Genetic Renal Disease Flashcards
Inherited glomerular disease
-Alport syndrome
-Thin glomerular basement membrane disease
-PKD
-Fanconi syndrome
-Renal tubular acidosis
Overview of Alport syndrome
-G: collagen type 4, X-linked recessive disorder dominant in 85%. The accumulation of abnormal collagen results in a progressive degeneration of the GBM. People with Alport syndrome have tiny blood vessels in the glomeruli of the kidneys that are damaged, which means they cannot filter the wastes and extra fluid produced by the body.
-E: second most common inherited disorder causing end stage renal disease, but accounts for only about 1% of those with a transplant or on dialysis
-P: haematuria to ESRD in late adolescence or their twenties. Female carriers of COL4A5 mutations usually have haematuria but less commonly develop significant renal disease. Bilateral sensorineural deafness (cochlea), Microscopic haematuria, progressive renal failure, lenticonus (protrusion of the lens surface into the anterior chamber), retinitis pigmentosa, renal biopsy (splitting of lamina densa seen on electron microscopy)
-I: young adults with longstanding microscopic haematuria (sometimes visible in infancy) develop proteinuria, often to nephrotic levels and sometimes severe, worsening kidney function. Molecular genetic testing, renal biopsy: electron microscopy: characteristic finding is of the longitudinal splitting of the lamina densa of the glomerular basement membrane, resulting in a ‘basket-weave’ appearance
-M: ACEi delays average age of dialysis/transplant from mid-20s to mid to late 30s+. Renal replacement therapy (RRT), as they are young and usually otherwise healthy. They can develop an immune response to the normal collagen antigens present in the GBM of the donor kidney and, in a small minority, anti-GBM disease develops and destroys the allograft.
Overview of thin GBM disease
-The condition may be familial and some patients are carriers of Alport mutations. This does not appear to account for all cases, and in many patients the cause is unclear.
-P: non-visible haematuria without associated hypertension, proteinuria or a reduction in GFR.
-I: The glomeruli appear normal by light microscopy but, on electron microscopy, the GBM is abnormally thin.
-M: Monitoring of these patients is advisable, as proteinuria may develop in some and there appears to be an increased rate of progressive CKD in the long term.
Overview of PKD
Genetics: Autosomal dominant (most common inherited). PKD1 is responsible for 80% of those needing dialysis/transplantation. PKD2 causes most of the rest. Small cysts lined by tubular epithelium develop from infancy or childhood and enlarge slowly and irregularly. The surrounding normal kidney tissue is compressed and progressively damaged.
E: 8-10% of long term transplant and dialysis populations in the UK. Cysts grow with time. Around 50% of patients develop end stage renal disease at an average age of 50-60 (52 PKD1, 70 PKD2), but some much younger, and some never. It is found equally in men and women. 85% type 1 (chromosome 16, presents with renal failure earlier), type 2 15% (chromosome 4)
P: Symptoms develop 30-40, vary severity, progressive. Pain in back and sides, headaches, UTI, high BP, kidney stones. Extrarenal features: hepatic and pancreatic cysts that can sometimes cause massive hepatomegaly, and berry aneurysms, which occasionally cause subarachnoid haemorrhage. Abnormal heart valves.
I: USS, screening for relatives. Ultrasound diagnostic criteria (in patients with positive family history)
=two cysts, unilateral or bilateral, if aged < 30 years
=two cysts in both kidneys if aged 30-59 years
=four cysts in both kidneys if aged > 60 years
M: Treatment with Tolvaptan, to block the effect of AVP, slows kidney cyst growth and delays ESRF in ADPKD. It causes marked polyuria. Criteria:
=they have chronic kidney disease stage 2 or 3 at the start of treatment
=there is evidence of rapidly progressing disease and the company provides it with the discount agreed in the patient access scheme.
Overview of Fanconi syndrome
-Generalised reabsorptive disorder of renal tubular transport in the proximal convoluted tubule resulting in:
=type 2 (proximal) renal tubular acidosis
=polyuria
=aminoaciduria
=glycosuria
=phosphaturia
=osteomalacia/ rickets
-Lose more sodium, potassium, phosphate, bicarbonate and some other things into urine than normal.
-They may then need to be supplemented by pills or diet.
Types of RTA
-Problem with way tubules work= problem getting rid of acid. All three types of renal tubular acidosis (RTA) are associated with hyperchloraemic metabolic acidosis (normal anion gap).
-Type 1 RTA (distal)
=inability to generate acid urine (secrete H+) in distal tubule
=causes hypokalaemia
=complications include nephrocalcinosis and renal stones
=causes include idiopathic, rheumatoid arthritis, SLE, Sjogren’s, amphotericin B toxicity, analgesic nephropathy
-Type 2 RTA (proximal)
=decreased HCO3- reabsorption in proximal tubule
=causes hypokalaemia
=complications include osteomalacia
=causes include idiopathic, as part of Fanconi syndrome, Wilson’s disease, cystinosis, outdated tetracyclines, carbonic anhydrase inhibitors (acetazolamide, topiramate), multiple myeloma, nephrotic syndrome
-Type 3 RTA (mixed)
=extremely rare
=caused by carbonic anhydrase II deficiency
=results in hypokalaemia
-Type 4 RTA (hyperkalaemic)
=reduction in aldosterone leads in turn to a reduction in proximal tubular ammonium excretion
=causes hyperkalaemia
=causes include hypoaldosteronism, diabetes
Overview of Hereditary nephrotic syndrome
-FSGS pattern of injury on histology.
-Inheritance may be autosomal dominant or recessive, the former conditions having a less severe and later-onset phenotype and often exhibiting incomplete penetrance.
-The involved genes almost all code for podocyte proteins
-Inheriting certain polymorphisms in the APOL1 gene, which occur predominantly in people of West African ancestry, leads to a greatly increased risk of kidney disease in adults, including FSGS.
Tubular genetic diseases
-Renal Fanconi Syndrome (some metabolic or toxic disorders) PCT (60% Na resorption, NHE3 transporter)
-Bartter (ALH, NKCC2, Loop diuretic 25% Na resorption)
-Gitelman (DCT, NCCT, Thiazide, 10%)
=Imbalanced electrolytes (fatigue, salt craving, thirst, urination, muscle cramping and weakness, dizziness, low BP)
-Liddle (Coll duct, ENaC, Spironolactone, 2-3%,
=Rare autosomal dominant condition that causes hypertension and hypokalaemic alkalosis. It is thought to be caused by disordered sodium channels in the distal tubules leading to increased reabsorption of sodium.
=Treatment is with either amiloride or triamterene)
-Diabetes insip (Coll duct, Aquaporin, Tolvaptan)
Tubulointerstitial disorders examples
-ADTKD
-Nephronophthisis
Describe 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
Overview of Nephronophthisis (NPHP)
G: autosomal recessive inherited disorder characterized by inflammation and scarring that impairs kidney function. There are at least 20 genetic variants
E: most frequent genetic cause of kidney failure in children
P: increased urine production, excessive thirst, general weakness, extreme tiredness. Fluid-filled cysts in the kidneys, usually in an area known as the corticomedullary region, anaemia.
=Liver fibrosis, cardiac malformations. When NPHP is combined with retinitis pigmentosa, the disorder is known as Senior-Loken syndrome (NPHP1); when it is combined with cerebellar vermis hypoplasia, the disorder is known as Joubert syndrome; and when it is combined with multiple developmental and neurologic abnormalities, the disorder is often known as Meckel-Gruber syndrome. Because most NPHP genetic abnormalities occur in the cilium, NPHP and the related syndromes are known as “ciliopathies.”
=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.
M: Transplant
C: kidney failure, classified by the approximate age at which kidney failure begins – around age 1 (infantile), around age 13 (juvenile), and around age 19 (adolescent).
Describe Autosomal Recessive Polycystic Kidney Disease
G: mutations in the PKHD1 gene, encoding fibrocystin. Chromosome 6
E: It is less common than autosomal dominant PKD (about 1:20 000 live births). Patients often present in infancy or young childhood with renal cysts and congenital hepatic fibrosis. Rare.
P: 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.
I: Diagnosis may be made on prenatal ultrasound or in early infancy with abdominal masses and renal failure. New-borns may also have features consistent with Potter’s syndrome secondary to oligohydramnios. End-stage renal failure develops in childhood. Patients also typically have liver involvement, for example portal and interlobular fibrosis.
=Renal biopsy typically shows multiple cylindrical lesions at right angles to the cortical surface.
Other basement membrane disorders
-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.
Describe reflux nephropathy
-Common diagnosis associated with focal renal ‘scars’ or maldevelopment, previously often labelled ‘chronic pyelonephritis’.
-An association with recurrent UTIs was for a long time considered 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.
Describe renal hypoplasia/dysplasia
Hypoplasia/dysplasia covers every abnormality of normal renal development, including unilateral missing kidney, and various anatomical malformations and under-development.
