Renal Pathology 2: Lecture Notes PDF

Renal Pathology and Pathophysiology 2 Dr Samantha Waugh Renal Pathology Lecture Series & Practical Cases Renal pathology 1 Renal pathology 2 u Normal renal histology – Practical Case 1 u Nephrotic vs nephritic syndrome u Kidney development and congenital abnormalities – Practical Case 2 u Acute glom...

Renal Pathology and Pathophysiology 2 Dr Samantha Waugh Renal Pathology Lecture Series & Practical Cases Renal pathology 1 Renal pathology 2 u Normal renal histology – Practical Case 1 u Nephrotic vs nephritic syndrome u Kidney development and congenital abnormalities – Practical Case 2 u Acute glomerulonephritis – Practical Case 5 u Vascular supply and renal artery stenosis – Practical Case 3 u Chronic glomerulonephritis – Practical Case 6 u Acute kidney injury: acute tubular injury/necrosis – Practical Case 4 u CKD u Pyelonephritis – Practical Case 7 u Inherited pathologies: polycystic disease – Practical Case 8 u Renal neoplasms: renal cell carcinoma – Practical Case 10 u Renal obstruction: renal stones and hydronephrosis – Practical Case 9 Glomerular Disease Glomerular Disease – Case 5 u Injury and inflammation of the glomerulus is called glomerulonephritis u It can be caused by one of two pathological mechanisms: u u Primary glomerular disease: when the kidney is the only or predominant organ involved u Secondary glomerular disease: glomeruli may be injured by diverse mechanisms in a number of systemic diseases (i.e diabetic nephropathy, amyloidosis, lupus nephritis). There are two major mechanisms of glomerular injury 1. Deposition of circulating antigen-antibody complexes in the glomerular capillary wall or mesangium 2. Antibodies reacting in situ within the glomerulus, either with fixed (intrinsic) glomerular antigens or with extrinsic molecules that are planted in the glomerulus Sites of immune complex deposition within the glomerulus: 1. Sub-epithelial deposits of immune complex 2. Membranous deposits 3. Sub-endothelial deposits 4. Mesangial deposits Glomerular Response to Injury 1. Swelling and/or proliferation of the normally flat endothelial cells lining the glomerular capillaries 2. Infiltration of leukocytes 3. Proliferation of the epithelial cells investing the outer surface of the glomerular capillary tuft (the podocytes) and the cells lining Bowman’s capsule (crescent formation) 4. Thickening of the glomerular basement membrane 5. Proliferation of the cells of the mesangium and excessive production of acellular mesangial material. Depending on the location and type of damage, glomerulonephritis can cause a nephrotic syndrome or a nephritic syndrome. u Glomerulonephritis may also manifest as asymptomatic haematuria, rapidly progressive glomerulonephritis, acute kidney injury, chronic kidney disease and end-stage renal disease. The aetiology and epidemiology of glomerulonephritis depends on the specific cause. Nephritic Syndrome u Nephritic syndrome: the key pathological change is inflammation causing glomerular capillary damage. This causes leakage of red blood cells and protein, often with acute onset. u Characterised by: u u Haematuria (red blood cells and red cell casts in urine) u Proteinuria (usually sub-nephrotic range; with or without oedema) u Azotemia u Hypertension Nephritic syndrome is the typical clinical presentation of most proliferative, post-infectious types of glomerulonephritis à the conditions that cause nephritic syndrome have in common the proliferation of cells in the glomerulus, accompanied by leukocytic infiltration. Nephritic Syndromes – Post-infectious glomerulonephritis u Acute proliferative (post-infectious and infection-associated) glomerulonephritis is a cluster of diseases characterised histologically by diffuse proliferation of glomerular cells with influx of leukocytes due to immune complex deposition. u u The inciting antigen may be exogenous (such as post-streptococcal glomerulonephritis) or endogenous (such as in lupus nephritis) The most common cause is post-streptococcal glomerulonephritis: appears 1-4 weeks post strep infection usually in children 95% of children recover fully with conservative therapy aimed at maintaining sodium and fluid balance. 1% develop rapidly progressive glomerulonephritis u Key differential is IgA nephropathy (discussed later) which presents similarly and is differentiated by the presence of IgA deposits in glomeruli Nephritic Syndromes: RPGN (rapidly progressive glomerulonephritis) u RPGN is a clinical syndrome associated with severe glomerular injury without a specific aetiology. u Characterised by rapid and progressive loss of renal function with severe oliguria and signs of nephritic syndrome. The most common histologic picture is crescents in the glomeruli (hence, also called crescenteric glomerulonephritis) which are produced by the proliferation of epithelial cells of Bowmans capsule. u RPGN may be seen in many renal diseases including: u Anti GBM disease: self-reactive IgG (against type IV collagen in the GBM) deposits in the glomerulus. In some cases, the anti-GBM IgG also deposit in the lung causing pulmonary inflammation and haemorrhages (Goodpasture’s syndrome) u Diseases caused by immune complex deposition in the glomuerulus (post-infectious GN, lupus nephritis, IgA nephropathy) Nephritic Syndromes: RPGN (rapidly progressive glomerulonephritis) u Morphologically appears as a severe glomerulonephritis with necrosis of glomeruli and proliferation of epithelial cells and leukocytes forming crescenteric shaped masses within the glomerulus. Nephritic Syndrome – IgA Nephropathy (Berger’s Disease) u IgA nephropathy is characterised by IgA deposits in the mesangium and recurrent haematuria. u The most common glomerulonephritis worldwide. u Usually arises 1-2 days post upper respiratory tract infection; autoIgA antibodies deposit in the glomeruli (unknown cause) à leads to proliferation of mesangium and leukocyte infiltration. A: Mesangial proliferation; B: IgA deposition Nephrotic Syndrome u Caused by a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins. The manifestations include: u Massive proteinuria (> 3.5g/day) u Hypoalbuminaemia (plasma albumin < 3g/dL) u Generalised oedema u Hyperlipidaemia and lipiduria u Nephrotic syndrome patients are vulnerable to infection due to mild loss of immunoglobulin proteins in urine. u They are also at increased risk of thrombosis due to loss of anticoagulant proteins (anti-thrombin III) Nephrotic Syndrome – Examples u Minimal change disease: mild, benign disease. Frequent cause of nephrotic syndrome in children. Due to effacement of podocyte foot processes in the absence of immune-complex deposition. Glomeruli will appear normal by light microscopy. Good response to treatment (>90% recovery) u Focal segmental Glomerulosclerosis: most common cause in adults and more commonly in AfricanAmerican populations. Characterised by sclerotic changes of some but not all glomeruli (focal) and in those affected, only some parts of glomeruli (segmental). Poor response to treatment; 50% progress to CKD within 10 years. u Membranous nephropathy: diffuse thickening of glomerular basement membrane and capillary wall due to IgG deposits. Basement membrane is laid down between deposits appearing as irregular “spikes” on silver staining. Autoimmune disease due to IgG cross-reactivity with PLA2 receptors in glomeruli. Poor response to treatment; 40% progress to CKD, 10% die from renal failure within 10 years. u Diabetic nephropathy: most common cause of nephrotic syndrome that occurs due to glycation of the GBM, leading to thickening and increased permeability. Membranous nephropathy: thickening of capillary walls Minimal change disease on electron microscopy FSGS with sclerosis of the upper portion Mixed Nephritic/Nephrotic – Membranoproliferative Glomerulonephritis (MPGN) u MPGN is separated into two groups: u Type I characterised by immune complex deposition containing IgG and complement u Type II (now called dense deposit disease) in which activation of complement is the important factor u Histologically, MPGN is characterised by alterations in the GBM, accumulations of mesangial matrix, proliferation of glomerular cells, leukocytic infiltration, and deposits in the glomerular capillaries and mesangium (made of immune complexes in Type I; and of unknown material in Type II). u Most patients present with a nephrotic-nephritic picture with haematuria or proteinuria in the non-nephrotic range. u Usually presents in children or young adults. Prognosis is poor for either type of MPGN with 50% of patients developing end-stage renal disease. MPGN showing mesangial cell proliferation, increased mesangial matrix (staining black), basement membrane thickening. Questions Discuss the glomerular changes and try to identify the type of glomerulonephritis A B Questions TYPE OF GLOMERULONEPHRITIS MATCH THE CORRECT PATHOLOGY Minimal change disease: Focal segmental Glomerulosclerosis: Membranous nephropathy Membranoproliferative glomerulonephritis: Post infectious glomerulonephritis: A= Sclerotic changes in some part of glomeruli. B= Diffuse thickening of GBM and capillary wall. C= Normal glomeruli D= Proliferation of glomerular cells and infiltration of leukocytes+. E= Accumulation of mesangial matrix Note: based on light microscopy Questions ACUTE GN NORMAL GLOMERULUS KEY PATHOLOGICAL CHANGES Proliferation of glomerular cells (______________, ___________________ & _______________) Infiltration of inflammatory cells (predominantly neutrophils) Structural changes in the glomeruli and tubules Questions A 25-year-old woman experiences sudden onset of fever, malaise and nausea. On examination her temperature is 38.7 oc, pulse 85/min, RR- 18/min & BP- 140/90. Urinalysis showed mild epithelial and RBC casts. Oedema was noted on the face and ankles. Renal biopsy results are shown below. Electron microscopy showed dense subepithelial “humps”. Likely diagnosis ? A- Membranous glomerulonephritis B- Acute glomerulonephritis- Post infectious C- Chronic glomerulonephritis- Membranous D- Acute tubular injury E- Amyloidosis Chronic Glomerulonephritis – Case 6 Chronic glomerulonephritis with glomerulosclerosis and chronic inflammatory infiltrate u Regardless of initial aetiology, acute glomerulonephritis may progress as the number of unaffected functional nephrons declines. The remaining functional nephrons are under significant haemodynamic stress to compensate for the declining GFR which results in fibrosis and thickening (glomerulosclerosis). u Tubular damage and interstitial inflammation may occur due to ischaemia of nephrons downstream from sclerotic glomeruli. If disease progresses, the net result is chronic kidney disease. Chronic Kidney Disease u u Chronic kidney disease is defined by a reduction of kidney function for at least 3 months. It is recognised by a reduced GFR and proteinuria (high urine albumin creatinine ratio). On imaging, the kidneys appear small and scarred (increased echogenicity on US). Chronic kidney disease can be asymptomatic for a long period of time due to reserve function of the kidneys. Significant glomerular loss has to occur before the GFR reduces and symptoms occur. Symptoms of chronic kidney disease include: u Anaemia (reduced EPO production) u Hypocalcaemia and secondary hyperparathyroidism u Hypertension u Uraemia: anorexia, nausea, vomiting, pruritis, pericarditis, confusion, lethargy, increased u Exacerbation of gout u Sodium and fluid retention -> pulmonary and peripheral syndrome. u Hyperlipidaemia and hypercholesterolaemia The three most common causes of CKD are diabetes mellitus, hypertension, and glomerulonephritis Chronic Kidney Disease Staging u CKD can be classified into stages based on GFR Questions A 62-year-old women presents with severe oedema, haematuria and RBC casts++ Her BP is 180/110 mmHg. BUN and creatinine levels are significantly elevated. Upon admission, the patient dies of a cerebral infarction. At autopsy, the kidneys are small with a granular surface. Microscopic examination reveals the following features. Likely diagnosis ? Pyelonephritis – Case 7 u Defined as inflammation of the kidney affecting the tubules, interstitium, and renal pelvis u Occurs in two forms: u u Acute pyelonephritis: usually due to bacterial infection u Chronic pyelonephritis: infection plays a dominant role but also may be due to reflux nephropathy or renal stones Pathogenesis: >85% of UTIs are caused by Gram-negative bacilli that are normal intestinal tract inhabitants. Most common are E.coli, Proteus, Klebsiella, and Enterobacter. Organisms reach the kidneys either through the bloodstream (as in sepsis) or via the lower urinary tract (more common) Acute Pyelonephritis u Acute inflammation of the kidney, often secondary to bacteria. u Clinical features: sudden onset pain at the costovertebral angle, fever, malaise, nausea, with evidence of urinary tract involvement (dysuria, frequency, urgency). Urine contains leukocytes, and leukocyte casts (which is specific for renal involvement as casts only form in the tubules). Urine culture can identify the causative organism. u Histologically, the hallmarks of acute pyelonephritis are patchy interstitial inflammation, intra-tubular neutrophils, and tubular injury. Glomeruli are relatively resistant to the infection. Acute pyelonephritis marked by neutrophilic exudate within tubules and interstitial inflammation. Rarely, pyelonephritis can result from predisposing conditions such as diabetes, urinary tract obstruction and sickle cell anemia. This can lead to ischemic damage to the renal pyramids resulting in _____________necrosis. Acute Pyelonephritis Large masses of intra-tubular neutrophils frequently extend within involved nephrons into the collecting ducts, giving rise to characteristic white blood cell casts in the urine. Identify 1- Renal tubule 2- Intratubular neutrophils Chronic Pyelonephritis u Chronic pyelonephritis is a disorder in which chronic tubulointerstitial inflammation and scarring involve the calyces and pelvis. May follow acute pyelonephritis but is commonly observed in two main conditions: 1. Renal obstruction (stones) or 2. Vesicoureteral reflux nephropathy u Although many diseases produce tubulointerstitial alterations, only chronic pyelonephritis affects the calyces making pelvocalyceal damage an important diagnostic clue. u Clinical Features: chronic pyelonephritis may have a long asymptomatic course or present with manifestations of acute recurrent pyelonephritis such as back pain, fever, pyuria, and bacteriuria. Hypertension develops as a late consequence of disease. If untreated, it can progress to chronic kidney disease. u Treatment is via management of the underlying cause (stones/reflux nephropathy/recurrent infection). u Morphology: the characteristic changes are usually seen on gross examination whereby the kidneys are irregularly scarred and asymmetrical in appearance (in contrast to glomerulonephritis where kidneys are diffusely and symmetrically scarred). The hallmarks are corticomedullary scars overlying blunted or deformed calyces and flattened papillae. u Histologically tubules show atrophy in some areas and dilation in others; dilated tubules may be filled with casts resembling thyroid tissue (called thyroidisation). There is often fibrosis and chronic inflammatory infiltrate. The transitional epithelium lining the renal pelvis may undergo metaplasia and transition to squamous epithelium due to chronic inflammation. Pyelonephritis- Chronic Chronic Inflammatory cells Both lymphocytes and plasma cells are seen in this case of chronic pyelonephritis. Interstitium: Patchy infiltrates of lymphocytes and plasma cells Renal Tubules: Atrophic and lined by flattened epithelium (thyroidisation) Renal pelvis: Squamous metaplasia of transitional epithelium The severity of disease depends upon the amount of remaining functional renal parenchyma. Pyelonephritis. How would you distinguish this from glomerulonephritis? Questions A 72-year-old man presented with fever and haematuria. He had been experiencing malaise with nocturia and polyuria for the past year. BP-164/98. Urinalysis- PH 7.5; proteinuria. BUN and creatinine levels were significantly elevated. Leukocytes were present in the urine. Upon admission, the patient developed renal failure and died of bronchopneumonia. Autopsy showed shrunken kidneys with asymmetrical size. Irregular scarring was also noted. Histopathology results are shown below. What is the MOST LIKELY cause of renal failure in this patient? A- Chronic Glomerulonephritis B- Essential hypertension C- Reflux nephropathy D- SLE E- Nephrosclerosis DIAGNOSIS: ? Polycystic Kidney Disease – Case 8 Two types of polycystic kidney disease are observed: 1. Autosomal dominant (Adult) polycystic kidney disease (ADPCKD) u Characterised by multiple expanding cysts in both kidneys that destroys the renal parenchyma leading to renal failure u Autosomal dominant inheritance of one faulty PKD1 gene (85% of cases) which encodes for polycystin-1 expressed in tubular cells; remaining cases are due to mutated PKD2 gene. Polycystin proteins are involved in mechanosensation by tubular cilia and calcium flux. Altered calcium flux and downstream signaling results in abnormal cell proliferation and cyst formation. u Likelihood of renal failure is > 95% by 70 years of age u Morphology: kidneys are bilaterally enlarged, external surface entirely composed of cysts which may be filled with clear, brown, turbid or haemorrhagic fluid. u Clinical features: usually asymptomatic until renal insufficiency develops. Progressive dilation of cysts or haemorrhage may produce pain. Individuals may have extra-renal congenital anomalies such as cysts in the liver, pancreas, or spleen. Berry aneurysms may occur in the circle of willis and mitral valve prolapse in 20-25% of patients. Autosomal dominant (Adult) polycystic kidney disease (ADPCKD) KEY PATHOLOGICAL CHANGES. In autosomal dominant adult polycystic kidney disease, kidneys will be readily palpable abdominally as masses extending into the pelvis. Gross pathology: Kidney will be composed of cysts up to 3-4cm in diameter with no/little intervening parenchyma. Cysts are filled with fluid which may be clear, turbid or hemorrhagic. Microscopic changes: Cystic epithelium will be atrophic. Expanding cysts will compress the nearby blood vessels and can lead to ischemic atrophy of renal parenchyma. 2. Autosomal recessive (childhood) polycystic kidney disease (ARPCKD) u Caused by mutations in the PKHD1 gene encoding fibrocystin which, similarly to polycystin 1 and 2, has been localised to the cilia of tubular cells. Function is unknown. u Morphology: kidneys are enlarged and have a smooth external appearance; on cut section there are numerous cysts in the cortex and medulla giving the kidney a spongelike appearance. In almost all cases, the liver has cysts. Many patients do not survive infancy. AD PCKD – external surface AD PCKD – cut surface AR PCKD – cut surface Adult polycystic kidney disease is characterised by multiple expanding cysts affecting both kidneys that ultimately destroy the intervening parenchyma. This disease is genetically heterogeneous and can be caused by inheritance of one of at least two autosomal dominant genes of very high penetrance. Tumours of the Kidney Benign Tumours u Angiomyolipoma u Oncocytoma: arises from the intercalated cells of collecting ducts (10% of all renal neoplasms) Malignant Tumours u Renal cell carcinoma (adult) u Nephroblastoma (Wilm’s tumor) u Malignant rhabdoid tumour The most common malignant tumour of the kidney in adults is the renal adenocarcinoma (renal cell carcinoma) derived from the tubular epithelial cells Angiomyolipoma Benign neoplasm consisting of vessels, smooth muscle, and fat originating from perivascular epithelial cells. Present in 25-50% of patients with tuberous sclerosis (a condition caused by loss of function mutations in the TSC1 or 2 tumour suppressor genes). The clinical importance of angiomyolipoma is their susceptibility to spontaneous haemorrhage. Angiomyolipoma consists of a variable mixture of adipose tissue (arrowhead), smooth muscle bundles (lower arrow), and blood vessels (big arrow). Renal Cell Carcinoma – Case 10 u Epidemiology: smoking is the most significant risk factor. Others include obesity, hypertension, asbestos exposure, petroleum products, and heavy metals. Most renal cancer is sporadic but familial autosomal dominant forms can occur (usually in younger patients). For example, hereditary forms have been seen in von-Hippel Lindau syndrome (VHL) whereby 2/3rds of patients develop bilateral, often multiple, renal cell carcinomas u Classification: the major types of renal cell carcinoma include: u Clear cell (70-80%) u Papillary (10-15%) u Chromophobe (5%) u Collecting duct carcinoma (rare) Renal Cell Carcinoma – Clear Cell Type u The most common type of RCC, accounting for 80% of cases. Tumours are composed of cells with clear or granular cytoplasm. Arise due to deletion of the VHL gene which encodes a protein important for targeting other proteins that need degradation. u Clinical features: costovertebral pain, palpable mass, and haematuria. Haematuria is often microscopic until the tumour size exceeds 10cm, by which time generalised constitutional symptoms may be present. u Paraneoplastic syndromes: polycythaemia (EPO production), hypertension (renin production), hepatic dysfunction, feminisation/masculinisation (sex hormone production), cushing syndrome, etc. u A troublesome feature of RCC is its tendency to metastasise early; most common location is the lungs (50%), bones (33%) followed by liver, adrenal glands, and brain. Radical nephrectomy is the treatment of choice. Gross morphology: bright yellow grey-white. Yellow due to prominent lipid accumulation in tumour cells; margins are sharply defined. Most tumours are well differentiated. One of the striking characteristics of RCC is its tendency to invade the renal vein which may grow as a solid column of cells that can sometimes extend all the way up the IVC to the heart. Renal Cell Carcinoma – Clear Cell Type Classic histologic appearance of a renal cell carcinoma: the neoplastic cells have clear cytoplasm and are arranged in nests with intervening blood vessels Questions A 54-year-old male presented to the emergency department with gross haematuria and right upper quadrant abdominal pain. Physical examination revealed a mass in the right upper quadrant. Murphy’s punch sign was positive. The following CT abdomen was obtained. A diagnosis of RCC – clear cell type was made. What is the classic histologic appearance of this neoplasm? Diagnosis: KIDNEY- Clear Cell Carcinoma Thank you! [email protected]