL1
• Oculocerebrorenal syndrome
include congenital cataracts,
mental retardation, muscular
hypotonia, and the renal Fanconi
syndrome.
• Proteinuria, glycosuria,
aminoaciduria, and phosphaturia
• proximal RTA with growth
retardation.
• Rickets
• Kidney failure is common
occurring earlier.
Dent disease
• Mutations that inactivate the
chloride transporter CLC-5.
• Confined to the kidney
• Proteinuria.
• Glycosuria, aminoaciduria, and
phosphaturia (less common)
• Rickets
• Hypercalciuria,
nephrocalcinosis, kidney stones
• Kidney failure is common
occurring in young adulthood

12. Disorders of transport in the medullary
thick ascending limb of Henle

13. • Classic and the antenatal type
• Autosomal-recessive disorders.
• Type I--- Bumetanide-sensitive Na-K-2Cl cotransporter
NKCC2
• Type II ---Apical potassium channel ROMK
• Type III--- Basolateral chloride channel ClC-Kb
• Type IV, with sensorineural deafness--- Barttin (ClC-
Kb-associated protein)
• Familial hypocalcemia with Bartter features ---CaSR
(activation)
1. Bartter syndrome:

14. Clinical features:
• Antenatal Bartter syndrome has been observed in
consanguineous families in association with
sensorineural deafness.
• Manifests in infancy or childhood with polyuria and
failure to thrive, often occurring after a pregnancy with
polyhydramnios.
• Volume depletion activation of the renin- angiotensin
aldosterone axis
• Hypokalemic
• Metabolic alkalosis with hypercalciuria
• Serum magnesium levels are usually normal
• These patients resemble patients chronically taking loop

15. Diagnosis:
Must be distinguished from vomiting, diuretic administration, and
laxatives abuse.
Urinary Cl− concentration:
Normal or increased in Bartter syndrome
Low in the vomiting patient.
The therapy:
Repair of the hypokalemia through inhibition of the renin-
angiotensinaldosterone system or the prostaglandin-kinin system,
using;
- propranolol, amiloride, spironolactone, prostaglandin
inhibitors, and angiotensin-converting enzyme inhibitors.
- Direct repletion of the deficits with potassium and magnesium.

16. • An autosomal recessive.
• Without ocular abnormalities Claudin-16 (paracellin-1).
With ocular abnormalities Claudin-19.
• Both claudin 16 and claudin 19 are expressed in the
thick ascending limb (TAL), but claudin 19 also is
expressed in the retina. These two proteins interact in
the tight junction to regulate cation permeability.
• kidney failure, kidney stones, hypomagnesemia,
hypercalciuria and hyperuricemia.
2. Familial hypomagnesemia with hypercalciuria
and nephrocalcinosis

17.  CASR inactivation.
 Hypercalcemia with relative elevation of PTH levels.
 Urinary calcium excretion is low.
 It is benign, because tissues are resistant to the high serum
calcium levels.
 A family history helps to differentiate FHH from primary
hyperparathyroidism, and parathyroidectomy should not
be performed.
 Neonatal severe hyperparathyroidism:
 Infants of consanguineous parents with FHH can be
homozygous for these mutations, resulting in a syndrome
of severe hypercalcemia with marked
hyperparathyroidism, fractures, and failure to thrive
3. Familial hypocalciuric hypercalcemia
(FHH)

18.  Familial hypercalciuric hypocalcemia---
CaSR (activation).
Hypocalcemia with hypercalciuria without elevated PTH
concentrations.
 Familial juvenile hyperuricemic nephropathy:
Uromodulin (i.e., Tamm-Horsfall protein)
Hyperuricemia and gout.
This syndrome overlaps with medullary cystic kidney
disease type 2.

19. Disorders of transport in the distal
convoluted tubule

20.  An autosomal-recessive
 Mutations in the NCCT
Clinical features:
 Metabolic alkalosis is associated with hypokalemia.
 Normal-to-low blood pressure, volume depletion with
secondary hyperreninemic hyperaldosteronism.
 Hypocalciuria and hypomagnesemia are useful in
distinguishing Gitelman syndrome from Bartter syndrome.
 Features mimic the effects of chronic thiazide diuretic
administration
 Gitelman syndrome becomes symptomatic later in life and
is associated with milder salt wasting.
Gitelman Syndrome

21. Treatment:
 A diet high in potassium and potassium salts and
magnesium supplementation
 Amiloride with dose escalation to as much as 10 mg twice
daily
 Amiloride may be used in combination with spironolactone
or eplerenone.
 Dietary salt should be limited and foods high in salt
avoided.
 Angiotensin converting enzyme inhibitors may be used in
selected patients for which frank hypotension is not a
complication.

22. Liddle Syndrome
 β and γ subunits of epithelial Na channel on the apical
surface of the principal cells of the cortical collecting duct--
-excessive sodium channel activity.
 A n autosomal dominant
 Severe hypertension and hypokalemic metabolic alkalosis
 It resembles primary hyperaldosteronism, but serum
aldosterone and renin levels are quite low, and, for this
reason, the disease also has been called
pseudohyperaldosteronism.
Disorders of transport in the collecting
tubule

23.  Spironolactone had no effect on the hypertension,
patients did respond well to triamterene or dietary
sodium restriction
 Renal transplantation in Liddle’s original proband led
to resolution of the hypertension, consistent with
correction of the defect intrinsic to the kidneys.

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