Chronic kidney disease

Chronic kidney disease (CKD), also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite. Often, chronic kidney disease is diagnosed as a result of screening of people known to be at risk of kidney problems, such as those with high blood pressure or diabetes and those with a blood relative with chronic kidney disease. Chronic kidney disease may also be identified when it leads to one of its recognized complications, such as cardiovascular disease, anemia or pericarditis.

Chronic kidney disease is identified by a blood test for creatinine. Higher levels of creatinine indicate a falling glomerular filtration rate and as a result a decreased capability of the kidneys to excrete waste products. Creatinine levels may be normal in the early stages of CKD, and the condition is discovered if urinalysis (testing of a urine sample) shows that the kidney is allowing the loss of protein or red blood cells into the urine. To fully investigate the underlying cause of kidney damage, various forms of medical imaging, blood tests and often renal biopsy (removing a small sample of kidney tissue) are employed to find out if there is a reversible cause for the kidney malfunction. Recent professional guidelines classify the severity of chronic kidney disease in five stages, with stage 1 being the mildest and usually causing few symptoms and stage 5 being a severe illness with poor life expectancy if untreated. Stage 5 CKD is also called established chronic kidney disease and is synonymous with the now outdated terms end-stage renal disease (ESRD), chronic kidney failure (CKF) or chronic renal failure (CRF).

There is no specific treatment unequivocally shown to slow the worsening of chronic kidney disease. If there is an underlying cause to CKD, such as vasculitis, this may be treated directly with treatments aimed to slow the damage. In more advanced stages, treatments may be required for anemia and bone disease. Severe CKD requires one of the forms of renal replacement therapy; this may be a form of dialysis, but ideally constitutes a kidney transplant.

Signs and symptoms
CKD is initially without specific symptoms and can only be detected as an increase in serum creatinine or protein in the urine. As the kidney function decreases:
 * Blood pressure is increased due to fluid overload and production of vasoactive hormones created by the kidney via the RAS (renin-angiotensin system), increasing one's risk of developing hypertension and/or suffering from congestive heart failure
 * Urea accumulates, leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy). Urea is excreted by sweating and crystallizes on skin ("uremic frost").
 * Potassium accumulates in the blood (known as hyperkalemia with a range of symptoms including malaise and potentially fatal cardiac arrhythmias)
 * Erythropoietin synthesis is decreased (potentially leading to anemia, which causes fatigue)
 * Fluid volume overload - symptoms may range from mild edema to life-threatening pulmonary edema
 * Hyperphosphatemia - due to reduced phosphate excretion, associated with hypocalcemia (due to 1,25 dihydroxyvitamin D3 deficiency). The 1,25 dihydroxyvitamin D3 deficiency is due to stimulation of fibroblast growth factor-23.
 * Later this progresses to secondary hyperparathyroidism, renal osteodystrophy and vascular calcification that further impairs cardiac function.
 * Metabolic acidosis, due to accumulation of sulfates, phosphates, uric acid etc. This may cause altered enzyme activity by excess acid acting on enzymes and also increased excitability of cardiac and neuronal membranes by the promotion of hyperkalemia due to excess acid (acidemia)

People with chronic kidney disease suffer from accelerated atherosclerosis and are more likely to develop cardiovascular disease than the general population. Patients afflicted with chronic kidney disease and cardiovascular disease tend to have significantly worse prognoses than those suffering only from the latter.

Causes
The most common causes of CKD are diabetes mellitus, hypertension, and glomerulonephritis. Together, these cause approximately 75% of all adult cases. Certain geographic areas have a high incidence of HIV nephropathy.

Historically, kidney disease has been classified according to the part of the renal anatomy that is involved, to wit:
 * Vascular, includes large vessel disease such as bilateral renal artery stenosis and small vessel disease such as ischemic nephropathy, hemolytic-uremic syndrome and vasculitis
 * Glomerular, comprising a diverse group and subclassified into
 * Primary Glomerular disease such as focal segmental glomerulosclerosis and IgA nephritis
 * Secondary Glomerular disease such as diabetic nephropathy and lupus nephritis
 * Tubulointerstitial including polycystic kidney disease, drug and toxin-induced chronic tubulointerstitial nephritis and reflux nephropathy
 * Obstructive such as with bilateral kidney stones and diseases of the prostate
 * On rare cases, pin worms infecting the kidney can also cause nephropathy.

Diagnosis
In many CKD patients, previous renal disease or other underlying diseases are already known. A small number present with CKD of unknown cause. In these patients, a cause is occasionally identified retrospectively.

It is important to differentiate CKD from acute renal failure (ARF) because ARF can be reversible. Abdominal ultrasound, in which the size of the kidneys is measured, is commonly performed. Kidneys with CKD are usually smaller (< 9 cm) than normal kidneys, with notable exceptions such as in diabetic nephropathy and polycystic kidney disease. Another diagnostic clue that helps differentiate CKD from ARF is a gradual rise in serum creatinine (over several months or years) as opposed to a sudden increase in the serum creatinine (several days to weeks). If these levels are unavailable (because the patient has been well and has had no blood tests), it is occasionally necessary to treat a patient briefly as having ARF until it has been established that the renal impairment is irreversible.

Additional tests may include nuclear medicine MAG3 scan to confirm blood flows and establish the differential function between the two kidneys. DMSA scans are also used in renal imaging; with both MAG3 and DMSA being used chelated with the radioactive element Technetium-99.

In chronic renal failure treated with standard dialysis, numerous uremic toxins accumulate. These toxins show various cytotoxic activities in the serum, have different molecular weights and some of them are bound to other proteins, primarily to albumin. Such toxic protein bound substances are receiving the attention of scientists who are interested in improving the standard chronic dialysis procedures used today.

Stages
All individuals with a glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for 3 months are classified as having chronic kidney disease, irrespective of the presence or absence of kidney damage. The rationale for including these individuals is that reduction in kidney function to this level or lower represents loss of half or more of the adult level of normal kidney function, which may be associated with a number of complications.

All individuals with kidney damage are classified as having chronic kidney disease, irrespective of the level of GFR. The rationale for including individuals with GFR > 60 mL/min/1.73 m2 is that GFR may be sustained at normal or increased levels despite substantial kidney damage and that patients with kidney damage are at increased risk of the two major outcomes of chronic kidney disease: loss of kidney function and development of cardiovascular disease.

The loss of protein in the urine is regarded as an independent marker for worsening of renal function and cardiovascular disease. Hence, British guidelines append the letter "P" to the stage of chronic kidney disease if there is significant protein loss.

Slightly diminished function; kidney damage with normal or relatively high GFR (≥90 mL/min/1.73 m2). Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies.
 * Stage 1

Mild reduction in GFR (60-89 mL/min/1.73 m2) with kidney damage. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies.
 * Stage 2

Moderate reduction in GFR (30-59 mL/min/1.73 m2). British guidelines distinguish between stage 3A (GFR 45-59) and stage 3B (GFR 30-44) for purposes of screening and referral.
 * Stage 3

Severe reduction in GFR (15-29 mL/min/1.73 m2) Preparation for renal replacement therapy
 * Stage 4

Established kidney failure (GFR <15 mL/min/1.73 m2, or permanent renal replacement therapy (RRT)
 * Stage 5

NDD-CKD vs. ESRD
The term non-dialysis dependent CKD, also abbreviated as NDD-CKD, is a designation used to encompass the status of those persons with an established CKD who do not yet require the life-supporting treatments for renal failure known as renal replacement therapy (including maintenance dialysis or renal transplantation). The condition of individuals with CKD, who require either of the 2 types of renal replacement therapy (dialysis or transplantation), is referred to as the end-stage renal disease (ESRD). Hence, the start of the ESRD is practically the irreversible conclusion of the NDD-CKD. Even though the non-dialysis dependent status refers to the status of persons with earlier stages of CKD (stages 1 to 4), patients with advanced stage of CKD (Stage 5), who have not yet started renal replacement therapy are also referred to as NDD-CKD.

Screening and Referral
Early identification of patients with kidney disease is recommended, as measures may be instituted to slow progression and mitigate cardiovascular risk. Among those who should be screened are subjects with hypertension or history of cardiovascular disease, those with diabetes or marked obesity, those aged > 60 years, subjects with indigenous (native American Indian, First Nations) racial origin, those with a history of renal disease in the past, as well as subjects who have relatives who had kidney disease requiring dialysis. Screening should include calculation of estimated GFR/1.73 m2 from the serum creatinine level, and measurement of urine-to-albumin creatinine ratio in a first-morning urine specimen as well as dipstick screen for hematuria. Guidelines for nephrologist referral vary among different countries. Nephrology referral is useful when eGFR/1.73m2 is less than 30 or decreasing by more than 3 mL/min/year, when urine albumin-to-creatinine ratio is more than 300 mg/g, when blood pressure is difficult to control, or when hematuria or other findings suggest either a primarily glomerular disorder or secondary disease amenable to specific treatment. Other benefits of early nephrology referral include proper patient education regarding options for renal replacement therapy as well as pre-emptive transplantation, and timely workup and placement of an arteriovenous fistula in those patients opting for future hemodialysis.

Treatment
The goal of therapy is to slow down or halt the progression of CKD to stage 5. Control of blood pressure and treatment of the original disease, whenever feasible, are the broad principles of management. Generally, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are used, as they have been found to slow the progression of CKD to stage 5. Although the use of ACE inhibitors and ARBs represents the current standard of care for patients with CKD, patients progressively lose kidney function while on these medications, as seen in the IDNT and RENAAL studies, which reported a decrease over time in estimated glomerular filtration rate (an accurate measure of CKD progression, as detailed in the K/DOQI guidelines ) in patients treated by these conventional methods.

Currently, several compounds are in development for CKD. These include, but are not limited to, bardoxolone methyl, olmesartan medoxomil, sulodexide, and avosentan.

Replacement of erythropoietin and calcitriol, two hormones processed by the kidney, is often necessary in patients with advanced CKD. Phosphate binders are also used to control the serum phosphate levels, which are usually elevated in advanced chronic kidney disease.

When one reaches stage 5 CKD, renal replacement therapy is required, in the form of either dialysis or a transplant.

The normalization of hemoglobin has not been found to be of any benefit.

People with CKD are at a markedly increased risk of cardiovascular disease, and often have other risk factors for heart disease, such as hyperlipidemia. The most common cause of death in people with CKD is therefore cardiovascular disease rather than renal failure. Aggressive treatment of hyperlipidemia is warranted.

Prognosis
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. The leading cause of death in patients with chronic kidney disease is cardiovascular disease, regardless of whether there is progression to stage 5.

While renal replacement therapies can maintain patients indefinitely and prolong life, the quality of life is severely affected. Renal transplantation increases the survival of patients with stage 5 CKD significantly when compared to other therapeutic options; 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 three times a week hemodialysis and peritoneal dialysis.

Epidemiology
In Canada 1.9 to 2.3 million people have chronic kidney disease.

In the US, the Centers for Disease Control and Prevention found that CKD affected an estimated 16.8% of adults aged 20 years and older, during 1999 to 2004.

UK estimates suggest that 8.8% of the population of Great Britain and Northern Ireland have symptomatic CKD.

Organizations
In the USA, the National Kidney Foundation is a national organization representing patients and professionals who treat kidney diseases. The American Kidney Fund (AKF) is a national non-profit organization providing treatment-related financial assistance to 1 out of every 5 dialysis patients each year. The Renal Support Network (RSN) is a nonprofit, patient-focused, patient-run organization that provides non-medical services to those affected by CKD. The American Association of Kidney Patients (AAKP) is a non-profit, patient-centric group focused on improving the health and well-being of CKD and dialysis patients. The Renal Physicians Association (RPA) is an association representing nephrology professionals.

In the United Kingdom, the UK National Kidney Federation represents patients, and the Renal Association represents renal physicians and works closely with the National Service Framework for kidney disease.

The International Society of Nephrology is an international body representing specialists in kidney diseases.