HEREDITARY

DISEASES OF
KIDNEY
DR.C.ANANDABABU ,JOPHDC ,JIPMER
• Today we will discuss some of the more common hereditary and congenital renal
diseases.
• There are broadly categorized into diseases associated with renal cysts and those
presenting with haematuria
 AUTOSOMAL‐DOMINANT POLYCYSTIC
KIDNEY DISEASE
• ADPKD is a common disorder, occurring in approximately 1 in every 400–1000 live
births, with more than half of the patients remaining undiagnosed during their lifetime.
• It is a multisystem disorder characterized by enlarged kidneys with multiple and
bilateral renal cysts, with cysts commonly seen in other organs such as liver and
pancreas.
• ADPKD is the fourth commonest cause of chronic kidney disease (CKD) after
diabetes, hypertension, and glomerulonephritis.
 AETIOLOGY AND PATHOGENESIS

• In 85% of patients and families with ADPKD there is an abnormality on chromosome

16 (PKD1 locus), whilst the rest have an abnormality on chromosome 4 (PKD2 locus).
• Mutations in PKD1 are associated with earlier clinical  presentation and higher
morbidity as well as mortality.
• Patients with both cystic fibrosis and ADPKD have less severe renal and liver cysts in
comparison to those who have ADPKD without cystic fibrosis.
 CLINICAL PRESENTATION

• Apart from the renal manifestations , there are multiple extra‐renal manifestations of
ADPKD which can lead to significant morbidity and mortality.
• Patients usually present in their fourth to sixth decades.
• Patients with PKD1 mutation present earlier and usually have worse prognosis then
those with PKD2 mutation.
• Acute flank and abdominal pain may be due to urinary tract and cyst infection,
nephrolithiasis or cyst haemorrhage.
• Chronic pain is usually due to massively enlarged kidneys, leading to either stretching
of the renal capsule or traction on the renal pedicle.
• Cystitis, pyelonephritis, cyst infection, and perinephric abscesses are more common in
patients with ADPKD compared to the general population.
• The route of infection in both pyelonephritis and cyst infection is usually retrograde
from the bladder.
• Renal stones are seen in up to 20% of patients with ADPKD.
• Hypertension is seen in up to 70% of patients with ADPKD before any significant
reduction in glomerular filtration rate (GFR) occurs and is a major contributor to
progression to CKD.
• Cyst expansion leads to focal areas of renal ischaemia, leading in turn to renin
production and activation of the renin–angiotensin system.
• Most patients with ADPKD have a mild concentrating defect. They suffer from
polydypsia, polyuria, nocturia, and urinary frequency.
 END‐STAGE RENAL DISEASE

• Despite ongoing increase in kidney size due to relentless growth of the cysts, renal
function is often maintained till the fourth or fifth decade of life.
• By the time renal function begins to decline, the kidneys are often massively enlarged
and distorted with multiple cysts.
 DIAGNOSIS

• The diagnosis of ADPKD rests on imaging revealing big kidneys with multiple cysts.
• Patients with a positive family history:
• Between 15 and 39 years of age, at least three unilateral or bilateral kidney cysts.
• Between 40 and 59 years of age, at least two cysts in each kidney.
• For those 60 years or older, at least four cysts in each kidney.
• Patients with a negative family history:
• The diagnosis of ADPKD should be suspected in those with no known family history
if there are 10 or more cysts in each kidney.
• These patients also mostly have bulky kidneys, with hepatic cysts often present.
• In up to 25% of cases, ADPKD is diagnosed in patients with no known family history.
 MANAGEMNET

• Treatment of ADPKD includes non‐specific measures, such as strict blood pressure

control, low‐salt diet and statins, which may prevent the progression of disease and
reduce cardiovascular mortality.
• No therapy has yet proven to definitely stop the progression of cysts, although there
are promising therapies on the horizon, including vasopressin receptor antagonists,
somatostatin analogues, and mTOR inhibitors.
 ALPORT’S SYNDROME
• AS is the commonest form of hereditary nephritis and is commonly associated with
sensorineural deafness and ocular abnormalities.
• It is caused by mutations that affect type IV collagen and has a prevalence of
approximately 1 in 50 000 live births.
• The four major types of collagen are:
• Type I: found in skin, bone, tendon, and cornea
• Type II: found in cartilage, intervertebral disc, and vitreous body
• Type III: found in blood vessels and foetal skin
• Type IV: found in basement membrane.
 PATHOGENESIS
• The three forms of AS identified are:
• X‐linked AS (XLAS): caused by mutations in the COL4A5 (alpha5 chain) is the
predominant form accounting for up to 80% of patients . Females are generally less
severely affected.
• Autosomal‐recessive AS (ARAS): caused by mutations affecting both the alleles of
COL4A3 (alpha3 chain) or COL4A4 (alpha4 chain),
• ARAS is seen in up to 15% of patients [23]. Both males and females tend to be
severely affected.
• Autosomal‐dominant AS (ADAS): heterozygous mutation in either COL4A3 or
COL4A4 causes a less severe disease [24]
 CLINICAL MANIFESTATIONS

• Renal Manifestations:
• Haematuria is the cardinal finding in AS. Males often have persistent microscopic
haematuria, with episodes of gross haematuria precipitated by upper respiratory
infections in the first two decades of life.
• Eventually patients developed proteinuria, hypertension, and progressive renal
insufficiency.
• ESRD develops in 90% of XLAS males by the age of 40 (compared with 12% in
females with XLAS)
• Hearing Loss :
• Bilateral sensorineural hearing loss may be detected by audiometry in 85% of males
and 18% of females with XLAS by 15 years of age.
• Ocular Defects :
• Anterior lenticonus, which is anterior conical protrusion of the lens, is pathognomic of
AS and seen in up to half of patients with ocular manifestations.
• Other ocular presentations include maculopathy and corneal defects.
 DIAGNOSIS

• AS should always be considered in the differential diagnosis of a young patient

presenting with ongoing haematuria once structural abnormalities have been ruled out.
• A carefully taken family history, ophthalmic evaluation, and audiometry are often
helpful.
• Renal biopsy and/or molecular genetic testing are diagnostic.
• There is no specific treatment for AS. 
• As in other causes of chronic renal disease, ACE inhibitors or ARBs are useful to
slow down the progress of proteinuria.
• Renal transplantation is the only available therapy.
• The disease does not recur as the donor kidney has normal GBM.
• A post‐transplant anti‐GBM like disease affects up to 5% of these patients.
 MEDULLARY CYSTIC KIDNEY DISEASE

• Medullary cystic kidney disease (MCKD) is a rare condition in which small, fluid-
filled sacs called cysts form in the center of the kidneys.
• Scarring also occurs in the tubules of the kidneys.
• Urine travels in the tubules from the kidney and through the urinary system. The
scarring causes these tubules to malfunction.
 TYPES OF MCKD

• Juvenile nephronophthisis (NPH) and MCKD are very closely related. Both conditions
are caused by the same type of kidney damage and result in the same symptoms.
• The major difference is the age of onset. NPH usually occurs between ages 10 to 20,
while MCKD is an adult-onset disease.
• In addition, there are two subsets of MCKD: type 2 (typically affects adults ages 30 to
35) and type 1 (typically affects adults ages 60 to 65).
 CLINICAL FEATURES

• The symptoms of MCKD look like the symptoms of many other conditions, making it difficult
to make a diagnosis.
• These symptoms include:
• excessive urination
• increased frequency of urination at night (nocturia)
• Low blood pressure
• weakness
• salt cravings (due to excess sodium loss from the increased urination)
• There is no cure for MCKD.
• Treatment for the condition consists of interventions that attempt to reduce symptoms
and slow the progression of the disease.
• In the early stages of the disease, increasing your intake of fluids.
• Salt supplement may be tried to avoid dehydration.
• As the disease progresses, kidney failure can result.
 BARTTER SYNDROME

• Bartter syndrome is a group of very similar kidney disorders that cause an imbalance of
potassium, sodium, chloride, and related molecules in the body.
• In some cases, Bartter syndrome becomes apparent before birth.
• They lose excess amounts of salt in their urine, which leads to dehydration, constipation, and
polyuria.
• In addition, large amounts of calcium are lost through the urine (hypercalciuria), which can
cause weakening of the bones (osteopenia).
• Some of the calcium is deposited in the kidneys as they are concentrating urine, leading to
hardening of the kidney tissue (nephrocalcinosis).
• Bartter syndrome is also characterized by low levels of potassium in the blood (hypokalemia)
 TYPES

• Bartter Syndrome is divided up into sub-types according to the different genetic causes
of the condition.
• Bartter Syndromes type 1 and 2 are clinically similar.
• Bartter Syndrome type 3 is often similar to Gitelman Syndrome and is dealt with
separately.
• Bartter Syndrome type 4 has the added problem of deafness. This deafness is of
sensori-neural type.
 DIAGNOSIS

• Blood tests to diagnose Bartter syndrome look for low levels of potassium, chloride,
magnesium, and bicarbonate in the blood as well as elevated levels of the hormones
renin and aldosterone.
• Urinalysis looks for abnormally high levels of sodium, chloride, potassium, calcium,
and magnesium in urine as well as the presence of prostaglandin E2.
 TREATMENT
• The primary goal of treating Bartter syndrome is to restore the balance of fluids and
electrolytes , depends on the severity of symptoms.
• Sodium, potassium chloride, and magnesium supplements are often used to correct
electrolyte imbalances.
• Other drugs, such as aldosterone antagonists, angiotensin II receptor blockers, and
angiotensin-converting enzyme (ACE) inhibitors, may be needed to reduce renin
levels and the risk of kidney damage.
• Kidney transplant can correct severe abnormalities and has, in rare cases, been
performed when someone has developed the complication of renal failure.
 GITELMAN SYNDROME
• Gitelman syndrome is an autosomal recessive inheritance pattern characterized by low
levels of potassium, low magnesium, and metabolic alkalosis.
• Around 80% of all cases are associated with a specific genetic mutation known as
SLC12A3. This anomaly directly affects the sodium-chloride cotransporter (NCCT).
• A secondary effect of the SLC12A3 mutation is the increase in calcium reabsorption in
the kidney. While this effect is also linked to the malabsorption of magnesium and
potassium.
 CLINICAL FEATURES
• The range of symptoms is directly related to hypokalemia, low hypomagnesemia,
hypochloremia, and hypercalcemia, in association with a low pH level.
• The most common signs of Gitelman include:
• Generalized weakness
• Fatigue
• Muscle cramping
• Excessive urination or urination at night
• Salt craving
•  Gitelman syndrome may also develop chondrocalcinosis, a form of pseudo-arthritis
caused by the formation of calcium crystals in connective tissues.
• Although people may initially have low or normal blood pressure, hypertension may
develop in later life.
 TREATMENT

• Lifelong treatment often includes liberal salt intake along with adequate potassium and
magnesium replacement as indicated.
• NSAIDs and agents that block the distal tubule sodium-potassium exchange (like
spironolactone) may be helpful in some people.
• Kidney transplant corrects the abnormality but has only very rarely been used .