Pathophysiology:

This paragraph deals with 1. Glomerulonephritis, 2. Renal insufficiency, 3. Acute tubular necrosis, 4. Diabetic nephropathy, 5. Nephrotic syndrome, 6. Urinary tract infection, 7. Tubulo-interstitial nephritis, 8. Gouty nephropathy, 9. Renal hypertension, 10. Urinary tract obstruction, and 11. Tumours of the kidney.

The severity and cause of kidney disease is evaluated by measurement of the GFR.

1. Glomerulonephritis

Glomerulonephritis is an immunologically mediated injury of the glomeruli of both kidneys.

The majority of patients suffer from postinfectious glomerulonephritis or immune complex nephritis. This is a disorder, where circulating antigen-antibody complexes are deposited in the glomeruli or free antigen is bound to antibodies trapped in the capillary network. Typically, the antigen is derived from Lancefield group Aß- haemolytic streptococci, but also other bacteria, viruses, parasites (malaria), and drugs may be the origin. A few patients produce antibodies against their own antigens (eg, host DNA in systemic lupus erythematosus, malignant tumour antigen, or anti-glomerular basement antibody, anti-GBM).

The inflammation is an abnormal immune reaction often caused by repeated streptococcal tonsillitis. An insoluble antigen-antibody complex precipitates in the basement membrane of the glomerular capillaries. The cells of the glomeruli proliferate, and disease will of course reduce GFR and to some extent, the RBF (measured as PAH clearance). Thus the infection depresses the glomerular filtration fraction (GFF = GFR/RPF).

The acute postinfectious glomerulonephritis occurs typically in a child, who has suffered from streptococcal tonsillitis a few weeks before.

Haematuria, proteinuria, and oliguria characterise acute nephritis with salt-water retention causing oedemas and hypertension. Pulmonary oedema and hypertensive encephalopathy with fits is life threatening.

Uraemia is a clinical syndrome dominated by retention of non-protein nitrogen (eg, urea, uric acid, NH4+ creatinine and creatine). Uraemic patients generally exhibit hyperkalaemia (plasma- [K+] above 5.5 mM) and metabolic acidosis (pH below 7.35 and a negative base excess). This is due to the inadequate secretion of K+, NH4+ and H+. In complete renal shutdown, the patient dies within 1-2 weeks without dialysis.

Dialysis is mandatory with severe uraemia. When serum creatinine rises above 0.7 mM, renal insufficiency is usually terminal (Fig. 25-4).

Recording of blood pressure and fluid balance with weighing is important in order to prevent hypertension and pulmonary oedema to develop into a life-threatening condition.

Fig. 25-19: Post-streptococcal glomerulonephritis.

The parietal and visceral epithelial cells of the glomeruli grow and proliferate, just as the mesangial cells (Fig. 25-19). This proliferation and the damage of the basement membrane with accumulation of insoluble complexes all impair the glomerular barrier and reduce the glomerular filtration rate (GFR). Production of cytokines and autocoids enhance the inflammation. Capillary injuries with reduction of the lumen also reduce the renal bloodflow (RBF) to some extent (Fig. 25-19).

Children with poststreptococcal glomerulonephritis are treated with a course of penicillin - often with an excellent prognosis.

Glomerulonephritis as a part of systemic lupus erythematosus (SLE) is frequent in female lupus patients - in particular during pregnancy, where hypertension may precipitate glomerular injuries. Oestrogens accelerate progression of SLE, and there is a genetic predisposition. In SLE there is hyperactivity of the B-cell system, which may involve any organ, but typically affects the kidneys, joints, serosal membranes and the skin (Chapter 32). The B-cell system releases many antibodies to host antigens both in and outside the cell nuclei (single- and double-stranded DNA, RNA, plasma proteins, cell surface antigens, and nucleoproteins). Lymphocytotoxic antibodies are also liberated, which may explain the inhibition of the T-cell system. The most important autoantibodies are those against nuclear antigens. Accumulation of immune complexes with double-stranded DNA probably causes the glomerular lesions as well as vasculitis and synovitis.

Fig. 25-20: Anti-GBM glomerulonephritis with anti-GBM of the IgG type. Complement is shown as a small circle.

Anti-GBM glomerulonephritis is a seldom disorder, where the patient produces antibodies (IgG type) against his own basement membrane. The antibody is known as anti-GBM or anti-Glomerular Basement Membrane antibody. The antigen is localised both in the glomerular basement membrane and in the basement membrane of the alveolar capillaries. The histological picture is characterized by proliferation of both parietal epithelial cells, and mesangial cells (Fig. 25-20).

The capillary basement membrane is disrupted, and there is red cells and fibrin in Bowmans space. The diagnosis is confirmed by identification of circulating anti-GBM (Y-shape in Fig. 25-20). Glomerulonephritis with pulmonary haemorrhage is termed Goodpastures syndrome. The recurrent haemoptyses can be life threatening.

2. Renal Insufficiency

Renal insufficiency is a clinical condition, where the glomerular filtration rate is inadequate to clear the blood of nitrogenous substances classified as non-protein nitrogen (urea, uric acid, creatinine, and creatine). The retention of nonprotein nitrogen in the plasma water is called azotemia, and the clinical syndrome is called uraemia. The number of filtrating nephrons falls below 1/3 of normal, as determined by measurement of a GFR below 40 ml/min.

Acute renal insufficiency accompanies extremely severe states of circulatory shock (prerenal cause). The prerenal causes are hypovolaemia with hypotension or impaired cardiac pump function or the combination.

Also a large group of renal causes to failure occurs (Box 25-2). Finally, the postrenal causes are all types of urinary tract obstruction.

Acute renal failure is a serious disorder, which leads to progressive uraemia and chronic renal insufficiency.

Box 25-2. Causes of renal failure
Prerenal Causes: Cardiogenic and hypovolaemic shock
Renal Causes: ACE-inhibitors and NSAID´s impair renal autoregulation
Fulminant hypertension.
Renal artery stenosis and embolism
Vasculitis in glomerular capillaries
Renal vein thrombosis
Toxic tubular damage (organic solvents, myoglobin, aminoglycosides, and X-ray contrast).
Postrenal Causes: Urinary tract obstruction is caused by obstructions of the lumen, the wall and by pressure from outside
Lumen: Tumours, calculus and blood clots within the lumen of the renal pelvis, ureter, and bladder
Wall: Strictures of the ureter, the ureterovesical region, urethra, and pinhole meatus.
Congenital disorders such as megaureter, bladder neck obstruction, and urethral valve.
Neuromuscular dysfunction in the urinary tract
Pressure: Compression by tumours, aortic aneurysm, retroperitoneal fibrosis or gland enlargement, retrocaval ureter, prostate hypertrophy, phimosis, and diverticulitis.

Two complications to chronic renal failure must be considered:

1. Renal osteodystrophy develops in patients with severe renal failure. The kidneys fail in producing sufficient 1,25-dihydroxy-cholecalciferol. This is active vitamin D or a potent steroid hormone. The active vitamin D metabolite stimulates the Ca2+-transport across the cell and mitochondrial membranes.

Lack of active vitamin D has the following two effects:

a. Poor gut absorption of dietary Ca2+, so that plasma [Ca2+] falls.

b.The PTH release is stimulated, because the normal inhibitory effect of active vitamin D is lost.

After some time a secondary hyperparathyroidism develops with increased resorption of calcium from bone and increased proximal tubular reabsorption of calcium in an attempt to correct the low serum calcium. The calcium release from bone results in osteomalacia and in osteoporosis. Osteomalacia or soft bones is the result of demineralisation of the osteoid matrix usually caused by insufficient active vitamin D. Osteoporosis or thin bones is characterized by a reduction in all components of the bones.

2. Normochromic, normocytic anaemia. When normal kidneys are perfused with hypoxaemic blood, the peritubular interstitial cells produce large amounts of the glycoprotein hormone, erythropoietin, with strong effect on erythrogenesis.

Chronic renal failure leads to erythropoietin deficiency, and thus to anaemia, which is of the normochromic, normocytic type.

Haemodialysis

The aim of haemodialysis is to eliminate nitrogenous wastes in patients with renal failure, and maintain normal electrolyte concentrations, serum glucose and normal ECV. In other words, the haemodialyzer or artificial kidney mimics the normal renal excretion of waste products (Fig. 25-21)

Fig. 25-21: An artificial kidney (dialyser) with an area of 1 m2 and a membrane thickness of 10 µm.

Blood from the patient is pumped through a container with series of semi-permeable membranes separating the blood from dialysate (Fig. 25-21).

Dialysate is a mixture of purified water with salts, and glucose in a composition comparable to normal fasting plasma apart from proteins. Bicarbonate or acetate buffer is present at a concentration about 35 mM.

Haemodialysis is performed with a bloodflow of 200-300 ml per min. The patient is often connected to the dialyzer by an arteriovenous shunt made by plastic cannulae between the radial artery and an adjacent vein. The arterial blood flows into the artificial kidney and after dialysis the blood is returned to the venous system (Fig. 25-21). Dialysate is pumped through the container at a rate of 500 ml each min.

A plastic shunt connects the two cannulae on the forearm between dialysis sessions, and the large arterial bloodflow is sufficient to avoid coagulation in the plast shunt. Also dual-lumen venous catheters placed centrally are in use.

If the sodium concentration of the dialysate is too high, the patient complains of thirst and the arterial pressure starts to rise. Low dialysate calcium may result eventually in secondary hyperparathyroidism, whereas a high dialysate calcium concentration causes hypercalcaemia.

An adult patient with acute renal failure (so-called shock kidney) requires 4 -5 hours dialysis 3 times a week.

Renal Transplantation

Fit patients with chronic renal failure are offered renal transplantation. Rejection of the transplant is due to complement-fixing antibodies in the blood, or later caused by cellular or humoral immunity. Rejection years after the transplantation is frequently caused by ischaemic damages of the kidney. Donation of a kidney leaves the donor with one kidney only.

Immediately after the removal, the GFR of the patient falls to half its original value, because half the functioning nephrons have been removed.

Soon, most individuals will increase their GFR towards normal values by compensatory work hypertrophia of the remaining kidney. The hypertrophia-factor is not known. Each remaining nephron must filter and excrete more osmotically active particles than before.

3. Acute Tubular Necrosis

This disorder has haemodynamic or toxic causes.

Cardiogenic and hypovolaemic shock cause acute renal failures just as renal vasoconstriction. Renal ischaemia leads to hypoxic damage, in particular damage of the renal medulla, which is especially susceptible to ischaemia, because of the normally relatively poor oxygenation. Ischaemic tubular damage also reduces the GFR further, because of reflex spasms of the afferent arterioles, and due to tubular blockage with accumulation of filtrate in the early part of the proximal tubules, and hypoxic damage of the proximal tubular reabsorption capacity.

Loss of appetite and energy, nausea and vomiting, nocturia and polyuria characterise the condition. Only when the GFR is severely depressed there is oliguria. Even a GFR of only 1 ml each min, as a contrast to the normal 125 ml per min, may result in a daily urine flow of 1440 ml (1*1440 min daily), if there is a total loss of tubular reabsorption and no luminal obstruction. This urine flow is normal, but unfortunately based on an almost total loss of glomerular and tubular function. Sufficient regeneration of the tubular epithelium allows clinical recovery.

Sometimes also the renal cortex is necrotic, and following healing of the injuries, the result is scarring with glomerulosclerosis. This condition is also found following radiation nephritis.

4. Diabetic nephropathy

Diabetic nephropathy includes glomerulosclerosis, with thickening of the basement membrane and damage of the glomerular filter by disruption of the protein cross-linkages and glomerular hyperfiltration. Excess NO production reduces the afferent arteriolar resistance and increases the glomerular capillary pressure. The earliest evidence of glomerular damage may occur 5-15 years following diagnosis in the form of microalbuminuria. The patient later develops intermittent albuminuria followed by persistent albuminuria. Diabetic nephropathy includes hypertension, persistent albuminuria, and a decline in GFR. One third of all insulin-dependent diabetics develop nephropathy. The mortality rate is high. The metabolic disturbance in diabetics causes hypertension and leaky renal glomeruli, but the mechanism remains uncertain.

Ascending infections result in interstitial lesions and diabetes typically show hypertrophy and hyalinization of afferent and efferent arterioles. Obstruction of the renal bloodflow (ischaemia) leads to hypoxic damage of the renal tissue. The tenuous bloodflow to the renal papillae via the vasa recta explains why renal papillary necrosis is frequent in diabetics.

Treatment with ACE- inhibitors reduce urinary albumin excretion. Prophylactic therapy also postpones the development of diabetic nephropathy and hypertension with persistent microalbuminuria. The effectiveness of this treatment suggests that relative oversecretion of angiotensin may be involved in the pathogenesis of diabetic nephropathy.

5. Nephrotic syndrome

The nephrotic syndrome refers to a serious increase in the permeability of the glomerular barrier to albumin, resulting in a marked loss of albumin in the urine. The albuminuria (more than 3 g per day) causes hypoalbuminaemia and generalized oedema.

The number and size of pores in the glomerular barrier increase due to disruption of protein-linkages. Negatively charged glycoproteins in the glomerular barrier repel negatively charged proteins. The amount of negatively charged glycoproteins is reduced in glomerular disease.

Oedema is visible in the face - especially around the eyes.

A serious but rare complication may develop when a large volume of fluid accumulates in the abdominal cavity as ascites.

6. Urinary Tract Infection

Urination (micturition) is controlled by the micturition reflex. Stretch or contraction of the smooth muscles in the bladder wall is sensed by mechanoreceptors and signalled via the pelvic nerve to the sacral spinal cord. Increased parasympathetic tone (via pelvic nerves and muscarinic receptors) cause sustained bladder contraction. Normally, contraction of the bladder muscles by micturition almost completely empties the bladder.

Recurrent infections of the urinary tract are frequent among females. Faecal bacteria are transferred to the periurethral region, and finally to the bladder via the short female urethra. Bladder urine is normally sterile owing to bladder mucosal factors and other local defence mechanisms. Bacteria adhere to the bladder epithelium and multiplicate, when defence mechanisms function insufficiently. Prolonged bladder catheterisation predisposes to bladder infection, and even a few days can be critical.

The diagnosis bladder infection is based on more than 100 000 bacteria per ml of clean-catch mid-stream urine. Quite a few patients with significant bacteriuria do not develop nitrite enough to be shown by dipstick tests.

Typical symptoms are frequent micturition (polyuria), painful voiding (dysuria), suprapubic pain and smelly urine perhaps with haematuria.

Echerichia coli and other coliform bacteria cause the majority of urinary tract infections; these infections are treated successfully with antibiotics (amoxyllin, trimethoprim etc) either as a single shot or for longer periods.

7. Tubulo-Interstitial Nephritis

Bacterial pyelonephritis typically causes interstitial inflammation of the kidneys, but the interstitial inflammation is more often caused by a hypersensitivity reaction to drugs (antibiotics, phenacetin and non-steroid anti-inflammatory drugs, NSAIDs).

Pyelonephritis begins in the renal pelvis, and then progresses into the renal medullary tissue.

The essential function of the medulla is to concentrate the urine during water depletion. Therefore, in patients with pyelonephritis, the ability to concentrate the urine is abolished/decreased (isosthenuria/hyposthenuria). The ability to dilute the urine deteriorates also. Thus, in isosthenuria the urine is always isotonic with the plasma.

The patient with acute nephritis has fever, skin rashes and acute renal failure with eosinophiluria and eosinophilia. First of all the offending drug must be withdrawn, and the renal failure may require dialysis.

Chronic tubulo-interstitial nephritis is caused by pyelonephritis, NSAIDs, diabetes mellitus, hyperuricaemia, irradiation damage etc. The major problem is that long lasting consumption of large amounts of analgesics leads to terminal renal failure. Nephrotoxic analgesics must be abandoned.

The patient presents with uraemia, albuminuria, polyuria, haematuria, anaemia, and most often a history of analgesic abuse. Papillary necrosis can be present with papillary tissue passed in the urine or obstructing the ureter or urethra. In patients with tubular damage of the renal medulla, the ability to concentrate the urine is abolished together with the ability to dilute the urine. Thus, the urine is always isotonic with the plasma (isosthenuria). The result is polyuria and salt wasting. As the inflammation progresses to the cortex also the glomerular filtration deteriorates with accumulation of non-protein nitrogen in the plasma water (azotaemia), and the clinical syndrome uraemia.

An isolated damage of the Na+ -reabsorption (salt-losing nephritis) is a condition in which the disease processes are mainly due to dysfunction in the renal medulla. There is a marked loss of Na+ in the urine and seriously low ECV and blood volume (hypovolaemia with threat of imminent shock). Thus the patient must have a high salt intake to prevent shock and keep alive.

8. Gouty Nephropathy

Acute hyperuraemic nephropathy occurs in patients, where the condition leads to rapid destruction of cell nuclei (at the start of treatment for malignant disorders or obesity). Large quantities of nucleoproteins are released, and the production of uric acid is increased. The urate concentration increases in the extracellular volume (ECV). Above a critical concentration of 420 mM, the urate precipitates in the form of uric acid crystals, provided the fluid is acid. This concentration threshold defines hyperuricaemia.

Precipitation in the joints with pain is termed gout (arthritis urica), and precipitation of uric acid crystals also occurs in the tubules, the collecting ducts and the urinary tract. Normally, urate ions are actively reabsorbed in the proximal tubules by a Na+-cotransport. Urate ions can also be actively secreted from the blood to the tubular fluid.

Allopurinol is prescribed during radiotherapy or cytotoxic therapy. Acute cases are also treated with allopurinol and forced alkaline diuresis.

Uric acid stones are found in patients with hyperuricaemia, and in patients secreting sufficient urate without hyperuricaemia. Calcium stones may be formed around a nucleus of uric acid crystals.

9. Renal Hypertension

Bilateral renal disease such as chronic glomerulonephritis is a frequent cause of hypertension (Chapter 12), whereas unilateral renal disease, such as renal artery stenosis, is a fairly seldom cause of hypertension. Stenosis (narrowing of the lumen) of one renal artery leads to renal hypotension with excess renin production (see below) and systemic (secondary) hypertension.

Exposure to fluid loss, reduced glomerular propulsion pressure, and increased sympathetic activity releases renin from the juxtaglomerular cells in the afferent glomerular arteriole, so the renin-angiotensin-aldosterone cascade is triggered (Fig. 24-5).

Angiotensin II stimulates the aldosterone liberation from zona glomerulosa of the adrenal cortex, and thus stimulates Na+ -reabsorption and K+ -secretion in the distal tubules. The result is salt and water retention with increase in blood volume and blood pressure. Angiotensin II also constricts arterioles, with an especially strong effect on the efferent renal arteriole. This reduces the renal bloodflow further and also the proximal reabsorption. The development of hypertension in high renin states is mainly due to salt-retention and systemic vasoconstriction.

Stenosis of one renal artery does not always lead to increased erythrogenesis. Stenosis of the renal artery implies a small renal bloodflow, a small glomerular filtration and a small NaCl-reabsorption with a related small oxygen consumption on the affected side. As long as the renal oxygenation is sufficient, the erythropoietin production is normal.

Severe renal artery stenosis implies renal ischaemia and hypoxia, which is probably always consequential with complications. A hypoxic kidney has a low creatinine and PAH clearance.

A long-term increase in sodium intake results in changes of the kidney function. Surprisingly, the changes are similar in hypertensive and normotensive humans! Most people increase their ECV and GFR without changing the absolute reabsorption rate of Na+ and water in the proximal tubules. Therefore, the rise in filtration rate of Na+ and water will reach the loop of Henle and the distal tubule. The arterial blood pressure and heart rate is unaffected by the amount of sodium in the diet. The plasma concentrations of active renin (Fig. 24-7), angiotensin II and aldosterone decrease with increasing Na+ intake, but atrial natriuretic factor (ANF) and cyclic GMP increase. Arginine vasopressin (ADH) in plasma does not change.

The reason why this increase in NaCl load to the loop of Henle is not counterbalanced by the TGF-system is due to resetting of the TGF-mechanism, so a contraction is avoided in spite of the increased salt load.These homeostatic reactions are all appropriate physiological responses in both healthy and hypertensive humans.

A rare cause of renal hypertension is due to Liddles syndrome. This is an autosomal dominant defect characterised by severe hypertension, hypokalaemia and metabolic alkalosis. The syndrome is similar to primary hyperaldosteronism, but the renin-aldosterone concentration in plasma is not increased. Liddles syndrome is caused by mutation of the gene for the amiloride-sensitive Na+-channel (Fig. 25-11), whereby the channel is wide open. The Na+-entry depolarises the membrane and favours secretion of K+ and H+.

10. Urinary Tract Obstruction

Obstruction of the urinary tract may occur at any location, and cause dilatation of the above structures. The obstruction is localised within the lumen (stone, sloughed papilla, or tumour), within the wall (neuromuscular dysfunction, stricture, congenital urethral valve, or pin hole meatus), or pressure from the outside obstruct the tract (eg, tumours, diverticulitis, aortic aneurysm, prostatic obstruction, retrocaval ureter).

Stretching of the renal calyces as they collect urine promotes their pacemaker activity and initiate a peristaltic contraction along the smooth muscle syncytium of the urinary tract.

Obstruction of the urinary tract for weeks may lead to irreversible damage of the renal function in particular when combined with infection. Obstruction of the upper urinary tract with backpressure damage of the kidney is especially dangerous.

Kidney stone disease (nephrolithiasis) attacks only a few percent of the Western population at any time. Most stones in male patients are composed of calcium complexed with oxalate and phosphate, whereas magnesium ammonium phosphate/acetate stones are more common in females. Only a few percent of all renal stones are composed of uric acid crystals or cysteine (mainly in children). Calcium-containing and cysteine stones are radiopaque, whereas stones of pure uric acid are radiolucent.

In the presence of infection with urea-splitting bacteria, urea is hydrolysed to form the strong base ammonium hydroxide:

CO (NH2)2 + H2O è 2 NH3 + CO2 ; NH3 + H2O è NH4+ + OH-.

Alkaline urine favours stone formation by crystallization in the supersaturated fluid. Magnesium ammonium phosphate stones are also termed mixed infection stones.

Obstruction or spasm of the ureter causes reflex constriction around the stone with ureteric or renal colic pain. The pain is an excruciating flank pain, with radiation to the iliac fossa and the genitals. The wall of the ureter is innervated with sensory nerve fibres running in the pelvic nerves. Renal colic is considered to be one of the most severe pain experience known.

Excretion urography and plain X-ray examination are important in the diagnosis of renal stone disease.

Percutaneous nephrolithotomy, pyelolithotomy or ureterolithotomy can avoid many cutting operations. Also shock-wave disintegration is in use (lithotripsy).

Nephrocalcinosis refers to diffuse renal calcification that is detectable on a plain abdominal X-ray. Patients with hypercalcaemia (eg, primary hyperparathyroidism, hypervitaminosis D, and sarcoidosis) or with hyperoxaluria precipitate calcium oxalate and calcium phosphate in the renal parenchyma. Patients with renal tubular acidosis fail to acidify their urine, which favour precipitation of calcium oxalate and phosphate.

Abdominal radiography

A plain X-ray can identify calcification at any site including the renal system.

Intravenous pyelography

An organic iodine-containing contrast substance is injected slowly. Serial X-rays are taken, while compression bands are applied to the abdomen in order to obstruct ureteral emptying. Hereby, the upper renal tract is distended by the excreted contrast medium. Following removal of the compression bands, the rate of excretion of contrast is studied with films before and after voiding.

11. Tumours of the Kidney

Benign and malignant tumours occur in the kidney.

Benign renal fibroma, cortical adenomas or simple cysts seldom cause symptoms and signs. Those of no clinical importance are found incidentally at autopsy. Juxtaglomerular cell tumours are seldom. They produce large amounts of renin, which causes hypertension.

Haemangiomas may bleed following trauma and cause fatal blood loss.

Malignant renal tumours are nephroblastoma and renal cell carcinoma.

Nephroblastoma (Wilms´ tumour) is the most frequent intraabdominal tumour in both girls and boys. It usually presents within the first three years of life. A large abdominal mass is found sometimes with signs of intestinal obstruction. The tumour grows rapidly and spread to the lungs. The diagnosis is confirmed with excretion urography, arteriography or scanning.

Radiotherapy and chemotherapy, combined with nephrectomy have improved the long-term survival rate.

Renal cell carcinoma (hypernephroma) accounts for more than 90% of all the malignant renal tumours in adults - in particular smokers. There is a strong association with a rare autosomal dominant inherited disease called Von Hippel-Lindau´ syndrome (haemangioblastomas in the cerebellum and the retina). The genetic locus is on chromosome 3p.The tumour arises from proximal tubular epithelium, and lies within the kidney, but the prognosis is worse, if the tumour penetrates the renal capsule. The tumour is often protruding and the neoplastic cells have an unusually clear cytoplasm.

Renal cell carcinoma is a likely source of ectopic hormone production. Increased production of erythropoietin leads to erythrocytosis and polycythaemia. Release of a parathyroid-hormone-like substance leads to hyperparathyroidism and hypercalcaemia. Release of abnormal quantities of renin triggers the renin-angiotensin-aldosterone cascade and leads to systemic hypertension.

Metastases to distant regions are frequently found in the lungs and in the bones (osteolytic metastases). Solitary tumours are treated by partial or total nephrectomy or with interferon.

Equations

· The plasma clearance is defined as follows:

Eq. 25-1: Clearance = (Cu ×V°u) /Cp [(mg/ml)×(ml/min)/(mg/ml)= ml/min].

Clearance can also be thought of as the volume of arterial plasma containing the same amount of substance as contained in the urine flow per minute.

· Excretion fraction (EF). EF for a substance is the fraction of its glomerular filtration flux, which passes to and is excreted in the urine.

EF = Jexcr/Jfiltr

Since Jexcr = (Cu ×V°u) and Jfiltr =(GFR × Cfiltr) it follows that:

Eq. 25-2: EF = (Cu ×V°u) /(GFR × Cfiltr)

Cfiltr is the concentration of the substance in the ultrafiltrate. The excretion fraction for inulin is one (1). Substances with an EF above one are subject to net secretion. Substances with an EF below one are subject to net reabsorption.

· Extraction fraction (E). E for a substance is the fraction extracted by glomerular filtration from the total substance delivery to the kidney via renal blood plasma.

Eq. 25-3: E = Jfiltr/Jtotal = (Ca - Cvr)/Ca.

Substances with an E of one are cleared totally from the plasma during their first passage of the kidneys. Inulin has an extraction fraction of 1/5. PAH has an extraction fraction of 0.9.

· Inulin clearance. The flux of inulin filtered through the glo­merular barrier per min is:

(GFR × Cp/0.94). All inulin molecules remain in the preurine and is excreted in the final urine.

Thus, the amount excreted is equal to the amount filtered:

GFR × Cp/0,94 = (Cu ×V°u) mmol/min

Eq. 25-4: GFR = ((Cu ×V°u) /Cp) × 0.94 = CLEARANCEinulin × 0.94.

· The Fick's principle (mass balance principle) is used to measure the renal plasma clearance at low plasma [PAH], since at low concentrations the blood is almost cleared (90%) by one transit. Thus the renal plasma clearance is equal to the effective renal plasma flow (ERPF):

Eq. 25-5: ERPF = Jexcr/Cp ; RPF = ERPF/EPAH

· The law of mass balance states that the delivery of PAH to the kidney is equal to its excretion rate at steady state. The Effective Renal Blood Flow (ERBF) is calculated by the help of a total body haematocrit (normally 0.45). If ERPF is measured to be 600 ml plasma per min, we can calculate ERBF: 600/(1 - 0.45) = 1090 ml whole blood per min at rest. This is 20-25 % of cardiac output. The true RBF is 10% higher than the measured ERBF (ie, 1200 compared to 1090 ml whole blood).

Self-Assessment

Multiple Choice Questions

The following five statements have True/False options:

A: The B-cell system releases antibodies to host antigens.

B: The glomerular barrier facilitates the passage of negatively charged polyanionic macromolecules.

C: Thiazide diuretics may have serious side effects such as hypercholesterolaemia, hyperglycaemia (eg, glucose intolerance), hyperuricaemia, hypokalaemia, and impotence.

D: Loop diuretics inhibit the reabsorption of NaCl in the thick ascending limb of Henle – and proximal pars recta - by blocking the cotransport process in the luminal entry membrane.

E: Aldosterone antagonists, such as spironolactone, act on the aldosterone receptors on the late distal tubule cell and inhibit the K+-excretion.

Case History A

A male office worker, 58 years of age, body weight 70 kg, suffers from insulin-dependent diabetes mellitus. The disorder is complicated with arterial hypertension, hypercholesterolaemia, albuminuria and open-angle glaucoma. The patient is in anti-hypertensive therapy with a ß-adrenergic antagonist. The open-angle glaucoma is treated with acetazolamide (a carboanhydrase-inhibitor used as a diuretic to reduce the intra-ocular pressure).

Scanning of the kidneys show a normal picture with an estimated normal kidney weight of 300 g. During renal catheterisation, a renal arteriovenous oxygen content difference is measured to 15 ml per l of blood, and the renal bloodflow is 1.2 l (normal). – The first 3 questions necessitate pharmacological knowledge.

Is it recommendable to treat hypertensive complications to diabetes with ß-blockers?

Describe the effects of carboanhydrase-inhibitor- treatment.

Are thiazide diuretics without risks when prescribed to diabetics?

Calculate the renal oxygen uptake. Calculate the renal oxygen uptake in percentage of the total oxygen uptake of 250 ml per min.

Calculate the kidney weight in percentage of the total body weight.

Is the renal bloodflow redundant compared to the renal oxygen consumption?

Case History B

A female patient (weight 57-kg) of 23 years, with an inherited defect in renal tubular function, has a lowered tubular threshold for glucose reabsorption. The patient has a blood- [glucose] of 1000 mg per litre, and just above this level glucose appears in the urine (her appearance threshold). The diuresis is 1.5 ml per min, the plasma -[creatinine] is 0.09 mM, and the urine [creatinine] is 6 mM. The normal blood-glucose level is 5-6 mM.

1. Is the above blood -[glucose] normal?

2. Calculate the creatinine clearance?

3. Calculate the glucose reabsorption at this glucose level and compare it to the normal maximal capacity: 1.78 mmol min-1.

4. Is the appearance threshold defined above equal to the saturation threshold?

Case History C

A 14-year old girl has a history of previous upper respiratory tract infections, and is now treated for another sore throat (ie, tonsillitis and high fever) with ampicillin for 10 days. Two weeks later she returns to her general practitioner (GP) complaining of tender knee joints from playing handball. There is abdominal pain.

The girl is obviously ill and has a higher blood pressure than normally (145/90 mmHg or 19.3/12.7 kPa). The tonsillitis is cured and there is no fever. The upper abdomen is tender. A freshly passes urine sample is examined with a combined quantitative stick test. There is found haematuria and albuminuria (300 mg l-1).

1. What is the cause of the arthritis?

2. What are the causes of the haematuria and albuminuria?

3. Does the GP admit the girl to a hospital?

Case History D

During her working hours a 24-year old nurse delivered an arterial sample for blood gas tensions. She had no symptoms or signs of disease, but doubted that an arterial sample could be taken without causing pain. The sample was taken from a radial artery with a fine needle following local anaesthesia and she experienced no pain. The arterial blood gas values were: CO2 partial pressure 24 mmHg, O2 partial pressure 102 mmHg, pHa 7.36, and Base Excess - 8 mM. The nurse had been starving for 24 hours.

1. What was the explanation of her acid-base disturbance?

2. What was the rational treatment?

Case History E

A young female (body weight 56 kg) with an inulin clearance of 125 ml of plasma per min is tested with para‑amino‑hippuric acid (PAH). The free fraction of PAH in the plasma is 0.80, and the rest binds to plasma proteins.

Her urine is collected in a period and the excretion flux of PAH is measured to 100 mg each min. The average concentration of PAH in plasma from the renal arterial and venous blood is 0.2 and 0.02 g per l, respectively. The haematocrit is 43%.

1. Calculate the clearance for PAH.

2. Calculate the tubular secretion flux for PAH at the blood plasma concentration concerned.

3. Calculate the renal blood flow (RBF).

The patient collects the urine in a second period, where the average concentration of PAH in plasma from the arterial blood is 1 g per l. The maximal tubular secretion rate for PAH is defined as Tmax for PAH and is 80 mg per min.

4. Calculate the excretion flux for PAH in the urine.

5. Calculate the new clearance for PAH.

Try to solve the problems before looking up the answers

Highlights

· Creatinine clearance provides a fair clinical estimate of the renal filtration capacity.

· The renal control of body fluid osmolality maintains the normal cell volume (ICV) by changes of renal water excretion.

· Normally, we excrete 1500 (range: 1200-1800) ml of water and 2-5 g of Na+ (= 5-12 g NaCl) daily.

· Renal excretion of waste products. Urea from amino acids is excreted with about 30 g or half a mol of urea per day. The daily renal excretion of uric acid, creatinine, hormone metabolites and haemoglobin derivatives matches their daily production.

· The daily renal excretion of metabolic intermediates and foreign molecules (drugs, toxins, chemicals, and pesticides) is carefully matched to the intake or production.

· Secretion of hormones: The kidney secretes erythropoietin, renin, kinins, prostaglandins and 1,25-dihydroxy-cholecalciferol.

· Acute Tubular Necrosis has haemodynamic or toxic causes. Cardiogenic and hypovolaemic shock cause acute renal failures just as renal vasoconstriction. Renal ischaemia leads to hypoxic damage, in particular damage of the renal medulla. Ischaemic tubular damage also reduces the GFR further, because of reflex spasms of the afferent arterioles, and due to tubular blockage with accumulation of filtrate in the early part of the proximal tubules.

· Bacterial pyelonephritis typically causes interstitial inflammation of the kidneys, but the interstitial inflammation is more often caused by a hypersensitivity reaction to drugs (antibiotics, phenacetin and non-steroid anti-inflammatory drugs, NSAIDs).

· Diabetic nephropathy includes hypertension, albuminuria and low GFR with glomerulosclerosis (thickening of the basement membrane and damage of the glomerular filter by disruption of the protein cross-linkages). The earliest evidence may be microalbuminuria. The patient later develops intermittent albuminuria followed by persistent albuminuria.

· Nephroblastoma (Wilms´ tumour) is the most frequent intraabdominal tumour in both girls and boys. A large abdominal mass is found sometimes with signs of intestinal obstruction. The tumour grows rapidly and spread to the lungs. The diagnosis is confirmed with excretion urography and arteriography.

· Renal cell carcinoma (hypernephroma) accounts for more than 90% of all the malignant renal tumours in adults (smokers). There is a strong association with a rare autosomal dominant inherited disease called Von Hippel-Lindau syndrome (haemangioblastomas in the cerebellum and the retina). The genetic locus is on chromosome 3p.

Further Reading

Nephron. Monthly journal published by the International Society of Neprology. S Karger AG, Allschwilerstrasse 10, PO Box CH-4009 Basel, Switzerland.

Rehberg, P. Brandt. "Studies on kidney function: I. The rate of filtration and reabsorption in the human kidney." Biochem. J. 20: 447, 1926.

Schafer, JA. Renal water and ion transport systems. Am. J. Physiol. 275 (Adv. Physiol. Educ. 20): S119-S131, 1998.