Tests of kidney (renal) function

Most patients on the MP experience temporary but well-defined increases in various markers of disease state and inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue., consistent with an immunopathological response. Doctors may want to assess kidney function by testing creatinine or BUN and measure other indicators specific to each patient for a baseline and retest as appropriate. Some lab work such as creatinine and BUN may become temporarily abnormal, due to immunopathologyA temporary increase in disease symptoms experienced by Marshall Protocol patients that results from the release of cytokines and endotoxins as disease-causing bacteria are killed. reactions, until the inflammation resolves.

For example, a higher than usual BUN and creatinine is not an indication that olmesartanMedication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. Also known by the trade name Benicar. should be discontinued but a sign that immunopathology may be occurring in the kidneys or other nearby organs. In all cases where physicians have allowed such levels to remain temporarily out of range, BUN and creatinine have returned to range as bacterial die-off in the kidneys subsides. For as long as they remained on olmesartan, there has been no dialysis needed in the MP cohort.

• blood urea nitrogen (BUN) – a measure of the amount of nitrogen in the blood in the form of urea; urea is a substance secreted by the liver, and removed from the blood by the kidneys
• creatinine – a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body (depending on muscle mass)
• creatinine clearance (CrCl) – measurement of the clearance of endogenous creatinine; the most accurate test of kidney function; often offered in the form of a 24-hour test
• glomerular filtration rate (GFR) – the volume of water filtered out of the plasma through glomerular capillary walls, which are located in the kidney

Blood Urea Nitrogen test is described here.

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Simple explanation of alteration in kidney function tests while on the MP

A lot of MP patients get worried by low eGFR and highish creatinines, and experienced MP doctors know its not important.

Here's a short explanation which I hope helps to explain whats going on.

How to understand the relationship between serum creatinine, eGFR, and creatinine clearance:

Think of the serum creatinine level as a water level in a river. Its a spot measurement.

Think of the 24 hr creatinine clearance as the actual amount of water flowing down the river over 24 hours. This has been measured in your case.

Think of eGFR as a calculation or projection of the water flow, based on the spot measurement of the water level. This is highly inaccurate in certain circumstances, due to several important factors left out. The main assumption is that it never 'rains'.

But on the MP, the harder you herx, the more it 'rains'. So the water level (the serum creatinine) rises. But in most people on the MP, the river flow is not compromised at all (ie kidney function as measured accurately by 24 hr creatinine clearance) . We already know this intuitively because we know that its 'raining', ie that you are having high cell turnover and making a lot of creatinine due to herx. And we can know this deductively because you did a 24hr urine, and measured the amount of creatinine cleared in 24 hrs, which was completely normal.

So, when on the MP, serum creatinine and especially eGFR are really NOT showing what is going on. Much more important is 24 hr creatinine clearance. When 24 hr creatinine clearance is normal, then you know that you can ignore eGFR and serum creatinine, because they are only telling you how hard it is 'raining', and not how well your kidneys are functioning at all.

And those who do have real kidney impairment need to be checking 24 hr creatinine clearances and spot potassium levels. Potassium levels are very important to cardiac function, and high levels or low levels can trigger cardiac arrythmias.

Personally in most MP patients, I would more likely order a 24 hr creatinine clearance for a rising potassium level than a rising creatinine level on its own. Rising creatinine on its own needs to be managed as a sign of herxing, and managed by modulating the herxing in the usual way (increase olmesartan, adjust antibiotics etc).

I hope this helps you understand the numbers and what they do and do not represent.

Dr. Nyrie Dodd

It is not uncommon for creatinine levels to rise while having immunopathology during the MP. All of the usual methods for managing immunopathology should be employed.

The creatinine test is described here.

A good article to review is “Misconception #6: If my blood work (particularly that which pertains to kidney function) goes out of range after starting the MP, that’s a bad sign.” by Amy Proal.

Also, for more information, see Dr. Marshall's talk to doctors at West China Hospital, where he addresses this particular test.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what to do if the serum creatinine and/or serum potassium concentration rises

Biff F. Palmer Department of Medicine, Division of Nephrology, University of Texas Southwestern Medical School, Dallas, TX, USA Correspondence and offprint requests to: Biff F. Palmer, MD, Professor of Internal Medicine, Department of Medicine, Division of Nephrology, University of Texas Southwestern Medical School, 5323 Harry Haines Boulevard, Dallas, TX 75390-8856, USA.

Keywords: angiotensin-converting enzyme inhibitors; angiotensin receptor blockers; hyperkalaemia; hypertension; serum creatinine

Introduction Guidelines governing the optimal treatment of blood pressure in patients with chronic renal failure emphasize the need for more stringent blood pressure control and the use of drugs that interfere with the renin–angiotensin system [1,2]. As this approach is adopted, physicians will commonly encounter patients where blood pressure control is accompanied by an increase in the serum creatinine concentration and patients who develop hyperkalaemia. How physicians respond to these events is of considerable importance.

In the patient with an increase in serum creatinine concentration, decreasing the dose of antihypertensive medications and allowing blood pressure to increase will cause the serum creatinine concentration to return to the original baseline. Unfortunately, such an approach is not optimal for the long-term preservation of renal function and should be discouraged. Small and non-progressive increases in the serum creatinine concentration accompanying better blood pressure control do not reflect structural injury to the kidney but rather reflect a favourable effect on renal haemodynamics and in particular a lowering of intraglomerular pressure. For those patients with hyperkalaemia, discontinuation of angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARBA drug which is an angiotensin receptor blocker. One of the ARBs is olmesartan (Benicar). Not all ARBs activate the Vitamin D Receptor.) therapy without first taking steps to minimize this complication is also not in the patient’s best interest given the potential cardiovascular benefits afforded by these agents. By taking several precautions, the majority of patients at risk for hyperkalaemia can be treated successfully rather than unnecessarily being labelled as intolerant to these drugs.

Blood pressure control and increases in the serum creatinine concentration

An increase in the serum creatinine concentration in the setting of better blood pressure control is seen primarily in patients with chronic renal failure. Loss of renal mass leads to disturbances in the autoregulatory ability of the remaining renal vasculature such that intraglomerular pressure begins to vary directly with changes in systemic arterial pressure [3,4]. In some patients, this impairment is severe enough that a completely pressure-passive vasculature is present where any change in mean arterial pressure is matched by a proportional change in intraglomerular pressure. Such changes explain why even modest degrees of systemic hypertension can be an important factor contributing to further renal function loss [5].

These same changes also explain why hypertensive chronic renal failure patients are more likely to develop an increase in the serum creatinine concentration when blood pressure is lowered. A blunted ability of the pre-glomerular circulation to vasodilate in response to better blood pressure control will cause an exaggerated fall in intraglomerular pressure. This change in renal function is haemodynamic in origin and does not represent structural injury to the kidney. In many patients, renal function will either improve or resolve with long-term blood pressure control, reflecting restoration of renal autoregulation back towards normal. In those patients whose renal function remains reduced, the long-term renal outcome is still improved as a result of better blood pressure control [6,7].

Renal dysfunction that accompanies antihypertensive therapy is a result of blood pressure lowering and is independent of the agent utilized. ACE inhibitors and ARBs are more commonly associated with this complication since any decline in intraglomerular pressure due to blood pressure lowering will be exaggerated by concomitant vasodilation of the efferent side of the glomerular circulation.

Consider a 52-year-old man with diabetic nephropathy and a baseline creatinine concentration of 1.8 mg/dl who on physical examination is noted to have a blood pressure of 148/92 mmHg. He is started on an ACE inhibitor, and 2 weeks later his blood pressure has fallen to 138/82 mmHg. A repeat serum creatinine concentration is now 2.2 mg/dl. Rather than discontinuing the ACE inhibitor potentially depriving this patient of an agent that can both slow the progression of his chronic renal disease and provide long-term cardiovascular protection, the appropriate response is to continue the drug and recheck laboratory values in 1 week to ensure the creatinine has stabilized at the higher value. One should not view a 20–30% increase in the serum creatinine concentration that then stabilizes as a contraindication to intensive blood pressure control or, as in this case, use of an ACE inhibitor [8].

In those situations in which the initial rise in creatinine is >30% or the repeat value shows a progressive increase, then the appropriate response is to discontinue the drug and initiate a search for other causes of renal dysfunction. There are several conditions in which use of ACE inhibitors or ARBs may cause exaggerated or progressive declines in renal function. The first setting involves significant (usually >70%) bilateral renal artery obstruction or unilateral renal artery obstruction to a solitary functioning kidney. Under these conditions, increased tone of the efferent arteriole acts to attenuate the decline in intraglomerular pressure that results from the arterial obstruction. The trade-off is that renal function and the glomerular filtration rate become dependent upon sustained constriction of the efferent vessel by angiotensin II. A similar dependence can develop in patients with polycystic kidney disease where the renal arteries become extrinsically compressed by large cysts [9]. Unless the underlying obstruction can be treated, then other classes of antihypertensive agents will have to be utilized.

ACE inhibitors and ARBs can also cause an azotaemic response under conditions of an absolute (gastroenteritis, aggressive diuresis, poor oral intake) or effective reduction in circulatory volume (moderate to severe congestive heart failure). In these settings, angiotensin II-mediated constriction of the efferent arteriole serves to minimize the decline in glomerular filtration rate that otherwise would occur as a result of the fall in renal perfusion pressure. In the volume-contracted patient, the appropriate response is to discontinue the drug and only restart it once the extracellular fluid volume has been replenished. In a patient with congestive heart failure, these drugs will increase the creatinine when the decrease in intraglomerular pressure resulting from efferent vasodilation is not offset by an increase in renal perfusion. This can occur in patients with severely depressed cardiac function in which afterload reduction can no longer increase cardiac output, or in the setting of aggressive diuresis.

A similar mechanism is responsible for renal dysfunction that occurs in patients given ACE inhibitors or ARBs in the setting of non-steroidal anti-inflammatory drugs (NSAIDs), cyclosporin A or early sepsis [10–12]. These settings are all associated with increased vasoconstriction of the renal vasculature. ACE inhibitor- or ARB-induced efferent vasodilation in the face of decreased perfusion pressure accounts for the fall in glomerular filtration rate.

Hyperkalaemia complicating the use of ACE inhibitors and ARBs

Use of ACE inhibitors or ARBs in patients with chronic renal disease can be associated with hyperkalaemia. As with a rise in the serum creatinine concentration, many physicians respond to even mild increases in the serum potassium by immediately discontinuing these drugs without first considering steps that might be taken to minimize this complication. In many instances, physicians are reluctant even to initiate such therapy simply because the patient has an elevated creatinine concentration. Such an approach is strictly to the patient’s disadvantage since patients with more advanced renal insufficiency derive a greater amount of protection from renal disease progression with these drugs [13]. While close monitoring is required, several steps can be taken to minimize the likelihood of developing hyperkalaemia. One should review the patient’s medication profile and, wherever possible, discontinue drugs that can impair renal potassium excretion. NSAIDs, either prescribed or those taken over-the-counter, are common offenders in this regard [12]. The patients should be placed on a low potassium diet, with specific counselling against the use of potassium-containing salt substitutes. Diuretics are particularly effective in minimizing hyperkalaemia. In patients with a serum creatinine <1.8 mg/dl, thiazide diuretics can be used but, with more severe renal insufficiency, loop diuretics are required. In chronic renal failure patients with metabolic acidosis (bicarbonate concentration <20 mEq/l), sodium bicarbonate should be administered. Decreasing the dose of the ACE inhibitor or switching to one that is not totally dependent on renal excretion may be of help. In one study of patients with mild chronic renal failure, use of an ARB was found to have less of an effect on increasing serum potassium when compared with an ACE inhibitor [14]. However, this difference was small and, at present, these agents should be viewed as having similar risks for developing hyperkalaemia. Intermittent use of a potassium-binding resin can be tried; however, this drug is poorly tolerated when used on a chronic basis and has been associated with gastrointestinal ulceration [15].

With implementation of these steps, the risk of hyperkalaemia severe enough to warrant discontinuation of ACE inhibitors or ARBs is quite low even in patients with moderate to severe renal insufficiency. In patients with chronic renal disease, the serum potassium should be checked within 1–2 weeks of starting an ACE inhibitor or an ARB. If the potassium concentration increases to a value >5.6 mEq/l despite the precautions noted above, then another class of antihypertensive therapy will need to be utilized. Conflict of interest statement. None declared.

References

Bakris G, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000; 36: 646–661 American Diabetes Association. Diabetes Care 2002; 25 [Suppl 1]: S85–S89 Bidani A, Griffin K. Long-term renal consequences of hypertension for normal and diseased kidneys. Curr Opin Nephrol Hypertens 2002; 11: 73–80 Pelayo JC, Westcott JY. Impaired autoregulation and vulnerability to hypertensive injury in remnant nephron. J Clin Invest 1991; 88: 101–105 Palmer BF. Impaired renal autoregulation: implications for the genesis of hypertension and hypertension-induced renal injury. Am J Med Sci 2001; 321: 388–400 Apperloo AJ, De Zeeuw D, De Jong P. A short-term antihypertensive treatment-induced fall in glomerular filtration rate predicts long-term stability of renal function. Kidney Int 1997; 51: 793–797 Hansen HP, Rossing P, Tarnow L, Nielsen F, Jensen B, Parving H. Increased glomerular filtration rate after withdrawal of long-term antihypertensive treatment in diabetic nephropathy. Kidney Int 1995; 47: 1726–1731 Palmer BF. Renal dysfunction complicating treatment of hypertension. N Engl J Med 2002; 347: 1256–1261 Chapman A, Gabow P, Schrier R. Reversible renal failure associated with angiotensin converting enzyme inhibitors in polycystic kidney disease. Ann Intern Med 1991; 15: 769–773 Curtis JJ, Laskow DA, Jones PA, Julian BA, Gaston RS, Luke RG. Captopril-induced fall in glomerular filtration rate in cyclosporine-treated hypertensive patients. J Am Soc Nephrol 1993; 3: 1570–1574 Schor N. Acute renal failure and the sepsis syndrome. Kidney Int 2002; 61: 764–776. Palmer BF. Renal complications associated with use of nonsteroidal anti-inflammatory agents. J Invest Med 1995; 43: 516–533 Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 2000; 160: 685–693 Bakris GL, Siomos M, Richardson D et al. ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. VAL-K Study Group. Kidney Int 2000; 58: 2084–2092 Abraham S, Bhagavan B, Lee L, Rashid A, Wu T. Upper gastrointestinal tract injury in patients receiving kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings. Am J Surg Pathol 2001; 25: 637–644 (Print this paper for your doctor)

Estimated glomerular filtration rate (eGFR) is derived and reported per 1.73 m2 body surface area. Race used from Foundations System: “NB” non-black, “B” black. GFR estimate has been multiplied by 1.21 if “B” is indicated in the system. GFR ranges: “>89” = Normal, “60-89” = Mildly reduced (CKD2*), “30-59” = Moderately reduced (CKD3 if > 3mos), “15-29” = Severely reduced (CKD4 if > 3 mos), “<15” = Kidney failure (CKD5 if > 3mos). GFR >60 is not diagnostic of CKD1 or 2 unless another marker of kidney damage is present (e.g. microalbumin or urine protein > 300 mg/day on two occasions, or renal biopsy or imaging abnormality).