Chronic renal failure

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Chronic kidney disease (CKD) defines a broad spectrum of disorders that disturb the structural or functional integrity of the kidney. Given the variety of underlying etiologies, varying severity, and different rates of progression the term only loosely outlines a very complex group of diseases. In 2000, a new definition of chronic kidney disease was introduced that ushered a shift from considering the disease an end-stage life threatening entity to a more prevalent entity of variable stages requiring early detection and preventative measures, in addition to management. ^[1] CKD was defined as: ^[2]

The KDOQI work group also recognized persons with a GFR between 60 to 89 mL/min/1.73 m2 without any evidence of kidney damage as having decreased GFR with several possible etiologies: ^[2]

• Age (infants and older adults)
• Vegetarian diet
• Unilateral nephrectomy
• Extracellular volume depletion
• Reduced kidney perfusion (heart failure and cirrhosis)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]Feham Tariq, MD [3]Leena Josephin Jetty, M.B.B.S[4]

The pathophysiologic mechanisms leading to chronic kidney disease stem from the underlying etiologies responsible for the primary renal damage. Maladaptive systemic and renal responses arise that maintain and perpetuate the existing renal disease. Broadly, 3 main mechanisms exist that are related in part to the activation of the RAAS: hyperfiltration, inflammation, and accelerated fibrosis. As loss of kidney function progresses, nitrogen waste products are no longer cleared by the kidneys, and patients develop uremia as these uremic solutes accumulate over time.

• The pathophysiologic mechanisms that lead to chronic kidney disease (CKD) stem from the underlying etiologies responsible for the primary renal damage.
• The initial insult is responsible for a decrease in the number of functional nephrons.
• However, beyond that initial insult, a form of maladaptive systemic and renal response arise that maintains and perpetuates the existing renal disease.
• With the activation of the renin-angiotensin-aldosterone system (RAAS), a combination of mechanisms herald a progressive loss of nephrons.
• Broadly, 3 main mechanisms exist related in part to the activation of the RAAS which are as follows:
  • Hyperfiltration
  • Inflammation
  • Accelerated fibrosis

• The landmark works of Brenner et al were the first to propose the maladaptive changes that occur after renal injury.
• The team showed that after significant loss of nephron mass, major alterations in glomerular hemodynamics occur.
• The changes lead to glomerular hypertension with an increase in single nephron glomerular filtration rate termed hyperfiltration.^[1]
• Hyperfiltration is a direct result of the increase in glomerular plasma flow and hydrostatic pressure in response to a decrease in preglomerular arteriolar resistance more than the decrease in postglomerular resistance with a net vasocontrictive effect on the efferent arteriole.^[2]
• The observed alterations occur due to the activation of the RAAS system.
• Initially, the juxtaglomerular apparatus increases the release of renin in response to the decreased perfusion pressure and solute delivery to the macula densa. Renin converts angiotensinogen to angiotensin I which is then converted to angiotensin II is then produced by angiotensin converting enzyme (ACE).
• Angiotensin II has been shown to be the main perpetrator in the maladaptation of the kidney to significant damage.^[3]

• Most animal models exploring glomerular hypertension and hyperfiltration show progressive glomerular sclerosis and eventual proteinuria that usually occurs at a linear rate compared to the extent of nephron loss.^[4][1][5][6]
• Furthermore, studies examining the prevention or reduction of glomerular hypertension and single nephron GFR have almost invariably shown a reduction in the rate of progression of renal disease.^[7][8]
• Among the proposed interventions include dietary protein restriction, ACE inhibitors, and angiotensin receptor blockers (ARBs).^[9]

• Angiotensin II has also been linked to and increase in inflammation after renal injury.
• It has been shown to activate the transcription factor NF-κB, an important player in the inflammatory response mediating transcription of several cytokines and chemokines.^[10]
• ATII has also been shown to stimulate endothelin-1 leading to the recruitment of T-cells and macrophages.^[11]
• Beyond that, it upregulates the expression of adhesion molecules notably integrins, intracellular adhesion molecule-1, and vascular cellular adhesion molecule-1 all of which lead to and increase in leukocyte concentration in the area.^[3]
• This creates a vicious cycle as lymphocytes can be a source of angiotensin II themselves amplifying its maladaptive effects.^[12][13]

• The increase in angiotensin II has also been directly associated with accelerated fibrosis in the remaining nephrons independently of the hemodynamic changes.
• Angiotensin II is thought to exert direct effects in the glomerular micromilieu leading to extracellular matrix (ECM) expansion.
• Angiotensin II has been shown to increase mRNA encoding type I procollagen and fibronectin in cultured mesangial cells.
• This effect is multiplied by the increase in expression of TGF-β further activating ECM protein production.^[14]
• In normal renal tissue, the balance between ECM synthesis and degradation is essential to prevent fibrotic glomerular changes.
• Beyond the increase in ECM production, angiotensin II also disrupts this balance.
• Via ATI receptors, it activates tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) both of which shift the balance towards ECM accumulation.^[3]
• Another method of accelerated fibrosis is a process called epithelial-to-mesenchymal transition (EMT) where tissue epithelial cells transform into active fibroblasts.
• Although previously recognized as a physiologic mechanism during embryologic development, it has come to light as a process that provides fibroblasts during organ fibrosis after injury.
• Experimentally, more than one third of fibroblast at the site of renal injury were shown to originate from the renal tubular epithelial cells.
• The prototypical factor linked to EMT is TGF-β which is usually elevated after renal injury; however, other local factors also induce EMT including epidermal growth factor (EGF), Insulin growth factor II (IGF-II), and fibroblast growth factor (FGF-2).^[15]

• The CKD poses a major public health challenge that affects roughly 800 million people globally.But many a times the cause for CKD is difficult to identify just based on clinical diagnosis. With the emerging idea that genetics play a significant role in the causation of CKD the KIDGO  The (Kidney Disease: Improving Global Outcomes organization  is advising physicians to consider genetic testing for patients with CKD to pinpoint the diagnosis and to tailor their management accordingly.

• The first gene connected with kidney disease was the locus for APCKD. Since then hundreds of genes have been identified.Several factors like the pattern in which the CKD cluster in certain racial and ethnic groups suggests genetic contributions.
• Even when a clinical phenotype based diagnosis supports a genetic cause ,it is suggested to get a variant-based diagnosis because it establishes precise cause which further can help personalised monitoring and treatment and for effective genetic family counselling.
• The genetic risk of CKD can be viewed as a spectrum of low penetrance to high penetrance variants.
• The diseases at the high end of the spectrum, the Mendelian diseases have tight genotype-phenotype correlations.
• In contrast the low penetrance variants are influenced by environmental factors.

Cystic kidney diseases are mostly due to ciliopathies, caused by alterations in the cilium-centrosome complex.Clinical phenotypes include

• • Multiple renal cysts as in ADPKD
  • Normal size or small echogenic kidneys as in Nephronophthisis.

• Genotype-phenotype correlation studies show that truncated PKD1 variants are associated with more severe disease when compared to PKD1 missense and PKD2 variants.
• Recently several genes have been implicated in rare cases of ADPKD.These include  IFT140, GANAB, NEK8, and DNAJB11 .

• Nephronophthisis is a group of genetically heterogeneous autosomal recessive diseases characterized by nonspecific, progressive deterioration in kidney function. 
• It can occur at any age like in childhood, adolescence or adulthood with symptoms like polyuria, growth retardation kids, and anemia. But the urine is generally bland.
• Homozygous variants in NPHP1 account upto 50% of cases ,remaining cases are caused by variants in 90 different genes involved in molecular pathways regulating cell polarity, sonic hedgehog signaling, the DNA damage response, or cyclic AMP signaling.
• Genotype-phenotype studies show that null variants are associated with younger age at presentation and more severe disease phenotypes.

1. Genetic Glomerular Diseases:

• Genetic glomerular diseases often involve mutant gene products that normally maintain podocyte function or pathogenic variants of proteins that make up the glomerular basement membrane (e.g., collagen type IV)
• Clinical presentations include the steroid-resistant nephrotic syndrome (SRNS) with focal segmental glomerulosclerosis (FSGS) on kidney biopsy or chronic proteinuria with or without hematuria.
• FSGS is a nonspecific lesion that represents a pattern of podocyte injury rather than a defined disease entity. Genetic forms of FSGS may be familial or sporadic. Extrarenal features may be present, depending on the involved gene.

• Variants in the genes encoding the α3, α4, and α5 chains of type IV collagen (COL4A3, COL4A4, and COL4A5, respectively) are the second most common genetic cause of CKD after ADPKD accounting for 2-3% of adults with advanced CKD.
• Over 30 years ago changes in type  IV collagen a major component of GBM (glomerular basement membrane) was found to be seen in patients with Alport syndrome a.k.a Familial nephritis.
• Further studies showed that the phenotypic variations are associated with difference in the modes of variation and the location and types of variant within the genes encoding type IV collagen.
• In. Cases of CKD due to aport syndrome without its classical features studies shows that under-appreciated variants in genes encoding type IV collagen are responsible for it.
• X-linked disease is caused by pathogenic variants in COL4A5 .
• Autosomal recessive or autosomal dominant inheritance of pathogenic variants in COL4A3 or COL4A4.
• Highest risk of renal failure is associated with X-linked and Autosomal Resistive inheritance.
• Disease resulting from pathogenic variants in two different genes encoding type IV collagen (digenic inheritance) may have worse clinical outcomes than disease due to a single-gene heterozygous variant.
• Truncated variants have worse outcome when compared to missense variants.

Missense variants affect glycine residues there by altering the assembly of collagen heterotrimer structure.

Identification of variants in the podocyte-associated genes encoding nephrin (NPHS1)and podocin (NPHS2) established podocyte disease as a cause of chronic proteinuria and progressive kidney failure.

• Autosomal dominant and recessive inherited alterations in more than 50 different gene products that maintain podocyte ultrastructure, mediate signal transduction, or control podocyte cytoskeletal rearrangements have been reported as genetic causes of nephrotic syndrome or chronic proteinuria.
• These variants often seen in children can sometime result in adult disease like FSGS.

R229Q is associated with increased risk of adult-onset FSGS.

• Single-gene causes of adult-onset proteinuria and FSGS include autosomal dominant variants in the cytoskeletal genes ACTN4 and INF2 and the cation channel protein encoded by TRPC6.

• Genetic conditions affecting renal tubular function (tubulopathies) involve ion channels or transporters.
• Autosomal dominant disease due to gain-of-function variants in UMOD is one of the most prevalent monogenic causes of adult CKD worldwide.
• Uromodulin (also known as Tamm–Horsfall protein) is a kidney-specific protein that is synthesized by the thick ascending limb of the loop of Henle and autosomal dominant disease due to gain-of-function variants in UMOD is one of the most prevalent monogenic causes of adult CKD worldwide.
• UMOD variants cause a spectrum of disorders that have been termed UMOD-related autosomal dominant tubulointerstitial kidney disease (ADTKD).
• ADTKD is characterized by insidious kidney failure between the third and sixth decades of life. Patients may also have hyperuricemia and gout related to reduced fractional excretion of urate, despite a normal GFR.
•  Most disease-causing genetic variants are missense variants, often located in exons 3 and 4; 60% involve a cysteine residue.
• Pathogenic UMOD variants cause protein misfolding, with subsequent retention of protein in the endoplasmic reticulum and mistargeting of uromodulin in the thick ascending limb of the loop of Henle.
•  Variants in MUC1 are the second most common genetic cause of ADTKD and should always be considered in UMOD-negative cases.

It is a multifactorial disease with a genetic component.

• Metabolic imbalances lead to urine crystallization and defective genes that normally encode proteins that maintain metabolic balance causes heritable forms of nephrolithiasis, sometimes leading to CKD.
• Genetic forms of kidney stone disease include adenine phosphoribosyltransferase deficiency, Dent’s disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, and primary hyperoxaluria, frequently lead to CKD and progress to kidney failure.
• These patients have the risk of recurrence after a transplantation as it doesnot address the underlying metabolic imbalance.

Syndromes like monogenic diabetes, monogenic hyperlipidemia or hypertension, and monogenic systemic lupus erythematosus are known to cause secondary kidney damage.

APOL1 is a protein that provides protection against Trypanosomc mediated African sleeping sickness.

• Two variants of APOL1 a linked pair of missense variants, S342G and I384M, and two consecutive amino acid deletions, N388 and Y389are suspected to be major contributors for several subtypes of progressive CKD.
• They are designated as G1 and G2 ,confer protection against an extended spectrum of Trypanosoma species compared with its ancestral G0 allele.
• Although they offer protection they also contribute to an increased frequency of CKD among the Sub Saharan African ancestry.
• APOL1 is associated with broad spectrum of Nephropathies like FSGS<Hypertensive Nephropathies,HIV associated nephropathies and lupus-associated nephropathies.They define a new spectrum of APOL1 related CKD.
• Success with inaxaplin in FSGS suggests glomerular podocyte as the target of cell injury more specifically  luminal endoplasmic reticulum trafficking of the aberrant gene product is thought to result in abnormal cell-membrane cation channel activity.

• Uremia (urine constituents in blood) is a clinical syndrome caused by progressive accumulation of nitrogen waste products among patients with kidney failure who with unable to clear these waste products by the kidneys.^[16]
• It is thought to account for the clinical features of chronic kidney failure that cannot be explained by other classical abnormalities of chronic kidney failure (abnormalities of ion concentrations or extracellular volume overload).^[16]

• Uremia is a progressive clinical syndrome that is not typically characterized by a specific onset.^[16]
• Progressive build-up of nitrogen waste products is usually detected among patients with eGFR below 50% of normal rate (normal GFR for a young healthy man approximately 100 to 120 mL/min/1.73m²).
• Clinical features of uremia are more evident with lower GFR values, and uremic features are often prominent as GFR drops below 10 ml/min/1.73m² (loss of approximately 90% of kidney function), signaling the need for renal replacement modalities (either dialysis or transplantation).

• The majority of uremic solutes are unidentified.
• A few solutes that are present in high concentrations are identified. The toxic effects of these solutes have been studied.
• Examples of uremic solutes that have been studied include^[16]:
  • Beta-2-microglobulin
  • Guanidines
  • Nucleosides
  • Phenols
  • Indoles
  • Furans
  • Polyols
  • Carbonyls
  • Other advanced glycosylation end (AGE) products

• Protein intake is thought to increase the concentration of certain uremic solutes.
• Chemical characteristics of individual solutes may determine the capacity of dialysis to appropriately filter these solutes. Large solutes, solutes bound to albumin, and sequestered solutes are generally poorly filtered by conventional dialysis techniques. The use of ultrafiltration methods and improvement in dialysis membrane sizes are active areas of research that aim to increase filtration capacity of toxic solutes.^[17][18]
• The association between high concentrations of uremic solutes and adverse clinical outcomes is still controversial and is currently under investigation.^[19][18]
• Although uremia is classically associated with chronic kidney failure, experimental studies have recently demonstrated a role of uremic solutes in acute kidney injury (acute uremia), but the pathophysiological significance of these solutes in the context of acute kidney injury is yet to be identified.^[20]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2] Luke Rusowicz-Orazem, B.S.

Common causes of chronic renal failure include diabetic nephropathy, hypertension, and glomerulonephritis. The commonest cause of stage 5 CKD in the U.S. is diabetes and is characterized by proteinuria and bilaterally enlarged kidneys. Hypertension is the second most common cause of Stage 5 CKD in the US, and often co-exists in diabetic patients.

• According to the National Kidney Foundation the 2 most important causes of CKD are diabetes and hypertension accounting for more than one third of all cases often indicating early detection strategies.^[1]
• Beyond diabetes and hypertension other causes like glomerulonephritis, inherited disorders, chronic infections, and urinary tract obstruction account for most of the remaining cases.^[2]

• Alport’s syndrome^[3]
• Amyloidosis^[4]
• Balkan endemic nephropathy
• Benign prostatic hyperplasia
• Chronic Glomerulonephritis
• Chronic Pyelonephritis
• Cystinosis^[5]
• Diabetic nephropathy
• Glomerulosclerosis
• Goodpasture’s syndrome
• Hemolytic uremic syndrome
• Hereditary nephritides
• Hyperoxaluria
• Hypertensive nephrosclerosis
• IgA nephropathy
• Interstitial Nephritis
• Light chain disease
• Lupus nephritis
• Malignant hypertension
• Medullary cystic kidney disease
• Medullary sponge kidney
• Membranoproliferative Glomerulonephritis
• Membranous nephritis
• Metastatic prostate cancer
• Multiple Myeloma
• Nephrolithiasis
• Nephrosclerosis
• Nephrotic Syndrome
• Nephritic Syndrome
• Normocytic normochromic anemia
• Obstructive uropathy
• Oxalosis
• Papillorenal syndrome
• Polycystic kidney disease
• Proteinuria
• Prostate cancer
• Pyelonephritis
• Reflux nephropathy
• Renal artery stenosis
• Renal cell carcinoma
• Renal vein thrombosis
• Renal tubular acidosis
• Rheumatoid arthritis
• Scleroderma
• Sepsis
• Sickle cell disease
• Systemic sclerosis
• Thrombotic thrombocytopenic purpura
• Renal tubular acidosis
• Vasculitis
• Vesicoureteral reflux
• Wegener’s granulomatosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]Feham Tariq, MD [3]

Differentiating chronic renal failure from acute renal failure and from the condition of having an increased BUN with a normal GFR are the most important diagnostic step in evaluating a patient with raised serum creatinine levels, as these conditions can be treated with therapy specific to the underlying etiology.

• Elevated creatinine levels from recent weeks or months suggest that the current disease process is more acute and hence reversible. On the other hand, long standing elevated serum values suggests a chronic disease process.
• Even if the elevated serum creatinine levels are chronic, there is a possibility of the patient having a superimposed acute process over a chronic condition such as: a urinary tract obstruction, infections, extra cellular fluid volume depletion, or nephrotoxin exposure.
• If the patient’s history suggests an array of recent onset symptoms e.g:fever, rash and/or polyarthralgia, it can be safely concluded that the renal insufficiency is a part of an acute process.

• The key differentiating factor between the condition of an increased BUN with a normal GFR and chronic renal failure is a normal glomerular filtration rate (GFR).

Uremia due to chronic renal failure should be differentiated from other diseases causing hypertension and hypokalemia for example:^{[1][1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]}

• Renal artery stenosis
• Cushing’s syndrome
• Congenital adrenal hyperplasia (CAH)
  • 17 alpha hydroxylase deficiency
  • 11 beta hydroxylase deficiency
• Liddle’s syndrome
• Diuretic use
• Licorice ingestion
• Renin-secreting tumors

• Prerenal azotemia
• Catabolic states
• High protein diet
• Gastrointestinal bleeding
• Glucocorticoids
• Tetracycline

1.Zeiger Roni F. “Harrison’s Textbook of Internal Medicine”. McGraw-Hill’s Diagnosaurus 2.0.

2.Bargman JM, Skorecki K. “Chapter 280. Chronic Kidney Disease. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed”. New York: McGraw-Hill; 2012.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

The incidence and prevalence of chronic renal failure varies enormously depending on the level of affluence of the country. Developed countries have a higher incident rate of treated end-stage renal failure, whereas the emerging countries have very low incident rates. There are currently about one million patients undergoing dialysis worldwide, with an incidence of 0.25 million patients each year.

• In 2003, the Third National Health Survey reported a prevalence of CKD in the general population (age 20 or older) of 11% (19.2 million).
• When divided by CKD stage^[1]
  • 3.3% of participants had stage 1
  • 3.0% had stage 2
  • 4.3% had stage 3
  • 0.2% had stage 4
  • 0.2% had stage 5
  • ESRD.
• The study also showed that beyond the classical risk factors notably diabetes and hypertension, age was a separate correlate with CKD prevalence with 11% of people older than 65 years of age having stage 3 or worse CKD in the absence of both diabetes and hypertension.
• Overall, 26% of the general population above 65 years of age has some form of kidney disease manifested by an eGFR <60 mL/min/1.73 m². Ethnicity was found to be related to CKD and ESRD prevalence.
• ESRD was slightly more prevalent in non-Hispanic blacks than in non-Hispanic whites.
• In contrast, less severe stages of CKD were more common among whites, and least common among Mexican Americans.^[1]

• Worldwide, CKD has been on rise especially over the past decade.
• In developed countries, the rise in incidence is expected to continue at an annual rate of around 5-8%.
• What is thought to play a role in the continued increase in incidence is the aging of the general population and increase in the incidence of type II diabetes.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

It is important to identify patients at risk for developing chronic renal disease, even in patients with a normal serum creatinine levels. Chronic renal failure, requiring dialysis or organ transplant, can often be prevented with early detection and treatment.

• The kidneys are able to recover from many insults without necessary progression to CKD and end-stage renal disease (ESRD).
• Several factors have been shown to increase the risk of progression.
• The most studied model of progression to CKD is diabetic nephropathy (DN).
• Studies have linked the risk of progression to CKD in DN to the following risk factors:
  • Hypertension
  • Poorly controlled diabetes
  • High urinary protein excretion (proteinuria/albuminuria).^[1][2][3][4]
• Other risk factors:
  • Chronic NSAID use^[5]
  • Cigarette smoking in diabetic patients.^[6]
  • Pre-existing cardiovascular disease including:
    • Stroke
    • Angina
    • Claudication
    • Transient ischemic attack
    • Coronary angioplasty or bypass
    • Recognized or silent myocardial infarction^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

The burden of chronic renal disease is not only limited to its implications for replacement therapies such as dialysis or organ transplant, but it also has an impact on the overall population’s health and costs. In fact, patients with chronic renal disease include those who are at risk for the progression of renal disease and the development of overt end stage renal disease. These patients have a high likelihood of developing a cardiovascular disease.

Hence, the objective of screening in these patients is for the early detection of asymptomatic diseases, at a time when intervention has a reasonable potential to have an impact on the outcome of the disease course.

Currently, screening for chronic renal failure is only accepted in patients with diabetes and hypertension. Some of the tests frequently used for screening are as follows:

• Serum creatinine levels
• Dipstick urine for proteinuria and hematuria
• GFR estimation
• Urine albumin : creatinine ratio ^{[1] [2]}

Various antibody based screening tests are also available, but are not used routinely as they require expensive laboratory facilities.

• Radioimmune assay
• Nephelometry
• Immunoturbidimetry
• ELISA ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

Chronic renal failure can be complicated by the development of disorders such as hyperuricemia, myopathy, congestive heart failure, pallor, nausea, anorexia, and peptic ulcers amongst other disorders. The prognosis of the disease is poor if mismanaged. If untreated, patients will develop symptoms and signs of uremia (accumulation of uremic solutes), and chronic renal failure (CRF) will progress to end-stage renal disease, which has a high morbidity rate.

If left untreated, patients progressively lose renal function and develop signs and symptoms associated with extracellular fluid overload, ion concentration derangements, and uremia. Patients with chronic kidney disease eventually reach end stage renal disease (ESRD) when GFR is below < 15 mL/min/1.73m²Usually and eventually necessitate renal replacement (either dialysis or transplantation) for survival. Usually, the time frame of progression to ESRD is very variable among individuals. Older age, male gender, and African American ethnicity are all associated with higher risk of progression. Tight blood pressure and glycemic control are essential to decrease the risk of development of ESRD in patients with pre-existing renal insufficiency.^[1] A population-based study of a Swedish cohort of with pre-existing stage 4 or 5 CKD showed that 80% of patients would progress to require RRT within 5 years, with a mortality rate of up to 39%. Half of the cohort was on renal replacement by 18 months follow up.^[2]

The cardiovascular system is closely related to renal function. Studies have shown that even minor decreases in GFR (60-89 ml/min per 1.73 m²) can double the risk of myocardial infarction and stroke compared to patients with normal GFR.^[3] The risk of adverse cardiovascular events also tends to increase with decreasing GFR. This underlines the impact of cardiovascular disease being the leading cause of mortality in patients with renal disease.

The prognosis of patients with chronic kidney disease is guarded as epidemiological data has shown that all cause mortality (the overall death rate) increases as kidney function decreases.^[4] The leading cause of death in patients with chronic kidney disease is cardiovascular disease, regardless of whether there is progression to ESRD.^[4][5][6]

Cystatin C adds to serum creatinine in predicting risk from chronic kidney disease.^[7]

While renal replacement therapies can maintain patients indefinitely and prolong life, the quality of life of the patient is severely affected.^[8][9] Renal transplantation increases the survival of patients with ESRD significantly when compared to other therapeutic options;^[10][11] however, it is associated with an increased short-term mortality (due to complications of the surgery). Transplantation aside, high intensity home hemodialysis appears to be associated with improved survival and a greater quality of life when compared to the conventional thrice weekly hemodialysis and peritoneal dialysis.^[12]

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