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Polycystic Kidney Diseases and Polycystic Kidney Diseases and Other Inherited Tubular DisordersOther Inherited Tubular Disorders
Vimar A. Luz, MD, FPCP, DPSNCenter for Renal Diseases
St. Luke’s Medical Center
Polycystic Kidney DiseasePolycystic Kidney Disease
Most common life threatening inherited disease worlwide
Fluid filled cysts causing large kidneysADPKD in adults, ARPKD is mainly a
disease of childhood
Polycystic Kidney DiseasePolycystic Kidney Disease
1. Etiology and Pathogenesis
Polycystic Kidney DiseasePolycystic Kidney Disease
Systemic disorder from mutations in PKD-1(polycystin, a receptor like molecule) or PKD-2 gene (ion channel protein)
Polycystic Kidney DiseasePolycystic Kidney Disease Systemic disorder from mutations in PKD-1(polycystin, a
receptor like molecule) or PKD-2 gene (ion channel protein)
Transmembrane proteins located in the luminal surface of 1’ cilia, focal adhesion complexes, lateral surface junctions
Polycystic Kidney DiseasePolycystic Kidney Disease Systemic disorder from mutations in PKD-1(polycystin, a
receptor like molecule) or PKD-2 gene (ion channel protein) Transmembrane proteins located in the luminal surface of 1’
cilia, focal adhesion complexes, lateral surface junctions
Independently or as complex, they regulate cell gene transcription, apoptosis,differentiation, and cell matrix interaction
Polycystic Kidney DiseasePolycystic Kidney Disease Systemic disorder from mutations in PKD-1(polycystin, a
receptor like molecule) or PKD-2 gene (ion channel protein) Transmembrane proteins located in the luminal surface of 1’
cilia, focal adhesion complexes, lateral surface junctions Independently or as complex, they regulate cell gene
transcription, apoptosis,differentiation, and cell matrix interaction
In ADPKD: unregulation proliferation, altered cell polarity, disorganization of extracellular matrix, excessive fluid secretion, abnormal expression of several genes
Polycystic Kidney DiseasePolycystic Kidney Disease Systemic disorder from mutations in PKD-1(polycystin, a
receptor like molecule) or PKD-2 gene (ion channel protein) Transmembrane proteins located in the luminal surface of 1’
cilia, focal adhesion complexes, lateral surface junctions Independently or as complex, they regulate cell gene
transcription, apoptosis,differentiation, and cell matrix interaction
In ADPKD: unregulation proliferation, altered cell polarity, disorganization of extracellular matrix, excessive fluid secretion, abnormal expression of several genes
Polycystic Kidney DiseasePolycystic Kidney Disease
Excessive fluid secretion
Vasopressin mediated elevation of cAMP levels in cyst epithelia plays a major role in cytogenesis by stimulating cell proliferation and fluid secretion into the cysts through apical chloride and aquaporin channels
Polycystic Kidney DiseasePolycystic Kidney Disease Systemic disorder from mutations in PKD-1(polycystin, a receptor like
molecule) or PKD-2 gene (ion channel protein) Transmembrane proteins located in the luminal surface of 1’ cilia, focal
adhesion complexes, lateral surface junctions Independently or as complex, they regulate cell gene transcription,
apoptosis,differentiation, and cell matrix interaction In ADPKD: unregulation proliferation, altered cell polarity,
disorganization of extracellular matrix, excessive fluid secretion, abnormal expression of several genes
Cysts begin in utero (< 5% are involved, cysts filled w/ fluid, separate from the nephron, compress renal parenchyma and compromise the renal function
Polycystic Kidney DiseasePolycystic Kidney Disease
1. Etiology and Pathogenesis
2. Genetic Considerations
Polycystic Kidney DiseasePolycystic Kidney Disease
ADPKD occurs in 1:400 up to 1:1000 worldwide
Polycystic Kidney DiseasePolycystic Kidney Disease
PKD occurs in 1:400 up to 1:1000 worldwide
Approximately 4% of ESRD
Polycystic Kidney DiseasePolycystic Kidney Disease
PKD occurs in 1:400 up to 1:1000 worldwide Approximately 4% of ESRD 90% are inherited as dominant (ADPKD)
85% in PKD-1 and the rest PKD 2
Polycystic Kidney DiseasePolycystic Kidney Disease
1. Etiology and Pathogenesis
2. Genetic Considerations
3. Clinical Features
Polycystic Kidney DiseasePolycystic Kidney Disease
Phenotypic heterogeneity
Polycystic Kidney DiseasePolycystic Kidney Disease
Phenotypic heterogeneity
Asymptomatic into 4th to 5th decade
Polycystic Kidney DiseasePolycystic Kidney Disease
Phenotypic heterogeneity Asymptomatic into 4th to 5th decade
Presenting S/Sx: abdominal discomfort, hematuria, UTI, incidental findings of HTN, abdominal mass, Screa, cystic kidney on imaging
Polycystic Kidney DiseasePolycystic Kidney Disease
Phenotypic heterogeneity Asymptomatic into 4th to 5th decade Presenting S/Sx: abdominal discomfort, hematuria, UTI,
incidental findings of HTN, abdominal mass, Screa, cystic kidney on imaging
Declines progressively in 10 to 20 yrs, but NOT all
Polycystic Kidney DiseasePolycystic Kidney Disease
Phenotypic heterogeneity Asymptomatic into 4th to 5th decade Presenting S/Sx: abdominal discomfort, hematuria, UTI,
incidental findings of HTN, abdominal mass, Screa, cystic kidney on imaging
Declines progressively in 10 to 20 yrs, but NOT all ADPKD-2 later onset and slow
progression
Polycystic Kidney DiseasePolycystic Kidney Disease
Phenotypic heterogeneity Asymptomatic into 4th to 5th decade Presenting S/Sx: abdominal discomfort, hematuria, UTI,
incidental findings of HTN, abdominal mass, Screa, cystic kidney on imaging
Declines progressively in 10 to 20 yrs, but NOT all ADPKD-2 later onset and slow progression
Risk factors to progression
Polycystic Kidney DiseasePolycystic Kidney Disease
Risk factors to progression 1. Younger age at diagnosis
2. Black race
3. Male
4. Hypertension
5. Polycystin-1 mutation
6. Rate of kidney enlargement (dull persistent flank
and abdominal pain, early satiety, GER)
Polycystic Kidney DiseasePolycystic Kidney Disease
Phenotypic heterogeneity Asymptomatic into 4th to 5th decade Presenting S/Sx: abdominal discomfort, hematuria, UTI,
incidental findings of HTN, abdominal mass, Screa, cystic kidney on imaging
Declines progressively in 10 to 20 yrs, but NOT all ADPKD-2 later onset and slow progression Risk factors to progression
Complications
Polycystic Kidney DiseasePolycystic Kidney Disease
Complications 1. Cyst rupture/ hemorrhage (flank pains or
signs of localized peritonitis) 2. Nephrolithiasis in 20% 3. Hematuria (from Ca or UA stones, infection, cyst rupture) 4. UTI usually G(-), urine cs maybe (-) should check blood cs
Polycystic Kidney DiseasePolycystic Kidney Disease
Phenotypic heterogeneity Asymptomatic into 4th to 5th decade Presenting S/Sx: abdominal discomfort, hematuria, UTI,
incidental findings of HTN, abdominal mass, Screa, cystic kidney on imaging
Declines progressively in 10 to 20 yrs, but NOT all ADPKD-2 later onset and slow progression Risk factors to progression Complications
Extrarenal Manifestations
Polycystic Kidney DiseasePolycystic Kidney Disease
Extrarenal Manifestations 1. Subarachnoid/Cerebral hemorrhage from intracranial aneurysm 2. Aortic annular anuerysm 3. MVP, AR 4. Hepatic cysts in 40% in pts > 60 y/o 5. Colonic diverticulae 6. Abdominal wall and inguinal hernias
Polycystic Kidney DiseasePolycystic Kidney Disease
1. Etiology and Pathogenesis
2. Genetic Considerations
3. Clinical Features
4. Diagnosis and Screening
Polycystic Kidney DiseasePolycystic Kidney Disease
UTZ (sensitivity of 100 % in > 30 y/o)
Polycystic Kidney DiseasePolycystic Kidney Disease
UTZ (sensitivity of 100 % in > 30 y/o)
Criteria: 2 cysts in 1 kidney and 1 in the contralateral in younger patients but 4 in >60 y/o
Polycystic Kidney DiseasePolycystic Kidney Disease
UTZCT scan for <30 y/o
Polycystic Kidney DiseasePolycystic Kidney Disease
UTZCT scan for <30 y/oStrong family history
Polycystic Kidney DiseasePolycystic Kidney Disease
UTZCT scan for <30 y/oStrong family historyGenetic screening (especially for
potential asx young donor candidates from relative)
Polycystic Kidney DiseasePolycystic Kidney Disease
UTZ CT scan for <30 y/o Strong family history Genetic screening (especially for potential
asx young donor candidates from relative) Screening for aneurysm only for those w/
FHx of Hge and in those w/ high risk occupations
Polycystic Kidney DiseasePolycystic Kidney Disease
1. Etiology and Pathogenesis
2. Genetic Considerations
3. Clinical Features
4. Diagnosis and Screening
5. Treatment
Polycystic Kidney DiseasePolycystic Kidney Disease
Largely supportive, no single tx to prevent ESRD
Polycystic Kidney DiseasePolycystic Kidney Disease
Largely supportive, no single tx to prevent ESRD
Control of HTN, target BP 130/85 or less is recommended, w/ ACE/ARB
Polycystic Kidney DiseasePolycystic Kidney Disease
Largely supportive, no single tx to prevent ESRD
Control of HTN, target BP 130/85 or less is recommended, w/ ACE/ARB
Low protein diet (?)
Polycystic Kidney DiseasePolycystic Kidney Disease
Largely supportive, no single tx to prevent ESRD
Control of HTN, target BP 130/85 or less is recommended, w/ ACE/ARB
Low protein diet (?) Antibiotics w/ good membrane
penetration quinolone and trimethoprim-sulfamethoxazole
Polycystic Kidney DiseasePolycystic Kidney Disease
Largely supportive, no single tx to prevent ESRD Control of HTN, target BP 130/85 or less is
recommended, w/ ACE/ARB Low protein diet (?)
Antibiotics w/ good membrane penetration quinolone and trimethoprim-sulfamethoxazole
Cyst drainage
Polycystic Kidney DiseasePolycystic Kidney Disease
Largely supportive, no single tx to prevent ESRD Control of HTN, target BP 130/85 or less is
recommended, w/ ACE/ARB Low protein diet (?) Antibiotics w/ good membrane penetration
quinolone and trimethoprim-sulfamethoxazole
Cyst drainage KT
Other Polycystic Kidney DiseasesOther Polycystic Kidney Diseases
1. ARPPKD
2. Nephronophthisis
3. Medullary cystic kidney diases
4. Tuberous Sclerosis
5. Von Hippel Lindau Disease
6. Medullary Sponge Kidney
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
Inherited forms of hypochloremic metabolic alkalosis w/ HTN
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
Inherited forms of hypochloremic metabolic alkalosis w/o HTN
1. Barter’s Syndrome
2. Gitelman’s Syndrome
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
Barter’s Syndrome
- a rare disease in the neonatal period or early childhood
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
Barter’s Syndrome
- a rare disease in the neonatal period or early childhood
- hypoCl, hypoK, decreased urinary concentrating and diluting ability, hypercalciuria w/ nephrocalcinosis, mild hypoMg, excess Pg production
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
Gitelman’s Syndrome
- more common than Barter’s Syndrome, milder course and later age of presentation
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
Gitelman’s Syndrome
- more common than Barter’s Syndrome, milder course and later age of presentation
- hypocalciuria, severe hypoMg, prominent muscular S/Sx weakness, fatigue, carpopedal spasms, cramps and tetany, no excess Pg production
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
DDx 1. Gitelman over Barter – severe hypoMg
and Hypocalciuria and relative age of patient
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
DDx 1. Gitelman over Barter – severe hypoMg
and Hypocalciuria and relative age of patient
2. Vomiting and Diuretic abuse – in contrast to salt losing tubulopathies urinary Cl are very low or undetectable in vomiting
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
Tx 1. K and Mg (esp in Gitelman’s) supplements
2. Spirinolactone or amiloride
3. NSAIDs/COX-2 in Barter’s
Hereditary Disorders of Na, K, and Mg w/ HTNHereditary Disorders of Na, K, and Mg w/ HTN
Hereditary Disorders of Na, K, and Mg w/ HTNHereditary Disorders of Na, K, and Mg w/ HTN
Liddle’s syndrome
Hereditary Disorders of Na, K, and Mg w/ HTNHereditary Disorders of Na, K, and Mg w/ HTN
Liddle’s syndrome
- mimics a state of aldosterone by (+) of early and severe HTN w/ hypoK and metabolic alkalosis
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
Liddle’s syndrome
- mimics a state of aldosterone by (+) of early and severe HTN w/ hypoK and metabolic alkalosis
- but plasma aldosterone and renin levels
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
Liddle’s syndrome - mimics a state of aldosterone by (+) of early
and severe HTN w/ hypoK and metabolic alkalosis
- but plasma aldosterone and renin levels - unregulated Na reabsorption in ENaC
(deletional mutation) in the CCD
Hereditary Disorders of Na, K, and Mg w/o HTNHereditary Disorders of Na, K, and Mg w/o HTN
Liddle’s syndrome - mimics a state of aldosterone by (+) of early and
severe HTN w/ hypoK and metabolic alkalosis - but plasma aldosterone and renin levels - unregulated Na reabsorption in ENaC (deletional
mutation) in the CCD - Tx Amiloride, salt restriction for both HTN and
hypoK
Hereditary Disorders of Water HandlingHereditary Disorders of Water Handling
Hereditary Nephrogenic Diabetes Insipidus
- rare, usually presenting in infancy with severe vasopressin resistant polyuria, dehydration, failure to thrive, dilute urine despite the presence of hypernatremia
Hereditary Disorders of Water HandlingHereditary Disorders of Water Handling
Hereditary Nephrogenic Diabetes Insipidus
- rare, usually presenting in infancy with severe vasopressin resistant polyuria, dehydration, failure to thrive, dilute urine despite the presence of hypernatremia
- Pathogenesis:
Normal Water HandlingNormal Water Handling
Vasopressin or ADH stimulates water reabsorption in the CD via the type 2 VP receptor (V2R) on the basal surface of principal cells-- adenyl cyclase-cAMP---activation of aquaporin 2 (AQP2) channels and insertion into the apical membrane---water enters from the tubular lumen via AQP2 then exits along an osmotic gradient into the hypertonic medulla and vasa recta via AQP3/4 channels
Hereditary Disorders of Water HandlingHereditary Disorders of Water Handling
Hereditary Nephrogenic Diabetes Insipidus
- rare, usually presenting in infancy with severe vasopressin resistant polyuria, dehydration, failure to thrive, dilute urine despite the presence of hypernatremia
- Pathogenesis: X linked mutations of V2R 90% and the rest from AQP2, resulting in inability to concentrate urine and conserve water
: penetrance can be variable in X linked NDI female carriers, can have moderate concentrating effect
Hereditary Disorders of Water HandlingHereditary Disorders of Water Handling
Hereditary Nephrogenic Diabetes Insipidus
- rare, usually presenting in infancy with severe vasopressin resistant polyuria, dehydration, failure to thrive, dilute urine despite the presence of hypernatremia
- Pathogenesis: X linked mutations of V2R 90% and the rest from AQP2
- Clinical Features: In adults NDI is usually 2’ to Ca, lithium therapy, partial chronic UTO
Hereditary Disorders of Water HandlingHereditary Disorders of Water Handling
Hereditary Nephrogenic Diabetes Insipidus
- rare, usually presenting in infancy with severe vasopressin resistant polyuria, dehydration, failure to thrive, dilute urine despite the presence of hypernatremia
- Pathogenesis: X linked mutations of V2R 90% and the rest from AQP2
- Clinical Features: In adults NDI is usually 2’ to Ca, lithium therapy, partial chronic UTO
: in contrast to Barter’s and Gitelman’s, ELECTROLYTES ARE NORMAL, Hypernat is because of loss of water
Hereditary Disorders of Water HandlingHereditary Disorders of Water Handling
Hereditary Nephrogenic Diabetes Insipidus
- rare, usually presenting in infancy with severe vasopressin resistant polyuria, dehydration, failure to thrive, dilute urine despite the presence of hypernatremia
- Pathogenesis: X linked mutations of V2R 90% and the rest from AQP2 - Clinical Features: In adults NDI is usually 2’ to Ca, lithium therapy,
partial chronic UTO : in contrast to Barter’s and Gitelman’s, ELECTROLYTES
ARE NORMAL, Hypernat is because of loss of water : Normal renal function, but can have ureter and bladder
dilatation and dysfunction
Hereditary Disorders of Water HandlingHereditary Disorders of Water Handling
Hereditary Nephrogenic Diabetes Insipidus
- rare, usually presenting in infancy with severe vasopressin resistant polyuria, dehydration, failure to thrive, dilute urine despite the presence of hypernatremia
- Pathogenesis: X linked mutations of V2R 90% and the rest from AQP2
- Clinical Features: In adults NDI is usually 2’ to Ca, lithium therapy, partial chronic UTO
- Diagnosis: Family History and Clinical Presentation, VP levels despite polyuria and hypotonic urine ( useful to differentiate from adults with partial NDI and central DI or psychogenic polydipsia)
Hereditary Disorders of Water HandlingHereditary Disorders of Water Handling
Hereditary Nephrogenic Diabetes Insipidus
- rare, usually presenting in infancy with severe vasopressin resistant polyuria, dehydration, failure to thrive, dilute urine despite the presence of hypernatremia
- Pathogenesis: X linked mutations of V2R 90% and the rest from AQP2
- Clinical Features: In adults NDI is usually 2’ to Ca, lithium therapy, partial chronic UTO
- Diagnosis: Family History and Clinical Presentation - Treatment: Adequate water intake, thiazide (w/
amiloride) diuretic and salt restriction
Hereditary Renal Tubular AcidosisHereditary Renal Tubular Acidosis
Inherited Renal Tubular Acidosis
- nonanion gap (hyperchloremic) metabolic acidosis either from proximal or distal tubular bicarbonate wasting or impaired net acid excretion
Hereditary Renal Tubular AcidosisHereditary Renal Tubular Acidosis
Inherited Renal Tubular Acidosis
- nonanion gap (hyperchloremic) metabolic acidosis either from proximal or distal tubular bicarbonate wasting or impaired net acid excretion
- Type 1 (Distal) and Type 2 (Proximal)
Type 4 acquired in renal dysfunction, hyperK
Distal Proximal
Transmission AD asymptomatic into adulthood, incidental in work up of stonesAR in infancy, failure to thrive and of growth
Usually secondary to various immune, drug induced, infiltrative and tubulopathies or tubular injury from inherited disorders
Urine acidification none Present (bicarbonate threshold)
Abnormality Inability of DT to acidy urine, failure distal acid excretion
Inability to reclaim filtered HCO3
K Hypo, but can have types which have hyper
hypo
acidosis acidosis Severe metabolic acidosis
Other features Osteoporosis, short stature, hypercalciuria (bone resorption), hypocitrturia, stone formation
hyperphosphaturia, hyperuricosuria, amino aciduria, glucosuria
Treatment Bicarb replacement, K citrate, large fluid intake
Bicarbonate with K and vit D supplementation