Genetic kidney diseases

An outline of genetic and congenital conditions. 30 mins.

Paul Phelan and Neil Turner. Part of renal teaching in the Edinburgh MBChB.

We’ve separated this into 4 sections:

• Tubular/Tubulointerstitial
  • Cystic is a major subheading of this
• Glomerular
• Congenital abnormalities (CAKUT)

Except for this last category, most are single gene disorders. As there are 400+ genes with predominant renal expression, we’re touching here on just some important or usefully illustrative examples.

TUBULAR AND TUBULOINTERSTITIAL

Remember those transporters in Renal physiology? There are scores of them, and you don’t need to know detail, just some key principles. Disorders associated with sodium/chloride handling and polyuria are a nice example to use, as they double up with explaining how the different classes of diuretics work.

Sodium absorption by nephron segment, diseases associated, transporter molecules, drugs targeting. Click to enlarge.

The diagram omits the SGLT2, glucose-Na cotransporter in the proximal tubule. It is the main glucose reabsorbing mechanism, though there is also a bit of SGLT1, the main transporter in the gut. Though it is responsible for only a small part of Na reabsorption, SGLT2 inhibitors are proving to be therapeutically powerful for heart and renal failure. Their diuretic action is probably only a part of the explanation.

Tolvaptan inhibits the effects of vasopressin (Anti-Diuretic Hormone) on the AVPR2 receptor in  collecting duct Principal cells. Aquaporin translocates to the cell surface in response. Congenital nephrogenic diabetes insipidus may be caused by mutations in these molecules. Insipidus = tasteless, versus diabetes mellitus meaning sweet. Yes medics really did sometimes taste urine in the 18th century (read about the discovery of diabetes insipidus and its relevance to PKD, which features below).

A number of metabolic disorders damage proximal tubular cells so that a range of reabsorptive mechanisms are impaired. Cystinosis is an example of an inherited condition in which lysosomes become overladen with cysteine, eventually damaging the cells and leading to Fanconi syndrome with leakage of salt, phosphate, amino acids, glucose. These are energy-intensive cells, affected also in a number of other metabolic disorders, and this can also occur after exposure to some toxins (including some immunoglobulin light chains, autotoxins. See interstitial diseases).

Tubulointerstitial disorders

ADTKD:  A number of uncommon inherited conditions cause an indolent interstitial nephritis. The autosomal dominant variants (Autosomal Dominant Tubulointerstitial Kidney Disease, ADTKD) may have  characteristic features, incompletely separated out by the half dozen or so genes affected, but they may also be entirely featureless, so hard to pick up.

Nephronophthisis:  The usually autosomal recessive ciliopathies bracketed under this heading, with many causative genes, commonly have  syndromic extrarenal features that vary from retinal blindness and CNS developmental disorders to skeletal anomalies. Classically they are polyuric and sodium wasting, though this is not through mutation of individual transporters. May have small cysts that don’t usually enlarge the kidney.

The differential diagnosis of these conditions is other causes of chronic interstitial nephritis. See interstitial renal disorders.

Autosomal dominant Polycystic Kidney Disease (ADPKD)

ADPKD is the diagnosis in 8-10% of long term transplant and dialysis populations in the UK. It is one of the more common significant autosomal dominant conditions. There will be staff/students in your hospital/University with this.

Cysts grow with time. Around 50% of patients develop end stage renal disease at an average age of 50-60, but some much younger, and some never. Mutation type is influential. PKD1 is responsible for 80% of those needing dialysis/transplantation. PKD2 causes most of the rest. It is likely that mutations in other genes, particularly those affecting function of primary cilia (and therefore responsible for some ‘interstitial’ renal disease) may influence severity, but also clear that several are still unknown.

Treatment with Tolvaptan, to block the effect of AVP, slows kidney cyst growth and delays ESRF in ADPKD, but not in other cystic diseases, where cysts usually shrink with time. It causes marked polyuria, to which many patients accommodate completely.

Patients with this disease usually have affected family members and become very knowledgeable about the condition, and about dialysis and transplantation. You should know a bit about it too – the Patient Info below should provide all you need. Note two of the important extrarenal features: hepatic cysts that can sometimes cause massive hepatomegaly, and berry aneurysms, which occasionally cause subarachnoid haemorrhage.

• edren.org/gotpkd links to further patient and professional info about the disease and its treatment.

Other cystic diseases

Autosomal Recessive Polycystic Kidney Disease is rare. It causes congenital hepatic fibrosis and prominent, sometimes massive kidney cysts in infancy. Affected individuals rarely survived into adult life in the past, but now many do. The renal cysts tend to become less prominent with time, but kidney function may slowly worsen, and hepatic fibrosis can be problematic.

Mutations of some other genes mentioned above, and others, can cause cystic disease in which cyst formation is usually less extreme. Some of these manifest more as interstitial renal disorders than cystic disorders.

GLOMERULAR DISEASES

Fall into two groups mirroring the spectrum of glomerulonephritis: those affecting GBM, and those affecting podocytes. It’s interesting that so far, no known single gene disorders specifically affect mesangial cells, and few affect endothelial cells.

Alport Syndrome and Basement Membrane disorders

Alport Syndrome is the second most common inherited disorder causing end stage renal disease, but accounts for only about 1% of those with a transplant or on dialysis. However Alport mutations are being identified increasingly frequently; they may make more of a contribution to end stage renal disease than we think.

Typically, young adults with longstanding microscopic haematuria (sometimes visible in infancy) develop proteinuria, often to nephrotic levels and sometimes severe, worsening kidney function – and sensorineural deafness, though the time this is picked up varies widely.

Renal failure may develop as early as mid teens in some. Treatment with ACE inhibitors seems to be delaying the average age of dialysis/transplant from mid-20s to mid to late 30s+; additional approaches may help further.

This is a disease it is worth being aware of. Hearing impairment and awareness of renal diagnosis typically come on during school or early adult years.

• Detailed patient info on Alport Syndrome gives a fuller account.
• Thom Green, drummer for AltJ, gives a frank account of the shock of diagnosis and starting dialysis in his late teens, and of dealing with deafness, and the transformation brought about by transplantation.

Other basement membrane disorders – Two rare examples to illustrate different mechanisms:

• Kidney-specific Laminin chain mutations are associated with proteinuria rather than mechanical failure of the GBM. This is likely to be related to podocyte signalling rather than a direct effect – see next section.
• LMX1B is a transcription factor, mutations may cause basement membrane and other abnormalities that may present as Nail Patella Syndrome. A minority of patients develop severe renal disease from this.

Podocyte mutations and proteinuria

Mutations causing congenital, or neonatal, or childhood steroid-resistant nephrotic syndrome, almost all affect the podocyte. Congenital nephrotic syndrome can be so severe that only nephrectomy and dialysis, followed by early transplantation, offer a prospect of survival. Mutations typically affect:

• SIit diaphragm structure – e.g. Finnish Congenital Nephrotic Syndrome.
• Podocyte cytoskeleton.
• Podocyte signalling – TRPC6, TRPC5 (calcium channels, activation of which leads to disruption of podocyte structure. Activating mutations increase channel ‘open’ time and cause nephrotic syndrome).
• Laminin mutations/absence in GBM as above.

CONGENITAL ABNORMALITIES OF THE KIDNEYS AND URINARY TRACT (CAKUT)

Only a few of these disorders can be pinned on specific mutations, even where there seems to be a familial tendency. As amniotic fluid is produced by kidneys, severe renal maldevelopment of any cause affects development of fetal lungs (and limbs) – known as Potter Syndrome. Severe abnormalities are not compatible with survival after birth.

We’ll mention just two examples of CAKUT here.

Reflux nephropathy and Renal hypoplasia/dysplasia

Reflux nephropathy is a common diagnosis associated with focal renal ‘scars’ or maldevelopment, previously often labelled ‘chronic pyelonephritis’. An association with recurrent UTIs was for a long time  considerered to be the major cause of deterioration of reflux nephropathy, but that is no longer so clear. Severe acute pyelonephritis can leave additional scarring, but reflux scars are present at birth, and prophylaxis or measures to reduce reflux have had no material impact on outcome. The phenomenon of ureteric reflux tends to lessen with time.

Hypoplasia/dysplasia covers every abnormality of normal renal development, including unilateral missing kidney, and various anatomical malformations and under-development.

• Edren Textbook on Reflux nephropathy – which is also mentioned under chronic interstitial nephritis.

Posterior urethral valves

As an example of a congenital obstructive problem. Affects just boys, impairs bladder emptying. Severe examples may be picked up on antenatal ultrasound, and in utero interventions may be possible, otherwise as soon as possible postnatally. Patients may be left with a distended, hypofunctional bladder and renal impairment that requires long-term monitoring and sometimes later dialysis/transplantation.