dr monika

1. Hereditary
tubulopathy
BY DR MONIKA
DM RESIDENT, SAVEETHA MEDICAL COLLEGE

2. introduction
 kidney tubules provide homeostasis by maintaining the external milieu that is critical for proper
cellular function.
 Without homeostasis, there would be no heartbeat, no muscle movement, no thought,
sensation, or emotion.
 The task is achieved by an orchestra of proteins, directly or indirectly involved in the tubular
transport of water and solutes.
 Inherited tubulopathies are characterized by impaired function of one or more of these specific
transport molecules.
 The clinical consequences can range from isolated alterations in the concentration of specific
solutes in blood or urine to serious and life threatening disorders of homeostasis

7. PHYSIOPATHOLOGICAL CLASSIFICATION OF HEREDITARY TUBULOPATHY
1. Inherited Disorders Associated with Generalized Dysfunction of the
Proximal Tubule (Renal Fanconi’s Syndrome)
1. Idiopathic
2. Dent’s Disease
3. Oculocerebrorenal Dystrophy (Lowe’s Syndrome)
4. Cystinosis
5. Glycogenosis (von Gierke’s Disease)
6. Tyrosinemia
7. Galactosemia
8. Wilson’s Disease
9. Hereditary Fructose Intolerance

8. 2. Inherited Disorders of Renal Amino Acid Transport
1. Cystinuria
2. Lysinuric Protein Intolerance
3. Hartnup’s Disease
4. Iminoglycinuria
5. Dicarboxylic Aminoaciduria

9. 3. Inherited Disorders of Renal Phosphate Transport
1. Renal Phosphate Excretion
2. Renal Phosphate Transporters
3. X-Linked Hypophosphatemic Rickets (XLH)
4. Autosomal Dominant Hypophosphatemic Rickets
5. Autosomal Recessive Hypophosphatemic Rickets
6. Hereditary Hypophosphatemic Rickets with Hypercalciuria
7. Familial Tumoral Calcinosis
8. Hereditary Selective Deficiency of 1α,25(OH)2D3
9. Hereditary Generalized Resistance to 1α,25(OH)2D3
10. Resistance to Parathormone Action

10. 4. Inherited Disorders of Urate Transport
Familial Renal Hypouricemia
5. Inherited Disorders of Renal Glucose Transport
1. Renal Glucosuria
2. Glucose-Galactose Malabsorption
6. Inherited Disorders of Acid-Base Transporters
1. Proximal Renal Tubular Acidosis (Type II RTA)
2. Distal Renal Tubular Acidosis

11. 7. Bartter’s and Gitelman’s Syndromes
8. Inherited Disorders with Hypertension and Hypokalemia
1. Congenital Adrenal Hyperplasia
2. Liddle’s Syndrome
3. Apparent Mineralocorticoid Excess
4. Autosomal Dominant Early-Onset Hypertension with Severe Exacerbation during
Pregnancy
5. Glucocorticoid-Remediable Hyperaldosteronism (GRA)
6. Familial Hyperaldosteronism (FH) Type II
9. Pseudohypoaldosteronism
1. Pseudohypoaldosteronism (PHA) Type 1
2. Pseudohypoaldosteronism Type 2

12. 10. Inherited Disorders of Renal Magnesium Processing
1. Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis
2. Familial Hypomagnesemia with Secondary Hypocalcemia
3. Isolated Dominant Hypomagnesemia with Hypocalciuria
4. Ca2+/Mg2+-Sensing Receptor–Associated Disorders
5. Isolated Recessive Hypomagnesemia with Normocalciuria
11. Diabetes Insipidus

13. Central Role of Salt
 On average, the human adult kidney filters approx150–180 L of water and 20–25
mol of sodium/day, of which typically >99% is then reabsorbed back into the
circulation by multiple sodium transport systems along the nephron
 The engine that drives tubular transport is the Na+K+ATPase, located on the
basolateral aspect of the tubular epithelial cells.
 It provides crucial electrochemical gradient that facilitates sodium entry from the
tubular lumen.
 Consequently, this gradient is used for the transport of many other solutes, such
as glucose,various amino acids and phosphate (by cotransport),protons and
potassium (by exchange), or calcium and uric acid (by facilitated diffusion)

15. Salt transport in the TAL of the loop of Henle. 0% to 20% of
filtered Na is reabsorbed here. The furosemide-sensitive
cotransporter Na-K-2Cl-ATPase (NKCC2, mutations of which cause
Bartter syndrome type 1 (BS1)) provides Na+ entry into the
epithelial cell. Apical K+ recycling through the ROMK channel (the
cause of BS2) ensures the efficient functioning of NKCC2,
establishing a lumen-positive transepithelial voltage that drives
paracellular cation reabsorption. Chloride exits through basolateral
Cl− channels, predominantly CLCNKB (the cause of BS3). The β-
subunit (barttin, cause of BS4) is necessary for normal functioning
of CLCNKB.
Salt transport in the DCT. 5-10% of filtered Na+ is reabsorbed
here via the thiazide-sensitive Na+-Cl− cotransporter (NCCT, the
cause of Gitelman syndrome) on the apical side. CLCNKB is
expressed here as well as in TAL; therefore mutations in this
channel cause BS3 (a TAL disorder), but can phenocopy Gitelman
syndrome (a DCT disorder).
Salt transport in principal cell of the CD. 2-5% of filtered Na+ is
reabsorbed here via the amiloride-sensitive ENaC. Loss-of-function
mutations in ENaC cause pseudohypoaldosteronism type 1 (PHA1),
gain-of-function mutations cause Liddle syndrome. Na+ uptake is
indirectly coupled to K+ (through ROMK) and H+ secretion (through
H+-ATPase in the neighboring intercalated cell). Aldosterone
activates the mineralocorticoid receptor, increasing activity of ENaC
and Na+,K+-ATPase, enhancing Na+ reabsorption and K+ and H+
secretion, resulting in hypokalemic alkalosis. Cortisol is also a ligand
for the mineralocorticoid receptor but is normally removed by

20. Activation of the basolateral arginine vasopressin type 2
receptor (AVPR2) initiates the signaling cascade that ultimately
results in insertion of the aquaporin 2 (AQP2) water channel in
the apical membrane, making it water permeable and thus
allowing water reabsorption and urinary concentration. Loss-of-
function mutations in AVPR2 cause X-linked nephrogenic
diabetes insipidus, whereas gain-of-function mutations cause
nephrogenic syndrome of inappropriate antidiuresis. Loss-of-
function mutations in AQP2 are the cause of autosomal
nephrogenic diabetes insipidus.

24. Renal tubular acidosis
 arises from the kidney’s inability to excrete enough acid or retain enough HCO3-, resulting in a clinical
syndrome characterized by nongap metabolic acidosis, hyperchloremia, and impaired urinary
acidification.
 These disorders can be primary, originating from genetic defects on tubular transport mechanisms, or
secondary to systemic diseases and to adverse drug reactions
 Distal RTA can be transmitted as either AD or AR trait, whereas isolated proximal RTA usually occurs as
an AR disease
 classified into 4 main subtypes:
 distal RTA, proximal RTA, combined proximal and distal RTA, and hyperkalemic RTA.
 Distal RTA (type 1) caused by the defect of H(+) secretion in the distal tubules, characterized by the
inability to acidify the urine below pH 5.5 during systemic acidemia.
 Proximal RTA (type 2) caused by an impairment of bicarbonate reabsorption in the PT, characterized
by a decreased renal bicarbonate threshold.
 Combined proximal and distal RTA (type 3) secondary to a reduction in tubular reclamation of
bicarbonate and an inability to acidify the urine in the face of severe acidemia.
 Hyperkalemic RTA (type 4) may occur as a result of aldosterone deficiency or tubular insensitivity to
aldosterone.

29. DRTA
 Type A intercalated cell of the collecting duct
displaying five pathophysiologic defects that
could result in classical distal renal tubular
acidosis:
 (1) defective H+–adenosine triphosphatase
(H+-ATPase),
 (2) defective H+-K+-ATPase,
 (3) defective HCO3–/Cl– exchanger,
 (4) H+ leak pathway, and
 (5) defective intracellular carbonic anhydrase
(type II).

30. A negative UAG (more than –20 mEq/L) provides evidence that sufficient NH4
+ is
present in the urine, as might occur with an extrarenal origin of the hyperchloremic
acidosis. Conversely, urine estimated to contain little or no NH4
+ has more Na+ +
K+ than Cl– (UAG is positive), which indicates a renal mechanism for the
hyperchloremic acidosis, such as in cDRTA (with hypokalemia) or hypoaldosteronism
with hyperkalemia.
Urinary ammonium concentrations of 75 mEq/L or more would be
anticipated if renal tubular function is intact and the kidney is
responding to the prevailing metabolic acidosis by increasing
ammonium production and excretion.
Conversely, values below 25 mEq/L denote inappropriately low urinary
ammonium concentrations.
In addition to the UAG, the fractional excretion of Na+ may be helpful
and would be expected to be low (<1% to 2%) in patients with HCO3
–
loss from the gastrointestinal tract but usually exceeds 2% to 3% in
patients with RTA

33. Net acid excretion is always decreased; however, the
urine pH can be variable. In structural disease of the
kidney, the predominant defect is usually decreased
distal H+ secretion and the urine pH is above 5.5. In
disorders associated with decreased mineralocorticoid
activity, urine pH is usually below 5.5.

38. Disorders of Sodium Handling
1. Hypokalemic alkalosis and low-normal BP (Bartter syndrome, Gitelman
syndrome, EAST syndrome)
2. Hypokalemic alkalosis and high BP (Liddle syndrome, apparent
mineralocorticoid excess, glucocorticoid-remediable hyperaldosteronism,
adrenal 17α-hydroxylase deficiency, adrenal 11β-hydroxylase deficiency)
3. Hyperkalemic acidosis and low-normal BP (PHA1, adrenal 21-hydroxylase
deficiency, adrenal aldosterone synthase deficiency)
4. Hyperkalemic acidosis and high BP (Gordon syndrome)

39. Bartter Syndrome
 Hypokalemia, Metabolic Alkalosis, and Low-Normal Blood Pressure
 genetically heterogeneous autosomal recessive disorder of salt reabsorption in the
TAL
 four causative genes-
 NKCC2 for BS1
 ROMK for BS2
 ClCKNB BS3
 BSND for BS4
 Bartter type 5 - familial hypocalcemic hypercalciuria, caused by activating
mutations in CaSR, encoding the calcium-sensing receptor, can cause Bartter-like
electrolyte abnormalities

40.  TAL is an important segment for Ca reabsorption, which occurs passively through
paracellular pathways, lined by claudins.
 Driving force for this is generated by the combined action of NKCC2 and ROMK.
 Whereas transport via NKCC2 is electroneutral, K is recycled back into the tubular lumen
via ROMK, establishing a lumen positive transepithelial potential.
 Consequently, Ca reabsorption in the TAL is impaired in BS1 and BS2, leading to
hypercalciuria and nephrocalcinosis, whereas it is typically unaffected in BS3 and BS4.
 CLCKNB is also expressed in the DCT, so symptoms of BS3 can overlap with Gitelman
syndrome.
 Hypomagnesemia is thus a common feature.
 Barttin is also critical for inner ear function, so affected pts have sensorineural deafness
in addition to Bartter syndrome.

41.  initial step of TGF occurs in the macula densa, which is part of the TAL
 reduced Cl− absorption in the macula densa initiates a signaling cascade
that includes enhanced PGE2 production with consequent activation of
renin and aldosterone.
 Because Cl− absorption is impaired in Bartter syndrome, these pts have
impaired TGF with elevated levels of PGE2, renin, and aldosterone, and it is
the latter that mediates the typical electrolyte profile of hypokalemic
metabolic alkalosis

42.  C/F –
 BS from mutations in NKCC2, ROMK, or Barttin usually has earlier onset than that caused by mutations
of CLC-Kb, mostly during pregnancy (antenatal Bartter syndrome), often called classic Bartter
syndrome, reflecting the phenotype originally described by Bartter and colleagues.
 Antenatal Bartter syndrome - polyuria, hypokalemic metabolic alkalosis, and high urine Cl- excretion
in a newborn with vomiting and failure to thrive and a h/o polyhydramnios and premature delivery.
 prenatal diagnosis of Bartter syndrome - demonstration of high Cl− concentrations in amniotic fluid, if
genetic testing is not informative.
 BS2, secondary to ROMK mutations, can have a different phenotype in the first days of life, because
ROMK is not only involved in salt reabsorption in the TAL, but also mediates K+ secretion in the CD.
 Consequently, pts with BS2 often present initially with hyperkalemia and hyponatremia, leading to an
erroneous diagnosis of PHA1.
 Over the course of the 1st few days to weeks, S K+ decrease, presumably as a result of the expression of
other K+ channels in the CD that compensate for the loss of ROMK function.
 Hypercalciuria and nephrocalcinosis are typical features of BS1 and BS2.

43.  Classic Bartter syndrome - mutations in CLCNKB (BS3).
 present mostly in the 1st decade of life with vomiting, polyuria, recurrent
episodes of dehydration, and hypokalemic metabolic alkalosis.
 Electrolyte abnormalities are typically more severe than in antenatal Bartter
syndrome.
 hypomagnesemia with renal Mg2+ wasting is common. some can
phenotypically mimic Gitelman syndrome.

44.  BS4 - sensorineural deafness, manifests as a severe form of BS3,
sometimes with extreme electrolyte abnormalities.
 typically experience progressive chronic kidney disease, although a milder
phenotype has been reported, presumably due to mutations with residual
Barttin function
 Presumably, in BS3, the closely related chloride channel CLC-Ka can
compensate for the loss of CLC-Kb function in the inner ear and to some
degree in the kidney.
 However, both channels require Barttin as a subunit, so that loss-of-
function mutations in Barttin are functionally equivalent to loss of both Cl-
channels.

45.  Diagnosis and Differential Diagnosis
 hypokalemic, hypochloremic alkalosis with evidence of renal Cl− and K+ wasting
and low or normal BP.
 evaluating the BP and urinary Cl- concentration
 clinical picture can be mimicked by extrarenal loss of Na, in diarrhea, vomiting,
or burns and is characterized by very low Cl− excretion in the urine, (FECl <0.5%)
 urinary Ca2+ excretion can help distinguish between the various forms of BS and
Gitelman syndrome
 Genotyping

47.  T/T - fluid and electrolyte correction
 KCL supplementation
 Addition of spironolactone or amiloride - improves hypokalemia and alkalosis but worsens
salt wasting ,increases the risk for hypovolemic shock. If used, sufficient salt
supplementation is critical
 dramatic swings in S K+ a/w large doses of intermittent supplementation may be more
harmful than consistent levels below the normal range.
 large doses of supplementation may cause gastrointestinal disturbances, such as ulcers and
diarrhea, that can worsen the electrolyte profile.
 Thus smaller but more frequent administration of electrolyte supplements may be better
tolerated and safer.
 In antenatal BS - COXi such as indomethacin (1 to 3 mg/kg/24 h).
Selective COX-2 inhibitors similar efficacy ,less toxicity.

48.  Outcome
 Cx – ICH & bronchopulmonary dysplasia, in antenatal BS
 arrhythmias, paralysis, rhabdomyolysis, and apnea
 Progressive CKD (prematurity), but also can be seen in patients with BS3
born at term and is common in BS4

49. Gitelman Syndrome
 autosomal recessive
 most frequently inherited tubulopathy
 Pathogenesis- defect in DCT, inactivating mutations in SLC12A3(gene encoding the
thiazide-sensitive transporter NCCT
 Loss of NCCT function results in Na+ and Cl− wasting from this segment, leading to
hypovolemia with secondary activation of RAS
 As in Bartter syndrome, the resulting increase in Na+ reabsorption in the CD is
counterbalanced by K+ and H+ excretion, causing hypokalemic alkalosis.
 hypocalciuria (enhanced PT Ca reabsorption, secondary to plasma volume
contraction)
 Renal Mg wasting (downregulation of the epithelial Mg channel TRPM6 in DCT)

50.  C/F and Diagnosis-
 generalized muscle weakness, inability to work for extended periods, salt
craving, and polyuria
 Cardiac disturbances, muscle cramps, and tetany rarely
 Chondrocalcinosis and sclerochoroidal calcifications can occur later in life
 hypokalemic hypochloremic metabolic alkalosis with hypocalciuria and
hypomagnesemia with elevated urinary Cl−, K+ and Mg2+ excretion.
 BP usually low-normal
 D/Ds - Bartter syndrome, especially BS3, HNF1B-related disease, EAST
syndrome, acquired disorders, such as thiazide abuse and Sjögren
syndrome.
 Genotyping- confirmatory
 T/T - liberal salt intake, K+ and Mg2+ supplements , K+-sparing diuretics
(may lead to salt wasting )

51. Liddle Syndrome
 autosomal dominant
 enhanced Na+ reabsorption through ENaC, independent of MR activation ,renin and aldosterone levels are
suppressed, no response to MR blockers, such as spironolactone or eplerenone
 Responds to triamterene and amiloride,
 Pathogenesis – gain-of-function mutations in ENaC
 Clinical Manifestations and Diagnosis-
 HT , typically presents in teenage children with hypokalemic metabolic alkalosis and low blood levels of renin and
aldosterone.
 onset as early as the newborn period has been described.
 distinguished from primary hyperaldosteronism or renal artery stenosis by the finding of low renin and aldosterone
levels.
 Other conditions with similar phenotype include apparent mineralocorticoid excess, and glucocorticoid-remediable
aldosteronism , as well as 11β-hydroxylase (steroid 11β-monooxygenase) or 17α-hydroxylase (steroid 17α-
monooxygenase) deficiency and can be separated by urinary steroid profiles and genetic testing.
 An activating mutation of the MR with exacerbation of hypertension in pregnancy has also been reported and
should be differentiated.
 T/T - triamterene or amiloride

53. Apparent Mineralocorticoid Excess
 autosomal recessive
 deficiency of the type II (renal and placental) isoform of the enzyme 11β-
hydroxysteroid dehydrogenase(metabolizes cortisol to cortisone)
 C/F - similar to Liddle syndrome, but symptoms typically present earlier (in
infancy) and more severely
 Carbenoxolone and glycyrrhizic acid (found in licorice compounds) are
potent inhibitors of this enzyme, consumption can lead to an acquired form
of AME.
 HSD11B2 is also expressed in the placenta(leading to IUGR)
 C/F - early onset of severe HT in childhood, hypokalemia, metabolic alkalosis,
with suppressed plasma renin and aldosterone, and increased metabolites of
cortisol in the urine.
 A h/o low birth weight and subsequent failure to thrive is typical.
 Untreated, stroke and other complications of severe hypertension are seen
even during childhood.
 Polyuria

54.  Diagnosis - urinary steroid profile is diagnostic (elevated urinary
hydrogenated metabolites of cortisol , tetrahydrocortisol plus
allotetrahydrocortisol, compared with cortisone tetrahydrocortisone).
 Ratio of urinary free cortisol to cortisone is also increased.
 Genetic testing confirms the diagnosis.
 Treatment - Blockers of MR (e.g., spironolactone or eplerenone)

55. Glucocorticoid-Remediable Aldosteronism
 autosomal dominant
 features typical of primary hyperaldosteronism: HTN, suppressed plasma renin
activity, and hypokalemia.
 Unlike primary hyperaldosteronism (secondary to aldosterone-producing adrenal
adenoma), hypersecretion of aldosterone in GRA can be reversed by the
administration of corticosteroids
 hemorrhagic stroke, largely from ruptured intracranial aneurysms.
 Pathogenesis – ACTH sensitive aldosterone production occurring in the zona
fasciculata of the adrenal gland, which is normally responsible only for cortisol
synthesis.
 The two isoenzymes of 11β-hydroxylase involved in the biosynthesis of aldosterone
and cortisol are steroid 11β hydroxylase (CYP11B1) and aldosterone synthase
(CYP11B2), respectively.
 On long arm of chromosome 8. Unequal meiotic crossovers may produce hybrid
genes by fusion of the promoter end of CYP11B1 with the coding sequence of
CYP11B2, so that CYP11B2 encoding aldosterone synthase is inappropriately
regulated by ACTH.

56.  Diagnosis –
 Suspect / candidates for GRA testing when –
 early-onset hypertension
 early cerebral hemorrhage (<40 years)
 hypokalemia before or after diuretic therapy
 refractoriness to standard antihypertensive medication
 especially in the presence of a family history of HTN or early death.
 Similar to other genetic forms of hypertension (Liddle syndrome, AME,
syndrome), plasma renin activity is low.
 Aldosterone levels normal to high and do not change with posture but are
suppressed by dexamethasone
 urinary steroid profile - increased levels of hybrid steroids (18-hydroxycortisol
and 18-oxocortisol). Genetic testing confirms the diagnosis
 T/T - low-dose corticosteroid , dexamethasone 0.125 to 0.25 mg or
prednisolone 2.5 to 5 mg is administered at bedtime
 MR antagonists (spironolactone, eplerenone)

57.  hyponatremia, hyperkalemia, metabolic acidosis, and low-normal BP have
features of mineralocorticoid deficiency either because of a synthetic
defect or because of end-organ resistance
• Pseudohypoaldosteronism –
• state of renal tubular unresponsiveness to the action of aldosterone.
• Symptoms start in infancy with marked salt wasting and failure to thrive
• PHA1 - autosomal dominant (adPHA1) and an autosomal recessive form (arPHA1).
• adPHA1 is due to inactivating mutations in the MR (NR3C2).
• In contrast, arPHA1 is due to inactivating mutations of the α, β, or γ subunits of ENaC
• presents typically in the first few days of life with weight loss, hypovolemia, and poor feeding.
• typical electrolyte profile shows mild to moderate hyponatremia, often severe (arPHA1) hyperkalemia, and
metabolic acidosis.
• Urinary Na+ is high, with virtually absent K+ excretion.
• Occasionally, patients with BS2 can present similarly
• PHA1 can be distinguished from aldosterone deficiency states, such as congenital adrenal hyperplasia, by
the massively elevated aldosterone levels in blood.
• confirmed by genetic testing.
• An acquired form of PHA1 can be seen with urinary tract obstruction and/or pyelonephritis.

58.  C/F - electrolyte abnormalities and hypovolemia, circulatory shock.
 ENaC is also expressed in the skin and lungs, where it mediates salt reabsorption.
 Consequently, patients with arPHA1 have increased sweat Na+ concentration and can
develop a miliary rash from blockage of the sweat glands.
 In addition, patients can have cystic fibrosis–like lung disease secondary to viscous high-
salt containing bronchial secretions.
 T/T - volume resuscitation with 0.9% saline
 Maintenance t/t -NaCl & NaHCO3 supplementation adjusted to maintain euvolemia,
normonatremia, and acid-base homoeostasis.
 In arPHA1, Na+ exchange resins
 adPHA1 typically improve spontaneously over 1st few months of life and maintain
normal serum electrolytes without supplementation, although may have increased
renin-aldosterone levels

59. A Condition with Hyperkalemia, Metabolic Acidosis, and Hypertension
Pseudohypoaldosteronism Type 2 (Gordon Syndrome)
 clinical mirror image of Gitelman syndrome,
 autosomal dominant
 characterized by HTN, hyperkalemia, and mild hyperchloremic metabolic acidosis
 Defect in 2 genes which encode 2 members of with-no-lysine kinase family: WNK1 and WNK4, expressed in convoluted tubule and CDs.
 WNK4 acts as a negative regulator of thiazide-sensitive NCCT function reducing cell surface expression of NCCT.
 WNK4 also downregulates ROMK and epithelial Cl- flux.
 Mutations in WNK4 are missense and cause loss of function, so that WNK4 loses its ability to suppress NCCT and ROMK, leading to Na+ and K+ retention.
 WNK1 prevents WNK4 from interacting with NCCT.
 Mutations in WNK1 are intronic deletions that increase WNK1 expression.
 Other causative genes : CUL3 and KLHL3.34
 Their encoded proteins form a ubiquitin-ligase complex that regulates WNK1 and 4 abundance.
 Mutations in KLHL3 also can be autosomal recessive.
 mutations in CUL3 frequently de novo, so the absence of a family history does not exclude the diagnosis.
 An acquired form of PHA2 may occur as a side effect of calcineurin inhibitors, especially tacrolimus, which affect WNK activity.
Clinical Manifestations and Diagnosis
 Hyperkalemia may be present from birth, but as in GRA, HTN may manifest later in life.
 hyperchloremic metabolic acidosis; plasma renin and aldosterone Low
 Patients with CUL3 mutations appear to be phenotypically more seriously affected with higher serum K+ levels, more pronounced acidosis and hypertension and consequently younger age at
diagnosis.
 most patients with CUL3 mutations have failure to thrive and growth impairment.
Treatment
 Thiazides

60. Inherited Disorders of Water Handling
Congenital Nephrogenic DI
 polyuric ,failure to concentrate urine despite elevated levels of vasopressin
 mutations in key proteins controlling water reabsorption in the CD.
 > 90% X-linked recessive NDI with mutations in AVPR2
 Mostly male, female carriers can have a urinary concentrating defect of variable
severity, presumably resulting from non-random X-inactivation
 AVPR2- expressed predominantly in kidney, also in vasculature, mediates
vasodilatation and release of VWF.
 <10% AR mutations in AQP2, final effector protein in the vasopressin-initiated
signaling cascade.
 rarely AD form of NDI, resulting from dominant negative mutation in AQP2
 Bartter syndrome and AME also can be a/w so-called secondary inherited NDI.

61.  C/F – usually present in 1st weeks to months of life
 Polyuria, failure to thrive, vigorous sucking f/b vomiting
 repeated episodes of hypernatremic dehydration, with delayed development
and cognitive impairment
 Cranial CT - occasionally show dystrophic calcification in the basal ganglia &
cerebral cortex
 Behavioral abnormalities –ADHD, impaired school performance
 An adult with congenital NDI usually drinks and voids about 10 to 12 l/day.
 Urinary tract dilatation can be seen, especially if there are voiding abnormalities.
 AVPR2 or AQP2 may retain partial functionality of the protein, leading to a
phenotype of partial NDI, in which urinary concentration is possible but
subnormal. Clinical symptoms are consequently milder, and the disease may
remain undiagnosed throughout life

62.  Diagnosis - inappropriately dilute urine in the context of hypernatremic dehydration
 absence of a response in urinary concentration after administration of DDAVP
 Limiting fluid intake equal to UOP during the
 DDAVP 0.3 mcg/kg IV- advantage of the shortest observation period (2 hours) combined with
certainty of administration.
-allows distinction between X-linked and autosomal NDI
autosomal NDI still express AVPR2, they will show the vascular effects in the form of a small drop
in BP, an increase in HR and release of VWF, whereas these changes are absent in patients with
AVPR2 mutations.
Serum levels of DDAVP with other modes of administration are not sufficient to appreciate these
changes.
1. A normal renal response to DDAVP - increase in Uosm >800 mOsm/kg
2. NDI - no response, Uosm <200 mOsm/kg
3. Intermediate response -partial NDI or simply a washout of the medullary concentration
gradient.
4. partial NDI can be confirmed by achieving a Uosm >800 mOsm/kg after repeated
administration of DDAVP.
5. As normal urinary concentrating ability develops only during the first year of life, a response
less than 800 (but >300) mOsm/kg may be normal in infants.

63. D/Ds-
 central DI or habitual polydipsia can be distinguished by a normal response to DDAVP.
 secondary inherited NDI typically have other electrolyte abnormalities, such as hypokalemia and hypercalciuria, in
addition to other features typical for the primary diagnosis, such as polyhydramnios in BS & HTN in AME.
 Onset of polyuria later in childhood or adulthood argues for acquired forms of NDI. Patients with partial NDI
represent a diagnostic challenge.
 underlying structural or parenchymal renal disease, such as nephronophthisis or tubulointerstitial or cystic kidney
disease.
 Genetic testing can help confirm
T/T –
 Thiazide (e.g., HTZ 1 - 2 mg/kg 12 hrly)
 reduction of salt intake.
 Thiazides inhibit salt reabsorption in distal convoluted tubules, which leads to mild volume depletion. Hypovolemia
stimulates fluid reabsorption in the PTs, thereby diminishing water delivery to the CDs.
 Combination therapy - amiloride 0.1 - 0.2 mg/kg 8 - 12 hrly, helps control the potential hypokalemia from thiazide
treatment and may enhance the antipolyuric effect
 COXi - Indomethacin 1 - 2 mg/kg/d
 Selective COX2i, such as celecoxib

64. Nephrogenic Syndrome of Inappropriate Antidiuresis
 mirror image to NDI
 gain-of-function mutations in AVPR2
 constitutive activation of the urinary concentrating mechanism in the CD,
irrespective of serum osmolality
 X-linked dominant, males are typically more severely affected
 inappropriately concentrated urine (>100 mOsm/kg) in the context of
hyponatremia and hypoosmolality.
 In contrast to SIADH, vasopressin suppressed.
 Genetic testing confirmatory
T/T –
Fluid restriction

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66. Fanconi syndrome
 In 1930s de Toni, Debré, and coworkers and Fanconi independently described several
children with the combination of renal rickets, glycosuria, and hypophosphatemia
 Global dysfunction of PT , characterized by glycosuria, phosphaturia, generalized
aminoaciduria, and type 2 RTA.
 Often there is hypokalemia, sodium wasting, hypouricemia, and dehydration.
 In children it typically is caused by inborn errors of metabolism, principally cystinosis.
 In adults it is mainly caused by medications, exogenous toxins, and heavy metals.

68.  Solute uptake by the brush border
membrane from the lumen is coupled to
Na+ influx.
 The favorable electrochemical driving
force for luminal Na+ is maintained by
the Na+,K+-ATPase pump.
 Transported solute is then either used by
the cell or returned to the blood across
the basolateral membrane.
 Fanconi syndrome could arise because of
a defect in one of six areas as shown.

69. Megalin-cubilin endocytic pathway in proximal tubular cells
• Low-molecular-weight proteins in the luminal fluid
bind to the megalin-cubilin complex and are
endocytosed.
• Recycling of megalin and further catabolism of
these proteins depend on acidification of the
vesicle by a proton pump.
• The ClC-5 chloride channel provides an electrical
shunt for efficient functioning of the proton pump.
• This endocytosis pathway plays a role in membrane
transporter recycling, and disruption of this
pathway interferes with absorption of other luminal
solutes.

71. Evaluation of glycosuria.
GFR, Glomerular filtration rate; TmP, tubular maximum reabsorptive capacity; TRP, tubular
reabsorption of phosphate.

73. T/T -
Treat underlying cause and replacing the lost electrolytes and volume.
avoidance of the offending nutrient in galactosemia, hereditary fructose intolerance, or tyrosinemia; penicillamine or other copper
chelators for t/t of Wilson disease; or chelation therapy for t/t of heavy metal intoxication.
proximal RTA (type 2 RTA) usually requires large doses of alkali for correction.
Some patients benefit from hydrochlorothiazide to minimize the volume expansion associated with these large doses of alkali.
Potassium supplementation usually is also needed, especially if there is significant RTA.
If given in combination with a metabolizable anion, such as potassium citrate, lactate, or acetate, these supplements will correct not only
the hypokalemia but also the acidosis.
A few patients will require sodium supplementation along with potassium, and even fewer will require sodium chloride supplementation
(especially those who have alkalosis as a result of volume contraction from large urinary NaCl losses).
Magnesium supplementation may be required.
Adequate fluid intake is essential.
Correction of hypokalemia and its effect on the concentrating ability of the distal tubule may lessen the polyuria
 Hypophosphatemia - 1 to 3 g/day of oral phosphate
 vitamin D – ergocalciferol or a vitamin D metabolite ,1,25-dihydroxycholecalciferol (calcitriol).
 calcium - indicated in those with hypocalcemia after supplemental vitamin D is started.
 Hyperaminoaciduria, glycosuria, proteinuria, and hyperuricosuria usually do not lead to clinical difficulties and do not require specific
t/t.
 Carnitine supplementation, to compensate for the urinary losses, may improve muscle function and lipid profiles, but the evidence is
inconsistent.

74. Cystinosis - rare disorder of children caused by the intra-lysosomal storage of
the amino acid cystine that leads to multiorgan dysfunction over time,
especially renal failure.
Cysteamine removes cystine from the lysosome and helps prevent renal
failure and other complications of the stored cystine.
Renal glycosuria - a benign disorder , mutation in gene coding SGLT2
glucose transporter
Cystinuria - autosomal recessive disorder that leads to impaired renal
reabsorption of 4 AA(cystine, lysine, ornithine, and arginine), accounts for 1%
to 2% of kidney stones.
T/T - increasing fluid intake, alkalinizing the urine, and a thiol compound such
as penicillamine or tiopronin

75. Tinsel-like refractile opacities in the cornea of a patient with cystinosis under slit-lamp
examination

76. Cystine crystals in the kidney in cystinosis.
(B) Electron micrograph of a renal biopsy specimen shows
hexagonal, rectangular, and needle-shaped crystals in
macrophages within the interstitium. (Original
magnification ×3000.)
(A) Crystals are seen in photomicrograph of alcohol-
fixed nephrectomy specimen, taken through
incompletely crossed polarizing filters. Birefringent
crystals are evident in tubular epithelial cells and
free in the interstitium.

78. Galactosemia
 autosomal recessive disorder of galactose metabolism
 deficient activity of the enzyme galactose-1-phosphate uridyltransferase
 intracellular accumulation of galactose-1-phosphate, with damage to the
liver, proximal renal tubule, ovary, brain, and lens
 A less frequent cause of galactosemia is a deficiency of galactose kinase,
which forms galactose-1-phosphate from galactose. Cataracts are the only
manifestation of this form of galactosemia

79. Lowe Syndrome(oculocerebrorenal syndrome)
 congenital cataracts and glaucoma, severe developmental delay, hypotonia with diminished
to absent reflexes, and renal abnormalities
 X-linked recessive trait
 defective gene codes for phosphatidyl inositol 4,5-bisphosphate 5-phosphatase, OCRL1,
involved with cell trafficking and signaling.
 ESRD usually does not occur until the third to fourth decade of life.
 LM - normal early in the disorder,
 EM - endothelial cell swelling and thickening and splitting of the GBM
PT cells - shortening of the brush border and enlargement of the mitochondria, with distortion
and loss of the cristae.
T/T -Only symptomatic treatment is available

80. Dent Disease
 X-linked recessive
 caused by a mutation in the CLCN5 gene leading to inactive ClC-5 chloride channel
function
 low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and
rickets
 Affected males often have aminoaciduria, phosphaturia, and glycosuria.
 Renal failure is common and may occur by late childhood.
 Hemizygous females usually have only proteinuria and mild hypercalciuria.
 X-linked recessive nephrolithiasis and X-linked recessive hypophosphatemic rickets
have similar features, and most have a defect in the renal ClC-5 chloride channel.
 Dent disease type 2 is a clinically similar disease affecting males, but there is a mutation
in the same gene that causes Lowe syndrome, but no brain or eye involvement

81. Mitochondrial Cytopathies
 Most of the mitochondrial cytopathies manifest with neurologic disorders
such as myopathy, myoclonus, ataxia, seizures, external ophthalmoplegia,
stroke-like episodes, and optic neuropathy.
 Other manifestations - retinitis pigmentosa, DM, exocrine pancreatic
insufficiency, sideroblastic anemia, SNHL, pseudo-obstruction of the colon,
hepatic disease, cardiac conduction disorders, and cardiomyopathy
 most common renal manifestation - Fanconi syndrome,
 FSGS, corticosteroid-resistant NS.
 Extrarenal disorders, mainly neurologic disease.
 Most patients present in <1 months of life and die soon afterward.

82.  Diagnosis –
 elevated serum or CSF lactate levels, especially in association with an altered lactate-to-pyruvate
ratio, suggesting a defect in mitochondrial respiration.
 The presence of “ragged red fibers,” a manifestation of abnormal mitochondria, in a muscle biopsy
specimen is another clue, especially with large abnormal mitochondria on EM of muscle tissue.
T/T -
 Low mitochondrial enzyme complex III activity can be treated with menadione or ubidecarenone.
 Deficient mitochondrial enzyme complex I activity may be treated with riboflavin and ubidecarenone.
 Ascorbic acid
 High-lipid, low-carbohydrate diet has been tried in cytochrome c oxidase deficiency.

83. Aminoacidurias

85. Hereditary Defects in Uric Acid Handling
1. Hereditary Renal Hypouricemia - autosomal recessive disorder characterized by
very low s UA(<2.5 mg/dl; [<150 µmol/l] in adult men and <2.1 mg/dl [<124 µmol/l]
in adult women) and increased uric acid clearance, ranging from 30% to 150% of
the filtered load
Defect in SLC22A12 gene which code for URAT1, SLC2A9(GLUT9)
Mostly asymptomatic
25% pt has Renal stone, but only 1/3rd UA stone
May have hypercalciuria, Exercixe induced AKI
T/T – high fluid intake, Urine alkalisation, Allopurinol

86. 2. FJHN & MCKD2 – rare autosomal dominant ds, characterized by
hyperuricemia, early onset gout, TIN
Defect in UMOD gene encoding Tamm Horsfall/uromodulin protein
Defective protein retailed in ER leading to inflammation, interstitial fibrosis &
functional derangement, decreased salt & water reabsorption
leading to increased PT UA reabsorption & hyperuricemia
Diagnosis – fractional UA excreation<5%
t/t – staring XOi early in life may help to reduce progression to CKD

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89. Thank you