Example of a University Clinical Case Study

1. Case Study Summary

An 89 year old male was admitted to hospital following an unwitnessed fall. Past medical history includes sick sinus syndrome, atrial fibrillation, bradycardia, repeated falls in the last six months, pacemaker implantation, acute kidney failure and chronic kidney disease. At present his symptoms include end stage renal failure, hypervolemia, delirium and a chest infection. The patient also reports feeling dizzy, blurred vision, dehydrated and fatigued. 

The patient is also bed bound, doubly incontinent and dependant on staff for all daily living activities. A mental capacity assessment was performed and a depravation of liberty application is in place. The patient is retired and lives alone within the micro-living environment of a two story house. 

Objective markers report a heart rate of 41 bpm, blood pressure 90/60 mmHg, Oxygen saturation 92% and urine output at below 0.3 ml/kg/hour for over 24 hours. Current medication includes AD Cal D3 750mg twice per day, fludrocortisone 50-250 mgs once per day (morning) and intravenous co amoxiclav 625 mgs three times per day, then same dose administered orally for another three days. Current intervention is a reduction in fluid intake to manage hypervolemia and oxygen therapy one to two litres per minute via nasal cannula. Chest physiotherapy is also required for clearance of mucus from chest infection. Projected outcome is for multidisciplinary team to discuss end of life care plan and final discharge destination.

2. Patients History and Clinical Pathophysiology

Repeated falls as a result of bradycardia instigated a systemic pathophysiological response. Then as a result of unsuccessful interventions, the patient remained in hospital until treatment became unviable and he was referred to palliative care. Section two describes the patient history and clinical pathology, using scientific evidence to support and detail the sequence of events that resulted in a palliative care referral.  

2-1. Cardiovascular system

The sinus node is the hearts natural pacemaker and functions by sending regular electrical impulses to the atrium, stimulating them to contract and pump blood into the ventricles. The atrioventricular node delays this impulse to allow the ventricles to fill with blood before they to contract, thus creating a steady rhythm of the heart. Sulem et al¹ concluded that age related dysfunction occurs within the sinus node leading to atrial fibrillation. The underpinning mechanism is thought to be either genetic or environmental changes. The more common environmental changes include muscular dystrophy or inflammation. On the other hand, Anderson et al² noted that genetic changes could result in sick sinus syndrome via mutations in the SCN5A and HCN4 genes. These genes are responsible for making proteins called ion channels. Mutations of these genes result in reduced transport of positively charged atoms into cardiac cells. The flow of these ions being essential for creating electrical impulse.³ 

In this patient, atrial fibrillation resulted in bradycardia with symptoms including dizziness, fainting and fatigue. These symptoms resulted in repeated falls in turn causing hospitalisation. At this point, it was determined pacemaker implantation would restore normal heart function. However, the administration of a pacemaker had little effect on heart rate and in time the patient was diagnosed with acute kidney injury (AKI), chronic kidney disease (CKD) and then end stage renal failure (ESRF).

2-2. Cardio-Renal Syndrome

Associations between cardiovascular dysfunction and kidney dysfunction have been well established within the literature and falls under the entity that is the ‘Cardio-Renal Syndrome’ (CRS).⁴ This syndrome is the theory that acute or chronic dysfunction of one organ will induce acute or chronic dysfunction of the other. CRS is therefore classified into subtypes depending on the severity and proposed primary affected organ. In this patient, failure to maintain adequate cardiac output resulted in AKI via decreased blood pressure and hypoperfusion. This would constitute a type 1 pre-renal diagnosis. This diagnosis is also supported by the patient’s delirium, as multiple organs would be affected and cerebral hypoperfusion causes symptoms of cognitive impairment and dementia.⁵  

2-3. Renal System

The kidneys function within the renal system to filter blood, excrete waste, and regulate blood volume, pressure and pH, whilst also balancing electrolytes and metabolites.⁶ As such the kidneys receive 20-25% of cardiac output, entering through the renal artery unfiltered and leaving via the renal vein cleaned. This filtration takes place within the nephron, where blood enters via the afferent arteriole and passes through a network of capillaries called the glomerulus, before leaving the glomerulus via the efferent arteriole. As this occurs, components of the blood are filtered into the Bowman’s capsule with hydrostatic perfusion pressure, before entering into the proximal convoluted tubule and continuing the process of filtration.⁷ 

The effects of inadequate cardiac output and decreased blood pressure on kidney function are multiple and complex. However, many regard the main driver to be renal congestion.⁸ In this process, low atrial pressure from deceased cardiac output leads to low renal perfusion pressure within the glomerulus. Kidney autoregulation compensates for this via the activation of the rennin-agiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS).⁹ Both systems induce glomerular arteriolar vasoconstriction to increase pressure but in turn decrease renal plasma flow. 

This reflex mechanism initially preserves the glomerular perfusion pressure and filtration rate (GFR). However, vasoconstriction is also observed in the efferent arteriole leading to pre-glomerular vasoconstriction. These alterations in haemodynamic and neuro-hormonal regulations result in sodium and water retention.¹⁰ This is due to the SNS, which stimulates the renal nerve to reabsorb sodium and water across the primary convoluted tubule to increase peripheral blood pressure. Additionally the RAAS functions to increase blood volume through the hormone angiotensinogen, released from the liver. In response, juxtaglomerular cells within the kidney synthesize and secrete the enzyme renin. When combined they form angiotensin I and through systemic circulation, renin reaches the lungs. The lungs response is to release angiotensin converting enzyme (ACE), which combines with renin to form angiotensin II. Angiotensin II also enhances reabsorption of sodium and water and effects the adrenal glands to form aldosterone.¹¹ Aldosterone in the kidney causes vasoconstriction of both the afferent and efferent arterioles. 

As a result of this process, there is a decrease in GFR and the kidneys are unable to function in the filtration and excretion of waste, as well as balancing electrolytes and metabolites. This creates a build-up of sodium and water and explains the patient’s hypervolemia.¹² Additionally, this increases the circulation of solutes including sulphate, phenol, potassium, chloride ions and hydrogen ions in the blood serum.¹³ In turn having a wider effect on the holistic wellbeing of the patient via additionally compromised physiological systems. 

2-4. Mechanism by which AKF leads to CKD

Following the explanation of heart failure causing AKI, arises the systemic process by which AKI becomes CKD. AKI is a reversible pathology, yet evidence indicates that AKI can initiate the development and accelerate the progression of CKD.¹⁴ In this patient, repeated falls from bradycardia resulted in multiple episodes of AKI. Many of which may have been reversed, however one episode resulted in the development of CKD. This due to tubulointerstitial fibrosis and tubular atrophy, which resulted in an incomplete recovery leading to persistent and progressive CKD.¹⁵ 

In this case, the pathophysiology of CKD may seem atypical to the common risk factor of hypertension.¹⁶ However without hypertension, we can theorise that the development of CKD is the result of accumulating solutes which would normally be excreted in urine. This condition being uremia.¹⁷ The imbalance of solutes caused cells within the tubular and surrounding structures to undergo apoptosis and necrosis. Therefore these cells did not regenerate, leading to nephron loss.¹⁸ 

In order to compensate for nephron loss, which would cause an overall decline in GFR, the remaining nephrons must increase performance. This is achieved through glomerular hypertrophy and hyperfiltration, which would result from peripheral hypertension.¹⁹ However, in the presence of uremia, this process of cellular proliferation becomes dysfunctional. Solutes in circulation cause tissue remodelling.²⁰ One solute in particular, indoxyl sulphate, is thought to be a primary inhibitor of fibrosis, via the augmentation of gene expression in metalloproteinase, intercellur adhesion molecule, type 1 collagen and transforming growth factor (TGF)-β.²¹ As a result, functional tissue is replaced by connective tissue, resulting in tubulointerstitial fibrosis and further nephron loss. This cycle repeats in CKD until the patient reached ESRF. 

3. Physiology Underpinning Additional Systems

Kidney failure is known to impact a number of homeostatic mechanisms and physiological processes that regulate the equilibrium between interdependent systems.²² From hereafter, section three reports the contributions of additional physiological systems that either led to the progression CKD or implications to multiple system failure. It is important to note that each system is divided into subsections, yet contributions from multiple systems are described in the pathophysiology.  

3-1. Immune System

It is well established that CKD is simultaneously associated with an immune response.²³ In this patient the immune systems key function was to remove and repair tissue that had been damaged by ischemia. The first step in this key function was an inflammatory cascade. Inflammation is the body’s natural response to infection, yet substantial evidence show this process can be maladaptive in the presence of renal failure.²⁴ A variety of factors contribute to this, including increased productions and decreased clearance of cytokines and chronic and reoccurring infections. The significance of this is the potential for systemic inflammation to result in atherosclerosis.²⁵ Not only does this outcome contribute to the progression of CKD, but also the progression of cardiovascular disease and immune disease.²⁶ 

Diminished renal clearance of cytokines is thought to be a major contributing factor to a chronic pro-inflammatory state. In addition, uremic milieu is associated with high oxidative stress, leading to an increased production of cytokines.²⁷ Systemic inflammation and oxidative stress result in endothelial dysfunction by decreasing the bioavailability of nitric oxide, and increasing the production of peroxynitrite.²⁸ This leads to oxidation of low-density lipoproteins (LDL). Monocytes form the immune system attach to oxidised LDL’s. However, a maladaptive positive feedback situation occurs when monocytes produce free radicals which oxidise more LDL’s.²⁹ Once a monocyte becomes saturated with LDL particles, it becomes a foam cell. Apoptosis occurs in these foam cells and the accumulating lipids and fragments of dead cells produce a plaque.³⁰ This plaque in the vessel wall is atherosclerosis, a major cause of cardiovascular disease.^{25, 26, 29, 30}     

Immune disease also occurs from an impaired immune response in uremia.³¹ This process is caused by abnormalities observed in monocytes, leukocytes, dendritic cells, T cells and B cells in the presence of CKD. The abnormalities include impaired chemotaxis, oxidative metabolism, phagocytic activity, degranulation and dysfunctional programmed cell death.³¹ This leads to a diminished immune response and increased incidence of recurrent infections. This pathophysiological response undoubtedly explains the patient’s chest infection, as CKD lead to an immune deficiency which in turn left the patient susceptible to infection. 

3-2. Musculoskeletal System 

Associations between kidney failure and the musculoskeletal system have been extensively documented within literature.³² In addition, this patient is bed bound yet previously independent until the onset of kidney failure. Therefore we can establish that kidney failure had an effect on this patient’s musculoskeletal system. The underpinning mechanism for this is thought to be chronic metabolic acidosis, as a result of uremia.³² 

The consequences of chronic metabolic acidosis include increased protein catabolism, decreased protein synthesis and a negative protein balance. This is due to an increase in circulating hydrogen ions and reduced bicarbonate synthesis from renal failure. Circulating hydrogen ions instigate protein degradation though increased gene transcription of the enzyme branched chain keto-acid dehydrogenase (BCKAD).³³ This enzyme degrades essential branched chain amino acids including leucine, isoleucine and valine.³³ In an optimal response to metabolic acidosis, the bicarbonate buffering system should intervene and manage hydrogen ions. However, renal failure has impaired this buffering system, leading to accelerated sarcopenia.³⁴ It has also been noted that protein catabolism also impairs the proliferation of satellite cells.³⁵ 

Secondly, metabolic acidosis is known to effect bone.³⁶ Bone not only serves as a supportive framework but also regulates blood pH though the proton buffer system. In a study by Swan and Pitts³⁶, 43% of infused acid was neutralised by the blood buffering systems, whereas 57% was neutralised by a process of exchanging sodium and potassium’s ions for hydrogen ions within the extracellular fluid of cells. From this experimental evidence, it is now clear that physico-chemical reactions are involved in the buffering of acid by bone. However in a chronic state of metabolic acidosis, this observed fall in sodium and potassium concentrations results in reduced bone mineral density. 

At the same time CKD also effects bone via altered calcium metabolism.³⁷ The underpinning mechanisms for this is secondary hyperparathyroidism (SHPT) from altered vitamin D metabolism.³⁷ Vitamin D regulates the parathyroid gland, However alterations result in the overproduction of the polypeptide parathyroid hormone (PTH). This hormone regulates calcium and phosphates, as well as homeostasis of bone metabolism. This condition is called renal osteodystrophy and refers to the pathophysiology of bone and mineral metabolism that results in bone disorders and disease.³⁸ In this process, increased PTH leads to bone breakdown via the stimulation of osteoclast activity. It has also been noted that uremia and the increased circulation of calcium leads to vascular and soft tissue calcification, provided further explanations for cardiovascular disease.  

3.3 Neurological System

As touched on earlier, this patient is experiencing cerebral hypoperfusion, with signs of cognitive impairment. One symptom, delirium, is characterised by an acute decline in brain function. It is often associated with fatigue, impaired concentration and motor impairment. The mechanisms for this include disturbances to the central nervous system (CNS) and peripheral nervous system (PNS). 

Uremic toxins have long been recognised as the cause of CNS injury in CKD patients.³⁹ The underpinning physiology for this can either be direct or indirect. The indirect effects occurs from systemic inflammation, endothelial dysfunction and atherosclerosis, mentioned earlier. This pathophysiology is termed ‘the vascular hypothesis to cognitive impairment’.⁴⁰ On the other hand, the direct effects can be explained by the observed increase in brain calcium content in CKD patients. This direct pathophysiology is termed ‘the neurodegenerative hypothesis of cognitive impairment’.⁴¹ 

In the vascular hypothesis to cognitive impairment, endothelial dysfunction leads to cerebral small vessel disease. This disease in turn leads to white matter lesions, which have been known to cause silent or asymptomatic cerebrovascular accidents, white matter disease and/or leukoariosis.⁴² All these conditions are linked with cognitive and physical decline, and explain alternate reasons for the symptom and outcomes displayed in this patient. 

The direct effect of uremic toxins, otherwise known as the neurodegenerative hypothesis of cognitive impairment. Is based on increased brain calcium content. Calcium is an intracellular messenger that facilitates brain function. In the condition of uremia, oxidative stress and lipid peroxidation promotes membrane depolarisation and calcium influx. This increases brain calcium content and renders neurons vulnerable to calcium mediated excitotoxicity.⁴³  

Secondary mechanisms to neurological impairment include pro-inflammatory cytokines, which may directly cause malnutrition via influences on the brain.⁴⁴ This is due to the suppression of hunger, resulting in energy conservation within the digestive system that would otherwise consume energy needed to develop an immune response. This could therefore be an alternative explanation for the patient symptoms of fatigue, dizziness, delirium and bed bound state. 

Considering this patient holistically, cognitive impairment is accompanied with feeling of confusion, fear and anger amongst others. At the same time cognitive impairment is often associated with memory loss and impaired decision making, often manifesting in a resistance to care. This brings into question the patients has ability to make rational decisions on his health care. As a result a mental capacity assessment was performed and a depravation of liberty application is in place. 

3-4. Respiratory System

As mentioned earlier, this patient is suffering from an infection due to an immune deficiency. In addition to this, the patient is also bed bound due to the effects of CKD on multiple systems. These outcomes, along with the symptoms of hypervolemia; left the patients highly susceptible to contracting a chest infection. 

Non-cardiogenic pulmonary edema in CKD patients, is caused by the inability to excrete fluid.⁴⁵ As a result, fluid build-up in blood vessels increases hydrostatic pressure within the pulmonary capillaries. Therefore fluid is secreted into the lungs interstitial space. This condition has been termed ‘uremic lung’.⁴⁵ At the same time the patient is constantly inhaling pathogens, which the already weakened immune system must fight off. Bacteria thrives in water which therefore further increases the probability of infection.⁴⁶ As a result, gas exchange becomes severely compromised which creates a build-up of carbon dioxide and reduction in oxygen. This further induces metabolic acidosis and if left untreated also leads to respiratory failure.⁴⁷

On a larger scale the effects of respiratory failure, uremic lung, infection and mucus production are likely to induce stress and panic. Further exacerbating chronic inflammation, immune deficiency and metabolism abnormalities, via the effects of chronic stress on homeostasis.⁴⁸     

3-5. Endocrine system

In addition to the RAAS system mentioned earlier, endocrine abnormalities arise from a number of different causes in CKD patients. These abnormalities include the secretion of erythropoietin (EPO), vitamin D metabolites (mentioned earlier), hypothalamic-pituitary-gonadal axis and the growth hormone and insulin like growth factor axis.⁴⁹ The cause of these abnormalities include direct effects of kidney failure or secondary effects of inflammation, metabolic acidosis and malnutrition.⁴⁹ 

Following hypoperfusion, the renal system synthesises hypoxia inducible factor (HIF) and activates the EPO gene. This would normally enhance oxygen carrying capacity via increased haemoglobin concentration. However, in the presence of chronic inflammation the renal system is unable to secrete EPO, leading to the condition known as anaemia.⁵⁰ Furthermore, inflammation suppresses anabolic hormones, such as growth hormones and testosterone. In this state, increased suppression of cytokine signalling is used to combat chronic inflammation. However this results in suppression of growth hormone signal transduction. This is of particular interest in adolescents, as this pathophysiology suppresses growth in children.⁵¹ 

Conversely in this patient, the significance is more associated with the growth hormone and insulin like growth factor axis’s effects on cellular proliferation.⁵² In this opposing process, the hypothalamus stimulates growth hormone release due to increased amino acids or decreased glucose in the circulation blood. For this patient uremia and malnutrition would instigate this process. Growth hormone then stimulates cell proliferation, cell movement and angiogenesis, whilst also suppressing apoptosis. The severe consequences of this opposing process could stimulate neoplasia and carcinogenesis.⁵³  

Lastly, In CKD patients the hypothalamic-pituitary-gonadal axis directly effects the reproduction system. In a typical disease process, CKD leads to increased levels of gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH), which would otherwise be secreted in the urine. In turn this leads to impairments in ovulation or spermatogenesis, resulting in infertility.⁵⁴ 

4. References 

1. Sulem P, Holm H, Gudbjartsson D, inventors; deCode Genetics EHF, Illumina Inc., assignee. Genetic risk factors of sick sinus syndrome. United States patent application US 13/988,268. 2013 Dec 19.
2. Anderson JB, Benson DW. Genetics of sick sinus syndrome. Cardiac electrophysiology clinics. 2010 Dec 1; 2(4):499-507.
3. Chandler NJ, Greener ID, Tellez JO, Inada S, Musa H, Molenaar P, Francesco D, Baruscotti M, Longhi R, Anderson RH, Billeter R. Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker. Circulation. 2009 Mar 31; 119(12):1562-75.
4. Aoun M, Tabbah R. Case report: severe bradycardia, a reversible cause of “Cardio-Renal-Cerebral Syndrome”. BMC nephrology. 2016 Dec; 17(1):162.
5. Meyer JS, Rauch G, Rauch RA, Haque A. Risk factors for cerebral hypoperfusion, mild cognitive impairment, and dementia. Neurobiology of aging. 2000 Mar 1; 21(2):161-9.
6. Humes HD, Buffington DA, MacKay SM, Funke AJ, Weitzel WF. Replacement of renal function in uremic animals with a tissue-engineered kidney. Nature biotechnology. 1999 May; 17(5):451.
7. Tryggvason K. Unravelling the mechanisms of glomerular ultrafiltration nephrin, a key component of the slit diaphragm. Journal of the American Society of Nephrology. 1999 Nov 1; 10(11):2440-5.
8. Damman K, Navis G, Smilde TD, Voors AA, van der Bij W, van Veldhuisen DJ, Hillege HL. Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. European journal of heart failure. 2007 Sep; 9(9):872-8.
9. Viswanathan G, Gilbert S. The cardio-renal syndrome: making the connection. International journal of nephrology. 2011; Sep 1-10.
10. Martin PY, Schrier RW. Sodium and water retention in heart failure: pathogenesis and treatment. Kidney International Supplement. 1997 Jun 2(59).
11. Brewster UC, Perazella MA. The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease. The American journal of medicine. 2004 Feb 15; 116(4):263-72.
12. Hung SC, Kuo KL, Peng CH, Wu CH, Lien YC, Wang YC, Tarng DC. Volume overload correlates with cardiovascular risk factors in patients with chronic kidney disease. Kidney international. 2014 Mar 1; 85(3):703-9.
13. Vanholder R, De Smet R, Glorieux G, Argilés A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, Descamps-Latscha B. Review on uremic toxins: classification, concentration, and interindividual variability. Kidney international. 2003 May 1; 63(5):1934-43.
14. Hsu CY. Yes, AKI truly leads to CKD. Journal of the American Society of Nephrology. 2012 Jun 1; 23(6):967-9.
15. Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. Journal of the American Society of Nephrology. 2010 Nov 1; 21(11):1819-34.
16. Collins AJ, Vassalotti JA, Wang C, Li S, Gilbertson DT, Liu J, Foley RN, Chen SC, Arneson TJ. Who should be targeted for CKD screening? Impact of diabetes, hypertension, and cardiovascular disease. American Journal of Kidney Diseases. 2009 Mar 1; 53(3):S71-7.
17. Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, Argiles A. Normal and pathologic concentrations of uremic toxins. Journal of the American Society of Nephrology. 2012 May 24:1-75.
18. Hodgkins KS, Schnaper HW. Tubulointerstitial injury and the progression of chronic kidney disease. Pediatric nephrology. 2012 Jun 1; 27(6):901-9.
19. Schmitz A, Christensen T, Jensent FT. Glomerular filtration rate and kidney volume in normoalbuminuric non-insulin-dependent diabetics-lack of glomerular hyperfiltration and renal hypertrophy in uncomplicated NIDDM. Scandinavian journal of clinical and laboratory investigation. 1989 Jan 1; 49(2):103-8.
20. Mutsaers HA, Stribos EG, Glorieux G, Vanholder R, Olinga P. Chronic kidney disease and fibrosis: the role of uremic retention solutes. Frontiers in medicine. 2015 Aug 31; 2:60.
21. Miyazaki T, Aoyama I, Ise M, Seo H, Niwa T. An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF‐β 1 in uraemic rat kidneys. Nephrology Dialysis Transplantation. 2000 Nov 1; 15(11):1773-81.
22. Williams DM, Sreedhar SS, Mickell JJ, Chan JC. Acute kidney failure: a pediatric experience over 20 years. Archives of pediatrics & adolescent medicine. 2002 Sep 1; 156(9):893-900.
23. Hauser AB, Stinghen AE, Kato S, Bucharles S, Aita C, Yuzawa Y, Pecoits-Filho R. Characteristics and causes of immune dysfunction related to uremia and dialysis. Peritoneal Dialysis International. 2008 Jun 1; 28:183-7.
24. Cohen G, Hörl W. Immune dysfunction in uremia—an update. Toxins. 2012 Nov; 4(11):962-90.
25. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. New England Journal of Medicine. 2005 Apr 21; 352(16):1685-95.
26. Recio-Mayoral A, Banerjee D, Streather C, Kaski JC. Endothelial dysfunction, inflammation and atherosclerosis in chronic kidney disease–a cross-sectional study of predialysis, dialysis and kidney-transplantation patients. Atherosclerosis. 2011 Jun 1; 216(2):446-51.
27. Libetta C, Sepe V, Esposito P, Galli F, Dal Canton A. Oxidative stress and inflammation: implications in uremia and haemodialysis. Clinical biochemistry. 2011 Oct 1; 44(14-15):1189-98.
28. Clapp BR, Hingorani AD, Kharbanda RK, Mohamed-Ali V, Stephens JW, Vallance P, MacAllister RJ. Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress. Cardiovascular research. 2004 Oct 1; 64(1):172-8.
29. Martinet W, Kockx MM. Apoptosis in atherosclerosis: focus on oxidized lipids and inflammation. Current opinion in lipidology. 2001 Oct 1; 12(5):535-41.
30. Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nature Reviews Cardiology. 2010 Feb; 7(2):77.
31. Kurts C, Panzer U, Anders HJ, Rees AJ. The immune system and kidney disease: basic concepts and clinical implications. Nature Reviews Immunology. 2013 Oct; 13(10):738.
32. Wolff AE, Jones AN, Hansen KE. Vitamin D and musculoskeletal health. Nature Reviews Rheumatology. 2008 Nov; 4(11):580.
33. Kopple JD, Kalantar-Zadeh K, Mehrotra R. Risks of chronic metabolic acidosis in patients with chronic kidney disease. Kidney International. 2005 Jun 1; 67:S21-7.
34. Pereira RA, Cordeiro AC, Avesani CM, Carrero JJ, Lindholm B, Amparo FC, Amodeo C, Cuppari L, Kamimura MA. Sarcopenia in chronic kidney disease on conservative therapy: prevalence and association with mortality. Nephrology Dialysis Transplantation. 2015 May 21; 30(10):1718-25.
35. Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M. Mechanisms regulating skeletal muscle growth and atrophy. The FEBS journal. 2013 Sep 1; 280(17):4294-314.
36. Swan RC, Pitts RF, Madisso H. Neutralization of infused acid by nephrectomized dogs. The Journal of clinical investigation. 1955 Feb 1; 34(2):205-12.
37. Winkelmayer WC, Levin R, Avorn J. The nephrologist’s role in the management of calcium-phosphorus metabolism in patients with chronic kidney disease. Kidney international. 2003 May 1; 63(5):1836-42.
38. Moe S, Drüeke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lameire N, Eknoyan G. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney international. 2006 Jun 1; 69(11):1945-53.
39. Herget‐Rosenthal S, Glorieux G, Jankowski J, Jankowski V. Progress in uremic toxin research: uremic toxins in acute kidney injury. InSeminars in dialysis 2009 Jul (Vol. 22, No. 4, pp. 445-448). Oxford, UK: Blackwell Publishing Ltd.
40. Werring DJ, Gregoire SM, Cipolotti L. Cerebral microbleeds and vascular cognitive impairment. Journal of the neurological sciences. 2010 Dec 15; 299(1-2):131-5.
41. Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA. Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. Journal of the American Society of Nephrology. 2013 Mar 1; 24(3):353-63.
42. Breteler MM, Van Swieten JC, Bots ML, Grobbee DE, Claus JJ, Van Den Hout JH, Van Harskamp F, Tanghe HL, De Jong PT, Van Gijn J, Hofman A. Cerebral white matter lesions, vascular risk factors, and cognitive function in a population‐based study The Rotterdam Study. Neurology. 1994 Jul 1; 44(7):1246-1253.
43. Choi DW. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends in neurosciences. 1988 Jan 1; 11(10):465-9.
44. Kalantar-Zadeh K, Block G, McAllister CJ, Humphreys MH, Kopple JD. Appetite and inflammation, nutrition, anemia, and clinical outcome in haemodialysis patients. The American journal of clinical nutrition. 2004 Aug 1; 80(2):299-307.
45. Zoccali C, Torino C, Tripepi R, Tripepi G, D’Arrigo G, Postorino M, Gargani L, Sicari R, Picano E, Mallamaci F, Lung US in CKD Working Group. Pulmonary congestion predicts cardiac events and mortality in ESRD. Journal of the American Society of Nephrology. 2013 Apr 1; 24(4):639-46.
46. Keith SC. Factors influencing the survival of bacteria at temperatures in the vicinity of the freezing point of water. Science. 1913 Jun 6; 37(962):877-9.
47. Doi K, Ishizu T, Fujita T, Noiri E. Lung injury following acute kidney injury: kidney–lung crosstalk. Clinical and experimental nephrology. 2011 Aug 1; 15(4):464-70.
48. Chovatiya R, Medzhitov R. Stress, inflammation, and defense of homeostasis. Molecular cell. 2014 Apr 24; 54(2):281-8.
49. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, Andress DL. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney international. 2007 Jan 1; 71(1):31-8.
50. Silverberg DS, Wexler D, Blum M, Tchebiner JZ, Sheps D, Keren G, Schwartz D, Baruch R, Yachnin T, Shaked M, Schwartz I. The effect of correction of anaemia in diabetics and non‐diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrology Dialysis Transplantation. 2003 Jan 1; 18(1):141-6.
51. Tsigos C, Chrousos GP. Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. Journal of psychosomatic research. 2002 Oct 1; 53(4):865-71.
52. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nature Reviews Cancer. 2008 Dec; 8(12):915.
53. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M. Circulating concentrations of insulin-like growth factor I and risk of breast cancer. The Lancet. 1998 May 9; 351(9113):1393-6.
54. Anantharaman P, Schmidt RJ. Sexual function in chronic kidney disease. Advances in chronic kidney disease. 2007 Apr 1; 14(2):119-25.