ICL 2.6: Inherited Diseases of the Kidney

Question 1

what is the inheritance of Bartter syndrome?

Answer 1

AR

Question 2

what is the cause of Bartter syndrome?

Answer 2

mutations that inhibit active sodium reabsorption in the thick ascending limb of loop of Henle, including Na+/K+/2Cl- cotransporter, ClC-Kb, and ROMK channels

there are TONS of gene mutations!!

ex. SLC12A mutation effects the NKCC2 channel which effects their concentrating capacity and diluting capacity

Question 3

what is the clinical presentation of Bartter syndrome?

Answer 3

1. hypokalemia
2. metabolic alkalosis
3. hypercalciuria*
4. high plasma renin and aldosterone levels
5. normotensive
6. serum Mg+2 usually normal*

electrolyte abnormalities are similar to patients with chronic ingestion of loop diuretics!

clinically similar to patients with surreptitious diuretic ingestion

Question 4

what is the inheritance of Gitelman Syndrome?

Answer 4

AR

less rare; 1 to 10 in 40,000

Question 5

what is the clinical presentation of Gitelman syndrome?

Answer 5

1. hypokalemia
2. metabolic alkalosis
3. hypocalciuria*
4. normotensive
5. high plasma renin and aldosterone levels
6. hypomagnesemia; sometimes severe*

similar to patients ingesting thiazide diuretics

an essential distinction between the two syndromes is the presence of hypocalciuria in Gitelman syndrome, in contrast to the hyercalciuria that occurs in Bartter syndrome.

Question 6

what causes Gitelman syndrome?

Answer 6

mutations in the thiazide-sensitive sodium chloride cotransporter (NCCT) in the distal convoluted tubule

Question 7

what is the cause of sickle cell disease?

Answer 7

single point mutation with substitution of valine for glutamic acid at position 6 in chromosome 11 resulting in unstable hemoglobin S

sickle cell anemia (HbSS) occurs in approximately 1-500 live births in African Americans

Question 8

how does sickle cell effect the kidney?

Answer 8

although a systemic disease, the kidney is especially susceptible due to low oxygen tension and sluggish blood flow in the renal medulla resulting in ‘sickling’ and microvascular obstruction

co-inheritance with ⍺-thalassemia has a protective effect on progression of chronic kidney disease in SCD –> it decreases HbS concentration so you have less sickling and less problems with infarction

Question 9

what is the common glomerular lesion in sickle cell disease?

Answer 9

focal segmental glomerulosclerosis

even though SCD is a systemic disease the kidney is really susceptible because there’s sluggish blood flow in the medulla which leads to small infarctions that over time will cause decreased blood flow and ESRD

Question 10

how common is sickle cell trait?

Answer 10

the prevalence of sickle cell trait (HbAS) in US is between 6%-9%

although more benign than SCD, renal manifestations are also the most common morbidities in sickle cell trait

similar to SCD, co-inheritance with ⍺-thalassemia seems to have a protective effect on the severity of urinary concentrating defect

Question 11

what is a common complication associated with sickle cell trait?

Answer 11

even though renal medullary carcinoma is rarely seen in SCD, it appears to be exclusively reported in patients with sickle cell trait

also, population studies in African Americans show that sickle cell trait maybe a risk factor for chronic kidney disease (but SCD for sure is)

Question 12

what is the age of presentation of renal disease in patients with SCD?

Answer 12

reversible hyposthenuria = urinary concentrating ability is decreased but it’s reversible early on

as they get older urinary concentrating ability is lost and you make a lot of dilute urine –> prone to dehydration –> HbS can get more concentrated = sickling crisis

patients can present with gross hematuria from infarction in the kidney or even chest pain

IV fluids and pain control to treat sickling crisis

Question 13

what are the renal manifestations in SCD?

Answer 13

1. glomerular hyperfiltration

increased GFR and albuminuria early on and then proteinuria, sickle glomerulopathy, and CKD as it progresses

2. proximal tubule: increased creatinine secretion, hyperphosphatemia, hyperkalemia secondary to hyporeninemic hypoaldosteronism
3. distal tubule/cortical dollection duct: metabolic acidosis (type 4 RTA), hyperkalemia, hyposthenuria
4. interstitium: hematuria, renal papillary necrosis due to ischemia secondary to chronic “sickling” in vasa recta, renal medullary carcinoma, CKD

Question 14

how do you prevent and manage sickle nephropahy?

Answer 14

1. avoiding nephrotoxic medications

NSAIDS, especiallyketorolac, should be minimized or eliminated during hospitalization

2. aminoglycoside antibiotics

broad spectrum antibiotics includingvancomycinandgentamicinare often required; dosing and drug levels is essential to prevent drug accumulation

3. radiocontrast material

contrast-enhanced imaging studies to evaluate acute chest syndrome, splenic or hepatic sequestration, or stroke; adequate hydration with low dose

4. iron chelators

chelation therapy with Deferasirox to remove excess iron from transfusional iron overload can cause AKI and needs to be dose adjusted

Question 15

what is a protective mechanism against many SCD complications?

Answer 15

hydroxyureais protective against many SCD complications, and its use is appropriate in most individuals with SCD who have vaso-occlusive complications

hydroxyurea is a mainstay of SCD therapy and is recommended for infants as young as nine months of age who have homozygous hemoglobin SS or sickle-beta thalassemia(B thalassemia is not protective against SCD)

mechanism of action of hydroxyurea is due to its ability to induce HbF production and reduce the overall production of HbS and may affect synthesis of nitric oxide and reduce hyperfiltration in children

Question 16

how do you treat sickle cell?

Answer 16

it’s similar to patients with chronic kidney disease

reduction of albuminuria/proteinuria with inhibition of renin-angiotensin-aldosterone system-screening begins at 10 years and then annually, if negative with initiation of therapy if detected

close monitoring of renal function and serum potassium with dose escalation –> sickling crisis breaks up RBCs which releases serum K+ and cause hyperkalemia

hydroxyurea maybe associated with a reduction in albuminuria and is indicated in the setting of frequent pain crisis, acute chest syndrome or severe anemia

ESRD interventions (dialysis and transplant): renal replacement therapy is appropriate for individuals with SCD who develop end-stage renal disease (ESRD), similar to the general population

Question 17

what is the prevalence of ADPKD?

Answer 17

Autosomal-dominant polycystic kidney disease is a systemic hereditary disorder which occurs throughout the world

the prevalence of ADPKD is 1:400 to 1:1000 and affects approximately 12.5 million people worldwide

approximately, 600,000 Americans have the disease, making ADPKD one of the most common hereditary disorders in the US

Question 18

what is the cause of ADPKD?

Answer 18

ADPKD is caused by mutations in PKD1 (85%) or PKD2 (15%)

PKD1 need renal replacement therapy in their 50s while PKD2 mutations don’t need therapy till their 70s

ADPKD = AD polycystic kidney disease

Question 19

what is the prognosis of ADPKD?

Answer 19

by the age of 55 years, half of all ADPKD patients require renal replacement therapy which is either dialysis or renal transplantation –> they do well because they don’t have any other systemic diseases

on average, PKD2 patients develop end-stage renal disease (ESRD) at a median age approximately 20 years later than PKD1

Question 20

what are the extra-renal manifestations associated with ADPKD?

Answer 20

1. HTN (78%)
2. hepatic cysts (75%)
3. diverticulosis coli
4. cardiac valve disorders
5. intracranial aneurysms
6. ovarian cysts
7. inguinal hernias (15%)

Question 21

what is polycystic liver disease? which disease is it associated with?

Answer 21

liver cysts occur in more than 80% of adults with ADPKD…liver imaging is a part of the initial assessment of all ADPKD patients.

cysts increases with age and is greater in multiparous women or those on hormone replacement

20% of patients with PLD will suffer compressive symptoms including abdominal pain and distension, back pain, early satiety and gastroesophageal reflux –> people with multiple liver cysts don’t have liver dysfunction but people with kidney cysts do have kidney failure as the cysts grow in size

in severe PLD, surgical treatment like cyst fenestration, liver resection or transplantation maybe required

medical therapy to date have been ineffective and have side effects that are poorly tolerated

Question 22

what is an intracranial aneurysm? how is it related to ADPKD?

Answer 22

ICAs occur in 9–12% of patients with ADPKD compared with 2–3% in the general population

Question 23

when do you screen a PKD patient for intracranial aneurysms?

Answer 23

widespread screening for ICA is NOT recommended

indications for screening in patients include family history of ICA or subarachnoid hemorrhage, previous ICA rupture, high-risk professions (e.g., airline pilots) and patient anxiety despite adequate information

time-of-flight (TOF) MRA without gadolinium enhancement is the screening method of choice

Individuals with small, untreated UIAs should be re-evaluated every 6 to 24 months

patients with a family history of ICA and a negative screening should be re-screened at 5–10 years intervals

Question 24

what are the signs and symptoms of ADPKD?

Answer 24

1. back and flank pain
2. HTN
3. gross hematuria
4. renal concentrating defect
5. palpable kidneys
6. hepatomegaly
7. systolic murmurs or clicks
8. microscopic hematuria/pyuria
9. proteinuria
10. chronic renal insufficiency

Question 25

what are the risk factors that have been identified for progressive renal disease in ADPKD?

Answer 25

1. genetic factors (PKD1 is worse versus PKD2)
2. hypertension
3. early onset of symptoms including proteinuria and hematuria
4. male gender
5. increased kidney size (kidney size is greater with PKD1 mutations)
6. increased left ventricular mass index (LVMI)
7. dipstick detectable proteinuria
8. low birth weight
9. decreased renal blood flow
10. increased urinary sodium excretion
11. increased low-density lipoprotein (LDL) cholesterol
12. increased plasma co-peptin (surrogate marker for vasopressin)
13. higher serum uric acid levels

Question 26

what is the clinical onset of PKD1 vs PKD2 ADCKD?

Answer 26

PKD1 mutation has an earlier onset and earlier ESRD than PKD2

Question 27

what is the CRISP study?

Answer 27

The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) was established to develop and implement studies to test whether imaging techniques can provide accurate and reproducible markers of progression of renal disease in patients with polycystic kidney disease

careful radiological imaging follow-up studies have shown that TKV increases by 4 to 10% per year in ADPKD patients. Glomerular filtration rate (GFR), however, remains stable in the early stages despite cyst expansion

a long lag time (up to 6 to 8 years) has been observed between changes in overall kidney structure (TKV) and function (GFR). Therefore a long follow-up period would be needed to see a beneficial effect on GFR.

summary: early on there are cysts in the kidney but GFR is pretty fine even though the CT scanning is showing enlarging kidneys –> once they hit a certain size there is a super rapid decline of kidney function and they die within 3-4 years; this is different from other diseases that just have a progressive decline in function over time –> total kidney volume is what predicts kidney failure!

Question 28

which drugs can maybe treat PKD?

Answer 28

1. rapamycin

2. vasopressin 2 receptor antagonists (slows CKD progression)

Question 29

what is the incidence of ARPCKD?

Answer 29

occurs in 1 in 20,000 live births

less common than ADPKD

Question 30

what causes ARPCKD?

Answer 30

mutations in the polycystic kidney and hepatic disease (PKHD1) gene on short arm of chromosome 6 which encodes fibrocystin

Question 31

what is the clinical presentation of ARPCKD?

Answer 31

1. characterized by fibrocystic kidneys and liver
2. severely enlarged kidneys
3. oligohydramnios
4. Potter phenotype with pulmonary hypoplasia and deformed facies, spine and limbs
5. HTN associated with reduced GFR
6. liver disease in ARPKD consists of dilation of intrahepatic (Caroli syndrome) and extrahepatic bile ducts-recurrent ascending cholangitis
7. biliary dysgenesis and periportal fibrosis-leads to portal hypertension, rarely leads to liver failure
8. growth retardation

super poor prognosis…

Question 32

what is the incidence of tuberous sclerosis complex?

Answer 32

AD, occurs in 1-6000 births

Question 33

what causes tuberous sclerosis complex?

Answer 33

caused by mutations in 1 or 2 genes-TSC1 encodes hamartin and TSC2 encodes tuberin

less severe in TSC1 compared to TSC2

hamartin and tuberin mutations prevent the formation of complexes resulting in constitutive activation of mTOR which plays a central role in the regulation of cell proliferation

combination of rapamycin (mTORi) and IFN-γ may have therapeutic benefit for management of TSC tumors

Question 34

how do you diagnose tuberous sclerosis complex?

Answer 34

diagnosis of TSC requires 2 major features or 1 major plus 2 minor features

Major features include renal angiomyolipoma, facial angiofibromas or forehead plaques, non-traumatic ungal or periungal fibroma, three or more hypomelanotic macules, shagreen patch, multiple retinal nodular hamartomas, cortical tuber, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangioleiomyomatosis.

Minor features include multiple renal cysts, nonrenal hamartoma, hamartomatousrectalpolyps, retinal achronic patch, cerebral white matter radial migration tracts, bone cysts, gingival fibromas, confetti skin lesions, multiple enamel pits

Question 35

what is the clinical presentation of tuberous sclerosis?

Answer 35

1. dark red/purple lesions, not blanchable on the buttocks, groin, umbilicus, and upper thighs
2. presents in adolescence or young adulthood
3. adenoma sebaceum, cafe-au-lait spots, shagreen spots, ash leaf spots

all ‘classic male’ hemizygotes; 30% of heterozygous females

biopsy shows dilated capillaries and parakeratosis (dry scaly skin) and endothelial inclusions

Question 36

what is von hippel-lindae disease?

Answer 36

rare autosomal-dominant disease, incidence of 1-36,000 live births

VHL is a tumor suppressor gene and disease causing mutations detected in almost all patients

it’s clinically characterized by benign and malignant tumors in many organs

Question 37

what is the clinical presentation of von hippel-lindae disease?

Answer 37

mutations in VHL tumor suppressor gene causes clinically benign and malignant tumors in many organs = hereditary renal cancer syndrome!

hemangioblastomas occur in 60-80% of VHL patients, although benign can cause mass effects and needs surgical resection; MRI screening of the brain and cervical spine is recommended every 1-2 years starting at age 16 years

retinal angiomas are the most common presenting feature of VHL disease, bilateral, vision loss in 35%-55% of cases

annual eye exams recommended from birth and most lesions respond well to laser photocoagulation

Question 38

what is the most common malignant tumors in von hippel-lindae disease? how do you treat/manage?**

Answer 38

renal cell cancers are the most common malignant tumors in VHL and are an important cause of death

they tend to be recurrent, bilateral and multifocal so you can’t remove a kidney since it’s both kidneys…

so you have to do close surveillance with serial imaging using MRI with and without contrast every 2 years starting at age 16 years

a kidney-sparing surgery or ablation is recommended with 5-and 10-year cancer survival rates similar to those obtained with radical nephrectomy – since the kidneys are both effects you can’t remove them both so you do partial nephrectomy

the NCI developed the “3 cm rule” for surgical intervention based on absence of documented metastasis from tumors smaller than 3 cm –> so you only remove a tumor if it’s 3 cm but you can still do ablation if it’s smaller than that

Question 39

what is nephronophthisis?

Answer 39

AR disease that results in ESRD within first 3 decades of life and therefore most common genetic causes in pediatric populatio

no known treatment to date ):

Question 40

what is the clinical presentation of nephronophthisis?

Answer 40

classic triad:
1. interstitial fibrosis with tubular atrophy

2. TBM disruption
3. corticomedullary cysts

it’s the most common genetic cause of renal disease in the pediatric population with no known treatment

earliest clinical manifestation of NPHP is a urinary concentrating defect resulting in polyuria, enuresis and nocturnal polydipsia

Question 41

what causes nephronophthisis?

Answer 41

several NPHP mutations are known

ex. NPHP1 codes for Nephrocystin 1 and NPHP2 codes for Inversin.

Question 42

what are the most common extra renal manifestations of nephronophthisis?

Answer 42

1. retinitis pigmentosa, leads to blindness in the first decade of life in about 10% of patients –> most common
2. growth retardation
3. anemia

Question 43

how do you diagnose nephronophthisis?

Answer 43

lab evaluation includes a UA of the first morning void to check for specific gravity, absence of proteinuria

the most relevant diagnostic test is US of kidneys which shows normal to slightly reduced kidney size, increased echotexture, and a loss of corticomedullary differentiation

occurrence of similarly affected siblings in the same family strongly suggests NPHP

Question 44

what is AD medullary cystic kidney disease? what is the cause and clinical presentation?

Answer 44

AD disease that results in ESRD between the fourth and seventh decades of life

no known treatment to date

it’s caused by mutations in MCKD1 which codes for Mucin1 and MCKD2 which codes for Uromodulin are known

the only extrarenal manifestation is hyperuricemia with gouty arthritis but no other distinctive findings on PE

lab findings include a urinary concentration defect with reduced fractional excretion of uric acid

US exam shows normal to slightly reduced kidney size, increased echogenicity, loss of corticomedullary differentiation, and medullary cysts

poor prognosis…

Question 45

what is the cause of medullary sponge kidney?

Answer 45

heterozygous mutations inPKHD1, the gene mutated in patients with autosomal recessive polycystic kidney disease (ARPKD), have been proposed as a molecular cause of medullary sponge kidney

although positive family history is often absent, family clustering of medullary sponge kidney may be common

Question 46

what is medullary sponge kidney?

Answer 46

1. dilated intramedullary collecting ducts that impart a sponge like appearance
2. defect in urinary concentration and dilution
3. nephrolithiasis (kidney stones**), hematuria, UTIs
4. all of the calyces are abnormal showing a brush-like appearance radiating outward from the calyces

Question 47

what is the prognosis of medullary sponge kidney?

Answer 47

excellent long-term prognosis

renal function usually normal in most cases

however, stone-induced episodes of obstruction can lead to transient episodes of AKI so you need to do prevention of recurrent episodes of obstruction and/or recurrent infection is important to prevent progression to end-stage renal disease

treatment is indicated for urinary tract infection (using appropriate antimicrobial therapy) and for recurrent stone formation

treatment of calcium stones in patients with medullary sponge kidney varies according to the specific underlying metabolic abnormality demonstrated by 24-hour urine collections

Question 48

what is alport syndrome?

Answer 48

it’s a disease of collagen affects the kidneys, usually ears and often the eyes = hematuria, nephritis and hearing loss early on

association of hereditary hematuric nephritis with hearing loss that affects males in adolescence

Question 49

what causes Alport syndrome?

Answer 49

mutation of COL4A5 that codes for the α5 chain of type IV collagen

85% of kindreds have X-linked disease

autosomal inheritance in 15% of cases

Question 50

what are the clinical features of Alport syndrome?

Answer 50

RENAL
1. microscopic hematuria from birth in affected males

2. hematuria after exercise or fever
3. proteinuria
4. hemizygous males progress to ESRD
5. heterozygous females are less severely affected

EXTRARENAL
1. hearing loss

2. ocular defects = “oil drop” appearance of anterior lenticonus, a pathognomonic feature of Alport syndrome!!
3. leiomyomatosis of the esophagus and female genitalia seen in families with x-linked Alert syndrome

Question 51

what does an EM of Alport syndrome show?

Answer 51

characteristic thickening, fraying, and laminations of the glomerular basement membrane

Question 52

how do you diagnose Alport syndrome?

Answer 52

1. finding of hematuria in many family members.
2. history of kidney failure in related males
3. kidney biopsy showing characteristic ultrastructural changes in the proband or a relative
4. positive staining with antibodies specific to GBM or to α5(IV)

lack of staining differentiates Alport syndrome from familial TBMD (Thin Basement Membrane Disease)

the key to diagnosis is clinical suspicion of Alport syndrome in any patient with otherwise unexplained hematuria, glomerulopathy and kidney failure

important to take a detailed family history

Question 53

how do you treat Alport syndrome?

Answer 53

no specific treatment for Alport syndrome…

retard progression to ESRD with good BP control preferably with ACE-I

studies have studied benefit of cyclosporine in reducing proteinuria and delay progression of renal failure- no controlled trials to date

males should wear hearing protection in noisy environments; hearing aids restore some hearing but tinnitus is resistant to therapy – retinal lesions do not commonly affect vision.

vsion impairment due to lenticonus and cataracts cannot be corrected with glasses or contact lenses –> lens removal with re-implantation of an intraocular lens is standard treatment

Question 54

what is Fabry disease?

Answer 54

X-linked lysosomal storage disorder resulting from absent or deficient activity of the enzyme α-galactosidase A

encoded by the GLA gene with more than 800 different mutations described to date

enzyme defect leads to progressive accumulation of glycosphingolipids in all organs

Question 55

what are the signs and symptoms of Fabry disease?

Answer 55

1. acroparesthesia = neuropathic pain in hands or feet
2. persistent proteinuria of unknown cause
3. hypertrophic cardiomyopathy
4. progressive CKD
5. cryptogenic stroke or transient ischemic attack
6. family history of ESRD, stroke or hypertrophic cardiomyopathy
7. persistent or recurrent abdominal pain
8. skin: Angiokeratoma, hypohidrosis

Question 56

how do you treat Fabry disease?

Answer 56

1. acroparesthesia; painful crisis –> avoid temperature changes, use NSAIDs
2. hypohidrosis –> appropriate temperature and environment
3. angiokeratoma –> cosmetic removal
4. proteinuria –> ACEi or ARB
5. kidney failure –> dialysis, transplantation
6. GI symptoms –> pain relief, H2-blockers, motility agents, pancreatic enzymes

Question 57

what are the new treatment options for Fabry disease?

Answer 57

1. enzyme replacement: recombinant human αGAL infusion

agalsidase (Replagal) is produced in human skin fibroblasts, approved in Europe and other countries but not in US

Agalsidase beta (Fabrazyme)-produced in Chinese hamster ovary cells-approved and available in US

treatment is expensive. In 2005, for example, the estimated retail cost of therapy with Fabrazyme for one year was $160,000 in Europe and $206,000 in the United States

2. pharmacologic chaperones = a small molecule that causes mutant proteins to fold and route correctly within the cell –> helps the lysosome to be broken down and not cause symptoms

migalastat hydrochloride, a potent αGAL inhibitor is an analogue of the terminal galactose of Gb3 and was approved for the treatment of Fabry disease based on results of phase 3 trials which showed improvement in GI symptoms, stable kidney function and improvement of left ventricular mass

therefore, there is important clinical potential for this new therapeutic tool alone or in combination with enzyme replacement therapy