Multiple myeloma and chronic kidney disease

Introduction

This dissertation is about two different diseases, multiple myeloma and chronic kidney disease. I will encompass the biological, social and psychological aspect of the disease with an integrative and reflective approach throughout the dissertation. I have also discussed one of the evidence I used in the dissertation in details. I was able to gain the experience of symptoms first hand from both my patients that I will refer to as Mr. Y and Mrs. Z. I have synonymously used the words renal failure and kidney disease in the dissertation; and also myeloma and multiple myeloma. Although none of my patients presented to their doctors primarily because of tiredness, their disease process meant that fatigue was a common symptom experienced by both. The two years that I have spent visiting the patients, talking to them and speaking to their family has been an emotional rollercoaster for me. I have been able to learn from the patient things that no textbook could have taught me. Despite the fact that none of my patients were medical academics, I considered them teachers as the depth with which they understood their diseases was very impressive. Throughout the dissertation, I will be comparing and contrasting the diseases, the patients and the effect of their conditions on their lives and that of their family. I will also be looking at how the experience of this course has had influence on my learning along with how it has shaped the way I hope to practise in the future.

Case Profile

Mr Y, my patient from primary care is a 40 year old printer married with two children. He leads a relatively healthy life and has always taken care of his health has he was a 'worrier'. He had never smoked, drank about 20 units of alcohol a week and was an active member of a local gym. Prior to him being diagnosed, Mr Y had no medical condition that he was receiving treatment for and thought that he was relatively well. In 1997, he started to feel tired which he did not attribute anything to. He then visited his GP for a supposed unrelated problem, erectile problem where his blood pressure was found to have been very elevated. This led to his GP referring him to a nephrologist where he had a renal scan. His heart was also scanned to check for cardiac causes of his hypertension. The scan showed evidence of 'parenchymal kidney disease'. He then had a renal biopsy which was inconclusive as there was not enough evidence to suggest that he had hereditary nephritis or hypertensive renal disease. I thought that they both could have played important role in MR Y's development of the disease. In his case both hypertension and kidney failure could have been the cause of the other whilst tiredness will still remain a symptom. From then onwards, his health went downhill until he reached end stage renal failure where he needed renal replacement therapy. As his mum died of kidney disease at the age of 34 and only remaining relative, his maternal aunty also had kidney failure, he needed to look for a non-related kidney donor. His wife then offered to be tested and was found a match. She was able to donate a kidney to him in 2006. Since then, he has felt much better although his kidneys are still failing. Whilst Mr Y did not think much to his erectile dysfunction, I later found out that his kidney disease or perhaps even the hypertension could have caused this symptom.

Mrs Z on the other hand is a 58 year old retired health care assistant married with two children. Also a non smoker, she also had led a healthy life up until her diagnosis. Her past medical history included carpal tunnel syndrome and asthma. She had also undergone a hysterectomy ten years before I met her. I did not think this had any relevance to her diagnoses. She first presented to her doctor after having pains in her lower back which was going down her legs. This was diagnosed as sciatica by her doctors and was given pay relief medicine. This did not provide her with any relief so she tried an alternative therapy, acupuncture. After this also had no effect on her symptoms, she started to think it might be worse. She had also been getting relatively tired as well as having bouts of infections. I realised that it is beneficial to look at the big picture sometimes; as when the symptoms of MM are looked at as separate entities like in my patient's case, might lead to a delay in diagnosis. This was one of the reasons why my patient was diagnosed relatively late after she first presented to her doctor.

As she had worked in an oncology ward before, she started to piece her symptoms together and came up with multiple myeloma as a feasible reason for all of her symptoms. She told her doctor about her fears and was referred to the hospital where her diagnosis was confirmed. This was really hard for her as she had to debate with herself and hoped that she was wrong. Even though she never thought that she could go through with the treatments, she did decide that she wanted to make use of her chances and to try and fight the disease. After several failed treatments, Mrs Z lost her battle and died in October 2008.

The fact that both my patients had paid no particular attention to their tiredness and attributed it to other things made me reflect one of the sociological theories of disease, the illness iceberg. The theory suggests that "the professional health services treat only a tip of the sum total of ill health" (1). Fatigue is very commonly experienced by many people in the population, and almost certainly ignored until it is considerably affecting their lives, accompanied by another symptom or just not going away.

Investigations

For CKD, specific questions should be asked in the history about family history of chronic kidney disease, history of diabetes or hypertension, etc. Physical examination will also help fine tune some of the findings in history and will help draw up a differential diagnoses. Investigations are therefore performed to make or confirm a suspected diagnosis.

Here are the different investigations that can be done in a suspected CKD.

Direct Glomerular filtration rate (GFR) measurement

The clearance of any substance by the kidney is the volume of plasma which is cleared completely of that substance in unit time, usually one minute. If a substance is not secreted, metabolized, synthesized or reabsorbed by the kidney, then the clearance of this substance can be used to measure the GFR. Since proper functioning of the kidneys on plasma filtration, the GFR can be used to measure the percentage of kidney function and assess when the system goes wrong. A direct GFR measurement can be used to establish the stage of renal failure. Different things can be used to measure the GFR include in decreasing order of accuracy Inulin clearance, Radionuclide, Iohexol clearance, 3 hr Creatinine clearance with Cimetidine, Prediction equations, Cystatin C, 24 hr urine Creatinine clearance and Serum creatinine (2). The Gold Standards are Inulin clearance and Radionuclide (125Iodine-iothalamate, technetium DTPA, 51Chromium-EDTA clearance). But these are not routinely used in clinics as they are time consuming, tedious, unavailable and expensive. Some significant problems have been shown with the use of serum creatinine in evaluating GFR. These include ethnicity, muscle mass, diet, age, gender and also the fact that serum creatinine has poor sensitivity for CKD (3). Estimated glomerular filtration rate (eGFR) is used instead of serum creatinine and the national service framework mandates the use of the Modification of Diet in Renal Disease (MDRD) prediction equation in the UK.

Ultrasound scans should be the first-line imaging study to evaluate people with undiagnosed kidney disease as it helps differentiate between CKD and potentially reversible acute kidney injury (3) . Other investigations include urinalysis (for proteinuria, haematuria and glycosuria), FBC, ESR, U&E, BUN, serum phosphate and calcium. Kidney Biopsy is performed in renal failure with unknown cause and normal-sized kidneys.

Mr. Y had to undergo both renal and heart scan to rule out cardiovascular causes of his high blood pressure. According to his notes, scans showed evidence of chronic parenchymal disease instead of the suspected polycystic kidney disease due to his family history and his urinalysis showed haematuria and proteinuria. A renal biopsy was also performed but this was also inconclusive.

Multiple Myeloma

There is currently an urgent referral policy for patients with suspected malignancy in the UK, the two-week wait. Investigations for MM include FBC, ESR (usually high) and Blood film for Roulex (clusters of 3 to 12 RBCs that occur in stacks) formation as a consequence of paraprotein (4,5). Serum & urine electrophoresis should be performed to quantify the amount of M-protein along with beta2 -microglobulin (as a prognostic test) (5)(4,5). Serum calcium should also be perfumed as well as serum creatinine to check for renal failure. Imaging includes skeletal survey and this usually shows lytic lesions or diffuse osteoporosis in about 80% of patients (5)(6).

Bone marrow biopsy and aspirate (can detect abnormal number of plasma cells in bone marrow. As one of the criteria for the diagnosis of MM is demonstration of monoclonal globulin in serum / urine, it is important to rule out other causes of this. They include monoclonal gammopathy of undetermined significance MGUS, AL amyloidosis, solitary plasmacytoma, B-cell non- Hodgkin lymphoma and chronic lymphocytic leukaemia. Diagnosis of MM is made based on one major and one minor criterion in asymptomatic patient or three minor criteria in patients exhibiting symptoms of MM which must include a and b (see figure below) (8)

Mrs. Z's investigations demonstrated bone marrow consistent IgG myeloma, hypercalcaemia, and skeletal survey concluded skull and pelvic involvement.

Pathophysiology

Before embarking on the pathology of the diseases, the relevant anatomy, physiology and histology need to be discussed. This will also help explain why some symptoms were experienced by my patients.

The kidneys lie in a retroperitoneal position in the posterior abdominal wall. Weighing about 150g each, the kidneys extend from approximately T11 to L 3 vertebral level with the right kidney slightly lower in position than the left kidneys due to its relation to the liver. The basic functional unit of the kidney is the nephron and each kidney contains approximately one million nephrons (see Figure I). Each nephron is made up of glomerulus, proximal convoluted tubule, loop of henle, distal tubule and collecting duct. Kidneys adjust plasma composition by three major mechanisms: glomerular filtration, tubular reabsorbtion and tubular secretion. Glomerular filtration is achieved by the net filtration pressure pushing filtrate across the filtration barriers. The barriers are the endothelial cell lining of the glomerular capillaries, the glomerular basement membrane and epithelial cells with foot processes. Any problem with either the process of filtration itself or the filtration barrier can lead to a detrimental effect in kidney function.

The kidney's function of maintaining the composition of bodily fluid by producing huge quantities of an ultra filtrate of plasma (i.e. plasma without the cells and large organic molecules). This process is metabolically active; the oxygen consumption of the kidney is very high, hence, the high blood supply to the kidney. The blood supply to the each kidney is via the left or right renal artery which is a branch of the abdominal aorta. The renal veins drain the kidneys into the inferior vena cava.

One of the other functions of the kidneys is to regulate the blood volume and osmolality hence reduced kidney activity leads to fluid and electrolyte imbalances. This is achieved by some of the kidney's endocrine functions.

Anti Diuretic Hormone (ADH): secreted in the posterior pituitary in response to high osmolality, ADH acts on cells in the collecting ducts to make them more permeable to water therefore increased reabsorbtion of water

The Renin Angiotensin Aldosteron System:

Renin released from the juxtaglomerular cells of the kidney in response to reduced renal perfusion, decreased serum sodium levels and stimulation of sympathetic activity in the juxtaglomerular cells activates a cascade of hormone action (see figure) to regulate blood volume, hence blood pressure.(9).

Anti Natriuretic Peptide

Released from the heart in response to the excess stretching of heart chambers by high blood volume, it acts by reducing all the action of angiotensin II therefore reducing blood volume.

Erythropoietin

Produced by the endothelial cells in the kidneys, erythropoietin is the main stimulus for the production of red blood cells. Reduced kidney function denotes reduced production of erythropoietin which leads to anaemia which often manifests itself as tiredness in patients.

1a-hydroxylase

This is the enzyme that leads to the conversion of naturally occurring vitamin D to metabolically active vitamin D, 1,25-dihydroxycholecalciferol (1,25-(OH)2D3). "The 1a-hydroxylase activity is increased by high plasma levels of parathyroid hormone (PTH), low phosphate and low 1,25-(OH)2D3." (5). Decreased kidney function means a relative lack of 1,25-(OH)2D3 which manifests itself as secondary hyperparathyroidism in patients. This can also be a contributing fact6or to the development of hypocalcaemia.

Another function of the kidney is the maintenance of acid-base balance of the body by regulating the reabsorption of bicarbonate. End state renal failure is therefore often associated with some degree of acidosis. Chronic renal failure is characterised by tubular atrophy, glomerulosclerosis, interstitial fibrosis and interstitial mononuclear cellular infiltrates. Once nephrons are damaged, they are unable to function appropriately causing other nephrons to adapt by enlarging and boosting their clearance capacity.(9)This means that initially there are a few abnormalities and often leads to patients presenting at a later stage with significant decrease in their GFR.

"Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulins and invade and destroy adjacent bone tissue" (11) . Plasma cells are derived from B lymphocytes. B lymphocytes (produced in bone marrow) are responsible for the synthesis of antibodies through plasma cells. Antibodies are immunoglobulin produced in response to antigens and are composed of two polypeptide chains: a light chain and a heavy chain. Once a B lymphocyte recognises a specific antigen, it proliferates rapidly and differentiates to give rise to plasma cells. Rarely found in the blood, plasma cells are found in the spleen, lymph nodes, etc whenever antibodies are being produced. Histologically, plasma cell can be recognised as oval shaped cells with basophilic cytoplasm due to its 'rough endoplasmic reticulum' rich cytoplasm. Plasma cells are of high importance in immune reaction as severe consequences occur when this process goes wrong in the case of multiple myeloma.

The malignant plasma cells in multiple myeloma are all from a single clone producing identical monoclonal antibodies. The most common antibody produced is of subtype IgG with which Mrs Z was diagnosed and is present in about 55% of multiple myeloma patients( cite Berenson james) . Other immunoglobulin types include IgA, IgD and free light chain only (Bence Jones protein) in 20%, 2% and 16% of patients respectively (11)(cite Hematologic malignancies) . Excessive accumulation of antibodies in plasma can lead to the presence of light chain antibody fragments in urine, in which case they are known as 'Bence Jones protein'. The finding of these antibodies either in plasma and/ or in the urine is diagnostic. Despite the increased number of antibodies produced by myeloma patients, they often present with infection as the antibodies are non-functional. These leave patients susceptible to encapsulated gram-negative bacteria and often mean that they require prophylaxis antibiotics (12). In multiple myeloma, normal programmed cell death of plasma cells do not occur leading to its proliferation and accumulation in the bone marrow. (12)Normally, plasma cells component of the bone marrow is about 5% but can rise to about 30-90% in a myeloma patient. (9). As plasma cells number increases, they begin to hamper the erythropoietic function of the bone marrow leading to the classic presenting symptoms of many myeloma patients, anaemia.

Malignant plasma cells also activate osteoclasts and suppress osteoblast causing lytic lesions pathological fractures especially in the pelvis, spine, ribs and skull(11). Secondary hypercalcaemia often results due to bone demineralisation.

As increased plasma concentration of antibodies are circulated around the body, they (especially Bence Jones proteins) become deposited in the glomerulus since they cannot be filtered by it. This leads to excess antibodies accumulating in the kidneys thus leading to tubular damage, proteinuria, and eventual renal failure (12).

Aetiology and risk factors

The aetiology of chronic kidney disease are vast and includes conditions affecting the kidneys, the urinary tract and / or those affecting the systemic circulation. They can also be congenital or hereditary. Some chronic Kidney disease cases do not have any identified cause. Diabetes and hypertension remain the leading the causes of end stage renal failure (14). The table below shows summary of causes of CKD and some of their examples.

Causes

Examples

Congenital and inherited disease

  • Polycystic kidney disease (adult and infantile forms)
  • Medullary cystic disease
  • Tuberose sclerosis
  • Cystinosis
  • Congenital obstructive uropathy

Glomerular disease

  • Primary glomerulonephritides including focal glomerulosclerosis, IgA nephropathy, etc.
  • Secondary glomerular disease (systemic lupus, Wegener's granulomatosis, amyloidosis, diabetic glomerulosclerosis, accelerated hypertension, haemolytic uraemic syndrome, systemic sclerosis, sickle cell disease)

Tubulointerstitial disease

  • Tubulointerstitial nephritis - idiopathic, due to drugs (especially nephrotoxic analgesics)
  • Reflux nephropathy
  • Tuberculosis
  • Schistosomiasis
  • Multiple myeloma (myeloma kidney)

Vascular disease

  • Hypertensive nephrosclerosis
  • Reno-vascular disease
  • Small and medium-sized vessel vasculitis

Urinary tract obstruction

  • Calculus disease
  • Prostatic disease
  • Pelvic tumours
  • Retroperitoneal fibrosis

Table: Causes of Chronic Kidney Disease (5)

Risk factors of CKD include susceptibility, initiation, progression and end stage factors (see table) (15)

Type Definition Examples Susceptibility factors Factors that increase susceptibility to kidney damage Older age, family history of chronic kidney disease, reduction in kidney mass, ethnic minority, etc. Initiation factors Factors that directly initiate kidney damage Diabetes mellitus, high blood pressure, autoimmune diseases, systemic infections, urinary tract infections, etc. Progression factors Factors that cause worsening kidney damage and faster decline in kidney function after kidney damage has started Higher level of proteinuria, higher blood pressure level, poor glycemic control in diabetes, smoking End-stage factors Factors that increase morbidity and mortality in kidney failure Anaemia, low serum albumin level, late referral for dialysis Fig: CKD risk factors summary (15)

The exact aetiology of multiple myeloma as with that of most cancers remains relatively unknown. Although a case control study is ongoing at the moment (16), the findings, validity, and significance of that study will be unknown until the results are published. It is thought that plasma cells activating factor Interleukin-6 (IL-6) is a growth and survival factor for myeloma cells as it prevents programme cell death. HIV has also shown to be an important factor in developing multiple myeloma with HIV patients(17) having an approximately 5 times more likelihood of developing multiple myeloma (17) . Other Risk factors that have been suggested include "chronic immune stimulation, autoimmune disorders, exposure to ionizing radiation, occupational exposure to pesticides or herbicides, occupational exposure to dioxin, and perhaps, prolonged use of certain hair colouring products"(4). Numerous abnormalities have been shown to occur in the genes of multiple myeloma and advances have been made in trying to explain genetic lesions with the disease initiation and progression. This information is now being used to make prognostic and therapeutic decisions as some specific gene abnormalities have been associated with worse prognosis (18).

Classification and Staging

National kidney foundation defines Chronic kidney disease as "the presence of objective kidney damage and/or the presence of a glomerular filtration rate of 60 ml/min/1.73m body surface area, or less, for at least 3 months, irrespective of the underlying aetiology of the kidney damage" (19) . The main staging for CKD is based on estimated GRF to measure kidney function. The table below shows the stages of CKD based on the international classification developed by the US National Kidney Foundation in their Kidney Disease Outcomes Quality Initiative (K/DOQI).

Stage Description GFR (ml/min/1.73m) 1 Normal or increased GFR with evidence of kidney damage >90 2 Kidney damage with slight decrease in GFR 60-89 3 Moderate decrease in GFR with or without other evidence of kidney damage 30-59 4 Severe decrease in GFR with or without other evidence of kidney damage. 15-29 5 Established Renal Failure <15 Table: Stages of Chronic Kidney Disease (20) The classical staging system of multiple myeloma is the Durie-Salmon Staging System which was used to differentiate patients with low, intermediate and high level of tumour mass. Stage Description Stage I Low cell mass (<0.6 x 10cells/m) Stage II Intermediate cell mass (0.6 - 1.2 x 10 cell/m) Stage III High cell mass (>1.2 x 10 cells/m) Sub stage A Serum creatinine value < 2mg/dl B Serum creatinine value 2mg/dl Fig: Durie-Salmon System of Staging (4)

With better understanding of multiple myeloma, a more recent classification system which separates into three prognostic groups irrespective of age, geography and type of therapy has been published (see figure below). This international staging system has simplified the staging to two blood tests; beta-2 microglobulin and albumin that can be easily obtained routinely in most myeloma clinics (18). It has also been shown to have better predictive values of prognosis than the Durie-Salmon System of Staging. Other prognostic factors include low c-reactive protein, absence of 13/13q chromosome abnormalities, low plasma cell labelling index ,absence of plasmablastic morphology =12 months prior treatment and low Interleukin-6 receptor (4).

Stage 2-microglobulin (mg/l) Albumin (g/dl) Median survival (months) I <3.5 =3.5 62 II <3.5 or 3.5-5.5 <3.5 45 III >5.5 29 Table : International Staging System (18)

Clinical features

Early stages of both my patient's diseases are often asymptomatic despite the underlying pathology. Hence most of the signs and symptoms that will be discussed here are due to complications.

Anaemia

Anaemia is a decreased in the level of haemoglobin in the blood. Patients with CKD often complain of tiredness. Anaemia in CKD is primarily caused by the kidney's decreased ability to produce erythropoietin and also the bone marrow's resistance to the hormone. Other causes include decreased RBC survival and blood loss through haematuria although not a major cause, can be a contributory factor. The symptoms of anaemia are loss of energy, headache, faintness, breathlessness (especially during exercise) and depression. Signs include pallor.

Renal Bone Disease

As CKD progresses, reduced eGFR leads to decreased levels of active vitamin D, calcitrol and increased levels of phosphate in the blood. Lower vitamin D means that there is decreased bone mineralization causing osteosclerosis, osteomalacia in adults, and rickets in children. As calcitrol increases the reabsorption of calcium from the intestine, its deficiency leads to lower level of calcium leading to increased parathyroid hormone (PTH). A high level of PTH leads to osteotitis fibrosa and cystica. Patients often complain of bone pain.

Effect on Cardiovascular System

One of the causes of mortality in patients with CKD is increased incidence of cardiovascular diseases particularly myocardial infarction, stroke and sudden cardiac death (21). As CKD progresses, water and electrolyte imbalance causes fluid overload. This often leads to hypertension which increases the risk of atherosclerosis and coronary heart disease. The effect of hypertension on its own includes cerebrovascular diseases, congestive heart failure, angina pectoris and left ventricular diastolic dysfunction. End stage renal failure also leads to left ventricular abnormalities often known as 'uremic cardiomyopathy'. Patients can also complain of precordial chest pain associated with percardiatis caused by uraemia. Other signs of cardiovascular complications include hypertensive retinopathy and cardiac arrhythmias from potassium imbalance.

Endocrine complications of CKD include hyperprolactinaemia, increased LH, decreased serum testosterone which may present as galactorrhoea, erectile dysfunction, oligomenorrhoea, and amenorrhoea; all these can lead to infertility. Growth hormone abnormalities often results in short stature in children.

Metabolic Complications

Other complications of CKD include metabolic acidosis due to high levels of phosphates, uric acid etc which presents as deep sighing breathing (kussmaul respiration), dyslipidaemia and peripheral & pulmonary oedema due to fluid overload.

Uremic symptoms

Increased levels of urea in the blood is associated with a number of symptoms which include nausea, vomiting , acute pain due to gout, restless legs, convulsion, headache , fatigue, muscle cramps, and pruritus and eventually seizures and coma as uraemia becomes severe. I realised the importance of history taking and how relevant it is in making a goo diagnoses. Although when I was taking Mr. Y's history I did not have adequate knowledge about CKD, I was surprised to learn that he had a lot of the symptoms that I had read about. It was very exciting learning experience for me as I realised that I easily remembered these symptoms and when I finally came to study the module I had the understanding of why he had those particular symptoms and not others. His symptoms included feeling very tired, itching, headache, nausea, vomiting a few times, night cramps and having difficulty to concentrate. Before his transplantation, he also developed some of the complications of kidney diseases such as hypercholesterolemia and erectile dysfunction.

Complications from transplant: Although the transplant operation was successful, Mr. Y has since developed post transplant diabetes mellitus. Corticosteroids used as immunosuppressant after transplant leads to peripheral insulin insensitivity and hyperglycaemia. This further exacerbates the insulin resistance that patient had in advanced renal impairment. Whether or not this could have been avoided in Mr. Y's case remains unknown although some research has suggested that early withdrawal of steroids reduced the incidence of diabetic mellitus in post transplant patients (22,23).

Multiple Myeloma

Pain

Pain is often associated with cancer and one of the most feared symptoms by cancer patients. In MM, patients often complain of persistent unexplained backache. Mrs. Z said she had a "lower backache with pain going down her legs with a feeling of numbness". This suggests of spinal cord or nerve root compression. Bone destruction may also manifest itself as pain in patients.

Anaemia: Plasma cells infiltration of bone marrow leads to anaemia. In MM anaemia can also be iatrogenic from chemotherapy used to treat it. Other symptoms of anaemia exhibited by Mrs. Z include shortness of breath, tightening chest pain at night, feeling light headed, palpitations and decreased vision. Bleeding is one of the factors of Mrs. Z's anaemia as she had skin bleeding and several episodes of severe epistaxis each lasting for about fifteen minutes. As one of the complications of MM is renal failure, this might exacerbate the anaemia as well.

Infection: Recurrent infection is a major concern in patient with MM as can sometimes lead to severe bacteraemia which can cause death. Compromised cellular immunity such as neutropenia (reduced neutrophil) caused by bone arrow infiltration often manifests as an increased incidence of herpes zoster. Humoral immunity is often compromised in MM patients caused by reduced number of functioning antibodies leading to susceptibility to bacteria particularly encapsulated ones. My patients had several episodes of viral and bacterial infections such as conjunctivitis, candiditis, pneumonia, shingles to name but a few. Apart from disease progression, infection is the main cause of death in about 25% to 50% of patients (13), indeed it was in the case of Mrs. Z as her cause of death was bronchopneumonia secondary to myeloma.

Renal Failure : this is mainly caused by deposits of bence jones protein in the nephron leading to 'myeloma kidney' (4).

Increased bone resorption may also lead to hypercalcaemia which in Mrs. Z's case presented as increased thirst, polyuria, constipation, and abdominal pain. It can also cause lethargy and nausea. Hypercalcaemia also exacerbates renal toxicity.

Treatment and Management

Management of the diseases varies on the stages of the different disease. In the case of CKD, lifestyle management such as weight control, healthy eating, exercising regularly and the cessation of smoking (where applicable should be encouraged along with effective health education. The basis of CKD management is to try and delay as much as possible its progression and to lessen complications associated with kidney failure. Symptom management is imperative in the treatment of CKD. Therefore it is important to control underlying cause of the disease. Particularly, hyperglycaemia should be managed in people with diabetes and hypertension should be controlled. NICE guidelines recommends that management should aim to keep the systolic blood pressure below 130mmHg (with target range of 120-129mmHg) and diastolic pressure below 80mmHg (3) . Both my patients were anaemic; hence the treatment of this anaemia often increases the quality of life of the patients. Research has shown that treatment of anaemia improves the quality of life measurement in patients (19). Exogenous erythropoietin is effective in treatment of anaemia in CKD. Mr Y told me that he was so tired that he could no longer play with his children and this bothered him a lot. In people with CKD, the aim is to keep the systolic blood pressure below 140 mmHg (target range (120-139 mmHg) and the diastolic blood pressure below 90 mmHg (3,20,20). Mr Y was prescribed diuretics to help manage his hypertension. He was also prescribed bicarbonate to treat his acidosis and statins for his hypercholesterolemia. ACE inhibitors and angiotensin II receptor blockers have also been shown to decrease then rate of eGFR decline.

Despite appropriate interventions and management, Mr. Y's kidney disease progressed to reach the end stage renal disease which meant that at this stage, renal replacement therapy would be required. Five years after he was diagnosed with chronic renal failure, Mr. Y was placed on the transplant list in July 2003.

There are two major types of renal replacement therapy; dialysis and transplantation.

Dialysis is a process in which waste products and excess fluid are removed from the blood whilst also trying to correct electrolyte imbalance in people with kidney failure. It is done by passage of blood through a semi-permeable membrane down a concentration gradient. Indications for initiation of dialysis include "uraemic" symptoms (symptoms associated with build up of urea in the blood), acidosis, pericarditis, fluid overload and hyperkalaemia. Dialysis is further subdivided into :

Haemodialysis

This is the most common type of dialysis. It is done by pumping the patient's blood through a specialised machine, the haemodialysis machine. It requires vascular access which is done by special intravenous catheter with two pumps: one to remove unpurified blood and one by which the clean blood is returned to the body. This requires trained staff and purpose built facility. Also when haemodialysis is prescribed, transportation arrangements should be thought of as patients will need to go to the centre about two to three times during the week. Because of the vascular access required in dialysis, anti coagulants is required.

Continuous ambulatory peritoneal dialysis

In this method of dialysis, peritoneal dialysis fluid moves by osmosis through the peritoneal membrane from blood vessels in the parietal and visceral peritoneal membranes. As no vascular access is needed and no blood is outside the body, anti coagulants is not needed. In Leicester, about 30% of dialysis patients are treated with peritoneal dialysis.

Renal Transplantation

All patients with progressive CKD or end-stage renal failure should be considered for transplantation except they have significant underlying medical conditions which will contraindicate this. Availability of organs is the main limiting factor in transplantation. Sources of organs include cadaveric, non-heart beating and living donors. Transplantation provides patients with them with close to normal renal function and allows mobility and "rehabilitation". This is perhaps the reason why I had second thought when I first meat Mr Y as he did not look like a patient who was fatigued. Kidney transplantation is also relatively cheaper than dialysis. The major problem with transplantation is that patient will require long term immunosuppressive drugs and are still left with continuous chronic renal failure. Mr Y received a transplant from his wife in May 2006 and has now developed post transplant diabetes mellitus. This means that Mr Y will need to be monitored even more closely as diabetes is an additional risk in his development of CKD. He is currently receiving sulfonylurea as treatment for his diabetes but may eventually need insulin treatment.

Currently, there is no NICE guidelines for the treatment of MM although guidelines for the diagnosis and management of MM have been compiled by the UK Myeloma Forum , the Nordic Myeloma Study Group and the British Committee for Standards in Haematology (24). The treatment depends on the stages of the disease as well as symptoms the patients present with and is usually tailored to the specific patient. There has been no advantage in initiating immediate treatment in asymptomatic patient although they should be monitored closely (24) . Supportive measures are used for symptom management and to control the effect of MM on other organs and tissue whilst definitive therapy are used to try and eliminate the underlying disease. Since Mrs. Z's also had pain, she was put on a few pain relief medications which included one for neuropathic pain. Radiotherapy should also be considered for pain relief as it is now used as a palliative treatment for painful bone lesion (25). Anaemia is common in MM therefore its management should be an integral part of patient care since it contributes to physiological functioning and quality of life in these patients(26). Treatment can be through blood transfusion which Mrs Z received or by exogenous erythropoietin. Infection control and treatment should also be established. The guideline recommends that any febrile myeloma patient should be treated rapidly with broad spectrum antibiotics; IV antibiotics should be given when infection is severe (24). Bisphosphonates should also be considered in the management of myeloma bone disease

Specific therapy for multiple myeloma ;

Historically, the treatment for MM was oral chemotherapy melphalan and prednisolone (MP) but before then, radiology was the only available therapy for plasma cell tumour management. But recent advance in research has evolved the treatment options for newly diagnosed MM and significantly improved the survival of patients. Treatments can be based on whether it is an initial treatment or treatment for relapse. Initial treatment can also be sub classified into whether or not patients are eligible for stem cell transplant (SCT). This eligibility is based on patients age, performance status and co morbidities. The initial treatment for patients eligible for SCT include VAD and High-dose dexamethasone. Newer treatments include Thalidomide-dexamethasone, Lenalidomide-dexamethasone and Bortezomib-based regimens (18,27,28). The treatments for patients ineligible for SCT are MP, MP with thalidomide, MP with Bortezomib and MP with lenalidomide (25)(29). Although research has shown them to be effective in the treatment of MM, the newer therapies including thalidomide, lenalidomide and bortezomib have not been recommended as first line treatment in England by NICE therefore the availability of this will vary geographically as it is not yet legally binding for the different authorities to provide this (30)(25)(31). Conventional therapies for the treatment of relapsed or refractory MM include Dexamethasone, VAD and SCT. Newer agents include Thalidomide, Bortezomib, and Lenalidomide alone or with other agents (25,27,32) . Other therapy for MM include cyclophospahmide and interferon.

Fig: Suggested Treatment Strategy after first relapse (24)

Mrs Z's initial treatment was VAD but five months later, she relapsed and was placed on Thalidomide. Although when she was initially assessed to be eligible for SCT, she was no longer giving this therapy due to her deteriorating condition. At this stage Mrs Z myeloma had metastasised widely to involve the mediastinum, head, femoral and the pelvic. Mrs Z myeloma did not also respond to the thalidomide and it was stopped after two months. At this point, I realised that Mrs Z was palliative; her larynx had also been infiltrated by myeloma. She then had a tracheotomy done to enable her breathe. But despite all the efforts and the varied treatment she received, Mrs Z succumbed to the hands of invasive MM and passed away nine months after first receiving her diagnoses. The rate at which the disease progressed was very new to me and when I received the news of her death, I was shocked. Even though I was not responsible for Mrs. Z's management, I still felt a twinge of sadness. I recognise that in my future career, despite all efforts, some patients will deteriorate quickly. But I do not expect to get used to the feeling of sadness when patients pass away as this is only natural. However, I realise that the degree of sadness might be different with different patients and I will need to use the appropriate counselling service available should the need arise.

Epidemiology and Demographics

I noticed that the epidemiology of chronic kidney disease was not hugely available. Conversely, facts about end stage renal disease were readily available due to the US Renal Data Service and the renal registry in the UK. Another one of this reason might be due to the fact that earlier stages of CKD are under recognised. There is some evidence to suggest that patients with earlier stages of CKD are more likely to die than require renal replacement therapy (19) . The incidence and prevalence of CKD in global perspective is high and increasing (33). In the last two decades, there has been a significant rise in the number of patients receiving renal replacement therapy in the UK due to an increase in the number of patients with end stage renal disease (ESRD). "A survey of blood samples carried out in the South East of England in 2000/01 found the prevalence of diagnosed CKD to be 5,554 per million population (pmp)" (20) . The US Renal Data Service (USRDS) estimates the incidence rate for renal replacement therapy in 2001 to be 334 cases per million population (pmp) an increase from 223 pmp in 1991 (19). The incidence rate for renal replacement therapy has also increased in a linear fashion in the UK (34). "From 1978 to 1991, the number of adults aged 20-74 years with stage 3-4 CKD in the UK grew from 2.6 million to 3.9 million - an increase in prevalence from 1970 to 2460 per 100 000" (35). In Leicestershire, the prevalence of STAGTE 3-5 IS 6.98% (36) Race is important in the incidence of ESRD as black Africans are three to four times higher than in caucaseans although the rate of incidence in Caucasian is fast increasing (19). Age is also of great importance as the rate of incidence of ESRD in those over the age of 7 is 100 times higher than in those less than twenty years of age (19).

Fig : US Unadjusted Incident Rates by Primary Diagnosis (per million population) (2)

Multiple myeloma is predominantly a disease of the old with median age at diagnosis being 71 years (4). Race and gender also has a significant impact on the incidence. Due to the increase in life expectancy in the UK, it is estimated that the incidence will steadily rise over the coming years (4). In the UK, multiple myeloma contributes to approximately 1% of all cancers causing about 2700 death in 2007 (37). It is 2 times more likely in black than in Caucasian and more common in males than females and has been estimated that the "lifetime risk of developing multiple myeloma is 1 in 148 for men and 1 in 186 for women" in the UK (4,37)

Fig: Five year relative survival rates for multiple myeloma by age at diagnosis (37)

Fig: Age specific incidence rates by sex in UK (37)

Screening

Screening is a type of secondary prevention used to detect or treat a disease or its risk factor early through the application of tests, examinations, or other procedures in order to prevent morbidity or mortality. Research has suggested that the progression chronic kidney disease can be delayed or even stopped when interventions are made early (38). This has initiated the different screening programmes in the US and the UK. In the US, "the Kidney Early Evaluation Program (KEEP) offers free screening for those at risk - anyone 18 years and older with high blood pressure, diabetes or a family history of kidney disease and is designed to raise awareness about kidney disease among high risk individuals and provide free testing and educational information, so that kidney disease and its complications can be prevented or delayed" (15). Although no national programme is fully available in the UK, routine checks are performed in those with high risk . The national service framework recommeneds that people that identified to have higher risk especially those with diabetes and hypertension should have their kidney function assessed and appropriately monitored, using estimated GFR (20) Also the "NHS Health Check Programme" is being developed and of full implementation of the programme is expected by 2012/13. It aims to help prevent heart disease, stroke, diabetes and kidney disease in people aged between 40 and 74 who has not already been diagnosed with one of these conditions, will be invited (once every five years) to have a check to assess their risk of these diseases and will be given support and advice to help them reduce or manage that risk (39).

Fig : Summary of screening criteria (39)

There is currently no effective screening programme for MM because it does not fulfil the screening criteria (see figure above). But since approximately 25% of people diagnosed with MGUS will progress to develop myeloma, these people are regularly monitored with routine checkups (37).

Role of Health Care Professionals

Due to the nature of illness in both my patients, multidisciplinary team working is imperative. Good team work is essential in order to deliver a high standard of care to patients. The different number of professional involved also means challenges to the continuity of care. CKD requires constant supervision and follow up by different healthcare professionals. In both my patients, the GP will be the first point of contact. Their GP will be expected to use their consultational and problem solving skills to evaluate what the diagnoses and management will be. They also refer patients to appropriate specialists for further investigations when required.

In CKD, management is usually led by the GP as they play a significant role in early diagnosis, patient education and referral to nephrologist. Other professionals who may be involved include, nurses, pharmacist, social worker, endocrinologist, surgeon, anaesthetist, clinical pathologist, radiologist, clinical psychologist, and urologist. The people involved will often depend on the cause of the renal failure, treatments and whether the patient has other co-morbid condition. Regardless of the number of professionals involved, it is important to have adequate communications between them so that the patient does not have overwhelming tests or repeated tests done. Also, this helps reduce the anxiety of patients. I noticed that with Mr. Y, it appears that there was not enough communications between the primary and secondary care involved in his management as he had the same screening test (for diabetic feet) carried out by both centres some within days of each other. When asked what he thought of this, he told me that although he liked access to his consultants as he got an early reply, he does not like that he had to go through exactly same tests twice and just does not turn up some of them; as he does not have the time to attend all of these different things. I wondered whether a central database with patients records from both primary and secondary care will be feasible but I realised that one of the major problems with such a database will be patient's confidentiality.

With MM, a consultant haematologist or oncologist will often lead the care but other professional will be involved. In Mrs. Z's case, this was delivered as part of a multidisciplinary team who will be familiar with both the patient and their clinical manifestations. The team will also normally contain clinical pathologist, radiologist, pharmacist (with chemotherapy expertise), palliative care nurses, physiotherapists, social worker and clinical psychologist. The team may also include neurosurgeon, orthopaedic surgeon, dietician and nephrologist depending on patients' complications. What I noticed was that most multidisciplinary meetings will not normally include the patient and I wonderd wwhether in the future it might be beneficial to have the patient there whenever possible so that they can be able to put in their opinion, after all it is their conditions that are being discussed.

Patient Satisfaction

Both my patient were generally satisfied with the care they were given in both primary and secondary care although they voiced some of their concerns. Mr. Y did not like the fact that after his diagnoses, his first GP surgery decided to drop him due to where he lives. He thought that he was a victim of 'postcode lottery' but it no longer bothers him much as he thinks his present GP practice is better and closer. More importantly, recently he had to check his kidney functions and the doctor involved did not explain the result to him even though the results were ready. The fact that he needed to wait for another appointment to know his results really unnerved him and made him anxious. I realised that as a future physician, what I say or do not say might have a huge effect on patients. It will not be just the physicians alone that will be looking for cues, both verbal and non verbal; patients will also be watching closely. I will need to bear this in mind when speaking to patients as it not just about what I say; it is also how I say it.

Mrs. Z's case was different as she had been in involved with the healthcare profession herself; she knew the right ways to make her opinion heard. The one thing that upset her was the fact that her chemotherapy was not started as soon as they had decided to give it to her as she knew too well the consequences of delay in treatment. I later found out that at that point, she could not have started chemotherapy as she had serious infection that chemotherapy could worsen very quickly which had to be treated first. She also thought that her concerns were not listened to about side effects of her medication and was quick to put in a formal complaint to the consultant in charge. Her complaint must have been handled very well as she wrote a letter saying that "she was grateful to her doctors for listening to her, acting on what she told them, addressing her concerns where possible and for offering her guidance". I realised that once in awhile I might do something to displease patients but listening to them, apologising and making amends makes a huge difference to the doctor-patient relationship. It will also serve as an opportunity to learn from my mistakes and how to avoid future incidence.

Psychological and Sociological Aspects of Illness

The biological, social and psychological entities of a disease are continuously interacting and together have an impact on trying to understand patients as whole, not just as a means to an end. Although I have discussed different aspects of the psychological and social aspects of my patients' diseases throughout the dissertation, I will discuss in more detail some specific aspect of the patients' disease. I have discussed the biological aspects of my patients in detail; I will concentrate on how the psychological and social aspect of my patient's diseases has impacted on them.

Chronic illness

My patients had illness that did not have an exact treatment; therefore this has had an impact on them and the way their illnesses are managed. Sociologists have identified that patient with chronic illness have to do some work in order to cope with their illness. These include illness work such as symptom management, everyday life work (the ordinary tasks of daily living), biographical and narrative work (reconstruction of their own biography), emotional work (managing their own emotions as well as that of others) and identity work (trying to maintain an acceptable identity). These works seem to interplay in my patients. The common illness work in both my patients was their fatigue which shaped their everyday life work. Mr. Y told me that he was unable to play with his children as he would normally do. In Mrs. Z's case, her bone pain had affected her mobility as well which meant that she had to depend so much on her husband. Mrs. Z also seemed to do more emotional work as she found it hard to tell her children; although she self diagnosed herself, she had 'hoped' that her predictions were not true so she would not have to break the news to her children.

Both my patients seemed to cope to some extent with their diseases as they had very good social support from their family. At a later stage, Mrs. Z became distressed with the fact that her husband, who was her main carer had broken his leg. This really had a huge effect on her as it was then very difficult for her to get things done around the house during the day but was able to get her children to help out in the evening. Mr. Y on the other hand was very anxious about his disease and has had panic attack because of this. As Mr. Y's condition may possibly have been inherited, he was worried that his children could also inherit the disease from him. He is also scared of being put on dialysis when his kidneys fail and thinks that this will disrupt his family. Although he has accepted that he might eventually need another renal replacement therapy, the fact that there might not be transplantation available on time for him really scares him; hence, he becomes very anxious whenever he needs to have routine tests done. Increased anxiety could increase his vigilance for threat, make him interpret ambiguous information as threatening and increase his recall of threatening memories, this aspect of his treatment had to be looked into. This led to his referral to a clinical psychologist.

Adherence and Concordance:

Both my patients had adhered well to their treatment regimes. Even in the case of Mrs. Z where her treatments gave her some undesired side effects, she still carried on and took it. It was probabaly due to the beliefs about their own health. They fully understood the severity of their diseases and recognised the benefit of adhering to their treatment regime. Mrs. Z was keen to 'fight the disease as she had so much to live for' .In the case of Mr. Y, he was upset about the fact that he had developed post transplant diabetes and thought that this was not explained to him properly at the time. I do not know whether this knowledge might have affected Mr. Y's adherence to his corticosteroids therapy. As a potential prescriber of drugs, I realise that I might have to prescribe drugs which might have adverse effect in patients of which they might not be too pleased with. I will have to try and maintain a balance and explain to patients what this effect might be so that I could reach a concordance with the patients.

Breaking Bad News

The way, place and when bad news is broken to patient is vey important as patients will often hang on to any hope. The news needs to be broken in such a way that it does not give patients or their families false hopes but at the same time it does not make them feel like it is an immediate death sentence. Whilst speaking to her husband, he told me that the death came as quite a shock even though they new she had cancer. This was because he had supposedly been told that the she could live for 7 to 10 years after diagnoses; perhaps this was given as a statistic that Mr. Y had misinterpreted. I understand that in future, I will need to be weary of the language I use whilst breaking news to patient and be careful about inference as patients might understand it differently. According to the GMC guidelines, the information patients have a right to know about their disease or conditions include diagnoses, prognosis, treatment options, likely time scale of treatments, outcomes of treatment, common and/or serious side effects of treatment and costs where relevant. Although I will need to respect patients' autonomy if they request not to want to know the details about any one of this information.

Dying and Bereavement

Patients who are dying go through a range of emotions which include denial, anger, bargaining, depression and acceptance. Not all patients experience all of this. Although death is inevitable in everyone, the sudden awareness that is probably sooner than later in patients facing death makes it difficult for them. When I met Mrs. Z, she appeared to have accepted what was happening to her. She said although the topic has not been discussed with her husband, she has come to accept that she is dying. Even though I felt awkward discussing death and dying with Mrs. Z, she seemed very comfortable discussing this topic with me. I realize that in my future practise, I will need to be sensitive to people with regards to discussing this issue and be wary that culture and religion might influence the willingness of patients to talk about death.

The grieving process may include shock, disbelief, guilt, anger, apathy, exhaustion, anxiety, depression, and disorganisation. Their needs to be an aim to let the grieving person or people accept death and learn to cope without the person who has died. There is a range of ways in which different people mourn. With Mrs. Z's husband, it appeared that he was coping well eventually without his wife. After discussing with him, I realised that there was much that meets the eye. 30 years after he had quit smoking, he has suddenly started smoking again. Perhaps, for him, thuis was a coping strategy but this is not necessarily good for his health. Also, his broken legs have taken longer to heal. Although Mr. Z was not my patient, I learnt a lot from him on the consequence of death in the lives of patients' family.

Reviewing the evidence

I will be reviewing one Meta analysis that I found whilst researching for evidence in my dissertation. I found out that all renal transplant recipients are given statins for the prevention of cardiovascular complications. I used the Ovid database to search for the evidence. My search terms were statins, kidney, transplant and transplantation. I used the Boolean operator 'or' for between transplant and transplantation; I then used 'and' as a Boolean operator for the result of that with statins, kidney. My limits were English language, adults, humans and Meta analysis. This provided me with four results from which I chose one after reading their abstract to check relevance. The study I chose was HMG CoA reductase inhibitors (statins) for kidney transplant recipients (40). The other results did not define the problem I wanted to review. After reading the article, I was able to deduce that it was a good study but could have been better. The objective of the study was very well defined. Their method was also properly explained and their results easy to understand. The outcome of the study was that statins reduced cholestrol level when compared to placebo but did not decrease all course mortality. Although their inclusion and exclusion criteria were very well defined, they used all randomised control trials which meant that they used good quality of studies. The only problem was that within each trial that was included in the Meta analysis, their randomisation and blinding was not very clear although they did point this out in their weaknesses. Could they have only chosen studies with strictly defined randomisations and those that were perhaps double blinded? I think that this might have significantly reduced the number of patients included in the study but again it might have improved the quality. As this was published this year, I think that in a few years time, there would have been more studies around. In the future, I will not only need to use evidence based medicine but also be able to interpret it appropriately. More patients are becoming experts in their disease, the media is also playing their parts in exaggerating research findings; hence I will need to be able to explain to patients why the reason behind my action with regards to their management and/ or treatment.

Conclusion

The process of writing this dissertation has provided me with an incredible learning experience. I have improved my history taking skills and have appreciated the doctor patient relationship. I also realised that whilst in their house, patients are more comfortable with communicating with you but I really found this aspect difficult as I do not like invading people's privacy. I was able to learn in more detail about both of my patients' diseases but even more importantly, the psychological impact of ill health on patients. Both CKD and MM are ongoing disease but the rate in which they progress is very different as I have noticed in both my patients. With the advancement in medicine, CKD can be well managed though the morality rate is still on the high side due to its several complications. Renal transplantation provides the best option for patients with end stage CKD but this option has its limit in the number of kidneys available. There is multiple factor with regards to MM's prognoses. Patients can survive from as little as three months from diagnoses to fifteen years. Research is still ongoing in trying to find the best treatment for MM that will improve the survival outlook for these patients. I will need to be aware that there might be several problems with regards to recognising patients' psychological problems but I need to overcome this by clearly paying attention to them. I hope to be able to improve on my weaknesses through learning in a reflective manner.

Patient Contact Log Patient Y - NS, 40 year old male, chronic renal failure: Patient Z - SC, 58 year old female, myeloma: Abbreviations ADH -Anti Diuretic hormone MM -Multiple myeloma CKD -Chronic kidney disease GFR -Glomerular Filteration rate eGFR -Estimated glomerular filtration rate PTH -Para-thyroid hormone FBC -Full blood count ESR -Erythrocyte sesimentation rate U&E - Urine and Electrolytes BUN -Blood, urean and nitrogen RBC -Red blood cells MGUS -Monoclonal gammopathy of undetermined significance ESRD -End stage renal disease GP -General practitioner SCT -Stem cell transplantation MP -Melphalan and prednisolone VAD -Vincristine, adriamycin and dexamethasone

Bibliogragy

(1) Scambler G. Sociology as applied to medicine. 6th ed. Edinburgh: Saunders; 2008.

(2) CKD Forum British Renal Society Available at: http://www.britishrenal.org/CKD/ckdforum.shtml. Accessed 9/30/2009, 2009.

(3) Nice guidance : Chronic kidney disease. Available at: http://guidance.nice.org.uk/CG73. Accessed 10/2/2009, 2009.

(4) Zaidi AA, Vesole DH. Multiple Myeloma: An Old Disease with New Hope for the Future. Available at: http://caonline.amcancersoc.org/cgi/content/full/51/5/273#SEC2. Accessed 9/30/2009, 2009.

(5) Kumar PJ, Clark ML. Clinical medicine. 6th ed. Edinburgh: Elsevier Saunders; 2005.

(6) McMillan JI. Chronic Kidney Disease (Chronic Renal Failure): Renal Failure: Merck Manual Professional. Available at: http://www.merck.com/mmpe/sec17/ch233/ch233c.html?qt=chronic kidney&alt=sh#sec17-ch233-ch233c-674. Accessed 10/1/2009, 2009.

(7) Sorenson SM, Gentili A, Masih S, Andrews CL. Multiple Myeloma: Imaging - eMedicine Radiology. Available at: http://emedicine.medscape.com/article/391742-imaging. Accessed 10/1/2009, 2009.

(8) Multiple Myeloma: An Old Disease with New Hope for the Future -- Zaidi and Vesole 51 (5): 273 -- CA: A Cancer Journal for Clinicians Available at: http://caonline.amcancersoc.org/cgi/content/full/51/5/273#SEC2. Accessed 9/30/2009, 2009.

(9) Copstead LE, Banasik JL. Pathophysiology : biological and behavioral perspectives. 2nd ed. Philadelphia, Pa. ; London: Saunders; 2000.

(10) Rad A. renin-angiotensin-aldosterone system. 2009;2009(September/29).

(11) Berenson JR. Merck manuals online, Multiple myeloma. 2008; Available at: http://www.merck.com/mmpe/sec11/ch144/ch144e.html. Accessed 29/09, 2009.

(12) Dvorak C. Common complaints, difficult diagnosis: multiple myeloma. J.Am.Acad.Nurse Pract. 2006 May;18(5):190-194.

(13) Gertz MA, Greipp PR. Hematologic malignancies : multiple myeloma and related plasma cell disorders. Berlin: Springer; 2004.

(14) Atkins RC. The epidemiology of chronic kidney disease. Kidney International - Supplement 2005 Apr(94):S14-8.

(15) National Kidney Foundation: Professionals Available at: http://www.kidney.org/professionals/. Accessed 10/2/2009, 2009.

(16) Etiology of Multiple Myeloma: A Case-Control Study - Full Text View - ClinicalTrials.gov Available at: http://clinicaltrials.gov/ct2/show/NCT00505999. Accessed 9/30/2009, 2009.

(17) Goedert JJ, Cote TR, Virgo P, Scoppa SM, Kingma DW, Gail MH, et al. Spectrum of AIDS-associated malignant disorders Lancet 1998 Jun 20;351(9119):1833-1839.

(18) Rajkumar SV, Kyle RA. Treatment of multiple myeloma and related disorders. Cambridge: Cambridge University Press; 2009.

(19) Pereira BJG, Sayegh MH, Blake PG. Chronic kidney disease, dialysis, and transplantation : a companion to Brenner and Rector's the kidney. 2nd ed. Philadelphia, Pa.: Elsevier Saunders; 2005.

(20) Department of Health. National Service Framework for Renal Services - Part Two: Chronic kidney disease, acute renal failure and end of life care : Department of Health - Publications. Available at: http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4101902. Accessed 9/30/2009, 2009.

(21) McCullough PA, Li S, Jurkovitz CT, Stevens L, Collins AJ, Chen SC, et al. Chronic kidney disease, prevalence of premature cardiovascular disease, and relationship to short-term mortality. Am.Heart J. 2008 Aug;156(2):277-283.

(22) Van hooff JP, Christiaans MHL, Van duijnhoven EM. Evaluating mechanisms of post-transplant diabetes mellitus. Nephrology Dialysis Transplantation 2004 December;19(Supplement 6):8-12.

(23) Walczak DA, Calvert D, Jarzembowski TM, Testa G, Sankary HN, Thielke J, et al. Increased risk of post-transplant diabetes mellitus despite early steroid discontinuation in Hispanic kidney transplant recipients. Clin.Transplant. 2005 August;19(4):527-531.

(24) Leukaemia Research Available at: http://www.lrf.org.uk/en/1/home.html. Accessed 10/3/2009, 2009.

(25) Rajkumar SV, Rosinol L, Hussein M, Catalano J, Jedrzejczak W, Lucy L, et al. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. Journal of Clinical Oncology 2008 May 1;26(13):2171-2177.

(26) Birgegard G, Gascon P, Ludwig H. Evaluation of anaemia in patients with multiple myeloma and lymphoma: findings of the European CANCER ANAEMIA SURVEY. Eur.J.Haematol. 2006 Nov;77(5):378-386.

(27) Offidani M, Corvatta L, Polloni C, Piersantelli MN, Gentili S, Galieni P, et al. Thalidomide-dexamethasone versus interferon-alpha-dexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a prospective, multicentre, randomised study. Br.J.Haematol. 2009 Mar;144(5):653-659.

(28) Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, et al. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Annals of Oncology 2007 Aug;18(8):1369-1375.

(29) Crother MA, Ginsber J, Schunemann HJ, Meyer RM, Lottenberg R. Evidence-based Hematology. First ed.: Wiley-Blackwell; 2008.

(30) Welcome to the National Institute for Health and Clinical Excellence Available at: http://www.nice.org.uk/. Accessed 10/3/2009, 2009.

(31) Dingli D, Rajkumar SV, Nowakowski GS, Gertz MA, Dispenzieri A, Lacy MQ, et al. Combination therapy with thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma not undergoing upfront autologous stem cell transplantation: a phase II trial. Haematologica 2005 Dec;90(12):1650-1654.

(32) Stadtmauer EA, Weber DM, Niesvizky R, Belch A, Prince MH, San Miguel JF, et al. Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma. Eur.J.Haematol. 2009 Jun;82(6):426-432.

(33) Meguid El Nahas A, Bello AK. Chronic kidney disease: the global challenge. Lancet 2005 Jan 22-28;365(9456):331-340.

(34) Boddana P, Caskey F, Casula A, Ansell D. UK Renal Registry 11th Annual Report (December 2008): Chapter 14 UK Renal Registry and international comparisons. Nephron 2009;111(Suppl 1):269-276.

(35) Hsu CY. Linking the population epidemiology of acute renal failure, chronic kidney disease and end-stage renal disease. Current Opinion in Nephrology & Hypertension 2007 May;16(3):221-226.

(36) EastMidlandsRenalNetwork.org.uk Available at: http://www.emrn.org.uk/display/templatedisplay1.asp?sectionid=408. Accessed 10/5/2009, 2009.

(37) Cancer Research UK : CancerStats Available at: http://info.cancerresearchuk.org/cancerstats/. Accessed 9/30/2009, 2009.

(38) Hallan SI, Dahl K, Oien CM, Grootendorst DC, Aasberg A, Holmen J, et al. Screening strategies for chronic kidney disease in the general population: follow-up of cross sectional health survey BMJ 2006;333(7577):1047 1047.

(39) UK Screening Programme. Available at: http://www.screening.nhs.uk/. Accessed 10/2/2009, 2009.

(40) Navaneethan SD, Perkovic V, Johnson DW, Nigwekar SU, Craig JC, Strippoli GF. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database of Systematic Reviews 2009(2):005019.

Please be aware that the free essay that you were just reading was not written by us. This essay, and all of the others available to view on the website, were provided to us by students in exchange for services that we offer. This relationship helps our students to get an even better deal while also contributing to the biggest free essay resource in the UK!