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Important complications of chronic kidney disease.

Dyslipidaemia

Chronic kidney disease (CKD) is associated with alterations in lipoprotein structure and function, including:

* reduced high-density lipoprotein cholesterol * increased intermediate-density lipoprotein * increased proatherogenic lipid particles.

Significance of dyslipidaemia control

* Successful treatment of dyslipidaemia is known to lower cardiovascular disease (CVD) risk and should also retard the decline of kidney function.

* Since statins have been shown to decrease urinary protein or albumin excretion, they are recommended for CKD with proteinuria.

* Remarks on statin use in stages 3-5 CKD are given in Table 1.

* Concurrent use of statins and fibrates increases the risk of rhabdomyolysis.

Target for low-density lipoprotein cholesterol

* The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend the following for dyslipidaemia therapy in CKD: in cases of low-density lipoprotein cholesterol (LDL-C) <3.5 mmol/L, the first step is lifestyle modification; in cases of LDL-C >3.5 mmol/L, drug therapy should be contemplated in addition to lifestyle modification, including diet therapy, weight control and exercise.

* It is essential that LDL-C be lowered to [less than or equal to]1.8 mmol/L.

KDOQI guidelines for cholesterol lowering in CKD patients (2013):

* Patients >50 years of age should receive a statin.

* Patients 18-49 years of age should receive a statin if another comorbidity is present.

* Kidney transplant recipients should receive a statin.

Treatment of hyperkalaemia and metabolic acidosis

Hyperkalaemia

* As CKD progresses in stage, acidosis and hyperkalaemia are observed. Hyperkalaemia is defined as a serum potassium level [greater than or equal to]5.5 mmol/L. Hyperkalaemia >7 mmol/L may potentially cause cardiac arrest; such cases should be treated as emergencies.

* If severe hyperkalaemia is observed, despite the absence of reduced kidney function, pseudohyperkalaemia, an artefact due to haemolysis of the blood specimen, should be considered.

* Hyperkalaemia is a risk factor for arrhythmias. In cases of severe hyperkalaemia, emergency levels should be confirmed by ECG abnormalities such as tenting T-waves, prolongation of PQ-times, followed by disappearance of the P-wave and widening of the QRS complex. Patients with life-threatening ECG findings, bradycardia and hypotension should be treated promptly, followed by treatment in conjunction with a nephrologist.

* Drug-induced hyperkalaemia in CKD is mostly caused by reninangiotensin-aldosterone inhibitors such as ACE inhibitors, angiotensin II receptor blockers (ARBs) and spironolactone or excessive intake of potassium-containing foods. Other causes include the administration of [beta]-blockers, digoxin, non-steroidal anti-inflammatory drugs (NSAIDs), trimethoprim or pentamidine.

* CKD caused by diabetic nephropathy may be associated with hyporeninaemic hypoaldosteronism, which may cause hyperkalaemia despite relatively well-preserved kidney function. This is known as type IV renal tubular acidosis.

Emergency treatment

* The first step is to stabilise the myocardium. The intravenous administration of calcium gluconate does not change plasma potassium, but transiently improves the ECG. The administration of calcium gluconate 20 mL intravenously over 1 minute can be repeated if there is no improvement in the ECG within 3-5 minutes.

* The second step is to shift the potassium from the extracellular to the intracellular compartment to try to rapidly decrease the serum potassium level. This can be done in three different ways:

* Intravenous insulin combined with glucose. Administer 10 U short-acting insulin combined with 50 mL of 50% dextrose as a bolus, followed by an intravenous infusion of 5% dextrose to prevent hypoglycaemia.

* [[beta].sub.2]-agonist. Administer 20 mg salbutamol, a [[beta].sub.2]-agonist, by inhalation over 10 minutes, with onset of action approximately 30 minutes. (This is not usually required.)

* Sodium bicarbonate in CKD patients who are not yet on dialysis. Bicarbonate administration can lower serum potassium by enhancing renal potassium excretion. The effect is very slow and not of use in an acute situation unless the patient has severe metabolic acidosis that needs bicarbonate treatment.

* Once the previous temporary measures have been performed, further interventions are undertaken to remove potassium from the body.

* Loop diuretics are only successful in patients with adequate kidney function.

* The resin exchanger sodium polystyrene sulphonate (Kexelate) removes potassium from the blood into the gut in exchange for an equal amount of sodium. It is slow acting and the plasma potassium only starts decreasing within 1-2 hours. It can be given orally or as a retention enema. The amount given varies from 30 g to 60 g. This can be repeated, but tends to cause constipation.

* Haemodialysis is the treatment of choice for patients with advanced CKD and severe hyperkalaemia.

Prevention

* Dietary counselling on potassium restriction.

* Avoid medications that interfere with renal excretion of potassium, e.g. potassium-sparing diuretics, NSAIDs, ACE inhibitors, ARBs.

* Avoid drugs that interfere with potassium shifts from the intracellular to the extracellular compartments, e.g. non-selective [beta]-blockers.

* In selected patients with sufficient residual kidney function treatment with a loop diuretic may be used to stimulate urinary potassium excretion.

Metabolic acidosis

Metabolic acidosis is characterised by:

* low arterial blood pH (acidaemia) (<7.35) * reduced serum HC[O.sub.3]- concentration * decreased pC[O.sub.2] (from respiratory compensation).

Systemic effects

Metabolic acidosis may lead to a variety of changes in tissues and organs, e.g.:

* cardiovascular changes such as tachycardia, bradycardia, hypotension and cardiac failure

* life-threatening hyperkalaemia * nausea, vomiting and abdominal pain * confusion, with depression of the central nervous system.

The associated symptoms and signs will depend on the rate and magnitude of fall in the pH and of the underlying pathology.

Uraemic acidosis

Metabolic acidosis occurs in renal failure owing to a decreased ability to excrete [H.sup.+] or an inability to produce ammonia.

In the early stages of CKD (GFR <40 mL/min), metabolic acidosis with a normal anion gap (AG) may become evident. As CKD progresses (GFR <20 mL/min), a high AG metabolic acidosis may result.

In advanced CKD, an increased AG is typical owing to the presence of retained acids such as sulphates, phosphates, urate and hippurate.

Treatment principles

Patients with metabolic acidosis are often very ill and their condition tends to deteriorate rapidly.

The routine administration of sodium bicarbonate is controversial, although it needs to be done to correct severe acidosis.

The potential complications of sodium bicarbonate administration include volume overload, especially in patients with renal or cardiac function impairment, hypernatraemia, hypokalaemia, hypocalcaemia and alkalosis.

The amount of bicarbonate required (mmol) can be estimated as follows:

target plasma HC[O.sub.3]- (mmol/L)--current plasma HC[O.sub.3]- (mmol/L) x 40% body weight (kg).

Anaemia in CKD

Anaemia is the most common complication of CKD and is associated with greatly reduced quality of life. Successful treatment of anaemia in renal disease may reduce the decline of kidney function. The target haemoglobin levels are 10-12 g/dL when treating anaemia in CKD. The treatment is costly and therefore rational consideration is mandatory.

Renal anaemia

Renal anaemia is typically normochromic normocytic. It is caused mainly by the impaired production of erythropoietin by the kidney and partly by uraemic toxins. Other causes that may play a role in CKD, especially in dialysis patients, are:

* erythropoietin resistance (most significant) * bone marrow toxins (none has been isolated yet) * bone marrow fibrosis, secondary to hyperparathyroidism * ongoing inflammatory processes, e.g. untreated infections * haematinic deficiency (iron, folate and vitamin [B.sub.12]) * increased red cell destruction * abnormal red cell membranes, causing increased osmotic fragility

* increased blood loss from occult gastrointestinal bleeding and blood sampling and during haemodialysis

* ACE inhibition.

Erythropoietin is a glycoprotein hormone that stimulates red cell production by binding to erythropoietin receptors, located on early erythroid progenitor cells in the bone marrow.

The binding of erythropoietin to these progenitor cells saves them from apoptosis and therefore permits cell division and maturation into red cells. In CKD, the erythropoietin levels may be normal, but inadequate for the degree of anaemia. The mechanisms impairing erythropoietin production in diseased kidneys remain poorly understood. Inhibition of erythropoiesis by uraemic inhibitors is also possible and may contribute greatly to the anaemia of CKD; such factors have not been identified. Dialysis can improve renal anaemia and the efficacy of erythropoietin-stimulating agents. Patients with renal disease may develop chronic infections and other chronic diseases. Chronic disease contributes to anaemia in such cases. The anaemia of chronic disease is mediated by inflammatory cytokines through the inhibition of erythropoietin production and efficacy and reduced iron availability.

Hepcidin is the key mediator of iron metabolism. In inflammatory states hepcidin blocks iron absorption in the gut and promotes iron sequestration in macrophages.

Other causes

Anaemia associated with CKD is most likely renal anaemia; however, the differential for other diseases must be considered true for stages 1-3 CKD.

The evaluation of anaemia in CKD patients should include a complete blood count with red cell indices (mean corpuscular haemoglobin concentration, mean corpuscular volume). Renal anaemia is usually normochromic and normocytic. Vitamin [B.sub.12] and folate deficiency may lead to macrocytosis, while iron deficiency or inherited disorders of haemoglobin may produce microcytosis. Iron studies should be performed to assess the level of iron in tissue stores or the adequacy of iron supply for erythropoiesis.

Anaemia may signify the presence of malnutrition or systemic illness. It is an independent risk factor for hospitalisation, CVD and mortality. ACE inhibitors can exacerbate anaemia.

Treatment of anaemia protects the heart

Anaemia exacerbates heart failure. Treatment of anaemia is beneficial for life expectancy and can also improve the prognosis of CVD. The quality of life is improved for those with a haemoglobin level within the target range.

Target level of haemoglobin

The Kidney Disease Improving Global Outcome (KDIGO) guidelines state that the haemoglobin level should range from 10.0 g/dL to 12 g/dL in CKD patients on dialysis. Pre-dialysis levels should be at 10 g/dL.

Role-sharing between nephrologists and primary care physicians

Early referral to a nephrologist is advisable. Once the treatment strategy has been decided, nephrologists and primary care physicians continue management in partnership.

Evaluation of iron deficiency

Evaluation of the iron deficit and correct iron supply is important in the treatment of anaemia. Anaemia may improve with the administration of iron supplements, even when the patient is not apparently iron deficient, as the use of recombinant erythropoietin may cause relative iron deficiency.

The KDOQI guidelines for recombinant human erythropoietin in CKD are:

* serum ferritin >100 ng/mL before dialysis * serum ferritin >200 ng/mL in dialysis patients * transferrin saturation >20%.

Iron can be given either intravenously or orally. Intravenous iron is more efficacious, especially for dialysis patients and those on erythropoietin treatment.

Use of exogenous erythropoietins

There are currently a number of erythropoietin-stimulating agents available, including older, shorter-acting drugs and new, longer-acting ones. The appropriate agent and dose depend on a number of factors, including cost, efficacy and convenience. As these drugs are expensive and have side-effects, their management is best left to a nephrologist.

Bone and mineral disorders

Hyperphosphataemia is the key abnormality that sets off a cascade of metabolic events, resulting in bone mineral density of CKD.

Phosphate is retained as renal function deteriorates--much the same as creatinine is retained. This retention becomes obvious as stage 3b CKD is reached. It will progressively worsen as end-stage is approached and must be lowered to within normal limits.

A high phosphate diet stimulates osteocytes to produce fibroblast growth factor 23 which, in turn, inhibits the hydroxylation of vitamin D to active 1,25 vitamin [D.sub.3]. Without vitamin [D.sub.3], calcium absorption and bone remodelling are decreased. The resultant hypocalcaemia is a major stimulus for parathyroid hormone (PTH) release, with the consequent development of renal bone disease. Serum alkaline phosphatase is a marker of increased bone turnover. Therefore, high blood levels show PTH activity.

Of note, both hyperphosphataemia and vitamin [D.sub.3] deficiency result in increased PTH secretion.

Initially the stimulus for PTH secretion may be controlled by increasing the serum calcium, reducing the phosphate levels in the blood and prescribing vitamin [D.sub.3]. This is the secondary hyperparathyroidism stage (Table 2). However, with time and uncontrolled, prolonged stimulation of PTH secretion, the parathyroid hormones become autonomous and the stage of autonomous hyperparathyroidism is reached (Table 3). Parathyroidectomy may now be necessary or expensive calcimimetic drugs must be administered to try to restore the disordered metabolic environment.

There is uncertainty about the interpretation of vitamin [D.sub.3] level measurements. If they are to be measured, then 25-OH-vitamin [D.sub.3] levels are recommended for assessment.

Therapy

The steps for therapy are shown in Table 4. Non-calcium-containing phosphate binders are recommended when there is significant metastatic calcification and/or when hypercalcaemia is present.

Calcimimetics, which sensitise the parathyroid glands to serum calcium, are useful to prescribe in hyperparathyroidism when the serum PTH levels are high (2-9 times above the normal range--check with the laboratory for normal ranges). They have a role to play in diminishing PTH levels in any of the clinical situations that occur in CKD.

Follow-up blood measurements

These are given in Table 5.

These follow-up times are guidelines only and the tests should be performed more frequently if there are significant abnormalities.

Special points to note

* Involve a nephrologist early in the course of CKD.

* Avoid over-suppression of the parathyroid glands, as this will lead to dynamic bone disease.

* The exact PTH level at which secondary and autonomous hyperparathyroidism is diagnosed is uncertain, because of varying assays. The biochemistry, as outlined above (together with radiographs of bones), must then be used to assist in the diagnosis.

* Be aware of trends in serum alkaline phosphatase levels; the level may be in the normal range but may have doubled from the previous reading.

* Osteoporosis accompanies bone disease that occurs in CKD. Bisphosphonates must not be used in stages 3-5 CKD patients.

I van der Walt, (1) MB ChB, MMed (Int), Cert Nephrology (SA); C R Swanepoel, (2) MB ChB, MRCP (UK), FRCP (Edin); B Mahala, (3) MB ChB, FCP (SA), MMed, Cert Nephrology (SA); A M Meyers, (4) MB BCh, FCP (SA), Cert Nephrology (SA), FRCP (Lond)

(1) Netcare Jakaranda Hospital, Pretoria, South Africa

(2) Division of Nephrology and Hypertension, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa

(3) Netcare Waterfall City Private Hospital, Johannesburg, South Africa

(4) Donald Gordon Medical Centre, Klerksdorp Hospital, and National Kidney Foundation of South Africa, Johannesburg, South Africa

Corresponding author: A M Meyers (nkfsa@mweb.co.za)
Table 1. Drugs for dyslipidaemia available in South Africa and
cautionary remarks regarding their use in CKD

Class              Generic name       Characteristics

3-hydroxy-3-       Pravastatin        Inhibits cholesterol
methyl-glutaryl-   Simvastatin        production in the
CoA reductase                         liver
enzyme
inhibitors
(statins)

                   Fluvastatin        Very effective to
                   Atorvastatin       decrease TC, LDL-C

                   Rosuvastatin       Adverse reaction:
                                      liver damage,
                                      rhabdomyolysis

                                      Prolongs QT-
                                      interval on ECG

Anion              Cholestyramine     Inhibits bile acid
exchange           Colestimide        circulation
resins                                (intestine-liver)

                                      Lowers TC, LDL-C

Fibrates           Bezafibrate        Lowers TG (very
                                      effective)

                   Fenofibrate        Increases HDL-C

                                      Rhabdomyolysis

                                      Do not use with
                                      statins

Nicotinic                             Lowers TG
acids
                                      Lowers Lp (a)

                                      Rash on face

Others             Eicosapentaenoic   Lowers TG
                   acid
                   Ezetimibe          Antiplatelet
                                      function: anti-
                                      atherosclerosis

                                      Prevents
                                      absorption of
                                      cholesterol

Class              Use in low GFR

3-hydroxy-3-       Main excretory route
methyl-glutaryl-   is the bile duct,
CoA reductase      i.e. it can be used
enzyme             in kidney damage
inhibitors         (pravastatin is
(statins)          excreted mainly in
                   the urine)

                   Rhabdomyolysis may
                   occur, although
                   there is a low
                   incidence in CKD. In
                   stages 3 and higher
                   CKD, careful follow-
                   up is necessary

                   Cyclosporine, which
                   is often used in
                   resistant nephrotic
                   syndrome, may have
                   adverse effects if
                   used simultaneously

Anion              No problems
exchange
resins

Fibrates           Do not use
                   bezafibrate or
                   fenofibrate in
                   kidney failure or
                   dialysis patients

                   Do not use for
                   stages 4 and 5 CKD

Nicotinic          No problems
acids

Others             No problems

TC = total cholesterol; TG = triglyceride; HDL-C = high-density
lipoprotein cholesterol; LPL = lipoprotein lipase; Lp (a) =
lipoprotein (a); GFR = glomerular filtration rate; ECG =
electrocardiogram.

Table 2. Diagnosis of secondary hyperparathyroidism *

Serum          Normal range
biochemistry

Calcium        Below or low normal range
Phosphate      High

* PTH 2-9 times the normal range (check with the laboratory which
assay and normal range) and low vitamin [D.sub.3] levels: measure
25-OH-vitamin [D.sub.3].

Table 3. Autonomous hyperparathyroidism *

Serum          Normal range
biochemistry

Calcium        Higher or high normal range
Phosphate      High

* PTH > 2-9 times the normal range (check with the laboratory which
assay and normal range).

Table 4. Steps for therapy

Steps       Stages 3-4 CKD               Stages 5-5d CKD

Lower the   Calcium carbonate or         Calcium carbonate or
serum       non-calcium-containing       non-calcium-containing
phosphate   phosphate binders, e.g.      phosphate binders, e.g.
            lanthanum carbonate or       lanthanum carbonate or
            sevelamer carbonate          sevelamer carbonate

Increase    First administer calcium     First administer calcium
the serum   carbonate, then vitamin D3   carbonate, then vitamin D3
calcium

Table 5. Follow-up blood measurements

Stage CKD   3-monthly                        6-monthly

3           --                               Calcium and phosphate
                                               levels
4           Calcium, phosphate and           PTH levels
              alkaline phosphatase levels    25-OH-vitamin D3
5           Calcium, phosphate and           PTH levels
              alkaline phosphatase levels    25-OH-vitamin D3
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Author:van der Walt, I.; Swanepoel, C.R.; Mahala, B.; Meyers, A.M.
Publication:South African Medical Journal
Article Type:Report
Geographic Code:6SOUT
Date:Apr 1, 2015
Words:2764
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