Chronic Kidney Disease

Chronic kidney disease (CKD) is a type of kidney disease in which there is gradual loss of kidney function over a period of months to years. Initially there are generally no symptoms; later, symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications include an increased risk of heart disease, high blood pressure, bone disease, and anemia.

Causes of chronic kidney disease include diabetes, high blood pressure, glomerulonephritis, and polycystic kidney disease. Risk factors include a family history of chronic kidney disease. Diagnosis is by blood tests to measure the estimated glomerular filtration rate (eGFR), and a urine test to measure albumin. Ultrasound or kidney biopsy may be performed to determine the underlying cause. Several severity-based staging systems are in use.

Screening at-risk people is recommended. Initial treatments may include medications to lower blood pressure, blood sugar, and cholesterol. Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are generally first-line agents for blood pressure control, as they slow progression of the kidney disease and the risk of heart disease. Loop diuretics may be used to control edema and, if needed, to further lower blood pressure. NSAIDs should be avoided. Other recommended measures include staying active, and certain dietary changes such as a low-salt diet and the right amount of protein. Treatments for anemia and bone disease may also be required. Severe disease requires hemodialysis, peritoneal dialysis, or a kidney transplant for survival.

Chronic kidney disease affected 753 million people globally in 2016: 417 million females and 336 million males. In 2015 it caused 1.2 million deaths, up from 409,000 in 1990. The causes that contribute to the greatest number of deaths are high blood pressure at 550,000, followed by diabetes at 418,000, and glomerulonephritis at 238,000.

Signs and symptoms

CKD is initially without symptoms, and is usually detected on routine screening blood work by either 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 the risk of developing hypertension and heart failure.
• Urea accumulates, leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy). Due to its high systemic concentration, 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.
• Fluid overload symptoms may range from mild edema to life-threatening pulmonary edema.
• Hyperphosphatemia results from poor phosphate elimination in the kidney. Hyperphosphatemia contributes to increased cardiovascular risk by causing vascular calcification. Circulating concentrations of fibroblast growth factor-23 (FGF-23) increase progressively as the kidney capacity for phosphate excretion declines which may contribute to left ventricular hypertrophy and increased mortality in people with CKD .
• Hypocalcemia results from 1,25 dihydroxyvitamin D₃ deficiency (caused by high FGF-23 and reduced kidney mass) and resistance to the action of parathyroid hormone. Osteocytes are responsible for the increased production of FGF-23, 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, kidney osteodystrophy, and vascular calcification that further impairs cardiac function. An extreme consequence is the occurrence of the rare condition named calciphylaxis.
• Changes in mineral and bone metabolism that may cause 1) abnormalities of calcium, phosphorus (phosphate), parathyroid hormone, or vitamin D metabolism; 2) abnormalities in bone turnover, mineralization, volume, linear growth, or strength (kidney osteodystrophy); and 3) vascular or other soft-tissue calcification. CKD-mineral and bone disorders have been associated with poor outcomes.
• Metabolic acidosis may result from decreased capacity to generate enough ammonia from the cells of the proximal tubule. Acidemia affects the function of enzymes and increases excitability of cardiac and neuronal membranes by the promotion of hyperkalemia.
• Anemia is common and 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.
• In later stages, cachexia may develop, leading to unintentional weight loss, muscle wasting, weakness and anorexia.
• 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 menstruation and problems with performing and enjoying sex are common.
• People with CKD are more likely than the general population to develop atherosclerosis with consequent cardiovascular disease, an effect that may be at least partly mediated by uremic toxins. People with both CKD and cardiovascular disease have significantly worse prognoses than those with only cardiovascular disease.

Causes

The three most common causes of CKD in order of frequency as of 2015 are diabetes mellitus, hypertension, and glomerulonephritis. About one of five adults with hypertension and one of three adults with diabetes have CKD. If the cause is unknown, it is called idiopathic.

By anatomical location

• Vascular disease includes large vessel disease such as bilateral kidney 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 drug- and toxin-induced chronic tubulointerstitial nephritis, and reflux nephropathy.
• Obstructive nephropathy, as exemplified by bilateral kidney stones and benign prostatic hyperplasia of the prostate gland. Rarely, pinworms infecting the kidney can cause obstructive nephropathy.

Other

• Congenital disease such as polycystic kidney disease.
• Mesoamerican nephropathy, is "a new form of kidney disease that could be called agricultural nephropathy". A high and so-far unexplained number of new cases 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 of about 36 °C (96 °F) is suspected, as are agricultural chemicals

Diagnosis

A 12-lead ECG of a person with CKD and a severe electrolyte imbalance: hyperkalemia (7.4 mmol/l) with hypocalcemia (1.6 mmol/l). The T-waves are peaked and the QT interval is prolonged.

Diagnosis of CKD is largely based on history, examination and urine dipstick combined with the measurement of the serum creatinine level (see above). It is important to differentiate CKD from acute kidney injury (AKI) because AKI can be reversible. One diagnostic clue that helps differentiate CKD from AKI 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). In many people with CKD, previous kidney disease or other underlying diseases are already known. A significant number present with CKD of unknown cause.

Screening

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 African American ancestry, those with a history of kidney disease in the past, and subjects who have relatives who had kidney disease requiring dialysis.

Screening should include calculation of the estimated GFR (eGFR) from the serum creatinine level, and measurement of urine albumin-to-creatinine ratio (ACR) in a first-morning urine specimen (this reflects the amount of a protein called albumin in the urine), as well as a urine dipstick screen for hematuria.

The glomerular filtration rate (GFR) is derived from the serum creatinine and is proportional to 1/creatinine, i.e. it is a reciprocal relationship:the higher the creatinine, the lower the GFR. It reflects one aspect of kidney function: how efficiently the glomeruli - the filtering units - work. Normal GFR is 90-120 mLs/min. The units of creatinine vary from country to country. But since the glomeruli make up <5% of the mass of the kidney, the GFR does not indicate all aspects of kidney health and function. This can be done by combining the GFR level with the clinical assessment of the person, including fluid status, and measuring the levels of hemoglobin, potassium, phosphate and parathyroid hormone (PTH).

Ultrasound

Kidney ultrasonography is useful for diagnostic and prognostic purposes in chronic kidney disease. Whether the underlying pathologic change is glomerular sclerosis, tubular atrophy, interstitial fibrosis or inflammation, the result is often increased echogenicity of the cortex. The echogenicity of the kidney should be related to the echogenicity of either the liver or the spleen (Figure 22 and Figure 23). Moreover, decreased kidney size and cortical thinning are also often seen and especially when disease progresses (Figure 24 and Figure 25). However, kidney size correlates to height, and short persons tend to have small kidneys; thus, kidney size as the only parameter is not reliable.

• 

  Chronic renal disease caused by glomerulonephritis with increased echogenicity and reduced cortical thickness. Measurement of kidney length on the US image is illustrated by '+' and a dashed line.

• 

  Nephrotic syndrome. Hyperechoic kidney without demarcation of cortex and medulla.

• 

  Chronic pyelonephritis with reduced kidney size and focal cortical thinning. Measurement of kidney length on the US image is illustrated by '+' and a dashed line.

• 

  End-stage chronic kidney disease with increased echogenicity, homogenous architecture without visible differentiation between parenchyma and renal sinus and reduced kidney size. Measurement of kidney length on the US image is illustrated by '+' and a dashed line.

Additional imaging

Additional tests may include nuclear medicine MAG3 scan to confirm blood flow and establish the differential function between the two kidneys. Dimercaptosuccinic acid (DMSA) scans are also used in kidney imaging; with both MAG3 and DMSA being used chelated with the radioactive element technetium-99.

Stages

Chronic kidney disease (CKD) staging - CKD G1-5 A1-3 glomerular filtration rate (GFR) and albumin/creatinine ratio (ACR)
				ACR
				A1	A2	A3
				Normal to mildly increased	Moderately increased	Severely increased
				<30	30-300	>300
G F R
	G1	Normal	90+	1 if kidney damage present	1	2
	G2	Mildly decreased	60-89	1 if kidney damage present	1	2
	G3a	Mildly to moderately decreased	45-59	1	2	3
	G3b	Moderately to severely decreased	30-44	2	3	3
	G4	Severely decreased	15-29	3	4+	4+
	G5	Kidney failure	<15	4+	4+	4+
Numbers 1 - 4 indicates risk of progression as well as frequency of monitoring (number of times a year). Kidney Disease Improving Global Outcomes - KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease

A glomerular filtration rate (GFR) ≥ 60 ml/min/1.73 m² is considered normal without chronic kidney disease if there is no kidney damage present.

Kidney damage is defined signs of damage seen in blood, urine, or imaging studies which includes lab albumin/creatinine ratio (ACR) ≥ 30. All people with a GFR <60 ml/min/1.73 m² for 3 months are defined as having chronic kidney disease.

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

1. Stage 1: Slightly diminished function; kidney damage with normal or relatively high GFR (≥90 ml/min/1.73 m²) and persistent albuminuria. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.
2. Stage 2: 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 tests or imaging studies.
3. Stage 3: 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.
4. Stage 4: Severe reduction in GFR (15–29 ml/min/1.73 m²) Preparation for kidney replacement therapy.
5. Stage 5: Established kidney failure (GFR <15 ml/min/1.73 m²), permanent kidney replacement therapy, or end-stage kidney disease.

The term "non-dialysis-dependent chronic kidney disease" (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 kidney failure known as kidney replacement therapy (RRT, including maintenance dialysis or kidney transplantation). The condition of individuals with CKD, who require either of the two types of kidney replacement therapy (dialysis or transplant), is referred to as the end-stage kidney disease (ESKD). Hence, the start of the ESKD 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), people with advanced stage of CKD (stage 5), who have not yet started kidney replacement therapy, are also referred to as NDD-CKD.

Management

Apart from controlling other risk factors, the goal of therapy is to slow down or halt the progression of CKD. Control of blood pressure and treatment of the original disease are the broad principles of management.

Blood pressure

Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are recommended as first-line agents since they have been found to slow the decline of kidney function, relative to a more rapid decline in those not on one of these agents. They have also been found to reduce the risk of major cardiovascular events such as myocardial infarction, stroke, heart failure, and death from cardiovascular disease when compared to placebo in individuals with CKD. ACEIs may be superior to ARBs for protection against progression to kidney failure and death from any cause in those with CKD. Aggressive blood pressure lowering decreases peoples risk of death.

Other measures

• Aggressive treatment of high blood lipids is recommended.
• A low-protein, low-salt diet may result in slower progression of CKD and reduction in proteinuria as well as controlling symptoms of advanced CKD to delay dialysis start. A tailored low-protein diet, designed for low acidity, may help prevent damage to kidneys for people with CKD.
• Anemia - A target hemoglobin level of 9–12 g/dL is recommended; raising hemoglobin levels to the normal range has not been found to be of benefit.
  • Guidelines recommend treatment with parenteral iron prior to treatment with erythropoietin.
  • Replacement of erythropoietin is often necessary in people with advanced disease.
  • It is unclear if androgens improve anemia.
• Calcitriol is recommended for vitamin D deficiency and control of metabolic bone disease.
• Phosphate binders are used to control the serum phosphate levels, which are usually elevated in advanced chronic kidney disease.
• Phosphodiesterase-5 inhibitors and zinc may improve sexual dysfunction in men.

Referral to a nephrologist

Guidelines for referral to a nephrologist vary between countries. Most agree that nephrology referral is required by Stage 4 CKD (when eGFR/1.73m² is less than 30 ml/min; or decreasing by more than 3 ml/min/year).

It may also be useful at an earlier stage (e.g. CKD3) when urine albumin-to-creatinine ratio is more than 30 mg/mmol, 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 education regarding options for kidney replacement therapy as well as pre-emptive transplantation, and timely workup and placement of an arteriovenous fistula in those people with chronic kidney disease opting for future hemodialysis.

Renal replacement therapy

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

In CKD numerous uremic toxins accumulate in the blood. Even when ESKD (largely synonymous with CKD5) is treated with dialysis, the toxin levels do not go back to normal as dialysis is not that efficient. Similarly, after a kidney transplant, the levels may not go back to normal as the transplanted kidney may not work 100%. If it does, the creatinine level is often normal. The 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. Uremic toxins are classified into three groups as small water-soluble solutes, middle molecular-weight solutes, and protein-bound solutes. Hemodialysis with high-flux dialysis membrane, long or frequent treatment, and increased blood/dialysate flow has improved removal of water-soluble small molecular weight uremic toxins. Middle molecular weight molecules are removed more effectively with hemodialysis using a high-flux membrane, hemodiafiltration and hemofiltration. However, conventional dialysis treatment is limited in its ability to remove protein-bound uremic toxins.

Prognosis

CKD increases the 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 kidney failure.

Chronic kidney disease results in worse all-cause mortality (the overall death rate) which increases as kidney function decreases. The leading cause of death in chronic kidney disease is cardiovascular disease, regardless of whether there is progression to stage 5.

While kidney replacement therapies can maintain people indefinitely and prolong life, the quality of life is negatively affected. Kidney transplantation increases the survival of people with stage 5 CKD when compared to other 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.

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

Epidemiology

About one in ten people have chronic kidney disease. In Canada 1.9 to 2.3 million people were estimated to have CKD in 2008. CKD affected an estimated 16.8% of U.S. adults aged 20 years and older in the period from 1999 to 2004. In 2007 8.8% of the population of Great Britain and Northern Ireland had symptomatic CKD.

Chronic kidney disease was the cause of 956,000 deaths globally in 2013, up from 409,000 deaths in 1990.

Chronic kidney disease of unknown aetiology

The cause of chronic kidney disease is in some cases not known; it is referred to as chronic kidney disease of unknown aetiology (CKDu). As of 2020^[update] a rapidly progressive chronic kidney disease, unexplained by diabetes and hypertension, had increased dramatically in prevalence over a few decades in several regions in Central America and Mexico, a CKDu referred to as the Mesoamerican nephropathy (MeN). It was estimated in 2013 that at least 20,000 men had died prematurely, some in their 20s and 30s; a figure of 40,000 per year was estimated in 2020. In some affected areas CKD mortality was five times the national rate. MeN primarily affects men working as sugarcane labourers. The cause is unknown, but in 2020 the science found a clearer connection between heavy labour in high temperatures and incidence of CKDu; improvements such as regular access to water, rest and shade, can significantly decrease the potential CKDu incidence. CKDu also affects people in Sri Lanka where it is the 8th largest cause of in-hospital mortality.

Although CKDu was first documented among sugar cane workers in Costa Rica in the 1970s, it may well have affected plantation labourers since the introduction of sugar cane farming to the Caribbean in the 1600s. In colonial times the death records of slaves on sugar plantations was much higher than for slaves forced into other labour.

Race

African, Hispanics, and South Asians, particularly those from Pakistan, Sri Lanka, Bangladesh, and India, are at high risk of developing CKD. Africans are at greater risk due to the number of people affected with hypertension among them. As an example, 37% of ESKD 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 kidney disease among black people, and additional treatment such as bicarbonate therapy is often required. While lower socioeconomic status contributes to the number of people affected with CKD, differences in the number of people affected by CKD are still evident between Africans and Whites when controlling for environmental factors.

Society and culture

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

United States

• The National Kidney Foundation is a national organization representing people with chronic kidney diseases 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 people undergoing dialysis 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 people undergoing dialysis .
• The Renal Physicians Association is an association representing nephrology professionals.

United Kingdom

It was said to be costing the NHS about £1.5 billion a year in 2020.

The UK National Kidney Federation and British Kidney Patient Association (BKPA) represents people with chronic kidney disease. The Renal Association represents Kidney physicians and works closely with the National Service Framework for kidney disease.

Australia

Kidney Health Australia serves that country.

Other animals

The total rate of CKD in dogs was 16 cases per 10,000 years. The mortality rate of CKD was 10 deaths per 10,000. The breeds with the highest rates were the Bernese mountain dog, miniature schnauzer and boxer. The Swedish elkhound, Siberian husky and Finnish spitz were the breeds with the lowest rates.

Research

Currently, several compounds are in development for the treatment of CKD. These include the angiotensin receptor blocker (ARB) olmesartan medoxomil; and sulodexide, a mixture of low molecular weight heparin and dermatan sulfate.

Unbiased research with complete reporting is required to determine the safety and effectiveness of acupuncture to treat depression, pain, sleep problems, and uraemic pruritus in people who are undergoing dialysis treatments on a regular basis.