Chronic Kidney Disease Flashcards
What is chronic kidney injury
The term ‘CKD’ has replaced terms such as chronic renal failure or insufficiency. CKD implies longstanding (more than 3 months), and usually progressive, impairment in renal func-tion. In many instances, no effective means are available to reverse the primary disease process. Exceptions include correction of urinary tract obstruction, immunosuppressive therapy for systemic vasculitis and Goodpasture’s syndrome, treatment of accelerated hypertension, and correction of critical narrowing of renal arteries causing CKD.
What is the clinical approach to the patient with chronic kidney disease or any other form of renal disease
History
Particular attention should be paid to:
• Duration of symptoms
• Drug ingestion, including non-steroidal anti-inflammatory agents, analgesic and other medications, and unorthodox treatments such as herbal remedies
• Previous medical and surgical history, e.g. previous chemotherapy, multisystem diseases such as SLE, malaria
• Previous occasions on which urinalysis or measurement of urea and creatinine might have been performed, e.g. pre-employment or insurance medical examinations, new patient checks
Family history of renal disease.
What are some symptoms of chronic kidney disease
The early stages of CKD are often completely asymptomatic, despite the accumulation of numerous metabolites. Serum urea and creatinine concentrations are measured in CKD, since methods for their determination are available and a rough correlation exists between urea and creatinine concentrations and symptoms. These substances are, however, in themselves not particularly toxic. The nature of the metabolites that are involved in the genesis of symptoms is unclear. Such metabolites must be products of protein catabolism (since dietary protein restriction may reverse symptoms associated with CD) and many of them must be of relatively small molecular size (since haemodialy-sis employing membranes which allow through only relatively small molecules improves symptoms). Little else is known with certainty.
Symptoms are common when the serum urea concentration exceeds 40 mmol/L, but many patients develop uraemic symptoms at lower levels of serum urea. Symptoms include:
• Malaise, loss of energy
• Loss of appetite
• Insomnia
• Nocturia and polyuria due to impaired concentrating ability
• Itching
• Nausea, vomiting and diarrhea
• Paraesthesiae due to polyneuropathy
“ ‘Restless legs’ syndrome (overwhelming need to frequently alter position of lower limbs)
• Bone pain due to metabolic bone disease
• Paraesthesiae and tetany due to hypocalcaemia
• Symptoms due to salt and water retention - peripheral or pulmonary oedema
• Symptoms due to anaemia
• Amenorrhoea in women; erectile dysfunction in men.
In more advanced uraemia CKD stage 5, these symptoms become more severe and CNS symptoms are common:
Mental slowing, clouding of consciousness and
seizures
• Myocionic twitching.
Severe depression of glomerular filtration can result in oliguria. This can occur with either acute kidney injury or in the terminal stages of CKD. However, even if the GFR is profoundly depressed, failure of tubular reabsorption may lead to very high urine volumes; the urine output is therefore not a useful guide to renal function.
How do you examine for a patient with chronic kidney disease
There are few physical signs of uraemia per se. Findings include: short stature (in patients who have had CKD in child-hood); pallor (due to anaemia); increased photosensitive pigmentation (which may make the patient look misleadingly healthy); brown discoloration of the nails; scratch marks due to uraemic pruritus; signs of fluid overload (p. 642); pericardial friction rub; flow murmurs (mitral regurgitation due to mitral annular calcification; aortic and pulmonary regur-gitant murmurs due to volume overload); and glove and stocking peripheral sensory loss (rare).
The kidneys themselves are usually impalpable unless grossly enlarged as a result of polycystic disease, obstruction or tumour. Rectal and vaginal examination may disclose evidence of an underlying cause of CKD, particularly urinary obstruction, and should always be performed.
In addition to these findings, there may be physical signs of any underlying disease which may have caused the CKD, for instance:
• Cutaneous vasculitic lesions in systemic vasculitides
• Retinopathy in diabetes and hypertensive retinopathy in hypertension
•Evidence of peripheral vascular disease and associated renal artery stenosis
• Evidence of spina bifida or other causes of neurogenic bladder.
An assessment of the central venous pressure, skin turgor, blood pressure both lying and standing and peripheral circulation should also be made. The major symptoms and signs of CKD
What are some investigations done in chronic kidney disease
The following investigations are common for all renal patients.
This includes patients with glomerular or non-glomerular disease, renal involvement in systemic diseases, AKI and CKD, as renal symptoms and signs are nonspecific.
Urinalysis
• Haematuria may indicate glomerulonephritis, but other sources must be excluded. Haematuria should not be assumed to be due to the presence of an indwelling catheter.
• Proteinuria, if heavy, is strongly suggestive of glomerular disease. Urinary infection may also cause proteinuria.
Glycosuria with normal blood glucose is common in CKD.
• Urine culture, including early-morning urine samples for TB.
Urine microscopy (see p. 569)
• White cells in the urine usually indicate active bacterial urinary infection, but this is an uncommon cause of CKD; sterile pyuria suggests papillary necrosis or renal tuberculosis.
• Eosinophiluria is strongly suggestive of allergic tubulointerstitial nephritis or cholesterol embolization.
• Casts. Granular casts are formed from abnormal cells within the tubular lumen, and indicate active renal disease. Red-cell casts are highly suggestive of glomerulonephritis.
• Red cells in the urine may be from anywhere between the glomerulus and the urethral meatus (Fig. 12.6).
Urine biochemistry
• Measurements of urinary electrolytes are unhelpful in
CKD. The use of urinary sodium concentration in the distinction between pre-renal and intrinsic renal disease is discussed on page 576.
• Urine osmolality is a measure of concentrating ability.
A low urine osmolality is normal in the presence of a high fluid intake but indicates renal disease when the kidney should be concentrating urine, such as in hypovolaemia or hypotension.
• Urine electrophoresis and immunofixation is necessary for the detection of light chains, which can be present without a detectable serum paraprotein.
Serum biochemistry
• Urea and creatinine.
• Calculation of eGFR.
• Electrophoresis and immunofixation for myeloma.
• Elevations of creatine kinase and a disproportionate elevation in serum creatinine and potassium compared with urea suggest rhabdomyolysis.
Haematology
• Eosinophilia suggests vasculitis, allergic tubulointerstitial nephritis, or cholesterol embolism.
• Markedly raised viscosity or ESR suggests myeloma or vasculitis.
• Fragmented red cells and or thrombocytopenia suggest intravascular haemolysis due to accelerated hypertension, haemolytic uraemic syndrome or thrombotic thrombocytopenic purpura.
• Tests for sickle cell disease should be performed when relevant.
Immunology
• Complement components may be low in active renal disease due to SLE, mesangiocapillary glomerulonephritis, post-streptococcal glomerulonephritis, and cryoglobulinaemia.
• Autoantibody screening is useful in detection of SLE
(p. 537); scleroderma (p. 539); Wegener’s granulomatosis and microscopic polyangitis (p. 854); and Goodpasture’s syndrome (p. 812).
• Cryoglobulins in unexplained glomerular disease, particularly mesangiocapillary glomerulonephritis.
• Antibodies to streptococcal antigens (antistreptolysin
O titre (ASOT), anti-DNAse B) if post-streptococcal glomerulonephritis is possible.
• Antibodies to hepatitis B and C may point to polyarteritis or membranous nephropathy (hepatitis B) or to cryoglobulinaemic renal disease (hepatitis C).
• Antibodies to HIV raise the possibility of HIV -associated renal disease.
Radiological investigation
• Ultrasound. Every patient should undergo ultrasonography (for renal size and to exclude hydronephrosis), and plain abdominal radiography and CT (without contrast) to exclude low-density renal stones or nephrocalcinosis, which may be missed on ultrasound.
• CT is also useful for the diagnosis of retroperitoneal fibrosis and some other causes of urinary obstruction, and may also demonstrate cortical scarring.
• MRI. Magnetic resonance angiography in renovascular disease. For gadolinium used as contrast in CKD, see this chapter.
Renal biopsy (see p. 572)
This should be performed in every person with unexplained
CKD and normal-sized kidneys, unless there are strong con-traindications. If rapidly progressive glomerulonephritis is possible, this investigation must be performed within 24 h of presentation if at all possible.
What are some complications of chronic kidney disease
Anaemia
Several factors have been implicated:
• Erythropoietin deficiency (the most significant)
• Bone marrow toxins retained in CKD
• Bone marrow fibrosis secondary to hyperparathyroidism
• Haematinic deficiency - iron, vitamin B12, folate
• Increased red-cell destruction
• Abnormal red-cell membranes causing increased osmotic fragility
• Increased blood loss - occult gastrointestinal bleeding, blood sampling, blood loss during haemodialysis or because of platelet dysfunction
• ACE inhibitors (may cause anaemia in CKD, probably by interfering with the control of endogenous erythropoietin release).
Red-cell survival is reduced in CKD. Increased red-cell destruction may occur during haemodialysis owing to mechanical, oxidant and thermal damage. Bone disease: renal osteodystrophy
The term ‘renal osteodystrophy’, more appropriately described as bone mineral disorder, embraces the various forms of bone disease that mav develop alone or in combination in CKD - hyperparathyroid bone disease, osteomalacia, osteoporosis, osteosclerosis and dynamic bone disease (Fig. 12.46). Most patients with CKD are found, histologically, to have mixed bone disease. Covert renal osteodystrophy is present in many patients with moderate CKD and in almost all of those with ESKD.
Skin disease
Pruritus (itching) is common in severe CKD and is mainly due to retention of nitrogenous waste products of protein catabolism as it improves following dialysis. Other causes of pruritus include hypercalcaemia, hyperphosphataemia, elevated calcium×phosphate product, hyperparathyroidism (even if calcium and phosphate levels are normal) and iron deficiency.
In dialysis patients, inadequate dialysis is usually the cause of pruritus. Nevertheless, a significant number of dialysis patients who are well dialysed and in whom other causes of pruritus can be excluded suffer persistent itching. The cause is unknown and no effective treatment exists.
Many patients with CKD suffer from dry skin for which simple aqueous creams are helpful. Eczematous lesions, particularly in relation to the region of an arteriovenous fistula, are relatively common. CKD may also cause porphyria cutanea tarda (PCT), a blistering photosensitive skin rash.
This results from a decrease in hepatic uroporphyrinogen decarboxylase combined with a decreased clearance of por-phyrins in the urine or by dialysis. Pseudoporphyria, a condition similar to PCT but without enzyme deficiency, is also seen in CKD with increased frequency.
Nephrogenic systemic fibrosis (NSF)
NSF is a systemic fibrosing disorder with predominant skin involvement. It is seen only in patients with moderate to severe CKD (eGFR <30 mL/min), particularly patients on dialysis. Gadolinium-containing contrast agents, which are excreted exclusively by the kidney, have been implicated in the causation of over 95% cases of NSF (see p. 1220).
The diagnosis is based upon a biopsy of an involved site, showing proliferation of dermal fibrocytes with excessive collagen deposition. Special testing may show gadolinium.
NSF usually follows a chronic and unremitting course, with 30% having no improvement, 20% having modest improvement and 30% dying. No single therapy or combination of therapies has shown consistent benefit in NSF with exception of improvement in renal function. Improvement in the NSF may follow renal transplantation. Prevention is by avoiding the use of gadolinium-based contrast agents in patents with severe CKD (eGFR <30 mL/min) or those on dialysis therapy.
Gastrointestinal complications
These include decreased gastric emptying and increased risk of reflux esophagitis, peptic ulceration, acute pancreatitis and constipation, particularly in patients on continuous ambulatory peritoneal dialysis (CAPD).
Elevations of serum amylase of up to three times normal may be found in CKD without any evidence of pancreatic disease, owing to retention of high-molecular-weight forms of amylase normally excreted in the urine.
Metabolic abnormalities
Gout. Urate retention is a common feature of CKD. Treatment of clinical gout is complicated by the nephrotoxic potential of NSAIDs. Colchicine is useful for the acute attack, and allopurinol should be introduced under colchicine cover to prevent further attacks. The dose of allopurinol should be reduced in CKD, e.g. 100 mg on alternate days.
Insulin. Insulin is catabolized by and to some extent excreted via the kidneys. For this reason, insulin requirements in diabetic patients decrease as CKD progresses. By contrast, end-organ resistance to insulin is a feature of advanced CKD resulting in modestly impaired glucose toler-ance. Insulin resistance may contribute to hypertension and lipid abnormalities.
Lipid metabolism abnormalities. These are common in CKD, and include:
• Impaired clearance of triglyceride-rich particles
• Hypercholesterolaemia (particularly in advanced CKD).
The situation is further complicated in ESKD, when regular heparinization (in haemodialysis), excessive glucose absorption (in CAPD) and immunosuppressive drugs (in transplan-tation) may all contribute to lipid abnormalities. Correction of lipid abnormalities by, e.g. HMG-CoA reductase inhibitor therapy (statins), is used in patients with CKD, although without formal proof of survival benefit.
Endocrine abnormalities
These include:
• Hyperprolactinaemia, which may present with galactorrhoea in men as well as women
• Increased luteinizing hormone (LH) levels in both sexes, and abnormal pulsatility of LH release
• Decreased serum testosterone levels (only seldom below the normal level). Erectile dysfunction and decreased spermatogenesis are common
• Absence of normal cyclical changes in female sex hormones, resulting in oligomenorrhoea or amenorrhoea
• Complex abnormalities of growth hormone secretion and action, resulting in impaired growth in uraemic children (pharmacological treatment with recombinant growth hormone and insulin-like growth factor is used)
• Abnormal thyroid hormone levels, partly because of altered protein binding. Measurement of thyroid-stimulating hormone (TSH) is the best way to assess thyroid function. True hypothyroidism occurs with increased frequency in CKD.
Posterior pituitary gland function is normal in CKD.
Muscle dysfunction
Uraemia appears to interfere with muscle energy metabo-lism, but the mechanism is uncertain. Decreased physical fitness (cardiovascular deconditioning) also contributes.
Nervous system
Central nervous system
Severe uraemia causes an unusual combination of depressed cerebral function and decreased seizure thresh-old. However, convulsions in a uraemic patient are much more commonly due to other causes such as accelerated hypertension, thrombotic thrombocytopenic purpura or drug accumulation. Asterixis, tremor and myoclonus are also features of severe uraemia.
Rapid correction of severe uraemia by haemodialysis leads to dialysis disequilibrium owing to osmotic cerebral swelling.
This can be avoided by correcting uraemia gradually by short, repeated haemodialysis treatments or by the use of peritoneal dialysis.
‘Dialysis dementia’ is a syndrome of progressive intellectual deterioration, speech disturbance, myoclonus and fits, which is due to aluminium intoxication; it may be accompanied by aluminium bone disease and by microcvtic anaemia. Low-grade aluminium exposure may also cause more subtle, subclinical deterioration in intellectual function.
Prevention involves removal of aluminium from source water used to manufacture dialysis fluid, and restriction or avoidance of aluminium-containing gut phosphorus binders.
Treatment is with the chelating agent desferrioxamine.
Psychiatric problems are common. Patients can have anxiety, depression, phobias and psychoses.
Autonomic nervous system
Increased circulating catecholamine levels associated with downregulation of -receptors, impaired baroreceptor sensitivity and impaired efferent vagal function are common in CKD.
Overactivity of the sympathetic nervous system in CKD is believed to play a part in the genesis of hypertension in this condition. All of these abnormalities improve to some extent after institution of regular dialysis and resolve after successful renal transplantation.
Peripheral nervous system
• Median nerve compression in the carpal tunnel is common, usually due to B2-microglobulin-related amyloidosis. This can be avoided by haemofiltration and haemodiafiltration.
• ‘Restless legs’ syndrome (p. 620) is common in uraemia. The syndrome is difficult to treat. Iron deficiency should be treated if present. Attention should be paid to adequacy of dialysis. Symptoms may improve with the correction of anaemia by erythropoietin. Clonazepam is sometimes useful. Renal transplantation cures the problem.
• A polyneuropathy occurs in patients who are inadequately dialysed.
Calciphylaxis
Also known as calcific uraemic arteriolopathy, this is a rare but serious life-threatening complication in CKD patients. It is increasingly recognized as a contributing factor to death in dialysis patients. Aetiological factors include reduced serum levels of a calcification inhibitory protein (fetuin-A) and abnormalities in smooth muscle cell biology in uraemia. It presents as painful non-healing eschars with panniculitis and dermal necrosis. The characteristic feature on histology is vascular calcification and superimposed small vessel thrombosis (Fig. 12.47).
Hyperparathyroidism and elevated concentrations of serum phosphate, morbid obesity and warfarin use remain consistent clinical features of most cases reported. Control of hyperparathyroidism is with either surgical intervention or with a calcimimetic agent.
Promising treatment options include hyperbaric oxygen therapy and sodium thiosulfate infusion. Benefits from bispho-sphonates and tissue plasminogen activator have also been reported.
Cardiovascular disease
Life expectancy remains severely reduced compared with the normal population owing to a greatly increased (16-fold) incidence of cardiovascular disease, particularly myocardial inf-arction, cardiac failure, sudden cardiac death and stroke.
Risk factors
Hypertension is a frequent complication of CKD. Diabetes mellitus is the commonest cause of CKD. Dyslipidaemia is universal in uraemic patients. Furthermore, smoking is as common as in the general population and male gender is over-represented in patients with CKD. Ventricular hypertrophy is common, as is systolic and diastolic dysfunction. Diastolic dysfunction is largely attributable to left ventricular hypertro-phy and contributes to hypotension during fluid removal on haemodialysis. Systolic dysfunction may be due to:
• Myocardial fibrosis
• Abnormal myocyte function owing to uraemia
• Calcium overload and hyperparathyroidism
• Carnitine and selenium deficiency.
Left ventricular hypertrophy is a risk factor for early death in CKD, as in the general population. Systolic dysfunction is also a marker for early death.
Coronary artery calcification. Traditional risk factors (e.g. smoking, diabetes) can only partly explain the risk in patients with chronic nephropathies.
Coronary artery calcification is more common in patients with ESKD than in normal individuals and it is highly likely that this contributes significantly to cardiovascular mortality.
Vascular calcification is frequent in all sizes of vessel in CKD.
In addition to the classical risk factors for atherosclerosis:
• A raised (calciumphosphate) product causes medial calcification.
Hyperparathyroidism may also contribute independently to the pathogenesis by increasing intracellular calcium.
• Vascular calcification in uraemia is now thought to be an active process whereby vascular smooth muscle cells acquire osteoblast-like characteristics, possibly in response to elevated phosphate or (calcium×phosphate) product.
• Inflammation is a potent mediator of vascular calcification by inhibition of fetuin (a glycoprotein synthesized by liver, which is a potent inhibitor of vascular calcification).
The impact of vascular calcification is the reduction of vascular compliance, which manifests by increased pulse pressure and pulse wave velocity, and increased afterload contributes further to left ventricular hypertrophy. In addition to myocardial abnormalities, vascular calcification with its associated biomechanical vessel wall alterations is a strong predictor of all-cause and cardiovascular morbidity and mortality in patients with CKD. Diffuse calcification of the myocardium is also common; the causes are similar.
Other cardiovascular risk factors. These include hyper-homocysteinaemia, Chlamydia pneumonia infection, oxidative stress and elevated endogenous inhibitor of nitric oxide synthase and asymmetric dimethyl arginine (ADMA) levels.
High ADMA levels in uraemia are in part caused by oxidative stress and can possibly explain the 52% increase in the risk of death and 34% increase in the risk of cardiovascular events in uraemic patients. The use of antioxidants, vitamin E or acetylcysteine has been associated with a significant reduction in all-cause and cardiovascular mortality. However, recent trials to reduce levels of homocysteine with folic acid, B6 and B12 supplementation have been unsuccessful.
The conclusion from a recent study of heart and renal protection (SHARP) in over 9500 CKD patients was that around one-quarter of all heart attacks, strokes, and revas-cularizations could be avoided in CKD by using a combination of ezetimibe and simvastatin to lower blood cholesterol.
This combination however did not confer any survival advantage or prevent the development of ESKD.
Pericarditis
This is common and occurs in two clinical settings:
• Uraemic pericarditis is a feature of severe, pre-terminal uraemia or of underdialysis.
Haemorrhagic pericardial effusion and atrial arrhythmias are often associated. There is a danger of pericardial tamponade, and anticoagulants should be used with caution. Pericarditis usually resolves with intensive dialysis.
• Dialysis pericarditis occurs as a result of an intercurrent illness or surgery in a patient receiving apparently adequate dialysis.
Malignancy
The incidence of malignancy is raised in patients with CKD and with dialysis. Malignant change can occur in multicystic kidney disease. Lymphomas, primary liver cancer and thyroid cancers also occur.
How is chronic kidney disease managed
Successful renal transplantation improves some, but not all, of the complications of CD, therefore attempts should be made to prevent these complications by careful monitoring with ECG, echocardiography, angiography (if necessary) and nuclear imaging. CT (spiral CT) and/or MRI are useful in the assessment of arterial calcification. Treatment is with the control of risk factors (p. 608) as well as the treatment of hypercalcaemia and hyperparathyroidism
How does chronic kidney disease progress
CKD tends to progress inexorably to ESKD, although the rate of progression may depend upon the underlying nephropa-thy. Patients with chronic glomerular diseases tend to deteriorate more quickly than those with chronic tubulointerstitial nephropathies. Hypertension and heavy proteinuria are bad prognostic indicators. A nonspecific renal scarring process common to renal disorders of different aetiologies may be responsible for progression.
Possible causes of glomerular scarring and proteinuria include:
• A rise in intraglomerular capillary pressure
• Adaptive glomerular hypertrophy due to reduced arteriolar resistance and increased glomerular blood flow when there is reduced nephron mass.
This glomerular hyperfiltration, in response to nephron loss, was postulated as a common pathway for the progression of CKD.
Since the afferent arteriolar tone decreases more than efferent arteriolar tone, intraglomerular pressure and the amount of filtrate formed by a single nephron rises. Angiotensin II produced locally modulates intraglomerular capillary pressure and GFR, predominantly causing vasoconstriction of postglomerular arterioles, thereby increasing the glomerular hydraulic pressure and filtration fraction. In addition, by its effect on mesangial cells and podocytes, it increases the pore sizes and impairs the size-selective function of basement membrane for macromolecules.
Angiotensin II also modulates cell growth directly and indirectly by upregulating TGF-B, a potent fibrogenic cytokine, increases collagen synthesis and also causes epithelial cell transdifferentiation to myofibroblasts which contribute to excessive matrix formation. Furthermore, angiotensin II by upregulating plasminogen activator inhibitor-1 (PAl-1) inhibits matrix proteolysis by plasmin, resulting in accumulation of excessive matrix and scarring both in the glomeruli and interstitium.
Renal interstitial scarring is also a factor. The cause of this progressive interstitial damage and fibrosis is multifactorial.
In addition to non-haemodynamic effects of angiotensin lI, proteinuria per se (by exposing tubular cells to albumin and its bound fatty acids and cvtokines) promotes secretion of pro-inflammatory mediators, which promote interstitial inflammatory cell infiltrate and further augment fibrosis and progression of CKD. The prognosis for renal function in chronic glomerular disorders is judged more accurately by interstitial histological appearances than by glomerular morphology.
Therapeutic manoeuvres (Box 12.6) aimed at inhibiting angiotensin II and reducing proteinuria mainly by ACEl and angiotensin-receptor antagonists have beneficial effects in slowing the rate of progression of CKD in both diabetic and non-diabetic renal diseases in humans.
How are the complications of chronic kidney disease corrected (hyperkalemia, acidosis, calcium and phosphate control and suppression of PTH)
Hyperkalaemia
Hyperkalaemia often responds to dietary restriction of potassium intake. Drugs which cause potassium retention should be stopped. Occasionally, it may be necessary to prescribe ion-exchange resins to remove potassium in the gastrointestinal tract. Emergency treatment of severe hyper-kalaemia is described on page 655.
Acidosis
Correction of acidosis helps to correct hyperkalaemia in
CKD, and may also decrease muscle catabolism. Sodium bicarbonate supplements are often effective (4.8 g (57 mmol) of Na* and HCO¿ daily), and the possibility of edema and hypertension owing to the so-called ‘extracellular fluid expansion’ was not borne out by a trial. Interestingly, correction of metabolic acidosis by sodium bicarbonate at a mean dose of 1.8 g/day was also associated with marked reduction in the rate of progression of CKD and development of ESKD in patients with stage 4 and 5 CKD. Calcium carbonate, also used as a calcium supplement and phosphate binder, has a beneficial effect on acidosis.
Calcium and phosphate control and suppression of PTH
Hypocalcaemia and hyperphosphataemia should be treated aggressively, preferably with regular (e.g. 3-monthly) measurements of serum PTH to assess how effectively hyperoar-athyroidism is being suppressed. Suppression of PTH levels to below two or three times the upper limit of ‘normal’ carries a high risk of development of a dynamic bone disease.
Dietary restriction of phosphate is seldom effective alone, because so many foods contain it. Oral calcium carbonate or acetate reduces absorption of dietar phosphate but is contraindicated where there is hypercalcaemia or hypercal-ciuria. Aluminium-containing gut phosphate binders are very effective but absorption of aluminium poses the risk of alu-minium bone disease and development of cognitive impair-ment. They are now rarely used in the developed countries but are still used in the developing countries because they are extremely cheap.
Anaemia
The anaemia of erythropoietin (EPO) deficiency can be treated with synthetic (recombinant) human EPO (epoetin-o or -B, or the longer-acting darbepoetin-a or polyethylene glycol-bound epoetin-B). The intravenous route is used, initially with 50 U/kg of epoetin-o over 1-5 min, three times weekly. Subcutaneous administration of epoetin-a can also be used (see below). Blood pressure, haemoglobin concentration and reticulocyte count are measured every 2 weeks and the dose adjusted to maintain a target haemoglobin of 110-120 g/L. Darbepoetin-a can be used once a week.
Continuous erythropoiesis receptor activator (CERA), a recently licensed epoetin in Europe, is a pegylated epoetin-B and can be given once a month. In trials, CERA has a similar activity to other types of epoetin. However, CERA use is extremely limited and data about loss of flexibility of dosing, overshooting the target haemoglobin and its efficacy in combination with short-acting epoetin are required before its widespread use.
The target haemoglobin to be achieved during the treatment of anaemia is being revised to between 110 and 120 g/L as studies in pre-dialysis CKD patients have not revealed any outcome benefits in patients who were treated to achieve higher haemoglobin targets (>120 g/L).
Failure to respond to 300 U/kg weekly, or a fall in haemo-globin after a satisfactory response, may be due to iron deficiency, bleeding, malignancy, infection, inflammation or formation of anti-EPO neutralizing antibodies. The demand for iron by the bone marrow is enormous when erythropoietin is commenced. Patients on EPO therapy are regularly monitored for iron status and considered iron deficient if plasma ferritin is <100 Mg/L, hypochromic RBCs >10%, transferrin saturation <20%. Functional iron deficiency due to poor mobilization of iron, despite adequate iron stores (ferritin
>500 Mg/L) and a transferrin saturation of >20%, is a common finding in patients with chronic inflammation. It is caused by hepcidin (see p. 377), an acute phase reactant produced by the liver in response to cytokines, particularly IL-6. Intravenous (rather than oral) iron supplements optimize response to EPO treatment by repletion of iron stores. A recent randomized trial has demonstrated a beneficial effect of i.v. iron even in patients with ferritin >800 ug/L and transferrin saturation of 20%.
Correction of anemia with EPO improves quality of life, exercise tolerance and sexual and cognitive function in dialysis patients, and leads to regression of left ventricular hyper-trophy. Avoidance of blood transfusion also reduces the chance of sensitization to HLA antigens, which may otherwise be a barrier to successful renal transplantation.
The disadvantages of erythropoietin therapy are that it is expensive and causes a rise in blood pressure in up to 30% of patients, particularly in the first 6 months. Peripheral resistance rises in all patients, owing to loss of hypoxic vasodilatation and to increased blood viscosity. A rare complication is encephalopathy with fits, transient cortical blindness and hypertension. Several reports of anti-EPO antibody-mediated pure red-cell aplasia in patients receiving subcutaneous EPO therapy (particularly EPO-0) have been described. The exact cause is unknown but interventions such as using the intravenous route and changes in manufacture of prefilled syringes have reduced the number of cases by 80%. Other causes of anaemia should be looked for and treated appropriately (see p. 375).
Several erythropoiesis-stimulating agents are in clinical trials. An EPO mimetic is an engineered peptide which stimulates EPO receptor but still has to be given by injection. Oral agents which inhibit prolyl hydroxylase and prolong the life of HIF (hypoxia inducible factors) 1o, a transcription factor for endogenous production of EPO, have shown promise in phase 2 trials.
Male erectile dysfunction
Testosterone deficiency should be corrected. The oral phos-phodiesterase inhibitors, e.g. sildenafil, tadalafil and varde-nafil, are effective in ESKD and are the first-line therapy. The use of nitrates is a contraindication to this treatment.
What is hemofiltration
This involves removal of plasma water and its dissolved constituents (e.g. K, Na, urea, phosphate) by convective flow across a high-flux semipermeable membrane, and replacing it with a solution of the desired biochemical composition (Fig.
12.52). Lactate is used as buffer in the replacement solution because rapid infusion of acetate causes vasodilatation, and bicarbonate may cause precipitation of calcium carbonate.
Haemofiltration can be used for both acute and CKD and is used in mainland Europe for CKD patients with haemo-dynamic instability. High volumes need to be exchanged in order to achieve adequate small molecule removal, typically a 22 L exchange three times a week for maintenance treatment and 1 L per hour in acute kidney injury. Financial costs of disposable items (such as filters and replacement fluid are high and only a selected group of patients with ESKD are managed in this way. Modern dialysis machines have built-in facilities to generate online ultrapure water, which has minimized the cost of the procedure and given an option to the clinician to use this technique either as haemofiltration or in combination with dialysis as haemodiafiltration to increase middle molecule clearance (e.g. B2-microglobulin) and prevent long-term dialysis complications such as dialysis-related amyloidosis, particularly in young, highly sen-sitized, non-transplantable patients.
What is hemodialysis
In haemodialysis, blood from the patient is pumped through an array of semipermeable membranes (the dialyser, often called an ‘artificial kidney’), which bring the blood into close contact with dialysate, flowing countercurrent to the blood.
The plasma biochemistry changes towards that of the dia-lysate owing to diffusion of molecules down their concentration gradients (Fig. 12.50).
The dialysis machine comprises a series of blood pumps, with pressure monitors and bubble detectors and a propor-tionating unit, also with pressure monitors and blood leak detectors. Blood flow during dialysis is usually 200-300 mL/ min and the dialysate flow usually 500 mL/min. The efficiency of dialysis in achieving biochemical change depends on blood and dialysate flow and the surface area of the dialysis membrane.
Dialysate is prepared by a proportionating unit, which mixes specially purified water with concentrate, resulting in fluid with the composition
What is the pathogenesis of renal osteodystrophy
Phosphate retention owing to reduced excretion by the kidneys occurs in the very early stages of CKD. This results in the release of fibroblast growth factor 23 (FF 23) and other phosphaturic agents by osteoblasts as a compensatory mechanism. FF 23 causes phosphaturia to bring the plasma phosphate level to within the normal range. FF 23 also downregulates 1a-hydroxylase in an attempt to reduce intestinal absorption of phosphate. However, consistently elevated levels of FGF 23 after a while cannot control phosphate levels and its effects are overwhelmed by development of secondary hyperparathyroidism. Elevated FF 23 levels are the strongest independent predictor of mortality in patients with CKD. This underscores the necessity of controlling phosphate levels during very early stages of CKD.
• Decreased renal production of the 1a-hydroxylase enzyme results in reduced conversion of 25-(OH)2D3 to the more metabolically active 1,25-(OH)2D.
• Reduced activation of vitamin D receptors (VDR)
in the parathyroid glands leads to increased release of parathyroid hormone secondary hyperparathyroidism).
• The calcium sensing receptors (CaR), expressed in the parathyroid glands, react rapidly to acute changes in extracellular calcium concentrations and a low calcium also leads to increased release of PTH.
• 1,25-Dihydroxycholecalciferol deficiency also results in gut calcium malabsorption.
• Phosphate retention owing to reduced excretion by the kidneys, also indirectly by lowering ionized calcium (and probably directly via a putative but unrecognized phosphate receptor), results in an increase in PTH synthesis and release.
• PTH promotes reabsorption of calcium from bone and increased proximal renal tubular reabsorption of calcium, and this opposes the tendency to develop hypocalcaemia induced by 1,25-(OH)D deficiency and phosphate retention. This ‘secondary’ hyperparathyroidism leads to increased osteoclastic activity, cyst formation and bone marrow fibrosis (osteitis fibrosa cystica). Radiologically, digital subperiosteal erosions and ‘pepper-pot skull’ are seen. Longstanding secondary hyperpara-thyroidism ultimately leads to hyperplasia of the glands with autonomous or tertiary hyperparathyroidism in which hypercalcaemia is present. Serum alkaline phosphatase concentration is raised in both secondary and tertiary hyperpara-thyroidism. Longstanding parathyroid hormone excess is also thought to cause increased bone density (osteosclero-sis) seen particularly in the spine where alternating bands of sclerotic and porotic bone give rise to a characteristic ‘rugger jersey’ appearance on X-ray.
1,25-(OH)D deficiency and hypocalcaemia result in impaired mineralization of osteoid (osteomalacia). Such impaired mineralization also occurs when osteoblasts are inhibited by, e.g. aluminium given as gut phosphorus binders, or accumulated in bone as a result of exposure to aluminium in source water used to make up dialysate for haemodialysis.
In this situation, serum alkaline phosphatase concentration tends to be low or normal.
The condition of ‘adynamic bone disease’ in which both bone formation and resorption are depressed (in the absence of aluminium bone disease or overtreatment with vitamin D is also seen. The pathogenesis of this condition is unclear and it is not known whether it leads to an increased risk of fractures or other complications. There may be hypercalcae-mia; the serum alkaline phosphatase is normal, the PTH is low. X-rays and dual X-ray absorptiometry (DXA) scan show osteopenia. No treatment is of proven benefit.
Osteoporosis is commonly found in CKD, often after transplantation and the use of corticosteroids. Monitoring is with yearly DXA scan.
