polycyctic kidney disease and other inherited tubular diseases

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