My Clinical Notes

Chronic renal failure

• Characterised by prolonged symptoms and signs of uraemia. It is an irreversible deterioration in renal function caused by the destruction of more and more nephrons over time. It is the impairment of metabolic, endocrine and excretory function that leads to the clinical syndrome of uraemia
• Chronic renal failure progresses through 4 stages;
  • Diminished renal reserve - when the GFR is about 50% of normal and the patient is asymptomatic. However they are more susceptible to develop uraemia with an additional renal insult
  • Renal insufficiency - when the GFR is between 20% to 50% of normal. Azotemia (elevated blood nitrogen and creatine levels) appears, generally associated with hypertension and anaemia. Polyuria and nocturia can occur and an sudden stress e.g. with nephrotoxins can precipitate uraemia
  • Renal failure - when the GFR is 20-25% . the kidneys cannot regulate volume and solute composition and the patient develops oedema, metabolic acidosis and hypocalcaemia. Overt uraemia can occur with neurological, cardiovascular and gastrointestinal complications.
  • End-stage renal disease - when the GFR is 5% of normal. This is the terminal stage of uraemia

 

Causes of chronic renal failure

• Glomerulonephritis (20%)
• Hypertension (20%)
• Diabetes (30%)
• Polycystic kidney (5%)

 

The principle systemic manifestations of chronic renal failure and uraemia;

Fluid and electrolytes

• Dehydration
• Oedema
• Hyperkalaemia
• Metabolic acidosis

Calcium Phosphate and Bone

• Hyperphosphataemia
• Hypocalcaemia
• Secondary hyperparathyroidism
• Renal osteodystrophy

Haematologic

• Anaemia
• Bleeding tendancy

Cardiopulmonary

• Hypertension
• Congestive heart failure
• Pulmonary oedema
• Uraemic pericarditis

Gastrointestinal

• Nausea and vomiting
• Bleeding
• Oesophagitis, gastritis, colitis

Neuromuscular

• Myopathy
• Peripheral neuropathy
• Encephalopathy

Dermatological

• Sallow colour
• Puritis
• Dermatitis

 

Acute renal failure

• Implies a rapid and generally reversible deterioration in renal function
• Occurs over a period of days or weeks
• Urine production falls to less then 400ml per day

 

Causes of acute renal failure

Pre-renal - decreasing renal perfusion

• Hypovolaemia
• Renal vein thrombosis and atheroembolic disease

Renal

• Infection
• Toxins/medications – NSAIDs, aminoglycosides, lithium, ionated contrast dye
• Rhabdomyolysis
• Haemolysis
• Glomerular nephritis

Post renal – obstruction of renal outflow

• Kidney stones
• Prostatic hypertrophy
• Abdominal tumour

 

• Most common cause of acute renal failure is acute tubular necrosis

 

The affects of other systemic diseases on the kidney

 

SLE

• Mainly causes glomerular lesions
• Symptoms can vary from asymptomatic proteinuria to renal failure
• Due to immune complex deposition in the basement membrane, leading to thickening, or deposition in the mesangium, leading to mesangial expansion
• Can result in;
  • Diffuse membranoproliferative glomerulonephritis associated with a mixed nephritic/nephrotic syndrome and rapid progression to renal failure
  • Focal segmental proliferative glomerulonephritis: associated with haematuria, proteinuria and slow progression
  • Diffuse membranous nephropathy: associated with nephrotic syndrome and slow progression to chronic failure
• SLE can also cause vascular abnormalities and interstitial nephritis

 

Diabetic glomerular sclerosis

• Advanced or end-stage renal disease occurs in 40% of diabetic patients
• Results in an increase in the permeability of the glomerular capillary basement membrane
• This can lead to proteinuria which can be on the scale of nephrotic syndrome
• Pathogenesis isn’t understood but includes;
  • Deficiency of proteoglycans that are responsible for the polyanionic nature of the membrane such as heparin sulphate proteoglycan. There is also an increase in the synthesis of collagen type IV and fibronectin
  • Glomerular hypertrophy
  • Thickening of the basement membrane
• Factors that mediate these changes may be due to;
  • Hyperglycaemia
  • Hyperfiltration with an increased in GFR and increased glomerular pressure. There is also glomerular hypertrophy resulting in an increased glomerular filtration area
  • Non-enzymatic glycosylation of proteins leading to advanced glycosylated end products
• Histologically three types of glomerular lesions can occur depending on severity;
  • Capillary wall thickening – resulting in mild proteinuria
  • Diffuse glomerulosclerosis – excess mesangial matrix formation in an even pattern throughout the glomerulus
  • Nodular glomerulosclerosis called Kimmelstiel-Wilson nodules – nodular expansion of the mesangium at the tips of the glomerular lobules
  • Diabetis sclerosis can also cause progressive hyalinization of glomeruli with obliteration of the capillary loops and death of the individual nephrons
• Over a around 5 years this leads to chronic renal failure

 

Amyloidosis

• This is a condition whereby the extracellular fibrillar protein, amyloid is deposited in a variety of tissues
• It causes nephrotic syndrome in adults
• Amyloid is deposited in the basement membrane and mesangium resulting in membrane thickening and increased mesangial matrix formation
• It results in;
  • Proteinuria  - due to increased permeability of the basement membrane
  • Nephrotic syndrome – increase protein loss
  • Chronic renal failure – combined effect of the amyloid deposition and increased mesangial matrix formation eventually leads to the expansion of the mesangium until the glomerular capillary system is compressed and renal failure results
  • Amyloid can also be deposited in the intrarenal vessels particularly the afferent arteriole

 

PAN

• Systemic disease causing inflammatory necrosis of the walls of small and medium sized arteries
• Causes small infarcts of the kidney
• Necrosis of arterioles and the glomerular tufts resulting in infarction of entire glomeruli
• This is visible as fibrinoid necrosis

Wegener’s granulomatosis

• Immune complex mediated systemic necrotising vasculitis
• Renal involvement is of varying severity causing;
• Focal segmental glomerulonephritis resulting in asymptomatic haematuria or nephrotic syndrome
• Rapidly progressing glomerulonephritis resulting in rapidly progressive acute renal failure

 

• Goodpasture syndrome, microscopic polyarteritis and Wegner granulomatosis are commonly associated with glomerular lesions and can be difficult to distinguishand are principally characterised by focal glomerular necrosis and crescent formation

 

• Essential mixed cyroglobulinaemia is a systemic condition whereby IgG-IgM complexes induce cutaneous vasculitis, synovitis and a proliferative glomerulonephritis. It is associated with hepatits C infection

 

• Multiple myeloma and other plasma cell dyscrasias are associated with amyloidosis, deposition of immunoglobulin and light chains in the basement membrane and distinctive nodular glomerular lesions resulting from the deposition of nonfibrillar light chains. Patients normally present with nephrotic syndrome, hypertension and progressive azotemia

 

Hypertension

 

Hypertension and the kidney are intimately linked as kidney disease can be both the cause and the consequence of high blood pressure

 

Benign nephrosclerosis

• Pathology associated with sclerosis of the renal arterioles and small arteries
• Vessels develop thickened walls and narrowed lumens resulting in focal ischaemia
• Occurs with age and more in black population than white
• Incidence increased with hypertension and diabetes

 

Pathogenesis

• Medial and intimal thickening due to haemodynamic changes, age, genetic effects or a combination of all three
• Hyaline deposition in arterioles caused partly by extravasation of plasma proteins through injured endothelium and increased deposition of basement membrane matrix
• Kidneys may shrink in size and the surface may have a fine granularity resembling leather
• Intralobular and arcuate arteries undergo fibroelastic hyperplasia consisting of medial hypertrophy, reduplication of the elastic lamina and increased myofibroblastic tissue in the intima, with consequent narrowing of the intima
• Results in patchy ischaemic atropy resulting in tubular atrophy and interstitial fibrosis and a variety of glomerular alterations

 

Clinical features

• Rarely causes renal failure but occasionally proteinuria can develop
• Three groups with benign nephrosclerosis are at risk of developing renal failure – black people, those with severely high blood pressure and diabetics

 

Malignant hypertension and accelerated nephrosclerosis

• Malignant nephrosclerosis is the form of renal disease associated with the malignant or accelerated phase of hypertension
• Generally occurs with the background of benign hypertension, secondary forms of hypertension and chronic renal disease such as glomerulonephritis
• It is a frequent cause of death in scleroderma patients
• Occurs in 1-5% of all patients with hypertension and is more common in black males

 

Pathogenesis

• Possible sequence of events is as follows;
  • Initial insult results in some form of vascular damage to the kidneys
  • This results in increased permeability of the small vessels to fibrinogen and other plasma proteins, endothelial injury, death of cells of the vessel wall and platelet deposition
  • This lead to fibrinoid necrosis of arterioles and small arteries, swelling of the vascular intima and intravascular thrombosis
  • Platelets release factors such as PDGF and this and other cells cause hyperplasia of the intimal smooth muscle resulting in hyperplastic arteriolosclerosis
  • This further narrows the lumen and the kidneys become markedly ischaemic
  • When the renal afferent arterioles are affected this stimulates the renin-angiotensin system. The resulting angiotensin II further vasoconstricts
  • Aldosterone levels are also elevated and the high salt levels probably contribute to the high blood pressure
• This perpetuates an ever-increasing cycle of escalating blood pressure
• The consequences of the markedly elevated blood pressure on the blood vessels throughout the body is known as malignant arteriosclerosis and in the kidneys it is called malignant nephrosclerosis

 

Morphology

• Size of the kidneys depends on the duration and severity of disease
• Small petechial haemorrhages may appear on the cortical surface resulting in a ‘flea bitten’ appearance
• Two histological characteristics occur in malignant hypertension
• Fibrinoid necrosis of the arterioles
• Onion-skinning – hyperplastic arteriolitis whereby there is intimal thickening due to proliferation of concentrically arranged smooth muscle cells together with concentric layering of collagen. This lesion correlates with renal failure
• Sometimes the glomeruli become necrotic are infiltrated with neutrophils and in the glomerular capillaries thrombose

 

Clinical course

• Characterised by a diastolic blood pressure of greater than 130 mmHg
• Associated with;
  • Papilloedema
  • Encephalopathy
  • Cardiovascular abnormalities
  • Renal failure
• Early symptoms are related to raised intracranial pressure such as headache, vomiting and visual impairment
• Hypertensive ‘crises’ can result in LOC or convulsions

 

Renal artery stenosis

• Responsible for 2-5% of cases of hypertension
• Is potentially curable as surgery is 70-80% successful

 

Pathogenesis

• Hypertensive effects is due to renal secretion by the cells of the juxtaglomerular apparatus and the subsequent production of angiotensin II
• Most commonly (70%) due to occlusion of the renal artery by an atheromatous plaque
• Occurs more frequently in men and is associated with age and diabetes
• The remainder are caused by fibromuscular dysplasia. This is a heterologous group of disorders  usually occurring in women aged in the 3^rd and 4^th decade and are characterised by nonarteriosclerotic intimal, medial or adventitial thickening
• The kidney is normally small and shows signs of diffuse atrophy with crowded glomeruli, interstitial fibrosis, atrophic tubules and inflammatory infiltration
• The arterioles in the ischaemic kidney are normally protected from the high pressure and show only mild arteriosclerosis
• The contra lateral kidney may exhibit more severe arteriosclerosis however

 

Congenital abnormalities

 

• About 10% of individual are born with significant malformations of the urinary system
• Renal dysplasias and hypoplasias account for 20% of chronic renal failure in childhood
• Autosomal dominant polycystic kidney disease becomes apparent in adulthood and accounts for 10% of chronic renal failure in humans

 

Agenesis of the kidney

• Total bilateral agenesis is incompatible with life
• Unilateral agensis is rare and the opposite kidney is enlarged as a result of compensatory hypertrophy
• Some patients develop progressive glomerular sclerosis in the remaining kidney which can result in chronic renal failure

 

Hypoplasia

• Failure of the kidneys to develop to normal size
• May occur bilaterally (resulting in renal failure in early childhood) but more commonly is unilateral
• True renal hypoplasia is very rare and more commonly is secondary to acquired scarring due to infection, vascular or other parenchymal disease
• It is difficult to differentiate but a true hypoplastic kidney should show no scars and should have a reduced number of renal lobes (6 or less) and pyramids

 

Ectopic kidneys

• Lie just above the pelvic brim or within the pelvis
• They are generally normal in size
• Because of their abnormal position there may be kinking of the ureters causing obstruction predisposing to bacterial infections

 

Horseshoe kidneys

• Fusion of the upper or lower poles of the kidneys resulting in a structure which is continuous across the midline anterior to the great vessels
• Is common, in 1 in 500-1000 people
• 90% are fused at the lower pole, 10% at the upper pole

 

Cystic diseases of the kidney

 

Autosomal dominant polycystic kidney disease

• Hereditary disorder characterised by multiple expanding cysts of both kidneys which ultimately destroy the lung parenchyma and cause renal failure
• Affects 1 in every 400 to 1000 births and accounts for 5 to 10% of chronic renal failure requiring transplantation or dialysis
• Cysts initially only involve portions of the nephrons so kidney function is retained until the 4^th or 5^th decade of life
• Disease is caused by mutations on chromosome 16 (PKD1) and chromosome 4 (PKD2)
• PKD1 accounts for 85% of cases and is associated with more severe disease
• Disease is a systemic disorder and cysts can be deposited elsewhere also including in the liver, lung and pancreas

 

• PKD1 gene encodes polycystin-1 which has an extracellular domain, multiple transmembrane domains and a cytoplasmic tail. It is localised to tubular epithelial cells. Seems to be involved in cell-cell and cell-matrix interactions. Seems to serve a repressor function and loss leads to hyperplasia of epithelial cells
• PDK2 encodes polycystin-2 which is an integral membrane protein and may act as a Ca channel in the ER

 

• The hypothesis is that cysts develop as a result of abnormal cell differentiation and some degree of increased apoptosis, transepithelial fluid secretion and remodelling of the ECM. The cysts become progressively enlarged

 

Morphology

• Kidneys may be very large – up to 4kg reported
• The external surface is covered in cysts up to 3-4cm in diameter with no intervening parenchyma
• Cysts may be filled with clear fluid or it maybe red/brown due to haemorrhage
• As the cysts enlarge they may press against calyces and pelvis and produce pressure effects

 

Clinical features

• Haemorrhage or progressive dilation can cause pain with excretion of blood clots causing renal colic
• Disease can begin by haematuria followed by other features of progressive renal failure
• Disease is accelerated in blacks (correlates with sickle cell disease) in males more than females and in the presence of hypertension
• Have cysts in other places such as the spleen, liver, lungs and pancreas
• Also have more intracranial berry aneurisms and increased risk of a SAH
• Patient can also have cardiac problems including mitral valve prolapse

 

Autosomal-recessive (childhood) polycystic kidney disease

• Rare. Perinatal, neonatal, infantile and juvenile subcategories have been defined depending on time of presentation and the presence of associated hepatic lesions
• Due to mutations on chromosome 6 due to the gene fibrocystin. This is highly expressed in both the adult and fetal kidney and is a membrane protein with Ig-like domains with a likely receptor function

 

Morphology

• Kidneys are enlarged but have a smooth outer surface
• On cut surface the kidney has a sponge like appearance
• Microscopically there is a cylindrical or saccule dilation of the collecting tubules
• Cysts are derived from the collecting tubules
• Disease is invariably bilateral
• In almost all cases the liver has cysts with portal fibrosis and well as proliferation of portal bile ducts

 

• Patients that survive infancy may develop a type of hepatic fibrosis characterised by bland periportal fibrosis and proliferation of well-differentiated biliary ductules. This condition is called congenital hepatic fibrosis. In colder children it is this hepatic picture that predominates and they may develop portal hypertension with splenomegaly

 

Nephronophthisis-Medullary Cystic Disease complex

• A group of progressive renal disorders that normally have their onset in childhood
• The common characteristic is cysts in the medulla, particulary concentrated around the cortico-medullary junction
• The initial insult likely involves the distal tubules with tubular basement membrane disruption, folled by chronic and progressive tubular atrophy involving both medulla and cortex and interstitial fibrosis
• Although the presence of medullary cysts is important it is the cortical tubulointerstitial damage that is the cause of eventual renal insufficiency
• Sometimes referred to as hereditary tubulointerstitial nephritis

 

• Four variants of this disease exist;
  • Sporadic nonfamilial – 20%
  • Familial juvenile nephronophthisis – 40-50% inherited as an autosomal recessive disease
  • Renal-retinal dysplasia – 15% which is also autosomal recessive disease in which the kidney disease is associated with ocular lesions
  • Adult-onset medullary cystic disease – 15% this shows autosomal dominant inheritance
• As a groups this disease is thought to be the most common genetic cause of end stage renal disease in children and young adults

 

• Affected children present with polydipsia and polyuria due to reduced concentrating effect of the tubules
• Sodium wasting and tubular acidosis also occurs

 

Pathogenesis

• At least five gene loci have been identified as for this complex
• NPH1, NPH2 and NPH3 define the juvenile forms of nephronophthisis and are inherited in an autosomal recessive manner
• MCKD1 and MCKD2 are transmitted in an autosomal dominant fashion and are involved in adult meduallry cystic disease

 

Morphology

• Kidneys are small with contracted granular appearance
• Cysts are in the medulla most prominently in the corticomedullary junction
• Small cysts can also be seen in the cortex
• Cysts are lined with flattened or cuboidal epithelial cells and are surrounded by either inflammatory cells or fibrous tissue
• In the cortex there is widespread atrophy and thickening of the basement membranes of proximal and distal tubules together with interstitial fibrosis
• Some glomeruli may be hyalinised but most are preserved
• Can be difficult to diagnose as the cysts can be too small to visualise radiographically

 

Hereditary syndromes of isolated haematuria

 

Alport syndrome

• When fully developed is manifested by nephritis progressing to chronic renal failure accompanied by nerve deafness and various eye disorders including lens dislocation, posterior cataracts and corneal dystrophy
• It is X-linked and males express the full syndrome whilst females are the carriers in which the disease is limited to haematuria. Rare autosomal recessive and dominant pedigrees also occur in which males and females are equally susceptible
• Histologically the glomeruli are always involved
• Defective GBM synthesis because of the production of abnormal collagen Type IV underlies disease.
• Disease is caused by mutations in the a5-chain of type IV collagen
• This interferes with the architecture of the protein and structure and function of the GBM
• Patients normally synthesise less of the other collagen components e.g. a3-chain of type IV collagen
• Most common presenting sign is haematuria frequently accompanied with erythrocyte casts
• Proteinuria can occur and rarely nephrotic syndrome occurs
• Symptoms appear at ages 5 to 20 and renal failure develops between ages 20 to 50

 

Thin Basement membrane disease (Benign familial haematuria)

• Common, clinically associated with asymptomatic haematuria and morphologically with thinning of the basement membrane to 150-250nm (should be 300-400nm)
• Renal function is generally normal

This entry was posted on Friday, December 21st, 2007 at 4:54 pm and is filed under Kidney. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.