Renal Pathology PDF

Renal Pathology and Pathophysiology 1 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 1 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 from protex to pelvis more extended circular filtering outermost tissue Normal Histology– Case 1 structure Renal Corpuscle The cortex has a grainy appearance as it contains mostly renal corpuscles and convoluted tubules; the medulla has a striped appearance as it contains vertical nephron tubes and collecting ducts. The nephron is the functional unit of the kidney and consists of two main parts: the renal corpuscle (glomerulus + bowmans capsule) located in the cortex and its associated tubule system located in the medulla. Cortex grainy - corpuscles and tubules Medulla - striped due to to vertical nephron tubes and collecting ducts back to venous circulation circular capillaries pass through proximal section first contact with distal convoluted tubule touches afferent arteriole fenestrated - pass solutes pass red blood cells only pass through if damage or pathology pass layers in filtering endothelium, podocytes (structure and support) and basement membrane u The glomerulus consists of capillaries lined by fenestrated endothelium lined by two layers of epithelial cells: a visceral layer composed of podocytes separated from the endothelium by the basement membrane and an outer parietal layer of simple squamous cells which lines the urinary space. Layer - podocytes, basement membrane and simple squamous u u u The filtration barrier is therefore composed of the endothelial cells, the glomerular basement membrane and the podocyte visceral epithelium need to communicate with afferent arteriole determine whether increase or decrease filtration communicate with afferent arteriole testing filtrate - increase or decrease The entire glomerular tuft is supported by the mesangium (the tissue between capillaries) composed of mesangial cells which are contractile, phagocytic, and capable of proliferation and secretion of Mesangium provides connective structure mediators. The afferent and efferent arterioles enter the nephron at the vascular pole. Nestled here is a collection of cells called the juxtaglomerular apparatus (JGA) composed of three cell types: macula densa, juxtaglomerular granular cells, and extraglomerular mesangial cells (Lacis cells). sample vascualr pole where aferent arteriole in support and structure large nuclei, light purple secrete vasoconstrictors - Renin change diameter supporter cells u Macula densa cells are found abutting the wall of the distal convoluted tubule; granular cells are reninsecreting smooth muscle cells usually near the afferent arteriole; and the mesangial cells are between the afferent and efferent vessels. testing filtrate at ends of nephron decide if concentrated or not u These regulate glomerular blood flow and systemic blood pressure. wrap around capillaries podocyte mesangial cells - structure, darker mesangial = darker Bowman's capsule and space lined by macula densa cells tubule Tubule Histology very prominent lateral borders more structure and robust CD u Proximal tubule: simple cuboidal epithelium with a brush border of microvilli. fluffy with microvilli Predominant site of reabsorption. u Nephron loop: simple squamous epithelium u Distal tubule: simple cuboidal epithelium without a brush border u Collecting ducts: cuboidal to columnar. Also contains principal cells which are pale staining (ion transport) and intercalated cells (for acid-base balance). Collecting ducts are easily distinguished by prominent lateral borders between cells. not fluffy drains into collecting duct DCT more so than Distal convoluted tubule DCT afferent arteriole comes in without microvilli simple squamous Kidney Development immature and developing kidney. Not know in detail u u u u In the embryo, the kidneys develop from three overlapping systems: the pronephros, the mesonephros, and the metanephros. Pronephros: appears at 4th week of development in the cervical region of the embryo. Segments into tubules called nephrotomes which join to form the pronephric duct (extends from cervical region to cloaca). Mesonephros: as the pronephric duct extends inferiorly, it stimulates epithelial cells to form mesonephric tubules in the lumbar region. These receive tufts of capillaries from the aorta (forming early glomeruli). These tubules drain into the mesonephric duct (a continuation of the pronephric duct). The mesonephric duct gives rise to the ureteric bud. Metanephros: appears at week 5, becomes functional at week 12. The ureteric bud forms the collecting system à dilates to form calyces, renal pelvis, collecting tubules. The remaining intermediate mesoderm forms the metanephric blastema which gives rise to the nephrons The definitive kidney initially develops in the pelvis and extends upward into the abdomen end week 5 - more functional non-functional receive blood supply after 4 weeks develop filtering ducts migrates down into pelvis stimulates intermediate mesoderm overshoots, rises and ascends into abdomen Congenital Anomalies: Horseshoe Kidney – Case 2 most common u Most common renal fusion anomaly. Occurs when the two developing kidneys fuse as they ascend from the pelvis into the abdomen. Mostly sporadic. u Affects 1 in 500; more common in males; associated with trisomies, often asymptomatic u Pathophysiology: several proposed factors contribute to the development of horseshoe kidneys such as fetal exposure to ethanol, ACE inhibitors, NSAIDs, cocaine, gentamicin however there is no definitive cause. stuck under inferior mesenteric artery u Usually, fusion occurs in the lower poles of the kidney (90%) and their ascent becomes arrested underneath the inferior mesenteric artery due to the point of fusion (the isthmus). During ascent, normal kidneys also rotate medially however this is impaired due to the fusion resulting in abnormal placement of the ureters. This can lead to urinary stasis and increased frequency of UTIs and renal stones. no increased renal cell cancer u Treatment: management focuses on treating the sequelae (UTIs/stones) if they arise. There is no benefit to symphysiotomy (separating the kidneys) as they often remain in the same position and the ureter has already developed at its aberrant site of attachment. rotate medially lower parts are stuck together increased kidney stone and infection risk isthmus - fused lower portion with upper Other Congenital Anomalies u Sigmoid kidney: occurs when the superior pole of one kidney fuses with the inferior pole of the other. Uncommon variant of the horseshoe kidney. u Multicystic dysplasia: most common form of renal cystic disease in childhood. Genetic basis i.e. PAX2 gene mutation resulting in abnormal formation of the metanephros. Dysplasia in this sense refers to a developmental rather than preneoplastic anomaly. The kidneys in this condition consist of irregular cysts. May be unilateral or bilateral. Often diagnosed at ~20-week gestation with Multicystic can be bilateral but polycystic affects one kidney morphology scans. u Renal agenesis: bilateral agenesis is incompatible with life and usually encountered in stillborn infants. Unilateral ageneis is uncommon but compatible with normal life if no other abnormalities exist. The solitary kidney undergoes hypertrophy to compensate. does not grow/form solitary kidney grows larger u Renal hypoplasia: failure of the kidneys to develop to a normal size. May occur bilaterally but more commonly unilateral. May be seen in low birth weight infants. tiny kidneys just mass of irregular cysts Identify the anomalies in these specimens: agenesis horseshoe bladder ureter isthmus much larger to compensate renal agenesis Vascular Supply and Renal Artery Stenosis – Case 3 u The renal artery typically divides into 5 segmental arteries upon entering the renal hilum. u Within the renal sinus, the segmental arteries branch to form interlobular arteries which branch into arcuate arteries and small cortical radiate arteries from which the afferent arterioles arise. then interlobar to segmental no segmental v Renal Artery Stenosis u The narrowing of one or both renal arteries, most often caused by atherosclerosis (90%) or fibromuscular dysplasia. The narrowing impedes blood flow to the kidney resulting in renovascular hypertension due to renin release by the ischaemic kidney. u The prevalence of atherosclerotic renal artery stenosis increases with age and is particularly common in patients with diabetes, aortoiliac occlusive disease, coronary artery disease, or hypertension. u Renal atrophy is an important pathological sequelae due to ischaemia. renal vascular hypertension increase renin age related atherosclerosis build up of plaque Renal Artery Stenosis u The ischaemic kidney is reduced in size and shows signs of diffuse ischaemic atrophy with crowded glomeruli, atrophic tubules, interstitial fibrosis, and focal inflammation. u asymptomatic except for hypertension Clinical features: few distinctive features suggest the presence of renal artery stenosis. On occasion, a bruit can be heard on auscultation of the affected kidney. Elevated plasma renin, renal scans, and intravenous pyelography may aid with the diagnosis but arteriography is required to localise the stenosis. stent to open u Treatment: anti-hypertensives à however these eventually fail, in which case surgical revascularisation with angioplasty +/- stenting is recommended. The cure rate after surgery is 70-80%. If revascularisation fails, nephrectomy of the affected kidney may significantly improve blood pressure. elevated plasma renin Fibromuscular Dysplasia u A non-atherosclerotic, non-inflammatory disease of the blood vessels resulting in focal irregular thickening of blood vessel walls with intimal hyperplasia and fibrosis. Most common arteries affected are the renal arteries and carotid arteries. same effect as atherosclerosis renal and carotid- larger arteries mostly genetic u Cause remains unclear; likely genetic abnormality. u More common in women ~30-40 years. u Often asymptomatic as with atherosclerotic renal artery stenosis. Diagnosis is via angiography of renal vessels which shows a “string of pearls” appearance along the renal arteries. bunching of renal arteries Questions 1. Identify the pathology at left Horseshoe kidney 1 4 3 2. Label structures 1-6 1 - Abdominal aorta 2 - Inferior mesenteric a. 3 - L renal a. 4 - R renal a. 5- Ureter 6- isthmus 2 isthmus 6 5 3. What is the significance of the structure labelled 2? ascent of kidneys arrested due to inferior mesenteric artery hooking over isthmus Questions In a hypertensive patient, when would you consider performing renal angiography to assess for the presence of renal artery stenosis? Bruits, referactory or progressive hypertension hypertensuion in young person 26.5𝜇𝑚𝑜𝑙/𝐿 within 48 hours; or u Increase in SCr to > 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days u Urine volume < 0.5 ml/kg/hr for 6 hours Staging: the RIFLE criteria aid in assessment of a person’s severity of renal injury. u Risk: 1.5 fold increase in SCr, or GFR reduced by 25%, or urine output < 0.5 ml/kg/hr for 6 hours u Injury: 2 fold increase in SCr, or GFr reduced by 50%, or urine output < 0.5 ml/kg/hr for 12 hours u Failure: 3 fold increase in SCr, or GFr reduced by 75% or urine output < 0.3 ml/kg/hr for 24 hours or anuria for 12 hours u Loss: complete loss of kidney function (i.e. requires dialysis) for more than 4 weeks u End stage kidney disease: complete loss of kidney function for > 3 months i.e. chronic kidney disease Urinary Casts u Microscopic cylindrical structures produced by the kidney and present in urine in certain conditions. u They form in the distal convoluted tubule and collecting ducts via precipitation of mucoproteins secreted by renal tubular cells. In certain conditions, addition of other proteins or lipids results in the formation of casts of varying shape and texture which aids in disease diagnosis. Acellular casts u Hyaline casts: nonspecific aggregation of mucoproteins secreted by tubule cells. May be normal. u Granular: acute tubular necrosis, chronic renal disease. Inclusion of plasma proteins with mucoproteins secreted by tubular cells. Muddy brown colour. u Waxy: advanced CKD. These suggest a very low urine flow rate. u Fatty: fat globule inclusions due to breakdown of lipid-rich glomerular epithelium as in nephrotic syndrome. u Pigment: formed by adhesion of drug pigments or metabolic breakdown products such as haemosiderin. Seen in haemolytic anaemias. u Crystal: crystallised urinary solutes (oxalates, urates, sulfonamides). Seen in many metabolic disorders. Cellular casts u Red blood cell casts: always pathological. Suggests nephritic syndrome or renal infection. u White blood cell casts: indicate inflammation or infection. Strongly suggests pyelonephritis. u Epithelial casts: formed by inclusion of desquamated epithelial cells of the tubule lining. Seen in acute tubular necrosis or toxic injury. Waxy cast Red blood cell cast Hyaline cast White blood cell cast Muddy brown granular cast Epithelial cast Disorders of the Renal Tubules and Interstitium u The tubules and interstitium may be primarily damaged as a result of hypovolaemic shock, by inorganic and organic toxins, or as the result of infection. u There are two common conditions which may present with acute kidney injury: tubulointerstitial nephritis and acute tubular injury/necrosis u Tubulointerstitial nephritis is uncommon and involves inflammation of the interstitium surrounding the nephrons which consists of the extracellular matrix. Usually it’s signs and symptoms are non-specific (flank pain, dysuria, haematuria) and diagnosis is based on renal biopsy showing interstitial oedema and inflammatory infiltrate. Treatment is by removal of the causative agent (antibiotic/medication). u We will focus on the histology of acute tubular injury/necrosis. Acute Tubular Injury/Necrosis – Case 4 u Presents with acute kidney injury with morphologic evidence of tubular damage, sometimes in the form of epithelial cell necrosis. The term “acute tubular injury” is preferred as necrosis is often not present. u It is the most common cause of AKI (50% of cases). u Causes of acute tubular injury include: u u Ischaemic ATI: Ischaemia due to interrupted blood flow as in hypovolaemic shock u Nephrotoxic ATI: Direct toxic injury to the tubules (myoglobin, monoclonal light chains in multiple myeloma, drugs, heavy metals, contrast dyes) Pathophysiology: tubular epithelial cells are sensitive to ischaemia and toxins. Injured cells detach from the basement membrane and cause luminal obstruction, further reducing GFR, as well as contributing to epithelial cast formation. to Morphology u Characterised by tubular epithelial injury at multiple points along the nephron, with large skip areas in between, often accompanied by rupture of the basement membrane and occlusion of tubular lumen by casts. Epithelial cell necrosis may be evident. u May also see interstitial oedema and inflammatory infiltrate. u Vacuolations in tubular epithelial cells are common due to large amounts of solutes (sugars) present in the tubule secondary to filtration membrane damage. This is termed osmotic nephrosis. u Nephrotoxic ATI is most prominent in the proximal convoluted tubules where the highest rate and concentration of toxic agents occurs due to glomerular filtration. necrosis and fibrosis white patches - vacuolisation osmotic stress causes this high solute concentration hypercellular epithelial cells shed Blue arrows: necrotic tubular cells Red arrows: sloughing off/detachment of tubular epithelial cells no nuclei no nuclei Questions Type of necrosis ? Coagulative - maintain architecture What is the pathophysiology of the vacuolations (arrow) noted in the tubules Degeneration, asmotic necrosis (sugar and chemical exposure) True or False ?: Tissue shows evidence of glomerular sclerosis F True or False ?: Patients are likely to have epithelial casts in the urine T Questions A 58-year-old man is discharged from hospital after management of his acute myocardial infarction. Three days later he represents with decreased urine output and increased BUN. The oliguria persisted increased waste for 5 days and then resolved. Which of the following renal lesions is the most likely cause for this presentation? A- Benign nephrosclerosis B- Acute renal infarction C- Acute tubular necrosis D- Progressive glomerulonephritis E- Hydronephrosis What is the cause of this renal lesion (ischaemic or nephrotoxic): ischaemic injury Discuss the pathophysiology in brief terms nephrotoxic contrast induced nephropathy hypotension Renal Obstruction: renal stones and hydronephrosis – Case 9 There are four main types of renal stones: u Calcium stones (70%), composed largely of calcium oxalate or calcium oxalate mixed with calcium phosphate u Struvite stones (15%) (composed of magnesium ammonium phosphate) u Uric acid stones (5-10%) u Cystine (1-2%) Although there are many causes for the initiation and propagation of stones, the most important factor is raised urinary concentrations of the stones’ constituents such that it exceeds their solubility. Pathophysiology u CALCIUM STONES: associated with hypercalcaemia and hypercalciuria. Changes in urine pH (high pH), and bacterial infections are key factors. Supersaturation of urine is the most important cause for renal calculi. Other mechanisms include absorptive hypercalciuria and renal defects in calcium reabsorption (renal hypercalciuria). u MAGNESIUM AMMONIUM PHOSPHATE (STRUVITE) STONES: Almost always occur in individuals with a persistently alkaline urine resulting from UTIs. In particular, infections with ureasplitting bacteria, such as Proteus vulgaris and staphylococci, predispose individuals to urolithiasis. They tend to get larger due to progressive accumulation of salts and branching. u URIC ACID STONES: Gout and diseases involving rapid cell turnover, such as leukemias, lead to high uric acid levels in the urine and the possibility of uric acid stones. Acidic urine (with a pH < 5.5) favors uric acid stone formation, in contrast with the high pH that favors formation of stones containing calcium phosphate. u CYSTINE STONES: caused by genetic defects in the renal reabsorption of amino acid, including cystine, leading to cystinuria. These form at low pH. Cystine stone Staghorn Calculi (struvite stones) Occasionally, a very large calculus (such as the one below) nearly fills the calyceal system, with extensions into the calyces that gives the appearance of a deer’s horn. The pale yellow to tan areas of the overlying cortex represent severe inflammation and atrophy due to hydronephrosis and chronic inflammation. Inflamed and atrophic cortex Staghorn calculi Hydronephrosis Hydronephrosis refers to dilation of the renal pelvis and calyces, with accompanying atrophy of the parenchyma, caused by obstruction to the outflow of urine. Caused by foreign bodies, proliferative lesions, inflammatory lesions, neurogenic etc. massively dilated - obstruction GU MED PATH MUSEUM SPECIMEN A B Which of these specimens shows features of hydronephrosis ? both What is a predominant gross pathological feature in increase dilation and pressure the renal cortex? cortical atrophy Questions Identify the type of renal calculi in this specimen staghorn/struvite What is the chemical composition of this calculus? magnesium ammonium phosphate What is the downstream complication seen in this specimen? hydronephrosis Any renal cyst/s present (YES/NO) ? GU MED PATH MUSEUM SPECIMEN yes Questions A 33-year-old man presents with severe pain in his left loin area and traces of blood in the urine. He is afebrile with no underlying illness and has been healthy all his life. Urine culture showed traces of epithelial casts and RBC casts. Serum calcium levels were elevated. pH on urinalysis was 7. CT can showed the following features. Which of the following substances is most likely to be increased in his urine ? 1. Cystine 2. Magnesium Ammonium phosphate 3. Uric acid 4. Calcium oxalate Based on the radiological features, what is the likely renal pathology ? Horseshoe kidney Thank you! [email protected]