BASIC SCIENCE IN MEDICAL PRACTICE

IMG_2303WHAT IS THE QUESTION?

I understand that some physicians are skilled basic scientists, and that many physicians enjoy reading about basic science. But how does a knowledge of basic science benefit the patients of physicians who have such knowledge?

There are two parts to this question. How can being a basic scientist benefit a physician in the practice of medicine, and how can a knowledge of the results of basic science benefit a physician in the practice of medicine. Of these two, I mean to consider only the second: How does a knowledge of basic science results benefit the practice of medicine. Of course, here, I mean practice of medicine concerned with kidney stones – the disease within the province of this site and my expertise.

I dismiss at the beginning questions about practical science – how we can do things. No one needs to ask how a knowledge of trials of treatments and tests benefits medical practice. It is the ‘other’ science I am asking about, the one that is not about trials but about how nature brings about what we observe.

EXAMPLES FROM KIDNEY STONE DISEASE

A BRUSHITE STONE FORMER

The patient has passed several brushite stones, and has multiple calcifications in each kidney. Urine testing shows a pH of 6.3 and a 24 hour urine calcium excretion of 400 mg. No other urine abnormalities are present and a standard renal panel is normal.

How Stones Form

A physician seeing this patient could know that,unlike kidneys of idiopathic calcium oxalate stone formers which usually have pristine papillae with stones growing over plaque, these kidneys will usually have apatite or brushite plugs in BD and IMCD with papillary epithelial damage and peritubular inflammation and fibrosis. The renal cortices commonly have fibrosis and tubular atrophy above normal levels, but the links between cortical and papillary injury are not proven.

How can knowledge of the particular renal tissue pattern in such a patient benefit practice?

24 hour urine testing, diagnosis of idiopathic hypercalciuria, and trial results for idiopathic calcium stones are listed in common reviews and textbooks. Although brushite stones are known to break less well with shock wave lithotripsy this fact does not require one know about tubule plugging.

Why Should Physicians Know About Tubule Plugging?

There are three possible ways knowledge about tubule plugging might alter practice: Passion, patient education, and subtlety.

PASSION

Consider the alternative patient with several calcium oxalate stones and a dislike or hesitancy about prevention. Papillary damage is not likely and cortices are normal, but as for all stone formers there is risk of pain, obstruction, bleeding, infection, and surgery. So a wise physician will attempt to prevent more stones.

In our case, all of the risks from stone passage are present along with papillary damage that will progress if more plugging occurs, and cortical injury of uncertain cause. Should this, and will this knowledge increase the intensity with which treatment is pursued?

If any trials had proven that treatment can prevent future plugging, or that plugging progresses to CKD or new onset hypertension above common rates the answer must be ‘yes’. But there is only basic science knowledge about plugging and tissue injury.

In the absence of trials and proven risk of CKD, will you tell the patient – with suitable precautions against undue alarm – about tissue injury? Will you be justified in hiding this fact, as though the brushite stones were no different in consequence from idiopathic calcium oxalate stones? Will you pursue treatment with more energy and passion than for an idiopathic calcium oxalate stone former?

PATIENT EDUCATION

Virtue

To know how the stones form enables one to instruct patients about what is wrong with them. If it promotes long term treatment or not patients who receive education will know more about their disease than otherwise. Only an informed physician can educate properly. So, to the extent that education of patients is a necessary component of practice, then to know basic science, in this example, enables physicians to do something.

The Internet

Google and PubMed have converted virtue into necessity. Patients search. Many will come to know about the odd and potentially damaging crystallizations in their kidneys, or, the internet being variable, with misinformation. Only a fully educated physician can respond fully to to an informed or misinformed patient.

SUBTLETY

Interpretation of Radiographs

We read kidney stone radiographs to determine, along with history and other observations, whether new stones are forming. In this patient, and patients like this, calcifications are of two types: Stones, and papillary tissue calcifications. One cannot tell these apart readily (). Therefore new crystallization appearances can be stones or progression of tissue calcification.

We do not know if treatments to prevent stones affect tissue calcification rates. It is true that intensification of treatment in response to new tissue calcifications may not be a bad action, it is just that it may not be worthwhile. Moreover, it is to be mislead and to mislead. Only ureteroscopy or other direct visualization can discriminate what is happening.

Urological Management

To a urologist who does not know about the tissue calcification pattern in brushite stone formers, multiple tissue calcifications that look like stones could lead to ill considered shock wave lithotripsy. A percutaneous nephrolithotomy undertaken to reduce stone burden might present the surgeon with only calcified tissue, and few if any free stones.

Basic and Applied are in the Context of Practice

For urologists knowledge of crystallization anatomy could well be gathered for applied research reasons – to figure out how to manage crystals in kidneys. In other words, from a surgeon’s perspective the details of tissue crystal anatomy or pathology enable the doing of right actions. For medical physicians the link is weaker.

So the very distinction is at once powerful and subtle. What is an applied vs. what is a basic science inquiry, so far as medicine is concerned, is determined ultimately in relation to what a physician does. To a urologist, recondite knowledge about BD and IMCD crystals can provide a way of doing something. To a medical physician interested in preventing stones it may not enable the doing of something except perhaps educating patients better. But, to think about the matter, is not the education part crucial for the medical kind of physician? Does doctor not mean teacher?

AN ACCELERATED STONE FORMER

The patient has had over 100 calcium oxalate stones, but the routine 24 hour metabolic profile does not reveal any specific abnormality; supersaturation values for calcium oxalate are in the middle of the normal range. Stones have led to few surgical procedures but, being very frequent and painful, interfere with work and family life and require considerable use of narcotic drugs.

Cause of Stones in Unclear

We and others have described such ‘accelerated’ stone disease. As in this case, conventional urine risk factors are minimal and procedures are few despite vast numbers of stones. Although there are no trials, conventional measures to lower urine supersaturations usually reduce new stones dramatically enough to convince physicians and patients of efficacy. In other words they are the arch paradigm of stone activity despite normal supersaturations, and reduce their stones as supersaturation is reduced, often far below the normal range.

Stone and Urine Proteome

Empirical basic research is documenting which urine proteins are present in kidney stones and likewise differences of urine proteome between normal people and stone formers. Physicians can know that the stone and urine proteome include many powerful kinetic retardants of crystal nucleation, growth and aggregation, which decouple supersaturation from crystal formation. Accelerated stone formers may well have urine proteome abnormalities, but to date proof is absent.

Why Should Physicians Know About the Proteomes?

I have eliminated the practical residue we found in the brushite example, in order to face the question of basic science knowledge in the context of practice. Nothing about the speculative relationships between crystal modifiers in urine and accelerated stone formation could directly affect practice. Will such knowledge affect passion, education or subtlety?

PASSION

Patients with hundreds of stones so desire treatment that no more enthusiasm can possibly be generated by additional knowledge.

EDUCATION

Here, education is an abstract virtue in that the knowledge can hardly alter treatment or behavior. The internet is unlikely to enlighten patients about the role of inhibitors in accelerated stone disease as the possibility is mainly theoretical and wanting new science.

SUBTLETY

The principle that supersaturations of an active stone former are too high in relation to the crystals of stones formed is general, but has a rationale only if one can understand the power of the urine inhibitors. So to the extent that understanding of the principle leads to its use, understanding of the proteome as a body of inhibitors leads to action. This is like the case of crystal plugging in relation to urological practice; basic science concerning inhibition explains why supersaturation can be too high for a given patient even when lower than the average found among normal people. But it is more indirect. One can believe the principle without understanding it and apply it to all patients.

AN IDIOPATHIC CALCIUM OXALATE STONE FORMER

The patient has formed 4 calcium oxalate stones and has a urine calcium excretion of 450 mg daily without other urine stone forming abnormalities. No systemic diseases are present that might have contributed to the stones. The diagnosis of idiopathic hypercalciuria requires only knowledge present in basic textbook chapters and clinical reviews. Likewise for clinical trials: Thiazide (3); reduced sodium and protein intake as compared to low calcium diet in males; potassium citrate (3).

Mechanism of Idiopathic Hypercalciuria (IH)

The physician could know from textbooks and reviews that familial and therefore presumably genetic hypercalciuria arises from reduced renal tubule calcium reabsorption, that bone mineral balance becomes negative unless diet calcium is very high, that serum 1,25 D levels tend to be high and increase GI calcium absorption, and that serum PTH levels are normal and not informative unless serum calcium is abnormal. Likewise, as an offshoot of the negative bone mineral balance of IH, bone mineral density is not infrequently decreased, and fracture rates exceed those of unselected normal populations ().

My focus here is on something less well publicized thiazide lowers urine calcium in part via increase of proximal tubule calcium reabsorption, reduced sodium intake also increases proximal tubule sodium reabsorption and lowers urine calcium. Therefore reduced diet sodium intake can substitute for thiazide in lowering urine calcium, or potentiate the thiazide effect.

Why Should Physicians Know About the Proximal Tubule?

PASSION

One must work hard to reduce daily sodium intake to levels (65 – 100 mEq/day) which have important effects to reduce urine calcium excretion in IH. Advice of a general nature will motivate some patients. Advice based on a powerful physiological rationale will have more power in it, because the person giving it understands how and why is will work. Patients who really grasp that lowering sodium intake will lower urine calcium excretion and who also know that high urine calcium excretion is a probable cause of kidney stones will have a stronger base upon which to support motivation and change in behavior. With only one sodium trial, applied research is still preliminary, so understanding adds importantly. One day, when we have low sodium prevention trials, basic science knowledge will no longer be needed for one to be passionate.

PATIENT EDUCATION

Virtue

Given the value of the knowledge, virtuous physicians will want to possess it. Likewise, for those who can be educated about the matter, which is almost all patients in my experience, education is a good quite apart from matters of passion already discussed. Education fosters long term treatment, as one will desire to do what one believes is helpful to maintain health.

The Internet

Diet sodium is everywhere on the internet, for better and for worse, so physicians must educate towards what is most true and against what is not true. In that sense, for so public and debated a topic, education is necessity. The exact details of tubule effects are, like the proteome, obscure enough that only some patients will find them and ask their physicians about the matter.

SUBTLETY

Trials document that lowering diet sodium below 100 mEq/day lowers average urine calcium significantly in IH patients. Therefore, one can use diet change first, and add thiazide as needed depending upon what patients achieve in diet and what diet achieves in patients. I do this as an inviolable rule. Conversely, in the face of high diet sodium intakes thiazide becomes mainly a way to produce hypokalemia and is often ineffective in lowering urine calcium excretion.

Basic and Applied are in the Context of Practice

As in the case of brushite stone formers, basic science knowledge becomes useful when it can be applied. Because sodium balance is mediated partly by changes in proximal tubule reabsorption, and because hypercalciuria and the thiazide hypocalciuria effect are both also thus mediated, reduced diet sodium and thiazide act in similar ways and can be synergistic: the use of one reduces the magnitude of the ‘dose’ of the other.

HOW SHALL I ANSWER MY QUESTION?

How does a knowledge of basic science results benefit the practice of medicine? That was my question. I had laid aside how being a basic scientist benefits physicians or their practices. Likewise, how a general knowledge of basic science benefits practice. It is only the results of basic science under question at this time: if a physician has such knowledge how can patients benefit?

My proposed answers from the three examples seem to fall into all three categories of possible means: Knowledge of basic science results can benefit patients through more passionate treatment, education, and subtlety, and the mix varies with the example.

PASSION

To know that tissue is being injured in brushite stone formers or that reduced sodium can lower urine calcium in IH is to raise the desire in both doctors and patients to enact corresponding treatment actions as compared to the desire without such knowledge – that is my proposition.

EDUCATION

Virtue

Because the very word ‘doctor’ derives from the latin work meaning to teach, and because one cannot teach what one does not know, I have proposed that in all three cases knowledge leads to virtuous action.

The Internet

Given the internet, knowledge is necessary if physicians are to be useful guides to what is right and wrong. I deign to mention the more vulgar issue of ignorance confronting an informed patient; the internet can be very informative, and some patients well informed.

SUBTLETY

This appears the winner in that it applies to all three examples with considerable force. I suppose one might paraphrase this way: Trials give one rules, knowledge gives one the right to break or bend them. Absent rules, like sailors before the map, knowledge gives one stars to sail by.

2 Responses to “BASIC SCIENCE IN MEDICAL PRACTICE”

  1. Rachel

    Hi Dr Coe! I wrote to you about a month ago on a different article. I was the one who had multiple stones and fractures and am following up with the Cleveland Clinic. I had another 24 hour urine last month after being on chlorthaladone (25mg) and potassium citrate (40). Results were as follows: Calcium 341, Citrate 144, Phosphorous 1112, Sodium Urate 2.33, and Brushite 5.76 (range <2). My phone was 6.5. All other results were within range. My kidney dr wants me to do another 24 hour urine through Litholink (yours, I believe) next month because she doesn't care for Quest. I had Shockwave treatment and uteroscopy in July to remove a stone lodged for a few weeks in my upper ureter. Since May, I have now collected 36 stones and haven't had my stones analyzed since the beginning of July. That resulted in a stone mixed with weddellite and dahllite. The urologist I saw in Cleveland (who didn't specialize in stone disease) looked at a recent ct scan and said that I have evidence of calcified papilla in both kidneys. That particular scan showed 16 stones in my left kidney and 15 in my right. Since starting the chlorthaladone, I've been struggling to get my serum potassium back in range and have finally done so by taking 80 meq's of potassium and 12.5mg of chlorthaladone.

    My question to you is, do you think I'm now making stones out of brushite with that number so high? I read somewhere that Shockwave treatment can change the stone make up to phosphate stones, which I already had at a lower percentage than the weddellite before the treatment. Also, my calcium didn't change much at all after taking 25mg of chlorthaladone for 2 months. I'm worried that it's going to be even higher this coming 24 hour urine with me taking 12.5mg now. My kidney dr mentioned possible mild renal tubular acidosis during our last visit as well. I'm thinking she may have meant incomplete renal tubular acidosis type 1. Should I be on sodium bicarbonate? Also, should I start majorly restricting sodium after I get my next 24 hour urine results? I think you mentioned that it's sometimes more effective than the medications at reducing hypercalciuria.

    I just had a renal scan yesterday with lasix to check for upj obstruction as I am showing minimal fluid constantly in my right kidney and having pain as if a stone is stuck. My urologist is going to meet with me next Tues to go over those results and to schedule a few upcoming procedures. I'm going to have stents placed bilaterally, then 2 weeks later surgery to try to remove all of the stones with laser, I believe. Do you think it's important for me to share this article about brushite? I'm worried that I have the tubal plugs, etc.

    Last question, is there any way I could travel to the University of Chicago to be treated/evaluated by you or someone on your team? I'm only an 8 hour drive away and lived in the Chicago area 5 years ago. 😉

    Thanks so much!
    Rachel

    Reply
    • Fredric Coe, MD

      Dear Rachel, You do indeed have a very complex problem, urological and medical, and your physicians seem aware of it. There is little anyone can do medically at this distance, and I hesitate to second guess physicians at Cleveland Clinic who are excellent and experienced. If you wish, I can see you at University of Chicago, and this would be especially worthwhile if your physicians there would find what I might have to offer of value. Regards, Fred Coe MD

      Reply

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