8.03 Chronic renal disease

Congestive cardiac failure, portal hypertension, nephrotic syndrome and renal failure.
Less commonly, idiopathic cyclical oedema, pregnancy, endocrine or drug-induced fluid retention and DVT

Pitting is oedema, non-pitting is lymphoedema.

Starling forces

Jv = K (Pc - Pi ) - (pc - pi ),
where Jv is the capillary ultrafiltrate flow, K is constant, P and p are the hydrostatic and colloid osmotic pressures, respectively, and the subscripts c and i, represent the capillary and interstitial compartments, respectively

The interstitial fluid returns to the blood by lymphatic drainage or by distal capillary reuptake along the length of the capillary lumen as hydrostatic pressure falls and colloid pressures increases.

Hypoalbuminaemia due to nephrotic syndrome, cirrhosis, protein-losing enteropathy or malnutrition

Venous obstruction (e.g. deep venous obstruction, inferior vena cava thrombosis, retroperitoneal neoplasia), cardiac disease (e.g. congestive cardiac failure, tricuspid regurgitation) or pulmonary hypertension (e.g. cor pulmonale)

Sepsis and ischaemia with endothelial damage.

In the interstitial compartment as oedema, having the 'anti-oedema forces' of lymphatic flow, plasma osmotic pressure and the negative interstitial pressure.

It is sensed by the renal juxtoglomerular apparatus, stimulates renin secretion leading to angiotensin II production. This causes widespread vasoconstriction, stimulated Na reabsorption in the proximal nephron and generates aldosterone which increases Na reabsorption in the distal nephron

The right atrial stretch receptors release atrial naturetic peptide (ANP which mediates and acute, corrective natriuresis. It's role in long term regulation is less certain

An active urine sediment with haematuria, proteinuria, fluid retention and consequent hypertension and oedema formation. Periorbital and dependent oedema are common. Failure of the kidneys to excrete the normal salt and water intake occurs in acute nephritic syndrome (exact mechanism controversial)

It is characterised by oedema, hypoalbuminaemia and heavy proteinuria (greater than 3.5 g/day). Hypoalbuminaemia results from excessive urinary protein losses, increased renal protein catabolism and blunted hepatic albumin synthesis. Oedema formation is due to a combination of reduction of plasma colloid osmotic pressure due to hypoalbuminaemia (p c is primarily determined by albumin concentration) and consequent shift of fluid from the vascular to the extravascular (interstitial) compartments, and renal salt and fluid retention.

Post-streptococcal glomerulonephritis.

It is usually caused by glomerulonephritis (minimal change GN, FSGS and membranous GN), diabetic nephropathy, vasculitis or renal amyloidosis.

The exact pathophysiology of the salt and water retention and oedema formation in nephrotic syndrome is controversial, with intravascular hypovolaemia and renal hypoperfusion being postulated causes. However, blood volume is often normal in nephrotic patients. Hence, other factors have been implicated, including plasma renin-aldosterone, antidiuretic hormone (ADH) and ANP. A markedly blunted natiuretic and diuretic response to ANP in nephrotic syndrome, may contribute to oedema formation. No one factor is a consistent single explanation, and further research is required.

Idiopathic oedema is a condition that usually occurs in young and middle-aged women, who are often obese, and is characterised by periodic (not really 'cyclical' or related to the menstrual cycle) swelling of hands, feet and face, accompanied by up to 5 kg in weight gain. The aetiology is debated, however diuretics which are often taken to treat the oedema seem to aggravate the condition, via volume depletion and activation of the renin-angiotensin aldosterone system.

They block renal prostaglandin synthesis, thereby stimulating sodium reabsorption at the loop of Henle

Liquorice (whose active component is glycyrrhizic acid) sensitises renal tubular cells to mineralocorticoid action, by inhibition of the 11-ß-OH dehydrogenase.

They are mostly reabsorbed and metabolised by proximal tubule cells

About 300mg/L, but it's sensitivity is greatest for albumin and poor for some proteins such as Bence Jones proteins

30 to 300 mg/24 hours- special analysis is required for detection

Endothelium, glomerular basement membrane and epithelial podocytes

The barrier function depends on intercapillary haemodynamics (pressure and flow rate), and the negative (anionic) charge at the epithelial surface slit pores due to glycosaminoglycans such as heparan sulphate and sialic acid. Specific slit pore molecules, such as nephrin, are pivotal components of the barrier to proteins.

Albumin predominates the proteinuria

Non-selective proteinuria

It arises due to impaired tubular reabsorption of low molecular weight proteins, or their loss from tubular cells, and is usually < 1 gram/24 hours

By urine microscopy (sensitivity 0.5x10 6 /L), by dipstick analysis (5x10 6 /L) and visually (5x10 9 /L)

Proteinuria and active urinary sediment (granular and cellular casts)

Lesions of the renal pelvis, ureter, bladder and urethra

A glomerular lesion

Non-glomerular haematuria

rinary tract sepsis (usually with classic symptoms and signs of cystitis or pyelonephritis), calculi (usually accompanied by pain) and renal tract tumours (frequently painless).

IgA disease and thin glomerular basement disease

When proteinuria is severe enough to cause hypoalbuminaemia which leads to oedema. The synthetic capacity of the liver is not enough to compensate for the protein loss and so the serum albumin level drops, leading to a fall in plasma oncotic pressure and a shift of fluid from the blood into the interstitium (Starling Forces). The decrease in plasma and blood volume will stimulate the kidneys to retain salt and water by increasing sympathetic tone and increasing renin-angiotensin-aldosterone levels. The retained fluid will continue to accumulate as oedema. Studies have shown that some patients with nephrotic syndrome have a normal or increased blood volume

Minimal lesion disease followed by focal sclerosing glomerulonephritis

Membranous glomerulonephritis followed by focal sclerosing glomerulonephritis

Initially in subcutaneous tissue and later in serous sacs (pleural, peritoneal fluid)

>3g/day

- Infection (fluid collections, fragile skin)
- Thromboembolic disease (anti-thrombin 3 in urine and decreased zymogens)
- Lipid abnormalities (Raised cholesterol, LDL and VLDL. Raised triglycerides if severe nephrotic syndrome. Due to increased protein production in the liver)
- Renal failure (acute: decreased circulating volume, chronic: underlying disease process)

Restrict salt to less than 100mM/day
Adequate (but not excessive) protein intake

- Diuretics (usually loop with the later addition of those that on proximal and distal DT)
- Decrease proteinuria: ACE inhibitors and Cyclosporin. Non-steroidal drugs decrease proteinuria by decreasing GFR and should only be used with great care with close observation of electrolytes and renal function.
- Control of lipid abnormalities in severe cases
- Anticoagulants if indicated

Glomerular injury occurs as if the glomerulus is a "bystander" injured after a particular antigen specific immune response is triggered.

The glomerulus is injured by the increased deposition of circulating IgA; in this disease a restricted antigen-specific response does not seem to be operative (i.e. the circulating IgA is directed at multiple different antigens).

- Triggering infections e.g. Hep B, Hep C, Streptococcus
- Autoantibodies
- Circulating immune complexes
- Immunoglobulin and complement deposition within the glomerulus on a renal cortical biopsy. The pattern may aide diagnosis

The only example of this disease is where there are anti glomerular basement antibodies (sometimes Goodpasture's disease)
In this disease glomerular injury is caused by the production of a complement-binding IgG antibody directed at a collagen epitope in the GBM
Because circulating IgG antibodies are pathogenic in this condition, part of the treatment involves removal of the antibody from the circulation using plasmapheresis.

Damage in these conditions occurs either as a consequence of binding of antibodies to antigens 'trapped' in the glomerulus as a result of filtration ('planted' antigens) or following deposition of circulating antigen-antibody complexes ('immune complexes') within the glomerular capillaries (e.g. in lupus nephritis). These immune complexes cause glomerular damage due to the activation of complement and inflammatory pathways. Treatment involves removal of the antigen if possible and reducing antibody production with immunosuppressive treatment.

Group-IgA nephropathy and Henoch-Schonlein Purpura (HSP)

Glomerular injury in these diseases is believed to be linked to local activation of complement proteins by the deposited IgA.

The polyclonal nature of deposited IgA as well as its normal presence in the serum probably accounts for the limited response of these conditions to immunosuppressive treatment.

The glomerular damage in these diseases occurs either as a consequence of injury to the extraglomerular blood vessels (which may not be seen in a renal biopsy) or glomerular capillaries themselves. Soluble inflammatory factors such as cytokines and growth factors also play a role in glomerular injury.

The glomerular damage in these diseases occurs either as a consequence of injury to the extraglomerular blood vessels (which may not be seen in a renal biopsy) or glomerular capillaries themselves.

These diseases usually show no significant complement or immunoglobulin deposition in the glomerulus on renal biopsy and are therefore sometimes described as having a 'pauci-immune' (literally meaning 'minimal inflammation') pattern.

The pathogenesis of vascular inflammation in these diseases is thought to involve a combination of humoral and cell mediated antigen specific immune responses-hence treatment usually involves dampening the immune response with immunosuppressive medication.

"Minimal changeM nephrotic syndrome and primary focal segmental glomerulosclerosis (FSGS).

In these diseases an as yet unidentified soluble factor directly injures the glomerular epithelial cell. Although these diseases are not associated with direct evidence of glomerular inflammation, a number of lines of evidence suggest that their pathogenesis is related to overactivity of the immune system (including the response of the minimal change nephrotic syndrome to corticosteroids); hence they are typically included in classification systems for glomerulonephritis.

The combination of accumulation of many uraemic compounds, fluid and electrolyte abnormalities, the development of acidosis, the breakdown of metabolic pathways such as vitamin D metabolism and the lack of humoral factors such as erythropoietin.

It can be asymptomatic in patients whose GFR is greater than 25 ml/min/1.73m. Symptoms are almost universal as the GFR reaches 10 ml/min/1.73m

Factors involved in the pathogenesis of heart disease include; fluid retention, anaemia, secondary hyperparathyroidism and metastatic vascular calcification, hyperlipidaemia, and the presence of an arteriovenous fistula.

Ureamia means that as patients near end-stage renal failure, they almost always complain of anorexia, nausea and vomiting. When these symptoms are added to the already restricted renal diet, weight loss and malnutrition often result.

Increased ammonia production by bacterial urease

Iron and folate deficiency, occult bleeding, shortened red cell survival and uraemia itself are important contributing factors to the anaemia of CRF.

A bleeding diathesis due to abnormal platelet function is a major complication of CRF. The most common manifestation of this is widespread, ecchymoses and purpura.

It is due to phosphate retention and decreased activation of vitamin D. It is one of the major contributing factors to the intractable pruritus these patients experience. Associated with these problems are abnormalities in bone turnover resulting in a constellation of skeletal complications termed renal osteodystrophy, which predominantly is a combination of osteitis fibrosa and osteomalacia.

Apathy, anorexia, altered sleep patterns and restlessness. If left untreated the encephalopathy progresses to stupor and coma and can be associated with a flapping tremor, twitching, fasciculations, asterixis and convulsions. In addition to the encephalopathy patients develop symptoms associated with a mixed motor and sensory peripheral neuropathy. These include restless legs, burning feet, paraesthesia, muscle weakness and autonomic neuropathy.

Growth retardation in children, impaired immune response, thyroid dysfunction and sexual dysfunction.

Products of protein and amino acid metabolism including urea, guanido compounds and acidosis. In isolation or in combination these compounds have major metabolic effects. Accumulation of these compounds is due to excretory failure.

These are the "middle molecules", which are retained in uraemia. These include such diverse compounds as growth factors, polypeptide hormones (intact or fragmented). Accumulation of these compounds is due to both failure of excretion and failure of catabolism in the kidney.

Impaired metabolism causing hyperlipidaemia (elevations of VLDL-triglycerides, lipoprotein (a) and reduction in HDL-cholesterol)

Increased protein catabolism is a feature

Impaired glucose tolerance (peripheral insulin resistance)

Peretoneal.

Restriction of dietary protein has in itself been shown to be extremely effective in improving the symptoms of uraemia. Not only is the contribution of nitrogenous waste products to the clinical and metabolic disturbances reduced, but there is an associated reduction in Na, K, phosphate, sulphates and acids, as food rich in protein contains high amounts of these compounds. Unless care is taken, implementation of dietary protein restriction may result in inadequate intake leading to protein malnutrition.

* Glomerulonephritis
* Diabetic renal diseases
* Polycystic renal disease
* Reflux renal disease
* Hypertension
* Analgesic Renal disease
* Obstructive Nephropathy

cyclopsorin, penicillamine

There is an increase in intrarenal vascular resistance with development of intimal and medial hypertrophy, glomerular hypertension, tubular cell injury and the development of progressive interstitial inflammation and fibrosis.

The use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers that exert a reno-protective effect beyond simple blood pressure control.