Clinical Challenge: African-American Woman with Urinary Frequency, Bladder Discomfort

Medullary cystic disease and juvenile nephronophthisis are genetic disorders affecting primary renal epithelial ciliary proteins, also termed ciliopathies. Medullary cystic disease is an autosomal dominant disorder.  There are two types with different ages of onset; type 1 occurs at an...

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Medullary cystic disease and juvenile nephronophthisis are genetic disorders affecting primary renal epithelial ciliary proteins, also termed ciliopathies. Medullary cystic disease is an autosomal dominant disorder.  There are two types with different ages of onset; type 1 occurs at an average age of 62 and is due to an abnormality of the MCKD 1 gene while type 2 is manifest at age 32 and has mutation of the MCKD 2 gene that encodes for Tamm-Horsfall protein (uromodulin). Medullary cystic disease is not associated with extra-renal lesions although patients do develop hyperuricemia and gout.

The pathology is characterized by chronic tubule-interstitial scarring with mononuclear inflammation (chronic interstitial nephritis) in the medulla and extending to the cortex. This is associated with cystic dilatation of tubules with abnormal branching and variable thinning and thickening with layering of the tubular basement membranes identified ultrastrucuturally.

In this patient, the autosomal dominant pattern of family member involvement, ages of presentation, elevated uric acid, and lack of extra-renal lesions indicates a diagnosis of medullary cystic disease type 2.

Juvenile nephronophthisis also is a disorder of renal tubular basement membranes which have a similar morphologic appearance. However, this is an autosomal recessive disorder that occurs in children. There are nine involved genes that are associated with different ages of disease presentation.  Abnormalities of the NPHP2 gene present at age 2 with the infantile form of the NPHP3 gene, at age 20 with the adolescent form, and the most common is the juvenile form presenting at average age 13 due to NPHP1 and 4-9 genes. Additionally, patients with juvenile nephronophthisis usually have extra-renal manifestations including retinitis pigmentosa, hepatic fibrosis, skeletal defects, and cerebellar aplasia.

Patients with chronic pyelonephritis often have a preceding history of reflux nephropathy, stones or UTI. Renal insufficiency would require both kidneys to be involved, which is unusual.  Morphologically, chronic interstitial nephritis of chronic infection has a plasma cell component. tubules typically do not have irregular branching and lack the extensive thickening and thinning of the tubular basement membranes. There is no association with increased uric acid levels or family history of renal disease.

Autosomal dominant polycystic kidney disease (ADPKD) may have a similar family history, with disease typically presenting in the fourth or fifth decade of life, although it may occur prenatally to old age. The majority of ADPKD patients have an abnormality on the PKD1 gene with a loss of polycystin 1, whereas 5%-15% of patients have an abnormal PKD2 gene with decreased polycystin 2.

The polycystin proteins regulate the configuration and polarity of epithelial cells. Kidneys reaching end-stage disease often are massively enlarged with extensive cyst formation throughout the renal parenchyma, involving all segments of the nephron.  There are extra-renal manifestations including cysts in the liver, pancreas and spleen, cerebral aneurysms, and heart valve abnormalities.

Acquired cystic kidney disease may occur with mild chronic renal insufficiency, but usually with more advanced renal failure. Biopsy should reveal an underlying disorder accounting for the renal failure such as hypertensive nephrosclerosis, a glomerular lesion, or other renal parenchymal abnormality. Unless there is an underlying genetic disorder causing the chronic kidney failure, there will not be a family history of renal disease.

The tubules that are involved are in all parts of the nephron, from glomeruli to collecting ducts. Tubular epithelial cell hyperplasia is common in some of the cystically dilated tubules, but kidneys lack the extensive ultrastructural changes of the tubular basement membranes seen in medullary cystic disease.  There may be papillary tubular cell neoplasms, and calcifications and oxalate deposits may occur. There is an increased incidence of renal cell carcinoma.  

Case submitted by Cynthia C. Nast, MD, Professor of Pathology, Cedars-Sinai Medical Center and UCLA School of Medicine.