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Valuable Nationwide Information
Arthur Rosenthal, Ph.D
Aluminum:
The normal kidney has little difficulty in freeing metal ions, such as aluminum, from their attachment to albumin and other proteins during filtration, presumably by exchange of metal for hydrogen on the protein carboxy groups. The artificial dialysis membrane, on the other hand, has a great deal of difficulty of allowing passage of metal bound to the protein, since it can not acidify the substances which are presented to it for filtration. Thus, the dialysis patient is always in danger of accumulating aluminum (and possibly other metals) up to a toxic level.
Aluminum toxicity is a potential ever-present danger for dialysis patients. Not only is their renal excretory function for aluminum virtually non-existent (probably largely due to the absence of the mechanism discussed above), but in addition the nature of their treatment itself poses potential dangers in this regard.
First of all, the tremendous volume of dialysis fluid which comes into contact with the patient's blood itself requires that only a small concentration of aluminum be present in the dialysis fluids in order to cause a severe accumulation of aluminum within the patients. Aluminum on the fluid side of the membrane will diffuse relatively rapidly, since it is unbound to protein or other large molecules, and pass into the patient's blood, where it is avidly taken up by albumin and other proteins. Secondly, the use of aluminum-containing binders and gastric medications (e.g., Carafate) which are aluminum rich, can be a substantial source of ingested aluminum. Added to this is the ubiquitous presence of aluminum in the environment (in food, drinking water, aluminum cooking utensils, etc.).
The decreased use of aluminum-containing phosphate binders probably makes this source of aluminum exposure less frequent then formerly, at least with regard to very high aluminum con-centrations in blood. Probably more catastrophic is the occasional clinic-wide breakdown of water quality which can occur from time to time and which has a number of potential causes. A defect in a reverse-osmosis system with some ancillary effect (e.g., human error in failure to monitor water quality adequately, contamination of a component of water system within the center, unexpected or unknown contamination of the incoming water supply with aluminum such as by a water authority adding alum to precipitate particulates, etc.) is probably the most frequent causes of potentially catastrophic aluminum intoxications. These cannot be adequately monitored by an annual or even semi-annual analysis of dialysis water, since they are prone to occur without warning and at any time. It is therefore recommended that patient monitoring of serum aluminum be done on a regular basis. By spreading out the actual time of monitoring so that some patients are being tested for aluminum throughout the year, the monitoring can serve to alert the center, as well as the laboratory, of an impending problem and steps can then be taken to correct it.
In addition to its well known neurological effects, aluminum can interfere with the action of erythropoetin in correcting anemia, and in interfering with calcitriol correction of bone metabolism; it also has a secondary effect in promoting anemia by interfering with the transfer of iron stores in ferritin into circulating transferrin. Thus, all of the major treatment modalities, other than the dialysis process itself, can be adversely affected by elevated blood and tissue aluminum levels.
In correcting a Center aluminum contamination problem, the laboratory is an essential and indispensable facility. Each part of the water system can be tested and its source can be traced in this way. Without laboratory input, it is very difficult or impossible to be certain that an aluminum contamination problem has been corrected.
CO2 Problems:
The analysis of total carbon dioxide in serum is an indirect means of estimating blood pH levels, and as such is a very important measurement for dialysis patients. Undercorrection of excess blood acidity caused by chronic renal failure promotes tissue wasting by continuous activation of lysosomal enzymes. Overcorrection causes its own problems, with attendant electrolyte imbalances. Thus, attention must be paid to the means by which specimens for CO2 analysis are preserved.
Many people believe that blood serum changes its CO2 value within a short space of time. Actually this is not at all true as long as the serum is well separated from cells by a barrier (e.g., gel) and the tube remains unopened. Experiments show that the values remain very constant at ambient temperatures even during the course of long-distance transportation for over 48 hours. However, once the tube is opened, even if it is reclosed, an appreciable drop in values is seen in as soon as 30-60 min. Thus the analysis must be accomplished within this period of time in order to show the required accuracy. Experiments of this type are sometimes performed by a dialysis-focused laboratory, but usually remain within the company as proprietary information and do not appear to have been widely published.
Experience shows that, beyond laboratory issues, the composition of the dialysis fluid is of paramount importance. It should contain at least 38 mmol/L of bicarbonate in order to correct the acidosis of renal failure properly. The laboratory will be pleased to help with analysis of dialysis fluids for bicarbonate.
Erythropoetin (EPO) Monitoring:
Given the loss of renal endocrine function in chronic renal failure, it is not surprising that virtually all dialysis patients in the present period are given exogenous EPO. In order to monitor the dose and the effects of this drug, a number of test parameters is commonly used. The simplest of all is the hematocrit level. It is usual to attempt to bring this up to 31-33% or perhaps more in certain cases, up to 36 %. Additionally, the hemoglobin level is normally measured; but as these parameters, together with numerous others are commonly part of a modern instrument-derived CBC, these additional test are obtained anyway in the course of measuring the hematocrit level. An increase in the reticulocyte count is also an important index to monitoring for a favorable response to EPO therapy.
Most recommendations today discourage any attempt to determine the effect of EPO administration by actually measuring the EPO level in the blood; it is considered preferable to follow therapy by the effects of EPO on blood cell formation and iron metabolism. During the initial or later attempts to obtain a stable EPO effect, it is recommended to perform hematocrit analyses about once per week. When a stable level in the target range is achieved, monitoring can then be decreased to about 2 per month.
It is usual to follow the reticulocyte count at a frequency of once every 1 to 3 months, the more frequent analyses being in generally those required during the stabilization phase for EPO dosing, and the quarterly frequency then being used in a stable value is achieved.
The measurement of the various compartments of iron metabolism is very important in monitoring the success of EPO administration. Iron itself is an important measurement, but it is essential that the method used be specific and especially should be insensitive to hemolysis. Most methods for the measurement of iron are unfortunately sensitive to interference by hemoglobin, a factor of considerable importance because of the particular fragility of red cells from dialysis patients. It can be considered that blood samples from dialysis patients will usually or perhaps almost always contain a certain amount of hemoglobin from subvisible hemolysis. Since these patients will also usually have a rather low iron concentration, the interference by hemoglobin can be very considerable.
In many automated methods, it is seen that a correction factor is employed in order to attempt to overcome the interference by hemoglobin in iron measurement. Unfortunately too, in many of these procedures, the hemoglobin interference is either under or over- corrected, sometimes leading to excess values or, on the other hand, negative values being found for the serum iron in patients with very low levels. In our laboratory, a measurement of iron is performed by a method which specifically is insensitive to hemoglobin interference up to very large values, so that the level obtained for iron can be considered specific and correct.
Iron-binding Capacity determinations are not always equivalent to direct measurements of Transferrin. Under conditions of iron overload, for example, a significant amount of iron is transported by albumin and other plasma proteins, making the estimation of transferrin by this indirect method unreliable. It has always been recommended as standard practice for dialysis patients that both iron-binding capacity and direct measurement of transferrin be done, usually on a monthly basis, to monitor the effects of both EPO and iron supplementation therapy.
To complete the picture of iron metabolism, Ferritin, representing the storage form of iron, should also be measured. It is probably the most sensitive, as well as the earliest, index of iron deficiency and forms an essential part of the total picture of iron metabolism. Monthly measurements as part of the entire EPO monitoring profile are strongly recommended.
B12 and Folate are usually measured together to provide for a complete picture of the tendency toward anemia in dialysis patients. Usually, they are measured as part of a monthly EPO monitoring profile, but some centers on some patients prefer to monitor these analyses less frequently. Vitamin B12 levels are somewhat complicated in dialysis patients. Chronic renal failure itself, in the absence of other relevant conditions, tends to raise the serum vitamin B12 level. On the other hand, vitamin B12 is cleared during the dialysis process, initially lowering the serum level. It is important that the vitamin B12 level be maintained in the normal range; erythropoetin itself sometimes tends to produce blood changes which can be confused with vitamin B12 deficiency, so that assurance is usually important that the level of this vitamin is maintained normally.
Of the two analyses, folate is perhaps the more important. In recent years, a great deal of attention has been given to the anti-atherogenic effect of folate. The mechanism for this action is that folate in sufficient doses tends to decrease serum levels of homocysteine, which apparently is the proximal stimulator of plaque deposition. It has been found that the average American diet is deficient or at best just barely sufficient in folate. However, even given this situation, the average serum folate levels of the U.S. population has increased significantly in the last ten years, perhaps in large part due to increased consumption of green leafy vegetables in which folate is abundant. Since heart disease of various types is the leading cause of mortality in dialysis patients, it seems prudent to recommend that folate be monitored fairly frequently at least to assure that this mechanism for potential prevention of additional coronary artery disease is effectively in place.
Calcitriol Monitoring:
The loss of ability to synthesize the bone mineral-regulating hormone calcitriol (1,25-dihydroxyvitamin D) by the kidney which occurs in chronic renal failure necessitates that as part of the overall dialysis treatment, calcitriol be given as a drug. This is usually administered intravenously, via the preparation know as Calcijex. The monitoring first of all requires that weekly calcium and phosphorus analysis be done on patient serum, and also requires that monitoring be done of parathyroid hormone and preferably also the bone-formation marker osteocalcin.
It is now strongly recommended that calcitriol itself not be measured, since the level found in the blood is not necessarily indicate the degree of effectiveness of calcitriol therapy. This is determined by many other factors, including the presence or absence of aluminum intoxication, and the general level of calcium and especially phosphorus.
Analysis of calcium and phosphorus is simple and inexpensive, and is recommended to be done weekly as a continual means of monitoring calcitriol effects. Such effects, of course, can be suboptimal, optimal, or produce calcium-phosphorus intoxication as a result of excessive calcitriol dosing.
As a means of determining the effects of calcitriol on its immediate target, parathyroid function, parathyroid hormone should be analyzed. It is now well established that the analysis of choice is intact parathyroid hormone analysis, such as the Nichols immunoluminescent method, as well as some earlier related radiometric methodologies, are specific for the intact PTH molecule and are not affected by the large amount of inactive metabolic fragments found in dialysis patients' serum.
Any parathyroid hormone analysis, even of the specific intact type, are known to give unreliable data unless scrupulous care is taken to preserve a specimen. Parathyroid hormone is know to be very unstable at room temperature in ordinary serum; EDTA plasma, by contrast, provides a very significant improvement in the degree of preservation. Alternatively, a serum specimen must be frozen and handled below room temperature in the laboratory until just before analysis. Performing PTH analyses only quarterly is done as a routine in many laboratories, but this is really more of a concession to cost considerations rather than an optimal schedule for patient monitoring. If possible, a more frequent schedule would provide important and possibly critical data on a more proactive basis.
Completion of the osteodystrophy picture can be achieved by showing that the Calcijex treatment has actually resulted in new bone formation. This is best done in dialysis patients by the measurement of Intact Osteocalcin (see above).
Nutritional Tests:
Since the nutritional status of dialysis patients is one of the major factors determining their survival, laboratory tests of specific nutritional markers are essential in patient management. Some of the important parameters are the following:
Prealbumin: This protein is not related to albumin, but derives its name from the fact that its electrophoretic mobility is unusual in that it is so negatively charged that it migrates ahead of albumin. Its normal function is that it is one of the main serum proteins which transport thyroid hormones throughout the body. From the point of view of dialysis patients, its main significance as a nutritional marker is a result of its extremely short half-life, about 12 hours. Thus, its concentration is a good indicator of daily protein synthesis. therefore, it can be used quite frequently, if there is any suspicion of subnormal protein biosynthesis. In fact, the test is used too infrequently, probably in part due to lost considerations. In contrast, albumin reflects protein synthesis averaged over the previous 20 days, while transferrin concentrations provide an 8-day average. The normal prealbumin concentration is 10-40 mg/dl.
Carnitine: This low molecular-weight substance is normally synthesized from amino acids in the body and is also obtained pre-formed in the diet. Its function is to combine with long-chain fatty acids so that they can be transported across cell membranes, particularly the mitochondrial membrane where the fatty acid then undergoes oxidation for energy production. Since from a quantitative standpoint fatty acid oxidation is the major source of energy for the body, any interference in this process can have serious consequences for a patient's metabolism. These can include muscle weakness, liver dysfunction, and hyperlipidemia.
The dialysis patient is at particular risk, since carnitine is readily dialyzed along with its biosynthetic precursor amino acids, lysine and methionine. Thus, there is a serious danger of depleting the body stores of carnitine as an unintended by-product of dialysis, if the patient is appreciably undernourished. It is therefore sometimes necessary to replace these stores with carnitine supplementation. For this reason, to obtain a picture of the carnitine status of a dialysis patient many facil;ities order a free and total carnitine analysis on a regular basis.
Albumin:
A great deal has been generally known and written about the important of maintaining patient serum albumin levels, so that this brief discussion will be confined only to some newer developments in the laboratory measurement of this protein.
Many nephrologists believe that of the two routine methods for determining serum albumin, BCP is more accurate than BCG. Recent studies have shown, however, that the opposite is the case. A study of these two methods compared with the reference "gold standard" immunonephelometrc method (which is itself too expensive for routine use) show that the BCG methodology gives values much closer to the reference method than does BCP. Therefore, the idea that laboratories should change to BCP must be rejected.
Zinc: The normal level of zinc in blood serum is slightly higher than serum iron. Zinc is bound to various serum proteins and these complexes may be lost in partients with chronic renal disease not on dialysis, producting possible zinc deficiency. This is characterized by weight loss, delayed wound healing, lethargy, and recurrent infection, depending on the duration and degree of severity of the depletion. Supplementation with exogenous zinc must be done very carefully to avoid toxic excess.
In the case of dialysis patients, the situation is more complicated. Especially in elderly patients and diabetics, zinc levels tend to decrease, in part due to inadequate dietary zinc. On the other hand, it may also increase abnormally due to excessive amounts of zinc in the food or water (these days, not usually the dialysis water). For all these reasons, the measurement of serum zinc is probably one of the most important under-utilized nutritional test in dialysis patients.
Cholesterol, HDL, and Triglyceride (Lipid Panel):
Due to the debilitated status of many dialysis patients, their total cholesterol tends to be low. There is, in fact, a rough inverse relationship between the cholesterol level and the degree of wasting. However, as a cardioprotective substance it is important that the HDL level be maintained at the highest possible level.
Unfortunately, triglyceride levels (and the LDL calculated therefrom) are only very approximately analyzable in dialysis patients. Their nutritional prescription prevents them from fasting for the time required to obtain an accurate triglyceride freed from chylomicrons (12-14 hrs). Thus, the actual LDL values tend to be higher than those measured using longer fasing period.
Liver Function Tests: Dialysis patients are particularly subject to liver diseases of various kinds, but especially of the infectious type. Thus is apparently due to the multiple opportunities affforded by their frequent treatment for acquiring blood-borne infection.
For general monitoring of liver function, the enzymes ALT (SGPT) and, less specifically, AST (SGOT), GGT, and alkaline phosphatase represent the "early warning" tests which can alert the physician to the onset of liver disease.
Hepatitis C is by far the most common serious liver disease found in dialysis patients. The test used is a total hepatitis C antibody test, which unfortunately does not distinguish between active disease and resolved prior exposure. Thus, a finding of positive hepatitis C antibody plus elevated liver enzymes, even without actual symptomatology, must considered presumptive evidence of active and probably infectious hepatitis C. Steps should then be taken to avoid infecting other patients and staff. Almost certainly the infection can be spread by blood, but not all the modes of transmission are understood.
Hepatitis B Tests are much better developed and can pin-point the stage and infectiveness of the disease in each case. However, the widespread use of hepatitis B vaccination has decreased the incidence of the disease. In many dialysis centers hepatitis B occurs at less than 1/10 the incidence of hepatitis C, but still the former usually excites more preventative activity when it occurs.
Hepatitis B surface antigen occurs early int he infection and indicates a high degree of infectivity. Hepatitis B core IgM is present at a later stage of active infection. The B surface antibody indicates resolution of the infection; in vaccinated patients elevated titers indicated immunity. Others hepatitis B markers indicate additional information of the progress of the disease.
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