Diseases, Disorders information

How do you evaluate type II RTA? Again, hyperchloremia, metabolic acidosis. But the anion gap is negative. Remember I told you that for distal RTA the anion gap was positive. This one is not a problem with making ammonia. This is a problem just with leaking lots of bicarb. So the anion gap is negative. The urine pH is greater than 5.5 when the plasma bicarb is what is normal to you and me, but when the plasma bicarb falls below the threshold, the urine pH is low.

I am going to … this is another way to evaluate it. Again, this is something that pediatric nephrologists do. It’s a fractional excretion but instead of a fractional excretion of sodium, it’s a fractional excretion of bicarbonate. And we can do this, and this allows us to do that. Again, they will not be asking you that.

A quick word about type IV RTA. There is no type III. There was a mistake. Somebody made a mistake and so they called… we called just type IV. Type IV is so-called low-renin hypo-renin hypoaldosteronism. This again is a non-anion gap acidosis but it has hyperkalemia. Urine pH can look like type II RTA with a pH less than 5.5. Highly unlikely that they will ask you about this. Very unusual. It’s caused by true aldosterone deficiency, conditions which decrease renin secretion and conditions where the kidney cannot respond to mineralocorticoids. This is a reiteration; the diagnostic workup of suspected RTA. We look first for he serum anion gap. We see whether it is elevated. The metabolic acidosis is elevated. If it is you work up for a gap acidosis. If there is a normal gap, you want to evaluate for RTA. Then I put in how you go with RTA’s, either type II or type I and type IV. I’m going to skip over this, and I’m going to skip over metabolic alkalosis except to remind you that the laboratory studies for metabolic alkalosis will show you that besides a blood pH that is high, there is a low chloride, a low potassium, increased bicarbonate or CO2 in the blood. The few physical signs; tetany. Underline tetany and convulsions. This is one of the things that can give you tetany and convulsions, metabolic alkalosis.

The types; it is associated with many many things, and I’ve listed a number of them here. Genetically transmitted disease, autoimmune diseases and disorders associated with nephrocalcinosis. If you hear nephrocalcinosis and acidosis, think type I RTA, and there are a couple of situations here. Drugs that have tubular toxicity; we talked about hypokalemia with cisplatin and amphotericin. Amphotericin will also give you a situation of RTA. Amphotericin also gives you renal failure in very sick patients, but in patients that are not so sick and we are using lower doses of amphotericin, there is a tubular toxicity, and that’s amphotericin-B I’m talking about. Others include pyelonephritis obstruction and kidney transplant.

Type II RTA is different than type I RTA. It’s not that you can’t excrete hydrogen ions. It’s that the kidneys leak bicarbonate. There is a low threshold in the blood for spilling bicarbonate in the urine. Normally you and I start to spill about 22 … or kids, actually, start to spill 22-24. In type II RTA they start to spill at 15-16, so they begin to lose their bicarbonate with relatively low serum bicarbonates. The clinical findings, again, hyperchloremia. I can’t stress enough, hyperchloremia – metabolic acidosis. With what in the potassium? Low potassiums, low or normal. That’s the way to recognize this. High chlorides, low or low normal potassium with an acidosis. The urine pH is greater than 5.5 when the bicarbonates, or the serum bicarbonates or the CO2 is normal. But it can decrease to less than 5.5 when you get very acidotic. Because then you get underneath the threshold and the body is able to reabsorb all the bicarbonate, and in this situation the distal tubule is working fine. It’s only the proximal tubule that is messed up and spilling all the bicarbonate. The K can be low or normal. Never high. This is seen usually with Fanconi’s syndrome, but it may be isolated.
Renal tubular acidosis
So what is the Fanconi’s syndrome? The Fanconi’s syndrome is a disease of the proximal tubule, that has all of the listed criteria, or many of the listed criteria; proximal RTA, they have amino aciduria, glucosuria, phosphaturia and hypophosphatemia and hypokalemia. They have uricosuria. They spill uric acid and decreased plasma uric acid. They have rickets, growth retardation, polyuria, dehydration, and sometimes low molecular weight globulin proteinuria.
Metabolic alkalosis
What are examples? This is the one they will ask you. Number one, cystinosis. Most frequent cause. Galactosemia, Wilson’s disease are others. Glycogen storage disease, Wilson’s disease, galactosemia, but cystinosis, nephropathic cystinosis, is the archetypal one. Here are some other selected causes. The full group is in your syllabus; heavy metal poisoning, cisplatin, biphosphamide, and then some other nephrologic ones, and glue-sniffing. Now if you have an isolate, those with Fanconi’s syndrome, I’ve listed some causes of isolated proximal RTA that are shown here. It is highly unlikely they will ask you any of these. And they are listed here: sporadic, genetic, carbonic anhydrase inhibition.

How do we recognize renal tubular acidosis? Number one, what I said before; first have a blood pH. You’ve got to have acidosis. I can’t tell you how often I have been consulted by some of you out there who will remain anonymous, in the audience, who say, “Low CO2, low bicarbonate, we obviously have an acidosis. Please evaluate the acidosis for us.” And it turns out, of course, that it’s a compensation because the blood pH, when we got it, was 7.6. So number one, be sure you know the acid-base status. Start stepwise. Start with your first step which is; know the primary disorder. Then these patients are hyperchloremic. They have a normal anion gap. Not a high anion gap. They have a relatively low serum K for the degree of acidosis, and this is true of type I and type II RTA’s. And they have an inappropriately high urinary pH. If you have all of these, you more than likely have an RTA. So these are the characteristics. This right here is something to look at. If you don’t look at anything else in RTA, look at this. Because this is the link, this is the association that will allow you to get it through the test.

Now there are different types. We nephrologists have an incredible amount of imagination and wit, so we of course call them type I and type II, with our great creativity. Type I is called distal RTA. It is caused by a problem in the distal tubule with the inability to decrease the urine pH to 5.5 during acidosis. Because the kidney can’t push out hydrogen ions out of the body. There is one of a number of molecular defects that cause the kidney to be unable to kick out hydrogen ions. You eat 3 milliequivalents per kilo of hydrogen ion per day in your phosphates and your sulfates and the things that you eat. You can’t get rid of them in RTA. Thus, you become a big walking hydrogen ion. The associated problems with type I – this is an important association – nephrocalcinosis. Another; we’ve said before, hypokalemia and low urinary citrate. Remember the two types of acidosis that give you low potassium, DKA – because you are peeing out all that K – and RTA. RTA, relative hypokalemia. It turns out that you get a secondary hyperaldosteronism and that’s why you get hypokalemia. What’s important to remember is low acidosis, low K; low or normal K – even a normal-ish K – you’ve got to really think about it because the K should be high when you are very acidotic. Think DKA or RTA.

How do you evaluate these patients? They have a hyperchloremic metabolic acidosis and they have a positive urinary anion gap. That’s because these patients don’t make very much ammonia. The urine – a lot of the positives that are over here to balance out the chlorides, etc. – is ammonia and usually the sodium plus potassium minus chloride normally is a negative number. But in distal RTA the sodium plus the potassium minus the chloride is a positive number in distal RTA. We’ll get to proximal RTA in a minute. And in normals, it’s a negative number. The urine pH, for the sake of this discussion here, is always greater than 5.5. There are situations where it may be below that but not in a million years will they ask you. So for the situation that we are talking about here, with regard to 98% of RTA’s, urine pH always greater than 5.5. You can bicarbonate load these patients and do a study called a urine PCO2 minus blood PCO2 and the values are given here. This is a question for pediatric nephrology Boards. Not for general peds Boards. You won’t get asked it.

Metabolic alkalosis; you are alkalotic, you have a high CO2 with retained bicarbonate. The compensation is low ventilation. You decrease your ventilation and you drive up your PCO2. The respiratory alkalosis, the PCO2 is low as you are blowing PCO2 off. The pH is high, the bicarbonate excretion is your compensation, so your CO2 will be low. When you are studying, make sure you have a clear view of this before you go to this. So make sure you understand clearly what the primary problem is, and then look at the compensation and that will help you with your study. Do it in a stepwise fashion. Don’t even bother with the compensations until you are clear what the primary problem is. See the primary problem then look to the compensation.
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Okay, now, the next thing you do if you have an acidosis, and in particular is to determine the anion gap. The anion gap is the sodium minus the bicarbonate and chloride. Normally it’s 9-12. An increase in the anion gap over normal represents unmeasured anions and those are usually things like lactate, beta-hydroxybutyrate, that’s the so-called gap acidosis. Where you are dumping acids into the blood. A gap acidosis, those include lactic acidosis, uremia, diabetic ketoacidosis or organic acidemias. Other exogenous acids like salicylate or ethanol. Non-gap acidoses; most are either loss of diarrhea or other base from the body, usually from the GI tract but it can be from other places, or renal tubular acidosis. So gap acidoses are when you are dumping acids into the blood, a pathologic process is dumping acids into the blood. A non-gap acidosis is when you are losing something from somewhere that is usually basic. And that something from somewhere is usually diarrhea and bicarbonate, bicarbonate in the diarrhea.

Acidosis; first we evaluate the primary disorder, and the definitions of the primary disorder. If you think about acid-base balance in a logical stepwise fashion, you may be able to remember it and figure it out. If you don’t do it in a logical stepwise fashion you are almost for sure not going to be able to do it, and even if you do think about it in a logical stepwise fashion, a lot of people have problems with it – like me. So it’s got to be logical and stepwise. So number one, we think of the primary disorder. What is the primary disorder? If there is metabolic acidosis, the pH is low compared to 7.4. If the primary cause is loss of bicarbonate, the lab finding; a low CO2. I make a big differential here between CO2 and of course PCO2. Because PCO2 is the respiratory component, the carbonic acid. If there is a respiratory acidosis – you have again, a low pH – you have increased carbonic acid and that’s an increased PCO2. So contrast these two. If it’s alkalosis the pH is high and metabolic alkalosis is caused by increased bicarbonate or low chlorides, and an increased CO2 is found in your electrolytes. Respiratory, again an increased pH, a low bicarbonate, a low PCO2. This is important to review. This seems simple. You guys have gone over it again and again, but this is important to review and be sure you’ve got cold.
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The compensations are likewise important. Remember, you can never overcompensate so you determine the primary changes first. Metabolic acidosis, low CO2. What is the compensation? The compensation is in the other system; increased ventilation, and the result is decreased PCO2. But the primary is an acid pH in the blood and a low CO2. Respiratory acidosis, the primary change, high PCO2. Retained PCO2. The compensation is renal bicarbonate absorption and a high CO2. If you are acidotic and you see these two things, you are going to know that first, this is what would give you the high … the respiratory acidosis. Below the 7.2 type of blood pH. Remember please, that you cannot make a distinction of whether a patient is acidotic or alkalotic unless you have either a venous blood gas or an arterial blood gas that shows a pH. These numbers in and of themselves cannot show you whether the patient is acidotic or alkalotic. Very important to remember.

Cocaine
Drugs and Chemicals Associated with Birth Defects
Cocaine (street names “coke;’ “snow;’ “lady;’ and “gold dust”) use is a major public health concern. Use of cocaine in the 1970s was primarily limited to the intranasal route. In the 1980s, a decrease in the street cost and wider availability of cocaine resulted in an increasing prevalence of intravenous and smoked (”free-base” or “crack”) routes of use. Consequently, the prevalence of cocaine-associated medical complications has increased. Cocaine is commonly used intranasally (”snorting”), by injection, and by smoking the free alkaloid form (crack). Crack (named after the cracking or popping sound that is made when the crystals are ignited in a pipe while smoking the drug) is a highly purified form of free alkaloid cocaine. In a survey of a number of urban hospitals nationwide, positive urine toxicology for cocaine metabolites was detected among 10-48% of pregnant women. The crack form of cocaine is believed to be more addictive than other forms. Administered systemically, cocaine blocks the presynaptic reuptake of neurotransmitters (norepinephrine and dopamine), causing these neurotransmitters to accumulate at postsynaptic receptor sites, resulting in intense vasoconstriction, acute arterial hypertension, and tachycardia.

The drug is metabolized primarily by plasma and hepatic cholinesterases to water-soluble metabolites (benzoylecgonine and ecgonine methyl ester). The most commonly used urine test detects benzoylecgonine at a sensitivity of 300 ng/mL. The elimination half-life of the parent drug is approximately 4-5 hours. Cocaine metabolites can be detected in urine for 24-48 hours. Pharmacokinetics of peri-natal cocaine use are poorly studied, but cocaine is known to cross the placenta readily. It is thought that urine tests in neonates exposed to cocaine in utero may be positive for a similar time as they are in an adult, although benzoylecgonine has been detected in neonatal urine for up to 4 days.

Potentially lethal medical complications associated with cocaine use, directly or indirectly, seem attributable to the intense sympathomimetic effects of the drug. They include acute myocardial infarction, cardiac arrhythmias, rupture of the ascending aorta, cerebrovascular accidents, seizures, bowel ischemia, and hyperthermia.

Use or abuse of cocaine during pregnancy is a major risk factor for the mother and her unborn child. Most pregnant cocaine users are patients with unplanned pregnancies of uncertain gestational age who seek prenatal care late (if at all) and have poor nutrition. They also tend to be abusers of multiple drugs, including tobacco and alcohol. It seems clear that there is, at minimum, a risk of 25% for preterm birth and 20% for infants that are small for gestational age, but studies are confounded by the effects of poor health and use of other substances of abuse. Studies have indicated as much as a 10-fold increase in the risk of abruption, suggesting an increase from 0.1% among all pregnancies to a 1% risk among cocaine-exposed pregnancies. Neurobehavioral abnormalities in neonates exposed to cocaine in utero are well documented, especially the tendency for hyperirritability and an inability to respond appropriately to stimulation. A purported increased incidence of sudden infant death syndrome among cocaine-exposed infants was suggested but has not been confirmed. An increased frequency of certain congenital anomalies among cocaine-exposed neonates has been reported. These anomalies include congenital heart disease, intestinal atresias, cerebral infarction, brain cavitation defects, and genitourinary defects.

It is thought that the increased risk of congenital anomalies among cocaine-exposed infants is associated with cocaine-induced vasoconstriction, which may cause infarction, severe hypoxemia, and hypoperfusion that may interrupt normal morphogenesis. A pattern of anomalies termed the vascular disruption syndrome has been described. The mechanism of vascular disruption is supported by animal studies that showed dose-dependent decreases in uterine blood flow and marked fetal hypoxemia, hypertension, hypoperfusion, and tachycardia in experimental animals that were administered cocaine intravenously.

Clinical evaluation of obstetric patients should incorporate the following protocol, which the clinician should consider for both medical and legal reasons:

• All pregnant women should be asked about previous and current drug use at the time of the first prenatal visit.

• The life-threatening implications of cocaine use during pregnancy for the patient and for her infant should be clearly explained to the pregnant woman admitting to cocaine use. She should be offered support services to aid in her abstinence.

• Continued abstinence from the use of cocaine should be reinforced and encouraged. Periodic urine testing for metabolites of cocaine is one way to discourage relapse in a pregnant woman admitting to cocaine use before or during pregnancy. The requirements for consent may vary from state to state.

• Urine testing of the mother, the neonate, or both may be useful in some clinical situations, such as unexplained fetal growth restriction, unexpected prematurity, or abruption in a woman not known to have hypertensive disease, even when cocaine abuse has not been previously suspected. The mother’s consent may need to be obtained before testing.

• Physicians should be familiar with their own state laws regarding consent for drug screening of pregnant women and newborns.

• Some state laws consider in utero drug exposure a form of child abuse or neglect and require the reporting of positive drug tests in pregnant women and newborns. Physicians should be familiar with state laws regarding testing and reporting.