Kidney Disease-2

FACTORS AFFECTING KIDNEY FUNCTION


1)Analgesics

2)Autoimmune

3)Congenital and Genetic

4)Drug Reactions

5)Homocysteine

6)Hypertension

7)Impaired Blood Supply

8)Infection

9)Inflammatory Cytokines

10)Metabolic

11)Tumors

12)Other

Adults lose renal function and capacity with normal aging. A number of factors, including drug reactions and degenerative disease not endemic to the kidneys, may bring added stress.


Analgesics
An analgesic is any medicine that is intended to kill pain. Analgesics that contain narcotics are for more severe pain and require a prescription from a physician. However, many analgesics can be purchased as over-the-counter (OTC) products (aspirin, ibuprofen, acetaminophen, and naproxen). OTC products require no prescription from a physician. OTC analgesics rarely present a problem for most people if they are taken according to the recommended dosage. However, some conditions such as chronic kidney disease or taking OTC analgesics for a long time or in combination with other analgesics make OTC analgesics dangerous. According to the NIDDK (1998), analgesics such as aspirin, ibuprofen, acetaminophen, and naproxen have been attributed to incidence of acute kidney failure in persons with lupus erythematosus or chronic renal conditions; persons of advanced age; or persons who have had a recent binge of alcohol consumption.

Some cases involved a single dose or no more than 10 days of analgesic use. Painkillers that combine two or more analgesics (e.g., aspirin and acetaminophen together) with caffeine or codeine are more likely to cause kidney damage. These mixtures are often sold in powder form. Single analgesics (e.g., aspirin alone) have been found to be less likely to cause kidney damage (NIDDK 1998). According to Fored et al. (2001), more research is required to determine whether the use of aspirin or acetaminophen contributes to kidney failure or whether people who have ailments that predispose them to kidney failure are more likely to use painkillers. Fored et al. (2001) recommended that each patient be considered individually with respect to their risk of kidney failure, length of time the painkiller will be taken, and other existing illnesses, particularly in the elderly and persons with chronic conditions. If possible, avoid acetaminophen-based analgesics, as these may be most toxic to the kidneys.


Autoimmune
Glomeruli, the tiny blood vessels in the nephrons where blood is filtered in the kidneys, can become inflamed by autoimmune disorders. When an autoimmune disorder occurs, the body attacks itself with its own immune system. Examples of an autoimmune disorder are Goodpasture syndrome and lupus erythematosus. In the kidneys, this type of inflammation is called glomerulonephritis (Glanze 1996; NIDDK 1999). While glomerulonephritis is usually caused by an autoimmune disorder, it can also be caused by infection (e.g., by streptococcal bacterial).


Congenital and Genetic
Congenital abnormalities of the kidneys are not uncommon. Sometimes the two kidneys are joined together at their base. Some people are born with only one kidney, both kidneys on the same side of the body, or with underdeveloped kidneys that are barely functional. Polycystic kidney disease is a genetic condition that may manifest at birth, but often appears in young adulthood or even middle age.


Drug Reactions
Acute kidney damage can result from an allergic reaction to a drug; taking large quantities of a drug for a long period of time; taking out-dated tetracyclines; taking long-term or large amounts of pain killers; taking potent antibiotics; accidental ingestion of poisons; toluene inhalation (e.g., industrial exposure and glue sniffing); or combining prescription drugs, over-the-counter drugs (aspirin, acetaminophen, ibuprofen, naproxen sodium), and alcohol (NIDDK 1998). Regular blood tests to assess kidney function are recommended for anyone who takes medicine known to damage the kidneys or who has a condition that puts them at risk for developing kidney disease.


Homocysteine
Discovered in 1932, homocysteine is a sulfur-containing amino acid normally found in small amounts in the blood of healthy persons. Homocysteine is derived from dietary protein (meat, milk, eggs) and is metabolized in the liver using vitamins B6 and B12. High levels of homocysteine can result from genetic disease (homocystinuria); kidney disease; hyperthyroidism; psoriasis; systemic lupus erythemotosus; drug treatment for chronic diseases; and dietary vitamin deficiencies (folic acid, B6, B12) (Welch et al. 1998).

Homocysteine levels tend to increase with age and are higher in men than in women. High levels of homocysteine can be very damaging to the kidneys and the vascular system (Dierkes et al. 1999; Marangon et al. 1999; Levin et al. 2002). Accumulation of toxic homocysteine has been associated with the development of cardiovascular disease (artherosclerosis, stroke, heart attack); pulmonary embolism and deep venous thrombosis; dementias (Alzheimer's disease, multi-infarct dementia); and kidney disease ESRD (Joosten et al. 1997; McCaddon et al. 1998; Welch et al. 1998; Dierkes et al. 1999; Levin et al. 2002; Seshadri et al. 2002). Cardiovascular disease (CVD) is common in patients with chronic kidney disease (CKD) and is responsible for the majority of morbidity and mortality in patients (Levin et al. 2002).

As early as 1969, researchers began to make clinical observations linking elevated homocysteine to vascular diseases (McCully 1969). Subsequent investigations confirmed these observations (Clarke et al. 1991; Ueland et al. 1992; Stampfer et al. 1992; 1995; Selhub et al. 1995; Welch et al. 1998). In CVD, there is evidence that elevated levels of homocysteine are related to arterial wall damage, but the mechanism is unclear (Welch et al. 1998). It may be that homocysteine has a toxic effect on the endothelial (cellular) lining of blood vessels. Data from a study on healthy U.S. physicians (14,916) with no prior history of heart disease demonstrated that highly elevated homocysteine levels are associated with a more than threefold increase in the risk of heart attack over a 5-year period. This finding was published in 1992 in the Journal of the American Medical Association (JAMA) as part of the Physicians' Health Study (Stampfer et al. 1992). The Framingham Heart Study (1041 elderly subjects) (Selhub et al. 1995) and other studies have also confirmed that elevated homocysteine is an independent risk factor for heart disease (Chaveau et al. 1993; van Guldener et al. 2000; Hoffer et al. 2001; Suliman et al. 2001).

In kidney disease, homocysteine levels in the blood increase because the kidneys do not properly filter homocysteine. Elevated levels of homocysteine are commonly seen in renal patients, sometimes three or four times higher than normal levels (van Guldener et al. 2000; Friedman et al. 2001; Herrmann et al. 2001; Suliman et al. 2001). Homocysteine is consistently elevated to very high levels in patients who require dialysis (Levin et al. 2002). Plasma homocysteine concentrations often decrease after dialysis (Welch et al. 1998). Therefore, to further help lower homocysteine levels, dialysis patients often require high levels of nutrients, including folic acid, vitamin B12, TMG (also known as betaine or trimethylglycine), and vitamin B6 (Bostom et al. 1996; Chauveau et al. 1996; Robinson et al. 1996; Sadava et al. 1996; Tucker et al. 1996; Welch et al. 1998; van Guldener et al. 2000; Herrmann et al. 2001; Levin et al. 2002).

Folic acid was used in a study conducted in 82 patients undergoing dialysis 3 times a week for 4 weeks (hemodialysis, 70 patients; peritoneal dialysis, 12 patients) (Dierkes et al. 1999). The results demonstrated that in both groups, homocysteine concentration was reduced by 35% after taking 2.5-5 mg of folic acid after each dialysis treatment.

As noted earlier, although dialysis has the effect of lowering homocysteine levels, folic acid further reduced homocysteine levels and, more importantly, had long-term effects even after supplementation was withdrawn (Dierkes et al. 1999).

Although the relationship between CVD and CKD is convincing, therapeutic strategies appear to be underused in the care of patients with kidney disease. CVD and CKD have similar traditional risk factors (diabetes, hypertension, dyslipidemia, obesity) as well as nontraditional risk factors (hyperhomocysteinemia, anemia, disturbed mineral metabolism, parathyroid excess). Because these risk factors are also specific to kidney disease and are modifiable, they should be identified and treated in persons with CKD (Levin et al. 2002). Patients with mild hyperhomocysteinemia have no clinical signs and are typically asymptomatic until the third or fourth decade of life (Welch et al. 1998).

For some time, physicians have recognized the danger of homocysteine and they recommend use of vitamin supplements to lower homocysteine levels (Tucker et al. 1996; Welch et al. 1998). The "normal range" used by commercial laboratories is 5-15 micromoles/L of blood. However, epidemiological data reveal that homocysteine levels above 6.3 result in a steep, progressive risk of heart attack, with each three-unit increase equaling a 35% increase in risk for heart attack (Verhoef et al. 1996; Robinson et al. 1996). There may be no safe "normal range" for homocysteine. A survey in Cardiologia reported that the average American's level of homocysteine is 10 (Andreotti et al. 1999).

For many persons, daily intake of TMG (500 mg), folic acid (800 mcg), vitamin B12 (1000 mcg), vitamin B6 (100 mg), choline (250 mg), inositol (250 mg), and zinc (30 mg) will keep homocysteine levels in a safe range. Unfortunately, without a homocysteine blood test, it is impossible to know if the proper amounts of nutrients are being taken. Therefore, the only way to be certain is to have a blood test to ascertain that your homocysteine level is below 7. Sometimes treatment must be individualized for complicated conditions. High levels of homocysteine can require up to 6 grams of TMG or vitamin B6 (in cystathione-B synthase deficiencies).


Hypertension
High blood pressure (or hypertension) creates a significant risk factor for kidney failure. This risk factor is amplified for persons who have ADPKD. Li Kam Wa et al. (1997) investigated the 24-hour blood pressure profile of ambulatory patients, particularly to measure nocturnal fall of blood pressure. The researchers found that in ADPKD patients, the reduction in nocturnal blood pressure was attenuated (lessened), indicating increased risk for kidney damage. Further studies are needed to evaluate the contribution that nocturnal hypertension makes on the overall progression of renal failure. However, in another related study of untreated children, it was found that nocturnal hypertension was a major risk factor for renal deterioration (Ligens et al. 1997).


Impaired Blood Supply
Any condition that impairs blood flow to the kidneys can damage or cause obstruction in the small blood vessels in the kidneys (e.g., diabetes mellitus, hemolytic uremic syndrome, physiological shock, lupus erythematosus).


InfectionA kidney may become infected when the flow of urine is restricted in the urinary tract (NIDDK 1998). An obstruction may lead to stagnation of urine in the kidney that allows infection to spread into the bladder. Possible causes of an obstruction are a congenital defect, a kidney stone, a bladder tumor, or enlargement of the prostate gland. Tuberculosis of the kidney occurs when infection is carried by the blood to the kidney from somewhere else in the body (usually the lungs).


Inflammatory Cytokines
Destructive cell-signaling chemicals called inflammatory cytokines contribute to degenerative, inflammatory, and autoimmune diseases (Van der Meide et al. 1996; Licinio et al. 1999). Degenerative diseases appear to be factors in or possible underlying causes of kidney failure and disease (congestive heart failure, anemia, rheumatoid arthritis, fibrinogen formation, fibrosis, diabetes, asthma, lupus, psoriasis). People who have multiple degenerative disorders often exhibit excess levels of pro-inflammatory markers in their blood. Therefore, seemingly unrelated inflammatory or autoimmune diseases can have a common link to kidney disease: inflammatory cytokines. In kidney failure, inflammatory cytokines restrict circulation and damage nephrons (the filtering units of the kidneys).

For those who have degenerative diseases, particularly multiple ones, cytokine profile and C-reactive protein blood tests are highly recommended (available through your own physician or Life Extension Foundation). If your cytokine test reveals excess levels of cytokines--tumor necrosis factor-alpha (TNF-alpha), interleukin-1b (IL-1b)--nutritional supplementation, dietary modifications, and low-cost prescription medications (pentoxifylline or PTX) are advised (see the Inflammation: Chronic protocol for a discussion of systemic inflammation and recommendations for reducing inflammatory conditions).


Metabolic
Kidney stones are more common in middle age and are usually caused by excessive concentrations of substances such as calcium, uric acid, or cystine in the urine (NIDDK 1998). Hyperparathyroidism, cystinuria, and hyperoxaluria are rare, inherited metabolic disorders that can cause kidney stones. In cystinuria, too much of the amino acid cystine can lead to the formation of stones made of cystine. In patients with hyperoxaluria, the body produces too much of the salt oxalate. Excessive oxalate in the urine cannot be dissolved, crystals settle out, and stones form. Absorptive hypercalciuria occurs when the body absorbs too much calcium from food. The extra calcium ends up in the urine and the high levels cause calcium oxalate or calcium phosphate crystals to form in the kidneys or urinary tract. Other causes are hyperuricosuria (a disorder of uric acid metabolism), gout, excess intake of vitamin D, and blockage of the urinary tract. Certain diuretics ("water" pills) or calcium-based antacids can increase the risk of kidney stone formation by increasing the amount of calcium in the urine (NIDDK 1998).


Tumors
Tumors in the kidneys, either benign or malignant, are rare. When malignant, the most common type is renal cell carcinoma, particularly in adults over 40.


Other
Urinary tract infections (UTIs) are frequently occurring health conditions that are caused by various urinary systemic infections, sexual contact, bacteria entering the kidneys via the bloodstream or the urethra, kidney stone blockages, and kidney damage (Glanze 1996). Infection can lead to impaired kidney function. Therefore, a kidney infection should be treated immediately to prevent more serious disease. A direct blow to the kidneys can also cause extensive damage (e.g., a car accident, industrial accident, sports injury, or accidental fall) (NORD 2002).


Autosomal Dominant Polycystic Kidney Disease (ADPKD)

ADPKD is one of the most common genetic diseases in humans. It is a systemic disease that is caused by at least three different genes: PKD1, PKD2, and PKD3. However, most of the mutations are found in the PKD1 gene (Merta et al. 1997; Sessa et al. 1997). ADPKD is a very serious disease. Worldwide, it is responsible for 8-10% of all cases of ESRD. Patients with ADPKD develop cysts in both kidneys. These cysts continue to grow over the lifetime of the patient and ultimately lead to hypertension, reduced kidney function, and eventually renal failure. Poor kidney function in ADPKD patients accounts for many kidney transplants each year. According to the PKD Foundation (Kansas City, www.pkdcure.org), 60% of individuals with ADPKD develop kidney failure or ESRD. The only treatment is dialysis or transplant. Interestingly, because ADPKD is genetic in origin, persons who receive kidney transplants do not reacquire their genetic mutation with transplanted kidneys. Common symptoms are frequent infections, blood in the urine, and back pain.