Renal disorder in systemic disease

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Renal disorder in systemic disease
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• A huge variety of systemic conditions can affect
  the function of the kidneys, from acute illnesses
  to drugs and more insidious illnesses.

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• Diabetic nephropathy
• Hypertensive nephropathy/nephrosclerosis
• Vasculitides
• Sickle cell disease

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Diabetic nephropathy

• Definition A microvascular complication of
  diabetes marked by albuminuria and a
  deteriorating course from normal renal function
  to ESRD.
• Diabetic nephropathy is the commonest cause of
  end stage renal failure (ESRF) in the developed
  world (about 3040 of cases of ESRF).
• Incidence rising in line with diabetes.
• It is more common as a complication of type 1
  diabetes mellitus but also affects a significant
  proportion of type 2 patients
• It usually affects patients who have had diabetes
  for gt10 years, with peak incidence of 3 per
  year in those who have had diabetes for 1020
  years

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The diabetic kidney

• The kidney may be damaged by diabetes in three
  main ways
• glomerular damage
• ischaemia resulting from hypertrophy of afferent
  and efferent arterioles
• ascending infection.

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Pathology

• Expansion of mesangial matrix with diffuse and
  nodular glomerulosclerosis (Kimmelstiel-Wilson
  nodules)
• Thickening of glomerular and tubular BM
• Arteriosclerosis and hyalinosis of afferent and
  efferent arterioles
• Tubulointerstitial fibrosis

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• Signs and Symptoms
• Approximately 25 to 40 of patients with DM 1
  ultimately develop diabetic nephropathy (DN),
  which progresses through five predictable stages.

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• Stage 1 (very early diabetes)
• Increased demand upon the kidneys is indicated by
  an above-normal glomerular filtration rate (GFR).
  
• Hyperglycemia leads to increased kidney
  filtration (see later)
• This is due to osmotic load and to toxic effects
  of high sugar levels on kidney cells
• Increased Glomerular Filtration Rate (GFR) with
  enlarged kidneys

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• Stage 2 (developing diabetes)
• Clinically silent phase with continued hyper
  filtration and hypertrophy
• The GFR remains elevated or has returned to
  normal, but glomerular damage has progressed to
  significant microalbuminuria (small but
  above-normal level of the protein albumin in the
  urine).
• Significant microalbuminuria will progress to
  end-stage renal disease (ESRD).
• Therefore, all diabetes patients should be
  screened for microalbuminuria on a routine basis.

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• Stage 3 (overt, or dipstick-positive diabetes)
• Glomerular damage has progressed to clinical
  albuminuria.
• Basement membrane thickening due to AGEP
• The urine is "dipstick positive," containing more
  than 300 mg of albumin in a 24-hour period.
• Hypertension (high blood pressure) typically
  develops during stage 3.

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• Stage 4 (late-stage diabetes)
• Glomerular damage continues, with increasing
  amounts of protein albumin in the urine.
• The kidneys filtering ability has begun to
  decline steadily, and blood urea nitrogen (BUN)
  and creatinine (Cr) has begun to increase.
• The glomerular filtration rate (GFR) decreases
  about 10 annually. Almost all patients have
  hypertension at stage 4.

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• Stage 5 (end-stage renal disease, ESRD)
• GFR has fallen to lt10 ml/min and renal
  replacement therapy (i.e., haemodialysis,
  peritoneal dialysis, kidney transplantation) is
  needed.

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Diagnosis

• The urine of all diabetic patients should be
  checked regularly for the presence of protein.
  detected by measuring the albumin/creatinine
  ratio on a spot urine sample
• Clinical suspicion of a non-diabetic cause of
  nephropathy may be provoked by an atypical
  history, the absence of diabetic retinopathy
  (usually but not invariably present with diabetic
  nephropathy) and the presence of red cell casts
  in the urine.
• Renal biopsy should be considered in such cases,
  but in practice is rarely necessary or helpful.
• The risk of intravenous urography is increased in
  diabetes, especially if patients are allowed to
  become dehydrated pri or to the procedure, and a
  renal ultrasound is preferable but not so
  informative.
• A 24-hour urine collection is performed to
  quantify protein loss and to measure creatinine
  clearance, and regular measurement is made of the
  plasma creatinine level.

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Investigation

• Urine microscopy
• Culture
• Serum protein electrophoresis
• Serum calcium
• Serum urate
• ESR
• Antinuclear factor.

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Management of diabetic nephropathy

• Tight glycaemic control, ideally achieved through
  combination of dietary modification,
  pharmacotherapy (including insulin regimen) and
  regular physical activity.
• Tight BP control of at least 130/80 through the
  use of ACE inhibitors/Angiotensin-2 receptor
  antagonists diuretics/beta-blockers.
• ACE inhibitors are of benefit in normotensive
  diabetics with microalbuminuria.
• Optimisation of other vascular risk factors
  through use of aspirin and statins (vastly
  increased cardiovascular risk caused by diabetic
  nephropathy).
• Renal replacement therapy (including
  transplantation) in those with established kidney
  disease.

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Hypertensive nephropathy/nephrosclerosis

• Renal disease can cause hypertension, but
  sustained hypertension damages the vasculature of
  the kidneys. This is particularly so in cases of
  accelerated or malignant hypertension.
  Hypertensive nephropathy accounts for about a
  quarter of all patients with ESRF. Hypertension
  causes a pathology known as nephrosclerosis due
  to ischaemia affecting the glomeruli, and
  hyperfiltration causing intraglomerular
  hypertension.

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• Hypertension also increases the risk of renal
  failure through the effects of
• Cholesterol embolisation to the kidneys
• The presence of renal artery stenosis
  (particularly if bilateral)

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• Most patients present with significant
  hypertension and/or its complications (e.g.
  cardiac failure, MI, stroke) or
  biochemical/clinical evidence of renal failure.
  There has usually been a history of hypertension
  for about 10 years, but some patients will
  present without having had any previous evidence
  of hypertension.

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Management

• Management is through use of a range of
  anti-hypertensive agents, particularly ACE
  inhibitors/angiotensin-2 antagonists and
  diuretics, but other agents are also used.
• The cohort of patients with hypertensive
  nephropathy are at risk of bilateral renal artery
  stenosis which may preclude the use of ACE
  inhibitors due to worsening of renal function.
• Renal parameters must be monitored very closely
  after introduction/dose-alteration of an
  anti-hypertensive agent.
• Close attention to modification of other
  cardiovascular risk factors and renal replacement
  therapy are also useful in improving long-term
  outlook.
• Revascularisation of the kidneys (via
  angioplasty/stenting) may be considered in cases
  of bilateral renal artery stenosis where there is
  evidence from captopril renography that it is
  significantly affecting renal function.

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Vasculitides

• Primary systemic vasculitides may cause renal
  dysfunction through their ability to cause a
  focal necrotising glomerulonephritis.
• They usually cause a pattern of renal disease
  known as rapidly progressive glomerulonephritis
  (RPGN).
• Vasculitides that affect the renal vasculature
  tend to be those that affect medium-sized
  arteries.

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Vasculitides that tend to cause renal impairment

• Wegener's granulomatosis
• Microscopic polyangiitis
• Churg-Strauss syndrome
• Polyarteritis nodosa

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Sickle cell disease

• Many children with sickle cell disease develop
  hyposthenuria, an inability to form concentrated
  urine, that may cause nocturnal enuresis and
  polyuria.
• Acute severe haematuria may occur due to renal
  papillary necrosis or sickling within the
  substance of the kidney and is usually treated
  with DDAVP/epsilon-aminocaproic acid.
• A post-mortem series of adult patients with
  sickle cell disease found that renal failure was
  the cause of death in about 20 of cases.
• The disease causes a glomerulopathy with
  proteinuria and progressive renal insufficiency,
  leading to ESRF renal papillary necrosis is
  another possible mechanism of acute renal
  syndromes.
• Albuminuria is a sensitive marker of glomerular
  damage and precedes the onset of renal failure.
• There are no effective therapies to prevent the
  onset of renal failure other than good management
  of the condition in order to reduce the incidence
  of, and ameliorate, sickling crises.

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Multiple myeloma

• Acute renal failure is relatively common in
  myeloma, occurring in 20-30 of affected
  individuals at the time of diagnosis, and is
  mainly due to the nephrotoxic effects of the
  abnormal immunoglobulins.
• Acute renal failure due to cast nephropathy is
  usuallyirreversible. Treatment of underlying
  myeloma is indicated

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• Cast nephropathy in a patient with multiple
  myeloma. Light microscopy picture showing
  characteristic fractured cast and giant cell
  reaction (arrows).