Prostaglandin Basics

A few basics about the prostaglandins, a major player in renal hemodynamics. Prostaglandins are fatty acid-based compounds which carry out a variety of cellular effects. The pathway begins with phospholipid within the plasma membrane, which is converted to arachidonic acid by the enzyme phospholipase A2. Arachidonic acid then goes to one of two pathways: either it is metabolized by lipooxygenase to the leukotriene pathway (important for inflammation) OR it is metabolized by cyclo-oxygenase to the prostaglandin pathway. A variety of chemical modifications lead to different classes of prostaglandin: PGD's, PGE's, PGF's, PGI's, and thromboxane.

There are many different classes of prostaglandin present in the kidney, but perhaps the most well-known is prostaglandin E2 (PGE2). PGE2 is at least in part responsible for the vasodilatation of the afferent arteriole which increases blood flow to the glomerulus; this phenomenon describes why NSAIDs (which inhibit prostaglandin synthesis) result in afferent arteriole vasoconstriction and why NSAIDs can cause a reduced GFR in patients who rely heavily on prostaglandin synthesis to maintain renal blood flow. PGE2 also is known to inhibit ADH-stimulated water permeability in the cortical collecting duct.

There are two isoforms of the cyclo-oxygenase enzyme which converts arachidonic acid to prostaglandin H2: COX-1 (which is the constitutively active "house-keeping" gene present in most cells) and COX-2 (an inducible form of the enzyme which is generally active with inflammation). The COX-2 inhibitors (Vioxx, Celebrex, Bextra) were designed to exploit this, having a greater specificity for inflammation-associated increases in prostaglandins. Interestingly, however, the kidney constitutively expresses COX-2, and therefore COX-2 inhibitors can lead to alterations in renal hemodynamics similar to the NSAIDs.

MDRD I

The Modification of Diet in Renal Disease (MDRD) Study is one of the landmark papers of Nephrology. The 1994 NEJM paper describing the initial results is freely available, and there are many interesting follow-up studies using the same group as well. In my mind, the MDRD Study is important for 2 reasons:

1. It established what is currently the gold-standard formula for calculating estimated glomerular filtration rate (GFR).

2. It suggested that strict adherence to a low-protein diet did not significantly diminish the rate of renal decline in patients with advanced chronic kidney disease (CKD), which up until that time had been a major therapeutic intervention offered by many nephrologists.

Looking more closely at (1), the MDRD formula to estimate GFR: while this formula has been widely criticized, it is also the most widely used, and has significant advantages over the much simpler Cockcroft-Gault Equation. There are actually variations of the MDRD formula which yield slightly different results; the most widely-used one is the "4-variable MDRD" which takes into account serum creatinine, age, gender, and race. A "6-variable MDRD" is also used which adds in serum BUN and serum albumin.

Two major issues with the MDRD formula: first, it has been validated in CKD, but not in acute kidney injury--so even though your hospital's in-patient computer system may spit back a GFR based on the MDRD Equation, the value may be totally meaningless. Second, the MDRD seriously underestimates GFR in healthy patients with GFR > 60mL/min.

More discussion on MDRD to follow...

Intra-abdominal Compartment Syndrome

The case: a 60 year-old woman with a history of metastatic ovarian cancer who presents with a markedly tense, distended abdomen and acute-on-chronic kidney injury, with a Cr which had risen from 1.4 mg/dL to 4.5 mg/dL and a drop in her urine output. An initial urine Na was <10>20mmHg (which can be easily measured via a Foley catheter with a device similar to that shown above) may result in altered renal hemodynamics and reduced GFR.

Treatment of ACS involves relief of the pressure, which is generally achieved by either surgical decompression or paracentesis. Diuretics may also be helpful.

Cardiorenal Syndrome

Any nephrology fellow running the Consult Service will rapidly realize that heart failure and renal failure often go hand in hand, earning the moniker "cardiorenal syndrome." The thought here is that decreased forward flow from pump failure results in renal hypoperfusion and a resultant decrease in the GFR.

The most joyous moments in the treatment of cardiorenal syndrome--and unfortunately this does not happen as often as we would like--are when a patient's creatinine starts decreasing WHILE the patient is getting diuresed.

How to explain this phenomenon of decreasing Cr with diuresis? One potential explanation would be that the patient is being brought onto a more favorable portion of the Frank-Starling curve (above) by fluid removal, thereby allowing increased cardiac output and increased renal perfusion.

However, according to many cardiologists (and according to the figure above), the Starling curve actually plateaus--there is no "downswing" with very high filling pressures. An alternative explanation for decreasing Cr during diuresis is that the high CVP during severe CHF results in a back-transduction of pressure through the glomerulus, thereby decreasing GFR. Reducing the CVP (e.g. with diuresis) would then result in an improved GFR.

What is the Resistive Index?

Often on the official radiology report for a renal ultrasound with Doppler flows, a number called the "resistive index" is listed.

What does this number mean and how is it derived?

The resistive index (RI) measures the resistance of renal arterial flow to the kidney. In a normal situation, flow through the renal artery occurs throughout systole and diastole. However during a variety of conditions--transplant rejection, inflammation, obstruction--there will be reduced to possibly even reversed flow through the renal artery during diastole. When this happens, the resistive index--which is calculated by measuring the arterial waveform throughout the cardiac cycle as described in the figure--is elevated. An RI <0.8>0.9 is considered elevated.

The differential diagnosis for an elevated RI should include transplant rejection, obstruction, ATN, pyelonephritis, severe hypotension, or an acute vascular event (e.g. renal vein thrombosis).

How To Measure Renal Plasma Flow (RPF)

Question: How is renal plasma flow (RPF) measured?

Answer: By measuring para-aminohippurate (PAH) clearance.

How does it work? Ideally, one would simply choose a substance which is neither synthesized nor metabolized by the kidney; the amount of such a substance entering the kidney per unit time via the renal artery should equal the amount leaving via the renal vein. However, it is not trivial to obtain blood samples from the renal vein in humans and therefore another approach is needed.

PAH works because although it is not filtered at the glomerulus, it undergoes tubular secretion in an extremely efficient manner: about 90% of all PAH is removed from the plasma via secretion while 10% remains in the renal vein. This 10% is ignored, and it is then assumed that the amount entering the kidneys equals the amount showing up in the urine. Mathematically, this can be expressed as the formula:

RPF (in cc/min) x [PAH] in plasma = [PAH] in urine x urine flow rate V (in cc/min).

Rearranging, RPF = [PAH] in urine x urine flow rate V (in cc/min)/[PAH] in plasma.

Although this test is rarely used in clinical practice, it is essential for research studies in which the hemodynamic effects of various drugs can be measured. For example, ACE-inhibitors are associated with a measurable increase in RPF.