Dr. Paget: It is a pleasure today to introduce Dr. Raymond Sherman, a recognized nephrologist who has a great deal of interaction with Hospital for Special Surgery and the patients that we have who develop kidney disease. Dr Sherman, why is the kidney so prone to being attacked or irritated by the diseases that we take care of at Special Surgery?
Dr. Sherman: That's a perceptive question, and we always wonder a bit about that. As you know, the kidney receives about 25% of the cardiac output, an enormous amount of blood flow. And we always feel that whenever there are circulating immune complexes and a number of things that are representative of immunologically mediated diseases, that the kidney is one of the prime areas where damage will occur. So I think blood flow is one phenomenon. The filtering capacity of the kidney is another phenomenon, because material, as you know the entire GFR (glomerular filtration rate) is filtered across the membrane, and then there are probably individual local factors which may play a role as well.
Dr. Paget: We use a lot of medications to control inflammation in some of our systemic disorders. What role do those medications themselves play in causing problems with the kidney?
Dr. Sherman: This is a very challenging area for us, and the chief culprits among the medications that you use right now are the nonsteroidals. They wreak havoc in the differential diagnosis because nonsteroidals can do a number of different things to the kidney. Certainly they can have a direct effect producing an interstitial nephritis and in doing so can mimic the types of abnormalities that one would see from the systemic disease itself. So we are confronted frequently with the patient who has some underlying immunologic, rheumatologic disease, gets a nonsteroidal, and develops a manifestation of renal disease. A prime example might be proteinuria, and proteinuria certainly does occur in many of the diseases that you take care of, and, of course, is a manifestation of nonsteroidal toxicity. And so we have to delve into history in some detail to see if we can sort out if it's the treatment, or if it's the underlying disease.
In addition to interstitial nephritis, one can get a full-blown nephrotic syndrome. Acute renal failure can certainly occur from the nonsteroidals, and then there is the all important hemodynamic effect, an effect on renal blood flow which occurs in the nonsteroidals, so you can actually get a rising BUN and creatinine in these people without seeing any of the proteinuria or hematuria.
So this is a challenge for the nephrologist and a very important area where the nephrologist and the rheumatologist have to work together to sort this out and to help the patient.
Dr. Paget: Nonsteroidals of one type or another, including the over-the-counter drugs, would have to be on the top ten list of medications used by people around the world. So to the patients and the physicians out there listening to this, should they avoid nonsteroidals or are there subsets of patients who have a higher risk of problems? And then, what is the monitoring that is needed?
Dr. Sherman: It is very hard to avoid the nonsteroidals because, as you know, they are a very potent part of the therapeutic armamentarium for managing a number of the diseases that you take care of. So my answer to that would be, you use it whenever you have to, and then we will go to the monitoring in a minute. The subsets of patients who would be, if you like, at some risk using these drugs with specific respect to the kidney would be the patients who have underlying kidney disease to begin with. Those who have some sort of elevation in the BUN and creatinine, impairment of kidney function, and those who have some proteinuria and hematuria would be at some increased risk as well.
Certainly superimposed on top of this would be any patient who is volume-depleted, a dehydrated patient. And the patients we see this in commonly, are those on diuretics, specifically the diuretics that are potassium-sparing, these distal acting diuretics, e.g., spironolactone, triamterene, amiloride, where there is a tendency for the potassium to go up; superimposed nonsteroidals will be a major factor in making this situation worse. So they have to be used cautiously.
The way in which monitoring would be most efficacious, of course, is the vigilant physician. So once you start patients on these medications, you follow the blood pressure -- I should have mentioned patients with hypertension also would be at some risk, because these medications can cause sodium retention and aggravate high blood pressure. You need to follow the urine test periodically. That is, I would probably get a urine test within several weeks or two or three weeks after starting the medication, and then every one to two weeks afterwards, depending on how much risk this patient has. And then, of course, you monitor blood pressure and you monitor BUN and creatinine levels.
So they have to be watched carefully, but I think it would be erroneous and unfair to dismiss this group of medications from our therapeutic armamentarium. They are valuable, as you know.
Dr. Paget: Now the kidney's involvement in various disorders that we deal with can be quite prominent, and the two disorders that come to mind are systemic lupus erythematosus and granulomatosis with polyangiitis. About 50% of lupus patients develop some type of kidney disease from mild to severe. How do they usually present, and what is the best way to assess them and define treatment in a given case?
Dr. Sherman: A very important question and obviously the answer to that must be individualized with the patient. The presentation, for people with lupus nephritis, -- about 50% of the patients will have clinically alert manifestations of lupus nephritis, and the presentation will be in a variety of ways. Sometimes it is simply that you test the urine and it's there, asymptomatic proteinuria, and this can be proteinuria ranging from several hundred milligrams, 500 or 600 mg per day or even less, up to nephrotic range proteinuria.
They can have asymptomatic hematuria. So getting a urine test is terribly important. And, of course, they can have a combination of hematuria and proteinuria, and that gives you the clue that you are dealing with a more aggressive type of lesion, the so-called "nephritic sediment" -the urine sediment that has red blood cells in it in addition to the protein. -- And if you find red blood cell casts, which means you have to be aware and look for this sort of thing or have your laboratory technician look for this sort of thing, it carries a different prognosis usually from simply asymptomatic proteinuria, particularly the lower grade proteinurias. They can present with hypertension, and when they do present with hypertension, that becomes a challenge as well. Frequently that is accompanied by some other manifestation of renal disease. The previous urinary sediment abnormalities that I mentioned, and elevated BUN and creatinine levels can occur as well, and this is clearly more ominous.
To go to the next part of your question, how are they managed? We need to get 24-hour urine creatinine clearances and urine proteins as a baseline to know what we are dealing with initially. I almost always want renal sonograms. I think they give you several bits of information. One is they tell you whether there are two kidneys, which is something you do like to know. They also tell you the size of the kidneys, which can be useful information; if there is a discrepancy in size of the kidneys, it raises the question of whether or not any hypertension you see might have another cause, like a renal vascular problem. So you get that information from the sonogram, and now we do Doppler studies of the renal artery, which can be very helpful as well in looking for a renovascular cause.
We also want to be certain that a sonogram tells you whether or not there is any obstructive problem, and hence what we are thinking about now is, are the BUN and creatinine elevation that we are seeing in a specific patient related to the underlying disease, lupus, or is there some other cause for the renal involvement. A sonogram helps you with that. So that is part of the evaluation.
We do rely to some extent on the evaluation that the rheumatologist has done. We would like to know whether or not there is serologic activity and almost invariably the rheumatologist has already done the work for us and tells us this patient is or is not serologically active, and there is some correlation between serologic activity and the activity of the renal disease.
One of the most prominent questions that comes up is do we need a kidney biopsy in order to specifically define what kind of a renal lesion we are dealing with and to plan therapy appropriately? The answer to that will vary. It varies with the nephrologist. It varies to some extent with the rheumatologist. And I like to say, because it works very well at our institution, as you know, a verbal partnership between the rheumatologist and nephrologist is very important in sorting out whether we go to biopsy and how we use the biopsy information in planning treatment. The value of the biopsy, and again not every patient with lupus and proteinuria needs a biopsy, but many do, lies in defining the histologic activity of the lesion and giving you some information about prognosis. We do know that the people who have active, diffuse, proliferative glomerulonephritis, the so-called WHO Class 4 lesion, are more aggressive in terms of their natural history and do require more aggressive therapy, unless the biopsy tells you that you've got chronic disease with very little activity. That would be valuable information as well.
So the answer to your question is: yes, some people do need biopsies. The nephrologist and rheumatologist should talk, review this together, decide together whether they think this is a useful procedure to do and how the information is going to be used in the treatment of the patient. Treatment does depend on all of the information you gathered plus the kidney biopsy (or even without the kidney biopsy) if you can intelligently plan.
The base, the cornerstone of treatment for lupus nephritis is still some form of steroid and almost invariably we will use steroids in some form in most of these patients. We try to limit it as much as possible, because they have very difficult-to-deal with side effects when used for long periods of time, but on the other hand, they can be very valuable drugs. Then we can use the steroids in various forms. We can use the high dose, low dose orally, intravenous pulse Solu-Medrol, all of which can have their places and be valuable in general, but the more aggressive and active the lesion, the more we are going to turn to a higher dose of steroid.
In addition to the steroids, there are a number of other medications that are available and can be used to treat these people. Those will include the more traditional intravenous Cytoxan regimen; sometimes people still use this by mouth, but we tend to use it intravenously here for the type 4 aggressive diffuse proliferative lesion. There is more and more talk now about using mycophenolate, also called CellCept, for the type 4 lesion, and there is some evidence that this may be helpful. So that is another part of the regimen that can be useful. Cyclosporin is used by some people for the treatment of lupus nephritis. There is not an enormous amount of data, but it's something else that is available out there. And there will be other medicines coming along which are going to be helpful in the management of this disease.
Again, I stress that individual decisions are targeted to the specific manifestations the patients have, what we believe the prognosis is, and a working partnership is very important.
Dr. Paget: Those points are very important, and that the earlier you treat, the better the outcome. So monitoring on the part of the rheumatologist is key, so that patients don't have smoldering disease for four or five years and all of a sudden you find there is a problem that might have been controlled early on.
Dr. Sherman: I couldn't agree with your more, absolutely. So from the time the lupus presents, you have to have the initial urine. Almost invariably, one of the questions the nephrologist asks is when were you told you had some abnormality of the urine, and when was your last normal urine test, because the first abnormal urine might have just represented the discovery of something that has been there for a year, three years, or five years. So targeting the last normal urine can be very, very helpful, but you are quite right -- we need to have this information early on and monitor closely.
Dr. Paget: Finally, granulomatosis with polyangiitis (GPA). This is a granulomatous vasculitis and certainly it can affect the kidney as one of its primary manifestations. How aggressive are we these days in trying to control that inflammatory process?
Dr. Sherman: In a word: very. It is a disease that was formerly, meaning 30 to 35 years ago, fatal. Now, with the modern approaches pioneered from studies which came from the NIH, which you know very well, it is treatable and to some extent curable. So renal disease is very common in GPA. It usually manifests itself in a similar way, the presence of hematuria. You normally do not get nephrotic range proteinuria in GPA. It happens occasionally, but not very commonly.
Again, steroids, usually in conjunction with some form of cyclophosphamide, is what is ordinarily used. The older treatment, azothiaprine, is not very commonly used. But you need to treat this aggressively, get it under control -- which you can usually do -- and then very carefully follow up, watching the urines and watching the blood tests.
The renal biopsy in GPA is not all that crucial, we could argue, except maybe for some prognostic indicators, because there is not an enormous amount on the biopsy other than the presence of granulomas, which will give you the diagnosis. It is usually a clinical diagnosis, and we make that diagnosis based on a constellation of factors and sometimes getting a biopsy from some place else, like the nasal septum or the lung or something like that.
Although these people are biopsied, to get the prognosis and to know how aggressive the lesion is, very frequently you don't get an answer as to whether or not this is GPA from the biopsy. You only find out how advanced the disease is.
Dr. Paget: Finally, the kidney is clearly linked to the rest of the body, and thus we have to have a global concept and, optimally, control lipids, try to stop them from smoking, control blood pressure, which is obviously a very important thing with regard to the kidney. Do you feel that type of approach is also important in the treatment of these patients?
Dr. Sherman: Unquestionably. It is absolutely critical. You really have to look at the kidney. I will just paraphrase what you said because you did it very nicely. You have to look at the kidney in the context of all of the risk factors that occur which can involve the kidney. And just to reiterate, blood pressure has to be well controlled. You want not to see blood pressures of 160/100. You want to see blood pressures in the 130/75 or 80 range if you possibly can. In some instances, we are looking to get it even lower than that. Smoking can be a risk factor for kidney disease. There is no question, both in terms of function and in terms of proteinuria, so people should stop smoking absolutely. Lipid control is key.
So all along the line, when you are treating the underlying disease, you are always looking for the superimposed factors that can involve the kidney. That would include infection and, of course, obstruction. In males, you have to worry about the prostate and that sort of thing, or any superimposed problem that can affect the kidney. Absolutely right.
Dr. Paget: Thank you very much Dr. Sherman.
Dr. Sherman was interviewed by Dr. Stephen A. Paget, Physician-in-Chief Hospital for Special Surgery