Which force promotes the movement of fluid from the blood into the glomerular capsule?

Stop-flow Pressure

Measurement of stop-flow pressure (PSF) in single nephrons was introduced as a method to estimate glomerular capillary pressure (PGC) in nephrons that do not possess superficial glomeruli (118). PSF can be measured reliably over extended periods of time, and it has therefore been used extensively as an index of TGF-dependent hemodynamic effects. In response to a saturating increase in loop flow mean PSF of 23 studies fell by 22%, from 39.0 ± 0.8 to 30.3 ± 0.8 mm Hg (for refs. [428]). A reduction in PSF was also observed in the dog when loop flow was increased from zero to normal and supranormal values (17, 317). In the mouse, TGF responses of PSF are similar in magnitude as seen in rats, but the sensitivity range is shifted to lower flows (431). Since multiple determinations of PSF can be made in the same nephron with small perfusion flow increments, the nonlinear relationship between loop of Henle flow and PSF was apparent long before a similar feedback function for SNGFR was defined (405). In 15 experimental series, the maximum PSF decrease averaged 7.9 ± 0.6 mm Hg with a mean V{1/2} of 20.1 ± 1.1 nl/min. The maximum sensitivity varied substantially between different studies, but in general was between 1 and 2 mm Hg min/nl (for refs. [428]).

Role of Altered Glomerular Permselectivity to Plasma Proteins

Another link between glomerular hypertension and progression of kidney disease is protein leakage. The permselectivity of the glomerular filtration barrier is impaired by high glomerular capillary pressure leading to proteinuria. The glomerular filtration barrier consists of the following components in series: fenestrated endothelium, basement membrane, and podocyte filtration slits (74, 265). The permeability characteristics are conceptually described by the assumption of cylindrical pores of varying diameter (74, 265). Altered penetration of macromolecules across the filtration barrier is determined by altered glomerular hemodynamics (e.g., changes in glomerular capillary plasma flow and glomerular capillary pressure [300]), alteration of the charge, submicroscopic changes of the crucial components of the filtration barriers (basement membrane, slit membrane), or morphological alterations of glomerular filtration barrier.

Seven to 14 days after partial nephrectomy, dextran-sieving studies in rats documented loss of selectivity of the glomerular barrier (300). In the isolated rat kidney, Ang II infusion caused loss of glomerular size selectivity and proteinuria (46, 98, 299). ARBs abrogate the functional abnormality of the glomerular barrier induced by exogenous Ang II (227), and also improve size selectivity in the remnant kidney rat model (254), suggesting a role of Ang II in the genesis of the proteinuria of the renal ablation model. It is unknown whether the proteinuric effect of Ang II results from hemodynamic changes or more complex alterations of the filtration barrier (46, 98, 299). Ang II depolarizes podocytes by opening chloride channels (122). It has been postulated that the podocyte contracts in response to Ang II, thus changing the microarchitecture of the slit diaphragm and increasing protein traffic (122). Of interest is the recent finding that podocytes produce Ang II, particularly in response to cyclical stretch (88), by pathways that are not inhibited by ACEIs (239).

Publisher Summary

This chapter presents various problem sets related to fluid volumes, glomerular filtration, and clearance, which include the amount of filtration coefficient and its magnitude when the average glomerular capillary pressure is about 55 mmHg, plasma oncotic pressure is about 28 mmHg, the hydrostatic pressure within Bowman's space is 20 mmHg, ultrafiltrate oncotic pressure is 0 mmHg, the glomerular filtration rate (GFR) is 120 mL min21, and each kidney weighs 125 g; the lean body mass of a person weighing 105 kg and having total body water of 48 L; and the calculation of the percentage of body fat in excess of the lean body mass when the person weighs 105 kg and has total body water of 48 L.

Aspirin renography

Aspirin-induced 99mTc-MAG3 and 99mTc-EC renography have been studied to compare its reliability with captopril renogram. Angiotensin II levels are elevated in poststenotic kidney due to activation of RAAS resulting in vasoconstriction in postglomerular arteriole. Preglomerular arterioles on the other hand maintains its caliber by increasing prostaglandin synthesis which cause vasodilatation. Aspirin inhibits prostaglandin synthesis causing preglomerular vasoconstriction which causes reduction in renal plasma flow and decreases glomerular capillary pressure and filtration rate. This effect of aspirin occurs to a lesser degree in contralateral kidney and thought to increase the asymmetry between stenotic and contralateral kidney and enhance the sensitivity of the test.

20 mg/kg of oral Aspirin is given one hour before the radiotracer injection and maximum effect seen within 45 min after injection. Image acquisition, processing, and interpretation are similar to captopril renography. Some studies have shown that aspirin renography increases sensitivity similar to captopril renography but does not improve the specificity in detection of RVH (Imanishi et al., 1998; Imanishi et al., 1994). Few other studies have shown that captopril and aspirin renography are equally sensitive in the detection of RVH (van de Ven et al., 2000) but aspirin is not superior to captopril.

Pressure Profiles along the Renal Vasculature and the Uriniferous Tubules

Events downstream, as in the ureter, may influence these structures and their function. Anatomical considerations suggest that there are three major areas of resistance in the renal vasculature. The two principal segmental resistances are presented by the afferent and efferent arterioles, and a smaller one is presented by the collecting veins as they drain the kidney. Each individual glomerular and peritubular capillary has a smaller diameter than an afferent or efferent arteriole, but their large numbers provide a larger cross-sectional area for flow. It is simple to measure the pressure of the blood as it enters and leaves the kidney in the renal artery and vein, but it is not easy to measure the hydrostatic pressure in the intervening vessels.

What is the pressure in the glomerular capillaries? The glomerular capillary pressure is the driving force for filtration, of course, and it is opposed by the hydrostatic pressure in Bowman's capsule and the colloid osmotic pressure exerted by the plasma proteins. (The filtrate can be considered to be essentially protein-free for these purposes.) The rate of filtration is proportional to the net pressure across the filtering membrane, termed the effective filtration pressure, and to the permeability and area of the membrane surface. The glomerular pressure is generally represented in physiology textbooks as about two-thirds of the mean arterial pressure. This representation is largely intuitive and has been arrived at, in part, from the maximum pressure that develops in the ureter when it is completely obstructed. The maximum stop-flow pressure plus the colloid osmotic pressure should equal the glomerular capillary pressure if there is no continuing filtration, a condition which may or may not occur. However, an increase in pressure in the ureter and the tubules is transmitted to the renal vascular system, and it appears likely that the pressure in the glomerular capillaries is elevated above normal values during ureteral occlusion, Also, the maximum stop-flow pressure varies markedly with the rate of solute excretion prior to obstruction, and this may or may not reflect differences in free-flow glomerular capillary pressure. To date no one has been able to measure directly the glomerular capillary pressure in the mammalian kidney. Hayman, however, measured it more or less directly in the frog using an individual Bowman's capsule as a Riva—Rocci cuff and found it to equal 54% of the mean arterial pressure [1]. The relevancy of this to the mammalian kidney is doubtful, however, because of the low arterial pressure in the frog and the double vascular system of its kidney.

Gertz has measured by micropuncture the maximum stop-flow pressure in individual proximal tubules blocked with a viscous oil [2]. He found an average pressure of 63 ± 4 mm Hg. Assuming a colloid osmotic pressure of 25 mm Hg, the glomerular capillary pressure was presumably 88 mm Hg. The pressure in the proximal tubule averages 13 mm Hg in rats during free-flow and, since this can be taken to equal the pressure in Bowman's capsule, Gertz's measurements indicate that the effective filtration pressure equals approximately 50 mm Hg. I find this estimate unexpectedly high, and it indicates that the glomerular filtration rate would be little affected by small changes in the pressure in the proximal tubules. I also find it difficult to reconcile this high effective filtration pressure with more recent reports by Gertz and Schnermann [3, 4] that the rate of filtration in an individual glomerulus can be significantly changed by the technique of withdrawing fluid from the tubule into a micropipette. When fluid was withdrawn from the tubule rapidly and the intratubular pressure fell, the filtration rate increased markedly in that glomerulotubular unit, suggesting a relatively small effective filtration pressure. I wonder if an individual Bowman's capsule distended by obstruction of its tubule might obstruct the outflow of blood from that glomerular tuft, thereby elevating its pressure. This would be somewhat analogous to an increase in pressure in all of the glomeruli in the kidney following ureteral obstruction.

The efferent arterioles of the kidney break up to form the peritubular capillaries in the cortex and the vasa recta in the medulla. A number of investigators [5–10] have measured the hydrostatic pressure in the cortical capillaries using a simple null-point method in which the hydrostatic pressure is taken to equal the pressure which must be applied to a saline solution-filled micropipette, so that blood does not enter the pipette nor does saline solution flow into the capillary. The method is accurate to within ±1 mm Hg. Under control conditions a nominal value for the peritubular capillary pressure is 13 mm Hg. The pressure can also be measured in the termination of the efferent arterioles just as they divide into a cluster of peritubular capillaries, and this pressure is demonstrably higher. Most investigators using this method of measurement have reported that under steady-state conditions the pressure in the small peritubular capillaries is the same as the pressure in the proximal tubules, within the error of the measurement (Fig. 1). The peritubular pressure remains equal to the proximal intratubular pressure when altered by various maneuvers such as increasing the rate of urine flow or blocking the ureter. This relationship has led to the conclusions that the walls of the proximal tubules and peritubular capillaries have little ability to withstand a transmural pressure gradient and that their pressures are very similar to the interstitial fluid pressure. Using a much more sophisticated method developed by Weiderhelm, Falchuk in Berliner's laboratory at the National Institutes of Health has found that the peritubular capillary pressure is 3–4 mm Hg less than the proximal intratubular pressure under control conditions and that these pressures approximate each other only when they are elevated [11].

The last segment of the renal vasculature that offers significant resistance to flow is in the area of the interlobar veins just as they leave the substance of the kidney. Normally, there is a 10–15 mm Hg pressure drop here, but it is greater during ureteral obstruction and at high rates of urine flow [12, 13].

13.5 Single nephron filtration rate

Single nephron filtration rates are similar to the total glomerular filtration rates that were discussed earlier. In general, the glomerular filtration rate (GFR) can be defined as

(13.7)GFR=Qurine([inulin]urine[inulin]plasma)

In a similar fashion the single nephron filtration rate (SNFR) can be defined as

(13.8)SNFR=Qtubule fluid([inulin]tubule fluid[inulin ]plasma)

Tubule fluid information would be obtained by periodic measurements of the tubule fluid contents and flow rate using micropuncture techniques. In fact, many of the data points and localization information that we have discussed previously were obtained from these types of experiments. In general, under physiological conditions, single nephron filtration rates average to approximately 100 nL/min, but can range from as low as 20 nL/min to as high as 200 nL/min. Using the single nephron filtration rate and the glomerular filtration rate, one can approximate the number of nephrons as 1.2 million.

Many groups have investigated the effects of glomerular capillary pressure on single nephron filtration rates. By applying a negative pressure within the glomerular capillaries, a decrease in the overall pressure within Bowman’s space was observed, however, the pressure within the proximal convoluted tubule was not altered, suggesting that this location partially acts as a nonlinear resistor to prevent the transmission of altered pressure from the glomerular capillaries throughout the nephron tubule system. Under these reduced pressure conditions, single nephron filtration rates were not altered significantly, suggesting the presence of regulatory mechanisms that aim to maintain the overall function of the kidneys (Section 13.8 will discuss some of these mechanisms in more detail). The single nephron filtration rate varies somewhat depending on where the values are recorded along the nephron tubule system. In general, the values vary by no more than 5 to 10 nL/min along a single nephron tubule length. As mentioned in an earlier section, the flow through cortical nephrons varies compared with the flow through the juxtamedullary nephrons. In general, the difference is on the order of 20 to 30 nL/min, with the juxtamedullary nephrons having a higher flow rate compared with the cortical nephrons. If one is comparing the single nephron filtration rates over a long time interval (e.g., years), the number of glomeruli is an important factor to consider. In general, with the loss of function of nephrons as one ages (or damage to the kidney, among other mechanisms that may damage the kidneys), the glomerular filtration rate does not decrease, but instead remains relatively constant. To accommodate this, the single nephron filtration rates increase with age, but if these filtration values are normalized by the number of active nephron units, the overall normalized single nephron filtration rate remains relatively constant with time.

There has been a significant amount of work that aimed to mathematically model the resistance of the renal microvasculature at various locations throughout the vascular network. The resistance of the afferent arteriole is an important value that can regulate the flow through the entire glomerular capillary bed and the peritubular capillary bed (or vasa recta capillaries). The resistance of the afferent arteriole (RAA) has been shown to be a function of the mean arterial pressure (PMA), glomerular capillary pressure (PGC), and glomerular blood flow rate (QG), as follows.

(13.9)RAA=PMA−PGCQG

The glomerular blood flow rate is a function of the hematocrit of the afferent arteriole, which should be equivalent to (or at least within the range of) the systemic arteriole hematocrit, the single nephron filtration rate and the single nephron filtration fraction (SNFF), as follows.

(13.10)QG=SNFRSNFF(1−Hct AA)

The single nephron filtration fraction is a means to quantify the ability of the glomerular capillaries to filter the blood and is calculated from the proportional difference between the efferent arteriole protein concentration and efferent arteriole hematocrit compared with the systolic protein concentration and hematocrit.

Using a similar approach, the resistance of each efferent arteriole can be approximated by the following formulation

(13.11)REA=PGC−PPCQEA

where PPC is the hydrostatic pressure within the peritubular capillaries (or vasa recta) and QEA is the efferent arteriole flow rate, which can be defined as

(13.12)QEA=Q G−SNFR

The total arteriolar resistance of the preglomerular to postglomerular vascular tree can be defined as

(13.13)RT=RAA+REA

In most animals the resistance of the afferent arteriole accounts for approximately 60% of the total arteriole resistance of the renal circulation, whereas the efferent arteriole accounts for approximately 40% of the total renal arteriolar resistance. Combining the arteriolar and venule resistance in a global renal vascular resistance term, the arteriolar side of the vascular tree accounts for approximately 90% of the vascular resistance, whereas the venous side accounts for approximately 10% of the vascular resistance. As with all vascular beds, changes to vascular resistance can occur as a function of changes to other fluid parameters. For instance, with an increase in the blood volume, the resistance of the afferent arteriole and the efferent arteriole reduces at a similar rate, allowing the glomerular capillary hydrostatic pressure to remain the same. A reduction in the mean arterial pressure tends to decrease the afferent arteriole pressure; however, this is accompanied by an increase in the efferent arteriole pressure, which acts to maintain the glomerular capillary hydrostatic pressure. Increases in hematocrit tend to increase the afferent and efferent arteriole resistance, again at a similar rate to maintain the glomerular capillary pressure. With a decrease in hematocrit, the resistances of the afferent and the efferent arteriole tend to reduce at similar rates. It is important to observe that although these changes can have a net effect on the flow through the glomerulus and the peritubular capillaries, there tends to be no net effect on the filtration, reabsorption, and secretion of materials from the glomerular capillaries, the peritubular capillaries, or the nephron tubule system.

Changes in Glomerular Function Following Acute Ureteral Obstruction

CHANGES IN THE HYDRAULIC PRESSURE GRADIENT

Changes in ureteral pressure appear to be instantaneously reflected in changes in proximal tubular pressure; the latter always being higher than the former (91). The extent of increase of proximal tubular pressure depends on the degree of hydration of the animal, being greatest when the animals are saline loaded, and whether one or both kidneys are obstructed. Nevertheless, independent of volume status within an hour of ureteral obstruction, intratubular pressure has increased (Fig. 1). At the same time, glomerular capillary hydraulic pressure increases as assessed by stop-flow pressure (Fig. 2) (240), but this is not proportional to the increase in intratubular pressure and there is a net decrease in the hydraulic pressure gradient across glomerular capillaries resulting in a decline in GFR. This may be the major factor responsible far the decline in GFR in the initial phase of ureteral obstruction. Within 5 hours of ureteral obstruction, proximal tubular pressure declines. In UUO, after 24 hours of obstruction, intratubular pressures are lower than or nearly equal to values before obstruction, but this does not result in an effective filtration pressure, because intraglomerular capillary hydraulic pressure declines at an even faster rate and goes below pre-obstruction levels. Following BUO, proximal tubular pressures are initially twofold higher than with UUO. By 24 hours, the levels have decreased, but not back to baseline (Fig. 1). At this time, glomerular capillary pressure is not different from pre-obstruction values (Fig. 2). Thus, in this setting, high intratubular pressures do contribute significantly to the decrease in GFR at this time point.

FIGURE 1. Pressure in proximal renal tubules (PT) before, during, and after release of complete obstruction of one ureter (UUO), both ureters (BUO), or single nephrons (SNO).

(From Wright FS. Effects of urinary tract obstruction on glomerular filtration rate and renal blood flow. Semin Nephrol 1982;2:5–16, with permission.)Copyright © 1982

FIGURE 2. Proximal tubule stop-flow pressure (PSF), a reflection of glomerular capillary pressure, before, during, and after release of complete ureteral obstruction of one ureter (UUO), both ureters (BUO), or single nephrons (SNO).

(From Wright FS. Effects of urinary tract obstruction on glomerular filtration rate and renal blood flow. Semin Nephrol 1982;2: 5–16, with permission.)Copyright © 1982

EFFECTS OF PROLONGED COMPLETE OR PARTIAL URETERAL OBSTRUCTION ON GLOMERULAR FILTRATION AND RENAL PLASMA FLOW

Following ureteral obstruction in the rat, GFR reaches 2% of control values by 48 hours and remains at this low level. Renal plasma flow also declines, but less so (Fig. 3) (219). Similar observations have been made in the dog (298). The effects of chronic partial ureteric obstruction depend on the degree and duration of obstruction. Whole-kidney glomerular filtration is reduced to one third of control values 2 to 4 weeks after partial ureteral obstruction in the rat. Single-nephron GFR (SNGFR), however, was only reduced by 20% of control levels, suggesting that the decline in whole-kidney function was a result of a loss in the number of functioning nephrons not accessible to micropuncture; that is, juxtamedullary nephrons (311).

FIGURE 3. Time course of the changes in left kidney fractional blood flow (percent of total renal blood flow [RBF]; solid circles) and left kidney glomerular filtration rate (percent of total glomerular filtration rate; solid triangles), after unilateral obstruction of the ureter of the left kidney. Data are expressed as means ± SEM, from three to six rats.

(From Provoost AP, Molenaar TC. Renal function during and after a temporary complete unilateral ureteral obstruction in rats. Invest Urol 1981;18:242–246, with permission.)Copyright © 1981

Following partial obstruction of 2 to 4 weeks’ duration, Ichikawa and Brenner (112) found a 30% decrease in the ultrafiltration coefficient; single-nephron plasma flow and glomerular filtration were maintained near normal as a result of an increase in glomerular capillary pressure, secondary to a decrease in afferent and efferent arteriolar resistances. This dilatation was prostaglandin-mediated because indomethacin increased both afferent and efferent arteriolar resistances and caused a decline in single-nephron glomerular filtration (112).

Pathophysiology

Acute kidney injury can best be understood in relation to its causes. The kidneys have a reduced ability to filter and process the blood into urine. The problems can occur before, after or within the kidneys. Prerenal AKI is the most common form and is due to impaired renal perfusion. This may be the result of a decrease in effective arterial blood volume or blood pressure delivered to the kidney glomeruli. Causes could include accumulation of fluid outside of the vascular space such as edema or ascites, lowered pressure and flow with congestive heart failure, peripheral vasodilation with toxic products of sepsis, or impaired renal blood flow or reduced glomerular capillary pressure from some drugs. Poor renal perfusion constitutes about 60% of the AKI cases, and most likely resulting from inadequate hydration. Unless prerenal causes of ischemia are recognized and corrected, acute tubular necrosis (ATN) may result.

Postrenal obstruction can also cause AKI, although this accounts for only about 5% of the causes. Ureteral or bladder obstructions by stones, tumors, fibrotic masses or structural anomalies can mechanically reduce filtration by increasing the back-pressure on glomeruli. Some drugs, including tricyclic antidepressants, occasionally constrict the bladder neck to limit urine outflow from the bladder.

In addition, intrinsic AKI may initiate within the kidneys and may damage the renal parenchyma. The source may be a variety of diseases or insults that affect the renal tubules, glomeruli, vasculature or interstitium. Tubular diseases most often result from ischemic or toxic insults to the kidney from drugs and toxins. Sloughing of renal tubule epithelial cells, brush border villi and proteins can form casts, or sausage-like fragments that can obstruct the nephrons. In addition, release of endogenous chemical biomarkers from lysed tubules may serve as sensitive indicators of early renal damage. This acute tubular necrosis (ATN) can be the precipitating cause of intrinsic AKI or can be a secondary consequence of poor renal perfusion. The glomeruli and the renal interstitium are also initiating sources of intrinsic AKI. Glomerulonephritis caused by various diseases can disrupt filtration and tubular function due to immune complex deposition and other disruptions of glomerular capillary membranes, and interstitial nephritis caused by drug allergies and toxins may also secondarily precipitate ATN and AKI (Schnellmann (2013)).

REFLEX CONTROL OF SELECTIVE FUNCTIONS

Attention has been focused on whether the renal innervation could selectively regulate either renal hemodynamics, or tubular fluid reabsorption or renin secretion. The findings of Luff et al. in the rabbit (137) and DiBona and Sawin in the rat (55) demonstrated that two types of structurally different nerve fibers exist within the nerve bundles and within the kidney itself. Studies have been undertaken to provide functional support for this hypothesis. Evidence has been produced in the rabbit where glomerular capillary pressure was measured as an indirect estimate of pre- and post-glomerular resistances (38–40). Using an Ang II clamp to remove any confounding influences of changes in endogenous Ang II levels, a hypoxic challenge increased glomerular filtration pressure. The authors interpreted these observations as reflecting selective neural regulation of postglomerular vascular resistance, possibly via one of the subtypes of nerve fiber, independent of the renin-angiotensin system.

DiBona and colleagues (41, 55), using the rat, analyzed the strength–duration relationship during direct electrical renal nerve stimulation in relation to renal blood flow and urine flow and sodium excretion, and found a higher stimulation threshold for the nerve fibers involved in regulating renal blood flow compared to those involved in regulating fluid excretion. Moreover, it was found that activity in single sympathetic fibers innervating the kidney could be selectively modified by different reflexes. Thus, arterial baroreceptors, central chemoreceptors, and thermoreceptors could activate a large proportion (88%) of fibers, thereby demonstrating spontaneous activity, whereas only thermoreceptors activated fibers that had no spontaneous activity. In a different series of studies, while examining patterns of renal sympathetic nerve activity by evaluating the peaks of activity and time between peaks, DiBona and colleagues were able to show that recruitment of nerve fibers was comparable to somatosensory (pinch) and heat stimuli, but it was only the heat stimulus that caused a decrease in renal blood flow. The authors suggested that these responses indicate a distinctly different control of sympathetic outflow that could selectively regulate hemodynamic, excretory, or renin secretory activity.

It would seem that there is a small, but persuasive, body of evidence for the view that there may be a degree of selectivity of functional control in the neural control of the kidney. More investigation of this particular topic is needed.

Early Hemodynamic Alterations in the Glomerulus

Altered renal hemodynamics is an early characteristic feature of diabetes in humans as well as animal models (196, 261). It is widely held that glomerular capillary hypertension in diabetes is the major hemodynamic alteration that contributes to progressive glomerular injury (99, 261). The increase in glomerular capillary pressure is accompanied by increased glomerular blood flow, which is caused by afferent arteriolar dilation but with little or no dilation of the efferent arteriole. An imbalance of a variety of vasoactive and growth factors including the renin-angiotensin-aldosterone system (RAAS), atrial natriuretic peptide, insulin-like growth factor-1, endothelin, prostanoids, and eicosanoids has been implicated in diabetic hyperfiltration, but evidence strongly implicates the NO system as the main mediator for afferent arteriolar dilation (48, 78). Three major theories have been put forward to account for the hemodynamic changes in the glomerulus: (1) a primary alteration in vascular function, (2) a primary alteration in tubular function, and (3) a primary growth of the total filtration surface area (part of the hypertrophic response), mediated by endothelial cell proliferation, capillary elongation, and new capillary formation (19, 172, 206).

It has been well characterized that diabetes is associated with impaired autoregulation at the afferent arteriolar level (89). This vascular theory suggests that vascular smooth cells, mesangial cells, and endothelial cells are primarily responding to a combination of high-glucose concentrations, local autocoids, and systemic signals to alter the normal autoregulatory response to the prevailing systemic pressure. Studies supporting a primary vascular role include impaired calcium transients in afferent arterioles from diabetic rats (26, 206). Numerous groups have found a persistent altered responsiveness to vasoconstrictors of vascular smooth muscle cells and mesangial cells obtained from diabetic rats (102, 104, 144, 206, 237, 238). Some of these studies, using mesangial and vascular smooth muscle cells cultured in high glucose or obtained from diabetic rats, have identified protein kinase C (PKC), reactive oxygen species (ROS), and TGF-β to be important mediators of vascular dysfunction.

A case for tubuloglomerular feedback as the initiating factor has been put forward by Blantz and coworkers (223, 224). These investigators have convincingly demonstrated that increased uptake of glucose and sodium in proximal tubular segments may limit sodium delivery to the macula densa, thus inhibiting tubuloglomerular feedback and preventing constriction of the afferent arteriole. Presumably the enzyme ornithine decarboxylase plays an important role in this pathway (223). Studies in diabetic animals and patients with salt loading lend further evidence to this hypothesis. NaCl restriction would cause a decrease in GFR in the normal situation; however, in animals with longstanding diabetes and in diabetic humans, salt restriction causes a surprising increase in GFR. This salt paradox could be explained by the further decrease in salt delivery to the macula densa and further afferent arteriolar dilation. However, several studies report unimpaired tubuloglomerular feedback in diabetes (183, 225); one group suggested that enhanced tubuloglomerular feedback may mitigate the increase in GFR (183). It is likely that much of the discrepant results are accounted for by variations in diabetes induction, degree of hyperglycemia, weight loss, insulin levels, and duration of diabetes. Without a standardized experimental approach it is virtually impossible to interpret the various results.

Regardless of the cause of hemodynamic alterations in diabetes, progressive renal injury eventually ensues. One potential scenario to explain this outcome has been put forward by Kriz and coworkers (129). With increased glomerular capillary pressure, there is stretching of mesangial cells with loss of tethering to the GBM. Loss of tethering may be contributed by altered integrin expression and growth factor production. This would lead to a ballooning of the capillary loop and denuding of the GBM on the epithelial side. Alterations in GBM composition may also play a role. Dropout of podocytes may ensue due to abnormal stretching of podocytes and loss of adherence to the GBM. Furthermore, abnormal stretch may stimulate TGF-β production by mesangial cells, leading to a sclerotic response (84, 190). This scenario would fit with the glomerular volume increase noted in experimental and human diabetes as well as the diffuse mesangial matrix expansion and podocyte dropout.

Enhanced tubular transport of solutes and water is correlated with glomerular hyperfiltration. The elevation in the glomerular transcapillary hydraulic pressure gradient as well as the increase in glomerular plasma flow leads to an increase in GFR. This, in turn, enhances the colloid osmotic pressure in postglomerular capillaries, which can facilitate the reabsorption of water and sodium in proximal tubules. These processes provide a mechanistic link between enhanced tubular transport and the primary abnormality of glomerular hyperfiltration. As an alternative explanation, a primary abnormality in sodium reabsorption, has been linked to glomerular hyperfiltration (224). This explanation suggests that an increase in reabsorption of sodium chloride in proximal tubules or loops of Henle leads to an increase in GFR by an intact macula densa mechanism. Diabetes-induced hypertrophy of tubules that mediate stimulated sodium chloride reabsorption could be pivotal in this process, again connecting the structural changes with the hemodynamic adaptation in diabetes (224). Therefore, both mechanisms could explain the increase in tubular reabsorption that occurs in diabetic nephropathy.