Inherited Renal Diseases

Ari Kostadaras, M.D.

 The following session will highlight the main features of four unrelated diseases: 1) Alport Syndrome; 2) Autosomal Dominant Polycystic Kidney Disease; 3) Medullary Sponge Kidney; and 4) Medullary Cystic Disease. Medullary sponge kidney is the disorder in this group which is not usually inherited but the name may be confused with Medullary cystic disease.


Alport Syndrome

Alport syndrome (AS) is defined as progressive hereditary hematuric non-immune nephritis characterized ultrastructurally by irregular thickening, thinning and lamellation of the glomerular basement membrane (GBM) associated in some patients with hearing losses, various ocular defects (15-30% of patients), abnormalities of platelets number and function, and esophageal, upper gastrointestinal and genital leiomyomatosis.

Alport syndrome is a genetic disorder of type IV (basement membrane) collagen with X-linked dominant inheritance. Alport locus was mapped to the long arm of the X chromosome (Xg 22) and gene (COL4A5) for BM collagen chain was identified. In addition to the X-linked dominant form of AS, autosomal dominant and autosomal receive varieties of disease are well documented.


Clinical Features of AS.

Persistent or episodic gross hematouria is the major presentation of the AS in boys (as early as 1 year old) and affected females (virtually always heterozygous). Proteinuria, usually absent at the beginning, appears eventually in affected males; NS is not unusual in these patients and indicate the worse prognosis.

Hypertension is found in increased percentage in AS affected males. End-stage renal disease develops inevitably in males but with variable frequency in females. Hearing losses are never congenital, usually clinically obvious by age 15, but can be detected earlier by audiometry (reduction in sensitivity to tones in 2000 - 8000 HZ range). Ocular defects include anterior lenticonus, protrusion of the lens into anterior capsule and variety of other ocular lesions.

 Thus, a careful family history, examination for hematuria, proteinuria, hearing loss, ophthalmologic abnormalities together with biopsy findings (which are not necessary, but helpful) are important for diagnosis of AS.

 There is no currently available treatment to alter the course of AS, although management of hypertension is mandatory on general grounds and dialysis and renal transplantation are indicated for patient with ESRD. Living related kidney donors for AS patients must be selected with care. Molecular genetic studies can identify asymptomatic carriers of Alport gene(s).

 Anti-GBM nephritis can develop in transplanted kidney, since the normal BM of transplanted kidney will be recognized as forgein Ag by AS patient. Transplanted AS males should be regularly screen for circulating anti-GBM Ab and they may benefit from treatment with plasmapheresis.


Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Cystic disorders account for approximately 11 percent of end-stage kidney diseases. Autosomal dominant polycystic kidney disease alone accounts for 8-10 percent. The rest (1-3 percent) of the patients who reach dialysis or transplantation is due to medullary cystic disease, renal-retinal displasia or, rarely, medullary sponge kidney.

 The prevalence of ADPKD is approximately 1:500-1:1000 in the US. There are at least three genotypes: ADPKD 1 (90-95%); ADPKD 2 and ADPKD 3 genotype has been also reported. None of the genes has been cloned. Clinical testing to determine genotype is possible and can be performed in individuals at risk. Each child of affected family member has 50/50 chance of having the defective gene.

 The diagnosis of ADPKD is usually suspected in those with an affected family members, those with clinical complains compatible with ADPKD, and those in whom multiple cysts are found incidentally during renal or abdominal imaging.

 Symptoms usually start by 2nd or 3rd decade of life and patients presents with flank pain due to hemorrhage into a cyst and/or pyelonephritis and hematuria; otherwise, the symptoms and signs are those commonly seen in hypertension or renal insufficiency.

 Hypertension is common in ADPKD (approximately 60% of patients), it starts before loss of renal function occurs, and most likely results from activation of rennin - AII-aldosterone axis due to cyst expansion resulting in stretch and attenuation of the intra-renal vessels.

 On physical examination the enlarged, irregular kidneys are easily palpable. The urine may contain leukocytes and red cells. The blood chemistry reflect the degree of renal insufficiency.

 Renal complications of ADPKD include urinary tract infection, perinephroic abscess, infected renal cyst, hemorrhage into cyst, renal calculi , (especially uric acid and calcium oxalate) and obstruction. Cyst infections are often refractory to antibiotic treatment and percutaneous aspiration and drainage may be required. Lipid soluble drugs such as ciprofloxacin or bactrim with high pKa have better excess to cysts then aminoglycosides.

 Intracranial aneurysms (IC) are detected in 5% in asymptomatic ADPKD patients using either dynamic CT imaging or MRI. 75% of deaths due to cerebrovascular events in ADPKD subjects are due to hypertensive stroke and 25% can be attributed to IC. Thus it is not cost effective to screen all patients with ADPKD but it is indicated to screen families with ADPKD with positive history of IC. Liver cysts are found in 40-60% of ADPKD patients; although liver can attain enormous size, its function remains normal. Other frequent findings in ADPKD patients are colon diverticula and aortic regurgitation and cysts in pancreas and ovaries. There are also many case reports of hypernephroma in polycystic kidney disease.

 Diagnosis is made by family history, clinical picture and imaging (CT, ultrasound). No specific therapy is available. Hypertension, infections and uremia are treated in conventional manner. Pain usually responds well to non-narcotic analgesic. Renal transplantation is as useful for ADPKD subjects as for other ESRD patients.


Medullary Sponge Kidney (MSK)

MSK is characterized by the presence of dilated collecting ducts and tubules in one or more renal papillae. The disorder is considered a developmental anomaly. However familial case with autosomal dominant inheritance has been reported. The incidence of the disorder in unselected patients undergoing urography is approximately 0.5%.

 MSK is asymptomatic unless complicated by nephrolithiasis, hematuria or urinary infection usually by the 2nd of 3rd decade of life, equally affects both sexes. In the absence of complications, urinalysis usually is normal and GFR is not impaired. However, the majority of patients will have mild impairment of urinary concentration and acidification secondary to tubular dysfunction (reduced excretion of titrable acid) but systemic acidosis is rare. Other functional abnormalities include high fractional excretion of sodium and hypercalcuria.

 Diagnosis is made by excretory urography that shows dilated collecting tubules giving the characteristic brushlike pattern to renal papillae, "bouquets of flowers" or "bunches of grapes". Ultrasound, angiography, CT has no role in diagnosis. The diagnosis should be suspected in patients with idiopathic calcium oxalate nephrolitiasis or hypercalciuria and urinary tract infections. When uncomplicated case on excretory urography is discovered, the patient should be informed of benign nature of disorder. Periodic urinalysis are advisable to detect early complications and prompt treatment.

 The long-term prognosis of the patients with MSK is excellent and development of ESRD in uncommon.


Medullary Cystic Disease (MCD)

Medullary cystic disease or juvenile nephrolithiasis is characterized by progressive renal failure and cyst formation in the medullary and cortico-medullary regions of the kidney.

 The disorder is inherited recessive in 85% of cases and primarily affect children and young adults and results in renal failure by age 4 in dominantly inherited disease and by age 13 in recessive inherited disease. Polydyspsia, polyuria and enuresis are the earliest presenting symptoms in the majority of affected children. Hepatic fibrosis, retinal dysplasia, hyperuricemia and gouty arthritis have been associated with medullary cyst kidney disease. The disease normally is not associated with cysts in other organs, and aneurysms of cerebral arteries in contrast to patient with ADPKD. Hematuria is rare and almost never grossly evident. Defect in urinary concentrating ability and renal sodium wasting are frequent findings in patients with MCD.

 Diagnosis is usually dependent on the family history, clinical picture and demonstration of characteristic medullary cystic changes on CT, within small kidneys. The prognosis is poor and ESRD develops in the course of disease. Genetic counseling and family planning can control the frequency of the disease.