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 not specific, 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 CKD. This disease may also be identified when it leads to one of its recognized complications, such as cardiovascular disease, anemia, or pericarditis. It is differentiated from acute kidney disease in that the reduction in kidney function must be present for over 3 months.

Chronic kidney disease is identified by a blood test for creatinine. Higher levels of creatinine indicate a lower 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 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 a reversible cause for the kidney malfunction is present. Recent professional guidelines classify the severity of CKD 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 often called end stage renal disease, end stage renal failure, or end-stage kidney disease, and is synonymous with the now outdated terms chronic kidney failure or chronic renal failure.

No specific treatment is unequivocally shown to slow the worsening of CKD. If an underlying cause to CKD, such as vasculitis, is found, it may be treated directly to slow the damage. In more advanced stages, treatments may be required for anemia and bone disease. Severe CKD requires renal replacement therapy, which may involve a form of dialysis, but ideally constitutes a kidney transplant.

Signs and symptoms

CKD is initially without specific symptoms and is generally only 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 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). Due to its high systemic circulation, urea is excreted in eccrine sweat at high concentrations and crystallizes on skin as the sweat evaporates ("uremic frost").
• Potassium accumulates in the blood (hyperkalemia with a range of symptoms including malaise and potentially fatal cardiac arrhythmias). Hyperkalemia usually does not develop until the glomerular filtration rate falls to less than 20-25 ml/min/1.73 m², at which point the kidneys have decreased ability to excrete potassium. Hyperkalemia in CKD can be exacerbated by acidemia (which leads to extracellular shift of potassium) and from lack of insulin.
• Erythropoietin synthesis is decreased.
• Fluid volume overload symptoms may range from mild edema to life-threatening pulmonary edema.
• Hyperphosphatemia, due to reduced phosphate excretion, follows the decrease in glomerular filtration. Hyperphosphatemia is associated with increased cardiovascular risk, being a direct stimulus to vascular calcification.
• Hypocalcemia, due to 1,25 dihydroxyvitamin D₃ deficiency, is caused by stimulation of fibroblast growth factor-23. Osteocytes are responsible for the increased production of FGF23, which is a potent inhibitor of the enzyme 1-alpha-hydroxylase (responsible for the conversion of 25-hydroxycholecalciferol into 1,25 dihydroxyvitamin D₃). 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., 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). Acidosis is also due to decreased capacity to generate enough ammonia from the cells of the proximal tubule.
• Iron deficiency anemia, which increases in prevalence as kidney function decreases, is especially prevalent in those requiring haemodialysis. It is multifactoral in cause, but includes increased inflammation, reduction in erythropoietin, and hyperuricemia leading to bone marrow suppression.

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

Sexual dysfunction is very common in both men and women with CKD. A majority of men have a reduced sex drive, difficulty obtaining an erection, and reaching orgasm, and the problems get worse with age. A majority of women have trouble with sexual arousal, and painful periods and problems with performing and enjoying sex are common.

Causes

The three most common causes of CKD are diabetes mellitus, hypertension, and glomerulonephritis. Together, these cause about 75% of all adult cases.

Historically, kidney disease has been classified according to the part of the renal anatomy involved.

• Vascular disease includes large vessel disease such as bilateral renal artery stenosis and small vessel disease such as ischemic nephropathy, hemolytic-uremic syndrome, and vasculitis.
• Glomerular disease comprises a diverse group and is classified into:
  • Primary glomerular disease such as focal segmental glomerulosclerosis and IgA nephropathy (or nephritis)
  • Secondary glomerular disease such as diabetic nephropathy and lupus nephritis
• Tubulointerstitial disease includes polycystic kidney disease, drug- and toxin-induced chronic tubulointerstitial nephritis, and reflux nephropathy.
• Obstructive disease is exemplified by bilateral kidney stones and diseases of the prostate.
• On rare cases, pinworms infecting the kidney can also cause nephropathy.
• Nontraditional causes of CKD (CKDu) are denoted if the common causes of CKD are not present:
  • CKD of unknown etiology is the subject of a major study by the Sri Lanka Ministry of Health and the World Health Organization 2009â€"2012.
  • Mesoamerican nephropathy, a form of CKDu, is "a new form of kidney disease that could be called agricultural 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 the renal impairment has been established to be irreversible.

Additional tests may include nuclear medicine MAG3 scan to confirm blood flows and establish the differential function between the two kidneys. Dimercaptosuccinic acid (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 and 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 protein loss is significant.

Stage 1

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 2

Mild reduction in GFR (60â€"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 3

Moderate reduction in GFR (30â€"59 ml/min/1.73 m²):. British guidelines distinguish between stage 3A (GFR 45â€"59) and stage 3B (GFR 30â€"44) for purposes of screening and referral.

Stage 4

Severe reduction in GFR (15â€"29 ml/min/1.73 m²) Preparation for renal replacement therapy

Stage 5

Established kidney failure (GFR <15 ml/min/1.73 m², permanent renal replacement therapy, or end-stage renal disease

NDD-CKD vs. ESRD

The term nondialysis dependent CKD (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 (RRT, including maintenance dialysis or renal transplantation). The condition of individuals with CKD, who require either of the two types of renal replacement therapy (dialysis or transplant]]), 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 NDD-CKD 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.

Diagnosis

Screening those who have neither symptoms nor risk factors for CKD is not recommended. Those who should be screened include: those with hypertension or history of cardiovascular disease, those with diabetes or marked obesity, those aged > 60 years, subjects with indigenous racial origin, those with a history of renal disease in the past, and subjects who have relatives who had kidney disease requiring dialysis. Screening should include calculation of estimated GFR 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 between 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 30 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 presence of CKD confers a markedly increased risk of cardiovascular disease, and people with CKD often have other risk factors for heart disease, such as high blood lipids. The most common cause of death in people with CKD is cardiovascular disease rather than renal failure. Aggressive treatment of hyperlipidemia is warranted.

Apart from controlling other risk factors, 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. Although the use of ACE inhibitors and ARBs represents the current standard of care for people with CKD, people progressively lose kidney function while on these medications, as seen in the IDNT and RENAL studies, which reported a decrease over time in estimated GFR (an accurate measure of CKD progression, as detailed in the K/DOQI guidelines) in people treated by these conventional methods.

Replacement of erythropoietin and calcitriol, two hormones processed by the kidney, is often necessary in people with advanced disease. Guidelines recommend treatment with parenteral iron prior to treatment with erythropoietin. A target hemoglobin level of 9â€"12 g/dl is recommended. Phosphate binders are also used to control the serum phosphate levels, which are usually elevated in advanced chronic kidney disease. The normalization of hemoglobin has not been found to be of any benefit. It is unclear if androgens help with anemia. Although the evidence for them is limited, phosphodiesterase-5 inhibitors and zinc show potential for helping men with sexual dysfunction.

At stage 5 CKD, renal replacement therapy is usually required, in the form of either dialysis or a transplant.

Prognosis

The prognosis of patients with chronic kidney disease is guarded as epidemiological data have 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.

Cancer risk

Patients with ESRD are at increased overall risk for cancer. This risk is particularly high in younger patients and gradually diminishes with age. Medical specialty professional organizations recommend that physicians not perform routine cancer screening in patients with limited life expectancies due to ESRD because evidence does not show that such tests lead to improved patient outcomes.

Epidemiology

Chronic kidney disease globally resulted in 735,000 deaths in 2010, up from 400,000 deaths in 1990.

In Canada, 1.9 to 2.3 million people have CKD. 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.

CKD is a major concern in African Americans, mostly due to increased prevalence of hypertension. As an example, 37% of ESRD cases in African Americans can be attributed to high blood pressure, compared with 19% among Caucasians. Treatment efficacy also differs between racial groups. Administration of antihypertensive drugs generally halts disease progression in white populations, but has little effect in slowing renal disease among blacks, and additional treatment such as bicarbonate therapy is often required. While lower socioeconomic status contributes to prevalence of CKD, significant differences in CKD prevalence are still evident between African Americans and Whites when controlling for environmental factors. Studies have shown a true association between history of chronic renal failure in first- or second-degree relatives, and risk of disease. In addition, African Americans may have higher serum levels of human leukocyte antigens (HLA). High HLA concentrations can contribute to increased systemic inflammation, which indirectly may lead to heightened susceptibility for developing kidney disease. Lack of nocturnal reduction in blood pressure among groups of African Americans is also offered as an explanation, which lends further credence to a genetic etiology of CKD racial disparities.

A high and so-far unexplained incidence of CKD, referred to as the Mesoamerican nephropathy, has been noted among male workers in Central America, mainly in sugar cane fields in the lowlands of El Salvador and Nicaragua. Heat stress from long hours of piece-rate work at high average temperatures (in the range of 96°F) is suspected, as are agricultural chemicals and other factors. In Sri Lanka, another epidemic of CKD of unknown etiology has become a serious public health concern.

Organizations

In the USA, the National Kidney Foundation is a national organization representing patients and professionals who treat kidney diseases. The American Kidney Fund is a national nonprofit organization providing treatment-related financial assistance to one of every five dialysis patients each year. The Renal Support Network is a nonprofit, patient-focused, patient-run organization that provides nonmedical services to those affected by CKD. The American Association of Kidney Patients is a nonprofit, patient-centric group focused on improving the health and well-being of CKD and dialysis patients. The Renal Physicians Association 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.

Kidney Health Australia serves that country.

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

Research

Currently, several compounds are in development for CKD. These include bardoxolone methyl, olmesartan medoxomil, sulodexide, and avosentan.

References

External links

• National Kidney Foundation
• Dialysis Complications of Chronic Renal Failure at eMedicine
• The Kidney Foundation of Canada
• Chronic Renal Failure Information from Great Ormond Street Hospital

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