Inherited tubular disorders - barrter gittleman liddle fanconi interstitial

1. INHERITED TUBULAR
DISORDERS
CHAIR PERSON: DR MAHABALESHWAR
MAYYA .
STUDENT: DR VASNTI KOPPAD.

10. Autosomal Dominant Kidney Disease
• Prevalence- 1:300 to 1: 1,000.
• Acoounts for 4% of ESRD.
• 90 % Cases are inherited as AD.
• 10% As Spontaneous Mutations.
• 2 Forms of ADPKD identified.
• ADPKD 1 – 85 % cases.
ADPKD 1 ADPKD 2
CHROMOSOME 16 p 13.3 CHROMOSOME 4q 21-23

14. ADPKD
• Kidneys are grossly enlarged, multiple cysts
present.
• Cysts - Spherical, vary in size , few mm to cm,
present in both cortex & medulla.
• Cysts contain straw coloured fluid .
• 1 – 5 % nephrons develop cysts , after a SECOND
HIT - somatic mutation in the normal allele of a
tubule cell – monoclonal proliferation of tubular
epithelium.
• Remaining renal parenchyma – varying degrees of
tubular atrophy, interstitial fibrosis,
nehrosclerosis is seen.

17. CLINICAL FEATURES
• ADPKD presents at any AGE.
• Most fequently presents in 3 rd / 4 th DECADE.
• Chronic flank pain – s/o enlarged kidneys .
• Acute pain - Infection , urinary tract
obstruction by clot / stone/ sudden
haemorrahage into cyst.
• Gross & microscopic haematuria are common.
• Impired renal concentrating ability – Nocturia.

18. • Nehrolithiasis – 15 – 20 % of pts.
• M/C - Calcium oxalate, uric acid stones.
• Low urinary PH , low urine citrate , urinary
stasis , distortion of the collecting system by
cysts- Stone formation.
• Hypertension 75 % cases.
• Hypertension is secondary to intra renal
ischaemia from distortion of renal
architexture- activation of RAS .

19. • Pts with HTN rapidly progress to ESRD.
• Infection of cyst – pyocyst.
• Pyocysts – difficult to diagnose.
• If blood culture +ve , new renal pain, failed to
improve clinically after a standard course of
antibiotic therapy - PYOCYST.
• 50 % ADPKD – ESRD BY 60 YRS of AGE.

20. EXTRA RENAL MANIFESTATION OF
ADPKD
• Hepatic cysts – 50- 70 %.
• Hepatic Cysts are asymptomatic , liver function is
normal.
• Cyst formation is also be seen in spleen, pancreas
& ovary.
• Sometimes Colonic diverticula are also seen.
• Intracranial aneurysms – 5 to 10 %.
• Pts with family h/o SAH – Screened for ADPKD .

23. A-Hepatomegaly, Large, Isolated Cyst
B-Multiple Large Cysts
C- Multiple Small Cysts In Hepatic
Parenchyma in Polycystic liver disease

25. TREATMENT OF ADPKD
• No specific treatment .
• BP control of 140/90 mmHg is recommended.
• To slow the renal disease progression & lower
cardiovascular risk.
• Infection of cyst- By Gram –ve organisms.
• Septran, quinolones, chloramphenicol for 4-6 weeks
(these penetrate the cyst wall)
• Treatment of kidney stones-
• Analgesics for pain relief.
• Good hydration.
• Chronic flank pain- Non narcotic &narcotic analgesics.

26. • Surgical decompression of cysts may be
necessory sometimes.
• 50% of ADPKD – ESRD – Requiring haemodialysis,
peritoneal dialysis, renal transplantation.
• Several clinical trials have been tried targetting
cell proliferation.
• Sirolimus, everolimus
• mTOR inhibitors ,Opc31260 & Tolvaptan- inhibits
cAMP pathway by antagonising d activation of
V2R in collecting ducts & reduces cell
proliferation by decreasing renal c AMP levels.

27. • Somatostatin analogues- Octreotide
• Reduce c AMP levels by binding to G – protein
coupled receptors, slowing d decline of renal
function.
• Nerve block – used to relieve pain in ADPKD.
• Upcoming Therapy-- Include targetting
abnormal cell signalling.

28. ARPKD
• ARPKD – Rare Geneteic Disease.
• Incidense – 1 : 20,000 live births.
• Localised to Chromosome 6p21.
• At birth – kidneys enlarged, smooth external surface.
• Distal tubules & collecting ducts are dilated into
elongated cysts , arranged in radial fashion.
• Interstitial fibrosis leads to renal function
deterioriation.
• Hepatic proliferation, dilatation of intrahepatic bile
ducts, periportal fibrosis indicates hepatic
involvement.

29. CLINICAL FEATURES
• Majority of cases are diagnosed in 1 st Year of
life.
• Present as b/l abdominal mass.
• M/C C/F-- Hypertension , impaired urinary
concentrating ability.
• Time for Progression to ESRD is variable.
• Older children present – congenital hepatic
fibrosis.
• Complications- hepatospleenomegaly, portal
hypertension, esophageal varices.

31. ARPKD
• DIAGNOSIS – By USG – Enlarged kidneys,
increased echotexture.
• Hepatic Fibrosis associated with cystic kidney
–diagnosis of ARPKD.

32. TREATMENT OF ARPKD
• No specific therapy for ARPKD.
• Goals of therapy --Nicu care,BP control.
• For ESRD – Dialysis &Renal transplantation.
• Hepatic fibrosis –Liver transplantation.
• Life thrteatening variceal bleeding –
Sclerotherapy & Portosystemic shunts are
advised.

33. TUBEROUS SCLEROSIS
• 1/3 rd cases are AUTOSOMAL DOMINANT, rest are
SPORADIC MUTATIONS.
• Mutations of TSC1( Chromosome 9q34) ,
TSC2(Chromosome 16p13)
• Majority of cases – Mutations TSC2.
• C /F – skin lesions, benign tumours of CNS.
• Renal involvement-Angiomyolipomas m/c & usually b/l
• Renal cysts are similar to ADPKD, cysts unique- cyst
lining cells are large, eiosinophilic staining cytoplasm &
hyperplastic nodules are seen.
• Also associated with mental retardation, polycystic
kidney.

35. VON HIPPEL LINDAU DISEASE
• AD .
• Gene present on chromosome 3p25.
• Haemangioblastomas of retina & CNS – M/C.
• Renal cysts are present in majority cases , B/L.
• Renal Cell Carcinoma present in 40 – 70 %
cases with VHL, multifocal.
• Yearly screening , CT scan advised to diagnose
renal cell carcinoma at an early stage.

38. INHERITED TUBULAR DISORDERS CLASSFICATION.

40. FANCONI’S SYNDROME
• Generalised defect in PCT transport –Amino
Acids,Glucose,Proteins,Phosphate,Uric Acid &
• Na+, K+,HCO3.
• AD form , + on Chromosome 15
• Lab abnormalities :
• Proximal renal tubular acidosis, glucosuria , with
normal serum glucose, hypophosphetemia,
hypouricemia,hypokalemia,amino acidurias,lmw
proteinuria.

41. PATHOLOGY OF FANCONIS
SYNDROME.

44. FANCONI’S SYNDROME
• Rickets & osteomalacia are secondary to
hypophosphetemia.
• Abnormal production of calcitriol present.
• Metabolic acidosis leads to bone disease.
• Polyuria, salt wasting, hypokaleia – severe
manifestation .

45. TREATMENT OF FACONI’S SYNDROME
• Phosphate supplementation.
• Calcitrol – to heal bone lesions.
• Alkali – For treatment of acidosis.
• Alkali – K+ salts – Rta , hypokalemia
• Liberal intake of salt & water .
• Amino aciduria, glucosuria, lmw proteinuria –
no treatment.

46. Bartter-like Salt Losing Tubulopathies
• In 1962, Frederic Bartter
– Reported two patients with
• Hypokalemic alkalosis.
• normal blood pressure despite high aldosterone
production.
• Growth retardation and mental retardation.
• Muscle weakness and cramps.
• Salt craving and constipation.
• Polydipsia and polyuria.
– Lab:
• K+ 2-2.2 meq/L, HCO3 -30-34 mmol/L, sCl 75-66 meq/L
• Hyperplasia of the zona glomerulosa.
• Renal bx: hyperplasia of the juxtaglomerular apparatus.

47. BARTER’S SYNDROME

48. Bartter’s Syndrome – clinical
manifestation
• Typically manifests early in life with
• Polyhydramnios, failure to thrive, growth
retardation, polydipsia, dehydration, salt craving,
and marked muscle weakness.
• Blood pressure is low or normal.
• The GFR is normal, but there is inadequate
urinary acid excretion after NH4Cl challenge.

49. • Nephrogenic diabetes insipidus also may
be seen.
• Sodium transport in erythrocytes and
salivary glands is impaired.
• Renal biopsy --Hyperplasia and hypertrophy
of the juxtaglomerular cells as well as of the
medullary interstitial cells, the site of PGE2
synthesis.

52. TREATMENT OF BARTER’S SYNDROME.
• Liberal intake of Na+, K+.
• Potassium supplementation is usually
required.
• Spirinolactone reduces K+ loss.
• NSAID’s in antenatal barter’s syndrome-
decreases prostaglandin production.
• ACE inhibitors – beneficial in some.

53. Gitelman’s syndrome
• Like Bartter’s an autosomal recessive disorder,
but not usually diagnosed early in life.
• Findings mimic administration of a thiazide
diuretic: the defect is in the Na-Cl transporter.
• Patients may complain of polyuria, cramps.
• They do not have hypercalciuria, but typically
have low serum magnesium levels.

54. GITLEMAN’S SYNDROME

55. GITELMAN’S SYNDROME

56. DEFINITION of RTA
• Renal tubular acidosis (RTA) is a disease state
characterised by a normal anion gap
(hyperchloremic) metabolic acidosis in the
setting of normal or near normal glomerular
filtration rate with defects in Tubular H +
secretion & urinary acidification.

58. PROXIMAL RTA DISORDER

59. DISTAL RTA DISORDER

60. Type 1 RTA
• First described, classical form
• The problem is inability to maximally acidify urine
• Distal defect : decreased H+ secretion
• H+ builds up in blood (acidosis)
• K + secreted instead of H+ (hypokalemia)
• Urine pH > 5.5
• Hypercalciuria
• Renal stones

61. Pathophysiology:
• Metabolic acidosis secondary to decreased
secretion of H+ ions in the absence of a marked
decrease in the glomerular filtration rate (GFR) is
characteristic of distal RTA.
• Patients with distal RTA have inappropriately low
H+ ion excretion when compared with the normal
rate of acid production.
• The deficiency here is secondary to either a –
secretory (rate) defect or a gradient
(permeability) defect.

62. • secretory defect:- the rate of secretion of H+ ions is
low for the degree of acidosis. It is due to defective
function of
– H+ ATPase,
– H+/K+ ATPase or
– Cl- /HCO3 - exchanger
– (“weak pump”).
• Gradient (permeability) defect:- there is normal
secretion of H+ ions but an increased back leak
resulting in dissipation of the pH gradient
• (“leaky-membrane”)
• as seen in RTA due to amphotericin B.
• The low titrable acidity and NH4 + secretion in distal
RTA leads to systemic acidosis.

63. • Hypokalemia:
– Increased potassium losses in the tubular lumen
– Urinary Na+ losses and volume contraction : aldosterone
production : increased tubular K + secretion and decreased
proximal K + reabsorption.
• Nephrocalcinosis:
– Chronic acidosis : decreased tubular reabsorption of Ca2+
renal hypercalciuria and hyperparathyroidism.
– Acidosis and hypokalemia stimulate the proximal tubular
reabsorption of citrate and decrease its urinary excretion.
– This hypercalciuria, hypocitraturia and alkaline urine leads to
calcium phosphate stone formation in the kidneys
(nephrocalcinosis and nephrolithiasis).

65. Clinical Profile:-
• Failure to thrive, Growth retardation (MC).
• Polyuria, Polydipsia
• Nephrocalcinosis, Nephrolithiasis
• Rachitic manifestations (later in childhood)
• Weakness, Transient paralysis (due to
Hypokalemia)
• Sporadic or autosomal recessive cases may have
associated SNHL that may present at birth or later

66. NEPHROCALCINOSIS

67. Type 1 RTA Treatment
• Electrolyte abnormalities should always be
corrected before treating acidosis.
• Acidosis is corrected by administration of alkali
solutions.
• Initial dose is 2-3meq/kg/day and can be
increased until the blood bicarbonate levels
become normal.
• The amount of bicarbonate required to maintain
acid base status may be as high as 5-
10meq/kg/day and the duration of therapy is
usually lifelong.

68. Various alkali solutions used are :
-Sodium bicarbonate solution (7.5%)
– Citrate solutions:
– Polycitra solution (2 meq/ml)
• 110 gm Potassium Citrate, 66.8 gm Citric acid,
100 gm Sodium Citrate, 1 L water
• 1 ml=2 meq base
.

69. Shohl solution (1 meq/ml)
• 140 gm Citric acid, 90 gm Sodium Chloride 1 L
water
1 ml = 1 meq base.
– Potassium alkali salts should be used if
hypokalemia is a persistent problem.
In case of associated rickets/osteopenia, VitaminD
supplementation may be given.
The relatives of patients with idiopathic type1 / RTA
should be screened for this disorder as timely
intervention can prevent growth retardation in
children.

70. Type 2 RTA (Proximal RTA)
• Proximal defect
• Decreased reabsorption of HCO3-
• HCO3 - wasting, net H+ excess
• Urine pH < 5.5, although high initially
• K +: low to normal

71. Pathophysiology:
• Primary defect:
– reduced renal threshold for HCO3 - : bicarbonaturia.
• Proposed mechanisms – defective pump secretion or
function of the H+/ATPase,
Na+/H+ antiporter,
Na+/K+ ATPase or
The deficiency of carbonic anhydrase in the brush border
membrane
increased urinary loss of HCO3 - : systemic acidosis.

72. • Type 2 RTA, also called proximal, is caused by
failure of bicarbonate reabsorption in the
proximal tubule : resulting in HCO3 loss in the
urine : systemic acidosis
• • The mechanisms of H+ secretion in the distal
tubule is intact : so urine pH is <5.5 even
though bicarb is lost in d urine.
• Bicarbonate is replaced by Cl in the circulation
resulting in Hyperchloremia.
• Incresed Na+ delivery to distal nephron
increses Aldosterone secretion,leading to
Hypokalemia.

73. • The acidosis is self-limited because acid
production and excretion are equivalent at
this reduced pH; the plasma HCO3 - remains
at 15 to 20 mEq/L.
• Because urinary citrate levels are not reduced,
stone formation does not occur despite
increased urinary calcium.
• This condition is more common in children,
and it can lead to growth retardation and
metabolic bone disease

77. Clinical Profile:
• Failure to thrive, growth retardation (mc).
• Polyuria, Polydipsia
• Dehydration (due to sodium, H2O Losses)
• Rachitic Manifestations.
• (Common in fanconi syndrome because of
Hypophosphatemia)
• Irritability, restlessness, anorexia or preference
for savory foods

78. Type 2 RTA (Treatment)
• Alkali supplementation(NaHCO3) remains the
treatment of choice.
• Children with proximal RTA require large amounts of
alkali per day (approximately 5-20 meq/kg/day).
• Thiazide diuretic can be used in conjunction with low
salt diet to reduce the amount of bicarbonate required.
• Thiazides act by causing extracellular fluid contraction
and increasing proximal bicarbonate reabsorption.
• Potassium supplementation is done to compensate for
the increased potassium excretion caused by thiazides

79. • Phosphate supplements and moderate doses of
Vitamin D may be required. Phosphate
supplements Strength:
(a) Joulie solution 1ml= 30mg
(b) Neutral phosphate solution 1ml=20mg
• Specific therapy for an underlying disorder
(cysteamine for cystinosis, D-penicillamine for
Wilson disease and lactose free diet in
galactosemia) is indicated in few patients.

80. RICKETS ASSOCIATED WITH RTA
• Rickets may be present in RTA , particularly
type 2 proximal RTA.
• Hypophosphatemia and phosphaturia is
common in that, causing rickets.
• Bone demineralization without overt rickets is
usually detected in type 1 distal RTA.

81. • This metabolic bone disease may be
characterized by bone pain, growth
retardation,osteopenia and occasionally
pathologic fractures.
• Bone demineralization in distal RTA probably
relates to dissolution of bone because the
calcium carbonate in bone serves as a buffer
against the metabolic acidosis due to the
hydrogen ions retained by patients.

82. Treatment
• DISTAL RTA: administration of sufficient
bicarbonate to reverse acidosis reverses bone
dissolution and the hypercalciuria.
• PROXIMAL RTA: treatment with both bicarbonate
and oral phosphate supplements heal rickets.
• In RTA,vitamin D levels are reduced in relation to
the degree of renal impairment.Vitamin D is
required to offset the secondary
hyperparathyroidism that complicates oral
phosphate therapy.

83. Type 4 RTA:
• The underlying defect here is the impaired
cation exchange in the distal tubules with
reduced secretion of H+ and K +
(hyperkalaemic acidosis).

84. TYPE 4 RTA

85. • Impaired Aldosterone secretion or distal tubule
resistance to Aldosterone
• Impaired function of Na+/K+-H+ (cation) exchange
mechanism
• Decreased H+ and K+ secretion : plasma buildup
of H+ and K+ (hyperkalemia)
• Urine pH < 5.5 (because the distal tubule H+
pump functions normally )
• Aldosterone increases Na+ reabsorption
(pseudohypoaldosteronism) and results in a
negative intratubular potential.
• Other factor that causes a decreased H+
excretion in type 4 RTA is the inhibition of
ammoniagenesis due to hyperkalemia

87. Clinical Profile: RTA type 4
• Growth retardation (MC)
• Polyuria, polydipsia, dehydration.
• Signs and symptoms of obstructive uropathy
and features of pyelonephritis.
• Bone diseases are generally absent.

88. What happened to Type 3 RTA?
• Very rare
• Used to designate mixed dRTA and pRTA of
uncertain etiology
• Now describes genetic defect in Type 2
carbonic anhydrase (CA2), found in both
proximal, distal tubular cells and bone
• This terminology is no longer used.

90. Take Home Message
• Review causes of Non-anion gap Metabolic Acidosis
• – Renal vs. GI losses
• Distinguish RTA Types 1, 2 and 4
– Type 1: renal stones, hypercalciuria, high urine pH
despite metabolic acidosis
– Type 2: think acetazolamide and bicarbonate wasting;
Fanconi syndrome
– Type 4: aldosterone deficiency and hyperkalemia
• Mainstay of treatment of RTA – Bicarbonate therapy