Medullary cystic kidney disease

Nephronophthisis, which means “nephron wasting”, and medullary cystic kidney disease, which refers to fluid-filled sacs in the medulla, are two kidney diseases that share some similar features: they’re both genetic, they both affect the nephrons, and both can lead to kidney cysts and renal failure over time.

To help understand these diseases, let’s first take a zoomed-in look at a nephron and talk about how it works. Alright so the outer layer of the kidney is called the cortex, and this is where the glomeruli live, which is where blood is initially filtered into the nephron, as well as the proximal convoluted tubule, where some of the filtered substances are reabsorbed back into the body.

The filtered substances, or filtrate, that don’t get reabsorbed then moves down through the medulla via the descending and then ascending parts of the loop of Henle.

The filtrate then goes back to the cortex briefly in the distal convoluted tubule, and then returns back to the medulla in the collecting duct.

Zooming back out a bit, the collecting ducts in each region of the kidney - called a renal pyramid, converge on the renal papilla, which dumps fully formed urine into a minor calyx.

From there the urine goes into the major calyx, and soon after, it goes into the ureter and the bladder.

And finally, zooming back in, surrounding each nephron’s tubule is the tubular interstitium, a hypertonic environment optimized to help resorb water and other substances from the tubules.

Alright so in nephronophthisis, which presents in childhood, the tubules atrophy and the interstitium gets infiltrated by macrophages and becomes fibrotic.

Inflammation of the tubules and the interstitium qualifies nephronophthisis as a tubulointerstitial nephritis, but don’t confuse this with nephritic syndrome, which is where red blood cells and protein escape in the urine as a result of damage to the glomerulus.

In nephronophthisis, the affected tubules lose their ability to concentrate the urine by reabsorbing water and other substances back to the body, so urine ends up being more dilute than usual, which leads to polyuria, excessive urination, and therefore polydipsia, or excessive drinking.

Sodium wasting also happens, which is where excess sodium gets excreted in the urine, but proteinuria or proteins in the urine as well as hematuria or blood in the urine typically aren’t seen in nephronophthisis.

Later on in the disease, the glomeruli can become sclerosed, or scarred, and cysts may appear in the medulla, particularly in the corticomedullary junction, which is where the cortex meets the medulla.

Over time, this leads to renal insufficiency, or poor renal function, which can cause uremia, or too much urea in the blood, and anemia from a failure of the kidneys to make erythropoietin. Eventually this leads to renal failure, usually in the teenage years.

Nephronophthisis is broken into subtypes by the age of onset (like for example infantile versus juvenile) or by the gene that’s mutated, of which there are over a dozen possible mutated genes, all of which are inherited in an autosomal recessive fashion, though the most common is NPHP1, which codes for nephrocystin 1 protein.

Most nephronophthisis genes encode for and therefore affect proteins in primary cilia or a related organelle, the centriole.