Inherited glomerular diseases & Cystic kidney diseases Dr. Mohammed Hannon Al Sodani C.A.B.M., F.I.C.M.S. For 5th year medical students 2012-2013 College of Medicine , University of Baghdad March,24th,2016

Inherited glomerular diseases Uncommon diseases may affect the glomerulus in childhood, -The most important one affecting adults is Alport’s syndrome - 5% of ESRD in childhood or adolescence. - Most common X-linked recessive 85%, from a mutation or deletion of the COL4A5 gene , encodes type IV collagen - less common autosomal recessive disease Mutations in COL4A3 or COL4A4 genes - The accumulation of abnormal collagen results in a progressive degeneration of the GBM .

Inherited glomerular diseases Alport’s syndrome Affected patients with - haematuria, - proteinuria (less than 1–2 g/day), - progressive to ESRD in their late teens or twenties. Female carriers usually have haematuria but rarely develope significant renal disease. - Cochlea involvement , high-frequency sensorineural deafness - Ocular involvement 15% anterior lenticonus and macular and perimacular retinal flecks

Alport’s syndrome No specific treatment is available, early , ACE inhibitors may attenuate proteinuria. experimental ;- that mesenchymal stem cells can transdifferentiate into podocytes and repair basement abnormalities and slow the progression. but patients with Alport’s syndrome are good candidates for RRT, as they are young and usually otherwise healthy. Some of these patients 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.

Immunohistochemistry (GBM) in X-linked Alport’s syndrome Normal male XL female AS

Diagrammatic structure of the normal GBM... The normal GBM (electron micrograph) contains mostly the tissues pecificα3, α4 and α5 chains of type IV collagen

In Alport’s syndrome this network is disrupted and replaced by α1 and α2 chains. Although the GBM appears structurally normal in early life, in time thinning appears, progressing to thickening, splitting and degeneration

Ocular abnormalities in Alport’s syndrome Ocular abnormalities in Alport’s syndrome. A, Anterior lenticonus shown by slit-lamp ophthalmoscopy. B, Perimacular flecks

Thin GBM disease There is glomerular bleeding, usually only at the microscopic or dipstick level, Without hypertension, proteinuria or reduction of GFR. light microscopy The glomeruli appear normal electron microscopy the GBM is abnormally thin. This autosomal dominant condition accounts for a large proportion of ‘benign familial haematuria’ excellent prognosis. Some families may be carriers of autosomal recessive Alport’s syndrome but this does not account for all cases.

Cystic kidney diseases

Cystic kidney diseases Solitary or multiple simple renal cysts ;- are common, with advancing age:- 50 % of > 50 years have one or more such cysts. No special significance except in the Diff. Dx of renal tumours. often asymptomatic, accidental finding on U/S exam. Occasionally they may cause ;- - pain and/or haematuria owing to their large size, - bleeding may occur into the cyst. -

Adult polycystic kidney disease AKPD - APKD a prevalence rate of 1:1000.,. I 3–10 % of all patients on regular dialysis in the West . Pathology;- - Small cysts lined by tubular epithelium - develop from infancy or childhood - enlarge slowly and irregularly. - surrounding normal kidney tissue is progressively attenuated. - Renal failure is associated with grossly enlarged kidneys .

Adult polycystic kidney disease AKPD - Inheritance Autosomal dominant. Mutations in ;- 85% PKD1 gene /chrom 16 , ESRD 50% , onset 50 yrs 15% PKD2 gene / chrom 4 , ESRD minority , 70 yrs These genetic abnormalities are distinct from the autosomal recessive form of polycystic disease (due to mutations in the PKHD1 gene on chromosome 6 , which is often lethal in early life

Adult polycystic kidney disease AKPD Clinical features - usually asymptomatic until later life. After the age of 20 . - insidious onset of hypertension. RAS (ACEI of choice) Early control of BP is essential as cardiovascular complications are a major cause of death in ADPKD - Abdominal pain ;- acute loin pain and/or haematuria owing to haemorrhage into a cyst, cyst infection or urinary tract stone formation loin or abdominal discomfort / increasing size of the kidneys - One or both kidneys may be palpable +/- nodular surface. - Haematuria (with little or no proteinuria) - Urinary tract or cyst infections

Adult polycystic kidney disease AKPD Progressive renal failure the most serious complication GFR below 50 mL/min, decline in averages 5 mL/min/year, which is more rapid than in other primary renal disorders Survival rates on haemodialysis and after renal transplantation in ADPKD are better than other primary renal diseases Symptoms of uraemia and /or anaemia associated with CRF PKD is not a pre-malignant condition

Adult polycystic kidney disease AKPD Associations;- 30 % Hepatic cysts , - 20% Mitral and aortic valves regurgitation - 10% Berry aneurysms of brain +/- SAH - Colonic diverticulae - Abdominal wall hernias may occur.

MRI images of kidneys. A Normal kidneys MRI images of kidneys. A Normal kidneys. B Polycystic kidneys; although the kidney enlargement is extreme, this patient had only slightly reduced GFR.

AKPD Investigations and screening Family Hx, clinical findings & U/S exam. U/S cysts in 95% of patients over 20 years , ( bilateral, multiple cysts, not just two or three). not detect small developing cysts in youngers sometime possible to make a specific genetic diagnosis, - Screening for intracranial aneurysms is not generally indicated, where non-invasive MR angiography is available, some centers screen patients in families with a history of subarachnoid haemorrhage .

Ultrasound criteria for diagnosis of ADPKD Ultrasound criteria for diagnosis of ADPKD. NPV,negative predictive value; PPV, positive predictive value

Markedly enlarged polycystic kidneys in comparison to a normal kidney in the middle.

Vascular manifestations of ADPKD Vascular manifestations of ADPKD. , Gross specimen demonstrating bilateral aneurysms of the middle cerebral arteries

polycystic liver disease. A, a very large, cyst. B several large cysts polycystic liver disease. A, a very large, cyst. B several large cysts. C, multiple smaller cysts

drugs that seem to slow cyst growth These therapies include;- AKPD Management drugs that seem to slow cyst growth These therapies include;- - the vasopressin V2 receptor inhibitor, roscovitine - anti proliferative therapy with sirolimus - Good control of BP is important - Good candidates for dialysis and transplantation. - Nephrectomy - large , to make space for a renal transplant. - source of pain or infection,

Patients with PKD and HrT at diagnosis have less probability of renal survival than those with normal blood pressure

Medullary sponge kidney Other cystic diseases Medullary sponge kidney - Cysts confined to papillary collecting ducts. - Cause is unknown ,not inherited - Patients usually present as adults with renal stones ,often recurrent, complications - Prognosis is generally good. The diagnosis is made by ultrasound or IVU. Contrast medium is seen to fill dilated or cystic tubules, which are sometimes calcified.

MSK. A, plain film shows medullary nephrolithiases MSK. A, plain film shows medullary nephrolithiases. B, IVU 10-min, clusters of rounded densities in the papillae discrete linear opacities (paintbrush appearance).

MSK. IVU contrast medium filling both the collecting system and cavities arising from collecting ducts, The cavities have been likened to bunches of grapes..

MSK Non enhanced CT reveals densely echogenic foci in the medulla.

Medullary cystic kidney diseases are a heterogeneous group of inherited disorders, known as nephronophthisis in children. Small cortical cysts are associated with progressive destruction of the nephron. The childhood variants are characterized by thirst and polyuria due to nephrogenic diabetes insipidus, often with a family history of similar disease. Sometimes, affected patients are ‘salt-losing’, Even when they are treated appropriately, serious renal failure is usual. ?? genetic basis

Acquired cystic kidney disease Other cystic diseases Acquired cystic kidney disease Very long history of renal failure, usually including many years of dialysis or transplanted. Cystic degeneration (formation of multiple cysts which enlarge with time) - associated with increased erythropoietin production - sometimes they develop malignant tumour formation ( renal cell carcinoma) More common than in the general population

Reflux nephropathy (chronic pyelonephritis) This is a chronic interstitial nephritis associated(VUR) in early life, - with the appearance of ‘scars’ in the kidney, by imaging . - The incidence about 12% Pathogenesis -Susceptibility with genetic component, - urine refluxes back from the bladder into the ureter, recurrent UTI in childhood, - Antenatal U/S ;- renal scars in utero in the absence of infection.

Reflux nephropathy (chronic pyelonephritis) Pathology Reflux diminishes as the child grows and usually disappears. It is often not demonstrable in an adult with a scarred kidney . unilateral or bilateral ,. Gross scarring of the kidneys, commonly at the poles, with reduced size and narrowing of the cortex and medulla. In patients who develop heavy proteinuria and hypertension, renal biopsies show glomerulomegaly and focal glomerulosclerosis, probably as a secondary response to reduced nephron number and functional mass.

Reflux nephropathy Clinical features Usually asymptomatic, at any age with hypertension , proteinuria or features of CKD. - +/- recurrent UTI. and aching lumbar pain., may renal calculi - Urinary white cells and proteinuria (usually < 1 g/24 hrs) - first present with hypertension and/or proteinuria in pregnancy. In some families there is a clear inheritance pattern Investigations U/S is an insensitive For detecting renal scars, BUT it will detect major dysplasia , dysgenesis, and exclude significant obstruction. Radionuclide DMSA scans are more sensitive imaging by MRI or CT maybe useful. micturating cysto-urethrography (MCUG)used less often.

Reflux nephropathy &Management - Infection, treated & prevented with prophylactic ABCS. reduce recurrences of UTI but there is no evidence that they protect against further renal scarring or dysfunction.’ nephrectomy - pyelonephrosis - unilateral renal infection or pain persists,. - hypertension is cured by when the disease is predominantly or entirely unilateral. As most childhood reflux tends to disappea spontaneously and trials have shown small or no benefits from anti-reflux surgery, such intervention is now less common

Reflux nephropathy &Management Prognosis - Children and adults with small or unilateral renal scars have a good prognosis, provided renal growth is normal. - With significant unilateral scars / usually compensatory hypertrophy of the contralateral kidney. In patients with more severe bilateral disease, prognosis is predicted by the severity of renal dysfunction , hypertension and proteinuria. If the serum creatinine is normal and hypertension and proteinuria are absent, then the long-term prognosis is usually good.

VUR (grade IV) shown by micturating cystogram VUR (grade IV) shown by micturating cystogram. The bladder has been filled with contrast medium through a urinary catheter. After micturition there was gross VUR into widely distended ureters and pelvicalyceal systems.