Physiology of Glomerular Filtration

GFR is the product of the filtration rate of the individual nephron and the number of functioning nephrons.⁷ A single nephron glomerular filtration rate (SNGFR), is defined by the Starling forces of the glomerular capillaries and the properties of the glomerular capillary wall.

where Kf is a capillary wall property known as the ultrafiltration coefficient and is the product of the surface area available for filtration and the hydraulic conductivity of the membrane. The Starling forces (or pressures) that affect filtration are the hydraulic pressure in the glomerular capillary (P_gc), the hydraulic pressure in Bowman’s space (P_bs), the oncotic pressure of the glomerular capillary (π_gc), and the oncotic pressure in Bowman’s space (π_bs), which is usually zero because the ultrafiltrate is essentially protein-free.⁸ P_gc favors filtration; Pbs and π_gc are opposing forces to filtration. The mean ultrafiltration pressure (P_uf) is the difference between the net change in hydraulic pressure and the net change in the oncotic pressure. Thus SNGFR may be modified by alterations in the glomerular capillary pressures, glomerular membrane characteristics, or the surface area available for filtration.

The kidneys are responsible for plasma water and electrolyte balance through filtration at the glomerular membrane and then reabsorption of this filtrate from the renal tubular epithelium. The loss of filtration and tubular reabsorption in AKI is the result of renal adaptive changes that initially function to preserve renal perfusion and glomerular filtration; however, when these are exhausted, the kidney’s compensatory mechanisms fail and renal dysfunction ensues.

Glomerular filtration depends on adequate renal perfusion; the kidneys receive approximately 25% of total cardiac output. The fraction of cardiac output perfusing the kidneys is related to the ratio of renal vascular resistance (RVR) and systemic vascular resistance.⁹ Renal blood flow (RBF) is determined by systemic blood pressure (SBP) and RVR, expressed by the formula RBF = SBP/RVR.⁹ Kidney autoregulation, which maintains a constant renal perfusion pressure, occurs through alterations in RVR in response to changes in systemic vascular resistance or intravascular volume. When SBP is within the normal physiological or autoregulatory range, the kidney can maintain constant blood flow and GFR by dilation of the preglomerular or afferent arteriole, which reduces RVR and increases RBF. This afferent arteriole dilation is accomplished by two known mechanisms, smooth muscle relaxation of the afferent arteriole in response to sensing a transmural pressure drop (the myogenic reflex³) and the tubuloglomerular feedback system. The tubuloglomerular feedback system is operational following a reduction of plasma flow. When solute and water delivery to the macula densa are reduced, the juxtaglomerular apparatus responds by relaxing the smooth muscle of the adjacent afferent arteriole. Thus a reduction in cardiac output or effective renal plasma flow is accompanied by vasodilation at the preglomerular arteriole, which in turn reduces RVR, thereby restoring RBF.

During states of reduced cardiac output or intravascular volume depletion, the systemic vasoconstrictors, angiotensin II and vasopressin, are released to help preserve vascular tone. The kidney counteracts the renal vasoconstrictor activity of angiotensin II and increased sympathetic tone through the intrarenal production of vasodilatory prostaglandins such as prostaglandin I2.¹⁰ These locally produced substances may attenuate renal vasoconstrictive forces and help preserve renal perfusion. Animal model data of congestive heart failure have provided evidence that enhanced prostaglandin synthesis is required for preservation of renal perfusion and GFR. Patients receiving prostaglandin synthetase inhibitors such as nonsteroidal antiinflammatory drugs (NSAIDs) have potentiation of renal ischemia because of an increase in renal vasoconstriction not antagonized by intrarenal prostaglandin synthesis.¹¹ Endothelium-derived relaxation factors (EDRFs), which are vasodilatory, and the potent vasoconstrictor endothelin, produced by the endothelium, may also affect the regional vascular tone.¹²

Constriction of the postglomerular capillary sphincter, the efferent arteriole, in the face of reduced RBF serves to increase the filtration fraction and preserve GFR, although this occurs at the expense of renal plasma flow, which may be further reduced. Vasoconstriction at the efferent arteriole is mediated by angiotensin II and, to a lesser extent, by the action of the adrenergic system by epinephrine.¹³ Elevation in postglomerular arteriolar resistance may be blocked by the angiotensin-converting enzyme inhibitors. When converting enzyme inhibitors are administered to the patient who requires efferent arteriolar constriction to maintain GFR, renal decompensation often results.¹⁴

As previously noted, reductions in effective intravascular volume and cardiac output are accompanied by increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system and increased circulating levels of vasopressin.¹⁵ Hormonal and neural systems signal the kidneys to increase the reabsorption of sodium and water to help restore the deficient intravascular volume, increase cardiac output, and consequently improve RBF. These, and the kidney’s homeostatic mechanism, by afferent arteriolar vasodilation and efferent arteriolar constriction, maintain the kidney’s glomerular filtration. The kidney’s homeostatic mechanisms, however, are not without limitation. The autoregulatory ability of the afferent arteriole is maximal once the mean SBP falls below 80 mm Hg. The renal autoregulatory range appears to be age-dependent, because younger animals can autoregulate over lower pressure ranges. The range of perfusion pressure over which the kidney can autoregulate may be limited in certain conditions so that vasodilation is maximal with a minor reduction in mean arterial blood pressure. Examples include extracellular fluid depletion, renal ischemia, or renal vascular disease (e.g., hypertension, diabetes, atherosclerosis).

As the stimulus for release of vasoconstrictors continues, afferent arteriolar constriction rather than vasodilation may predominate, and the result is a decrease in renal plasma flow and filtration rate.

Constriction of the afferent arteriole may be stimulated by increased sympathetic nervous system activity and increased levels of endogenous or exogenous circulating catecholamines such as dopamine or norepinephrine. Thus the administration of these vasoactive-inotropic agents may actually compromise the kidney’s adaptive mechanisms. Excessive vasoconstriction eventually results in diminished filtration rate and oxygen delivery to the kidney.

Pharmacological agents may alter renal perfusion by changing SBP through an action on systemic vasculature or by direct effects on renal vasculature (Box 71-1). Vasodilators, such as hydralazine, lower SBP without changing renal perfusion pressure, because the decrease in SBP is accompanied by decreased RVR. Conversely, epinephrine increases SBP but decreases RBF by its vasoconstrictor effect on intrarenal blood vessels.

Morphologic Changes in Renal Injury

Morphologic changes seen in acute renal injury, especially those in the tubules, depends on the duration of injury as well the eliciting mechanism.

The kidney’s complex structure, with heterogeneous segments within the kidney receiving differential regional perfusion and thereby oxygenation, sets up a common form of renal failure, that of the tubulointerstitium. This region is at greatest risk for ischemia because of its gradient of regional perfusion and oxygenation. In addition, vascular disease, including glomerular disease, often occurs in children and results in AKI, but there are studies that suggest the extent of damage to the tubulointerstitium has the greatest prognostic implication to the degree of final renal recovery.¹⁶

Initial structural changes in tubular cells are seen as apical and basal surface changes of simplification, with microvilli of the brush border shortening and disappearing by either detachment from the apical surface or being internalized within the tubular cells.¹⁷

In this scenario, enzymes of the brush border (alkaline phosphatase and gammaglutamyl transpeptidase), may be found in the urine and may be used as markers of early tubular injury.¹⁸ The loss of microvilli surface area leads to loss of enzymes and transport sites for transcellular absorption and apical uptake. Additionally, loss at the basolateral interdigitating infoldings of the tubular cells then results in further reduction of surface area for transport and loss of the Na-K-adenosine triphosphatase (ATPase) that is localized to this membrane and involved in many transport processes.¹⁹

Morphologic changes in distal tubules and outer medulla also occur and may be found even when proximal tubular injury is not readily identified on biopsy. Experimentally, the outer medulla has been identified as sensitive to hypoxia, including that induced by toxins such as radiocontrast agents and cyclosporine.²⁰

Injury at this outer medulla region may be missed on biopsy since this site often is not sampled. Tubular cell detachment with exposed, denuded regions of the basement membrane can be found on biopsies, as a result of altered cell-matrix attachments.²¹

Renal tubular sensitivity to ischemic injury is primarily influenced by the individual renal cell’s energy requirements, its glycolytic capacity, and the extent of hypoxic stress upon the cell. Glycolysis and oxidative phosphorylation both supply the ATP required by the cell to drive its metabolism, and it follows that cells with a greater capacity for glycolysis (distal tubular cells) are less sensitive to oxygen deprivation than the cells that rely mainly on mitochondrial derived energy, (proximal tubular cells).²²

In vivo and in vitro studies may be discordant in identifying susceptiblity to hypoxia. Medullary straight portions of the proximal tubule have a higher glycolytic capacity than the cortical segments of the proximal tubule but, due to the regional distribution of perfusion within the kidney, the medullary portions operate in a lower oxygen-tension environment and therefore are more susceptible to hypoxia/ischemic injury.²³ The individual cell’s energy requirements to conduct its transport activities further influences its risk to hypoxic injury. The outer medullary proximal tubular cell (pars recta), due to the high energy requirements for its transport functions, has a greater injury risk than the deep inner medullary tubular cell with its low-oxygen environment, but also a low energy requirement to maintain its transport function.²⁴

When energy stores are rapidly depleted, the normal Na-K ATPase pump begins to fail and the most basic of cell function, membrane integrity, is jeopardized, with resultant accumulation of Na, Cl, and water within the cell; this cell swelling (oncosis) is a hallmark feature of necrosis.²⁵ Not all cells that fail to maintain their energy requirements die through necrosis; apoptosis, which appears morphologically as cell shrinkage, is also a result of inadequate energy support. Apoptosis is an asynchronous cell death triggered over hours to days, with the earliest cellular element involving mitochondrial changes including loss of transmembrane potential and release of mitochondrial cytochrome c into the cytosol.³⁰ It is mitochondrial function/dysfunction that primarily determines the fate of the cell for recovery and survival or death, and by what form: apoptosis or necrosis.

Pathogenesis of Reduced Glomerular Filtration Rate in Acute Kidney Injury

The mechanisms responsible for GFR reduction in acute renal injury have been studied extensively with experimental models of AKI. Multiple mechanisms are often operational in mediating hypofiltration. Whereas one factor may have greater importance in the initiation of injury and decreased filtration, others are involved in the sustained reduction in GFR during the maintenance phase of AKI. Four major mechanisms result in reduced GFR during AKI: reduced blood flow, decreased Kf, tubular obstruction, and backleakage of tubular fluid.³¹ Each factor is discussed regarding its role in both the initiation and maintenance phases of AKI.

A reduction in RBF can be demonstrated during the initiation phase of many forms of AKI and seems to play a predominant role in ischemic injury and rhabdomyolysis.³¹ Proposed theories for the reduction of RBF include (1) a proportional increase in the afferent and efferent arteriolar resistances in response to activation of the renin-angiotensin system; (2) vascular endothelial cell swelling and damage with release of vasoactive peptides such as endothelin; and (3) hyperemic congestion of the medullary peritubular capillaries.

Kf may be reduced in both nephrotoxic and ischemic forms of renal failure. Endothelial or mesangial cell swelling reduces the surface area available for filtration; altered permeability induced by humoral factors such as angiotensin II and vasopressin may also decrease Kf. Circulating levels of both hormones are increased during AKI.

Renal tubular cells are the primary site of injury in both ischemia and nephrotoxin-induced renal injury. Tubular cell injury may be sublethal or lethal and result in cell necrosis or apoptosis. Once this injury occurs, cells detach from the supporting basement membrane and obstruct the tubule lumen. In addition, even with sublethal injury, tight junctions may be disrupted, and the intact layer may be lost. The loss of epithelial integrity allows backleakage of ultrafiltrate, which contains creatinine and urea, through paracellular pathways into the renal interstitium, creating further diminution of excretory function and reduced urine formation. Necrosis of a selected region of the renal tubule is accompanied by tubular obstruction and eventual filtration failure by that entire unit or nephron.

Intratubular obstruction occurs in most forms of acute renal injury, either as a contributing factor in the initiation phase or during the maintenance phase.³¹ Tubular obstruction with cellular debris and precipitated protein is a prominent finding in both the initiation and maintenance phases of ischemic injury. In the case of nephrotoxic injury, the degree of injury may determine the extent of tubular obstruction. In an experimental model of gentamicin nephrotoxicity, the drug dose was positively correlated with the contribution of tubular obstruction to reduced GFR.³¹ Tubular obstruction and loss of epithelial integrity caused by tubular cell injury result in the backleakage of tubular fluid and solutes. Excretion of solute and fluid is decreased, and this decrease possibly signals a further reduction in the GFR by stimulation of the tubuloglomerular feedback mechanism.³¹ Backleakage of fluid involves tubular factors and is not a result of hypofiltration, although it does impair the excretory function of the kidney. Consequently, a falsely low estimation of actual GFR may occur because tubular fluid containing urea and creatinine leaks back into the vascular space and interstitium. Prevention of the tubular obstruction may alter the course of renal failure, even in those states in which the primary mechanism of injury is not obstruction.

AKI may be viewed as an evolving process into three phases³²: (1) an initiation phase in which the primary mechanism of injury is operational; (2) a maintenance phase during which renal function remains poor and other factors may contribute to sustained injury; and (3) a recovery phase during which there is regeneration of cells and restoration of function. Although the primary initiating event may be hypoperfusion with ischemia, often it involves multiple contributing factors that mediate additional cellular damage, usually through alterations in energy supply. From a clinical perspective, it may be most helpful to consider acute renal dysfunction syndromes according to the cause of the inciting event; however, it is equally vital to understand the other contributing mechanisms that ultimately affect outcome.

Recently, endothelial injury and vascular dysfunction have been postulated to occur during the initiation and particularly during the maintenance phases of AKI. Although most studies have focused on the tubular cell as the primary site of injury leading to dysfunction, recent studies have provided insight into the potential role for endothelial injury in continued reduced RBF and altered vascular function.³³ Sutton et al. propose that an additional phase be added to the current model for AKI: after the initiation phase, an extension phase occurs that is due to microvascular injury related to ischemic damage to endothelial cells, infiltration of leukocytes, and activation of the coagulation system. This process is thought to predominate in the corticomedullary and outer medullary microvessels and may occur in the face of early tubular cell regeneration so that limiting the extension process provides a potential mechanism for aiding recovery.

Mechanisms of Renal Cell Injury

The renal tubular cell expends energy in the form of ATP to maintain a high intracellular concentration of potassium and a low intracellular concentration of sodium. This concentration gradient depends on the continuous activity of the Na⁺/ K⁺-ATPase and is the driving force for the reabsorption of sodium. Active reabsorption of sodium is the primary driving force for water reabsorption and the coupled transport of amino acids, carbohydrates, organic acids, and other compounds. Thus all transport functions, as well as many other vital cell functions, depend on normal activity of the Na⁺/K⁺ pump, which, in turn, depends on an adequate supply of energy. In addition, membrane fluidity or integrity is important to transport functions in tubular cells. Processes that result in alterations in the membrane or in the supply of energy are common final pathways for renal tubular cell death.

A decrease in the cellular ATP content occurs in many forms of renal injury, possibly as the result of primary alterations in the cell’s ability to perform oxidative phosphorylation or as the end result of other perturbations. Heterogeneity exists in the susceptibility of nephron segments to oxygen deprivation with more distal segments being relatively resistant. This is related to the greater glycolytic capacity of the distal tubule compared with the proximal tubule, which relies on oxygen-consuming pathways for ATP generation. Therefore the net result of renal injury is usually a depletion of energy in the form of ATP, with the inability of the cell to perform vital functions, including transport and maintenance of cell integrity.

Cellular injury may be modified by the requirements made on its energy stores. If more transport is required of the cell, more energy is consumed, and less energy is left for cell maintenance. Evidence exists to support this theory. If transport requirements are reduced by the administration of diuretics or by the stimulation of the glomerulotubular feedback mechanism, then further injury may be attenuated. The feedback mechanism, whereby there is reduction of GFR in the face of reduced reabsorption by the proximal tubule, is a protective signal that conserves cell energy by reducing metabolic demands made on the cell.

Heat shock proteins (HSPs) are a family of proteins that appear to protect cells from injury as a result of hyperthermia, ischemia, or toxins. The HSP induction by sublethal thermal stress has been found to attenuate subsequent injury in the kidney.³⁴ Renal transplants from animals that underwent short-term hyperthermia had better initial function and subsequent survival. Furthermore, in cultured inner medullary collecting-duct cells, induction of HSP-1 by preconditioning hyperthermia attenuated the alterations in mitochondrial function and glycolysis that were observed after cells were exposed to high temperatures. Investigations into potential mechanisms to use this natural cell defense mechanism are under way.

The ability of renal tubular epithelial cells to undergo regeneration determines in large part the degree of renal recovery. Therefore much work has recently been done to study ways that cells regenerate and mechanisms that might enhance recovery. Early in ischemic injury there is induction of early response genes such as c-fos and Egr-1.³⁵ By 2 days after ischemia, the proliferating cell nuclear antigen is detected, followed by expression of other dedifferentiated cell markers, which seem to be a sign of early recovery. Other cells appear to undergo apoptosis or cell death. Postischemic regeneration seems to be a recapitulation of early renal tubular cell development. Growth factors such as insulin-like growth factor-1 (IGF-1) and epidermal growth factor 1 (EGF-1) have been associated with enhanced recovery as well. Renal levels of hepatocyte growth factor (HGF) increase after two models of renal failure, postnephrectomy, and following CCL4 (chemokine [C-C motif] ligand 4) injection, and this increase supports a role for HGF in renal repair.³⁶ Exogenous EGF has been shown to enhance renal tubular cell regeneration and to lessen the severity and duration of hypoxia and toxin-induced renal failure. EGF receptor levels increase within hours of ischemic injury in the rat. Elevation of soluble EGF occurs along with morphological evidence of tubular injury within 12 hours of ischemia, which is followed by cell proliferation and a decrease in soluble EGF by 24 to 48 hours after ischemia.

Hemodynamically Mediated Acute Kidney Injury

Renal hypoperfusion with ischemia is a common form of acute renal damage, especially in the setting of the ICU. This form of renal injury is often accompanied by oliguria and results from alterations in renal perfusion after a period of hypoxia, hypotension, cardiac dysfunction, or any condition that promotes hemodynamic instability, decreased effective plasma volume, or both states. This condition is commonly referred to as acute tubular necrosis because it is characterized by necrosis of tubule cells; however, this is a nonspecific term that may also define nephrotoxic injury. A preferred term is vasomotor nephropathy or hemodynamically-mediated renal failure.⁴⁰ The same physiological alterations that initiate renal injury in this form of nephropathy may potentiate renal failure in conditions whose primary inciting event may not have been vascular.

Vasomotor nephropathy commonly follows a period of renal compensatory changes that may be termed prerenal failure,⁹ which are discussed in the preceding section on physiology. When the kidney has fully used normal compensatory mechanisms, renal oxygen delivery is critically impaired, and this impairment results in cell damage or tubular cell necrosis. Thus it is apparent that acute tubular necrosis is the end result of a continuum of renal adaptive mechanisms. Acute cortical necrosis is an exaggerated and more advanced form of renal ischemia.

When vascular or hemodynamic abnormalities persist or are profound, renal compensatory mechanisms are unable to preserve RBF and maintain sufficient oxygen delivery and GFR. At a mean renal perfusion pressure of 80 mm Hg, afferent, arteriolar dilation is maximal, and below these systemic pressures, RBF dramatically declines.^9,40 In addition, loss of the ability to autoregulate as a result of ischemia may cause further damage. Renal cell injury develops as the result of deficient oxygen delivery, depletion of cellular energy, loss of membrane integrity, and release of reactive oxygen species. Without sufficient oxygen, the kidney cannot support cell functions that maintain architectural integrity and complex transport functions.

Although total RBF is decreased in vasomotor nephropathy, outer cortical blood flow is preferentially reduced. The medulla is not spared, however, because of its increased susceptibility to alterations in renal perfusion.⁴¹ Oxygen delivery to this segment of the kidney is precarious. Medullary partial pressure of oxygen (PO₂) is approximately 10 mm Hg in the rat and dog. This oxygen level approaches the critical minimum level required to support oxidative phosphorylation and ATP synthesis for cell function. In general, however, the proximal tubule sustains the greatest injury. The renal arteriogram of human subjects with vasomotor nephropathy reveals marked narrowing of the arcuate arteries and absence of peripheral vasculature, providing further evidence for the marked vascular resistance enhancement.⁴⁰

The primary event in vasomotor nephropathy is injury of the renal tubule. The initiation of this injury, however, is microvascular in origin. Maximal renal compensation with marked efferent and afferent arteriolar vasoconstriction reduces glomerular plasma flow with resulting hypofiltration and compromises postglomerular blood supply to the renal tubule. Tubular cell necrosis with sloughing of tubular cells into the lumen results in obstruction of flow and backleakage of filtrate through the injured epithelium. Alterations in tubular cell function in cells receiving sublethal or lethal injury increase fluid and salt delivery distally, and this increase signals the glomerulotubular feedback system to cause vasoconstriction of the afferent arteriole and limit the fraction of plasma filtered at the glomerulus.⁴⁰ Although the initial reduction in GFR is the result of decreased RBF and tubular factors such as obstruction and backleakage, continued hypofiltration during the maintenance phase is related primarily to continued vasoconstriction and renal hypoperfusion.⁴⁰ Recovery from postischemic AKI is biphasic. Initially, an increase in GFR occurs with relief of tubular obstruction and subsequently, improved filtration in association with renal vasodilation.

Oliguria in the presence of renal hypoperfusion has been referred to as acute renal success by investigators who propose that the response of an intelligent organ to a perceived reduction in blood flow is to reduce fluid and electrolyte losses by vasoconstriction to reduce the fraction of plasma filtered and by maximal reabsorption of fluid and salt to restore the circulation. In addition, increased distal delivery of water and solutes because of tubular cell necrosis reflects failure of the renal tubule to absorb what is filtered. The appropriate response of an intact nephron is to reduce filtration by release of angiotensin II into the interstitium. Angiotensin II mediates arteriolar vasoconstriction, which decreases glomerular plasma flow, and retraction of the glomerular tuft, which reduces Kf, the net effect being decreased glomerular filtration.⁴¹

The classic form of hemodynamically-mediated AKI was oliguric, by definition; however, nonoliguric acute vasomotor nephropathy is increasingly recognized.^41,42 This form of less severe disease has been referred to as attenuated acute tubular dsyfunction and has allowed the recognition of three stages of AKI that actually represent a continuum of worsening disease: first, abbreviated renal insufficiency occurs after a single event of renal hypoperfusion, such as aortic cross-clamping, in the face of adequate volume repletion and SBP. This syndrome is characterized by an acute drop in the GFR with gradual return to normal within a few days. The inability to concentrate the urine or to conserve sodium provides evidence of tubular injury. The second phase or form is referred to as overt renal failure. An example of this situation is aortic cross-clamping followed by continued renal hypoperfusion because of poor cardiac function. A more prolonged period of hypofiltration lasts for several days to weeks with a gradual return of the GFR. If recovery of renal perfusion is impaired by repeated episodes of ischemia/hypotension, sepsis, or hypoxia, the third pattern may be observed in which a protracted course may be observed and chances for recovery may be doubtful.⁴² One situation in which the last example could exist is aggressive hemodialysis (ultrafiltration) with hypovolemia and, consequently, renal hypoperfusion in the recovering phase of renal failure. Clinical experience has supported this theory. Patients with multiple renal insults have a more protracted course and increased morbidity.⁴³

Using the Schwartz formula for estimate of creatinine clearance (GFR) in infants and children, a modified RIFLE classification (pRIFLE) has been developed.

The pRIFLE classification is defined by the percent reduction in eCrCl and/or the amount of diminishing urine output² (Table 71-1).

Table 71–1 pRIFLE Classification

Prevention/Attenuation of Acute Renal Failure

Prevention or attenuation of ARF has been the subject of numerous studies, as most agree that protection of the kidney from damage or enhancing recovery after damage would be preferable to the currently available supportive therapies. Primary prevention of AKI in the ICU is limited to those conditions in which the timing of injury is predictable, such as exposure to radiocontrast dye, cardiopulmonary bypass, nephrotoxic medications, or chemotherapy. In contrast to most cases of community-acquired AKI, nearly all cases of ICU-associated AKI result from more than a single insult.⁴⁶ Protective agents have been studied extensively with animal models of acute renal injury. Some of these agents have ultimately been used in clinical situations with variable success. In general, methods to reduce renal injury have been aimed at manipulation of RVR or alteration of the metabolic processes of the renal tubular cell.

Hyperkalemia

The major reason for the development of hyperkalemia (serum potassium concentration more than 6 mEq/L) is the release (or infusion, or both) of potassium into the extracellular space at a rate greater than the kidney’s ability to excrete potassium. Further the intracellular potassium is in the concentration range of 140 to 150 mEq/L, adding to the total source of potassium. The fact that AKI and oliguria have developed does not mean that hyperkalemia will develop. By the same token, hyperkalemia may develop rapidly in situations of extensive tissue destruction even without oliguria and “full-blown” AKI. Thus in the clinical situation of a crush injury or the tumor lysis syndrome, hyperkalemia should be anticipated and careful anticipatory monitoring begun.

Severe Hypertension

Hypertension is frequently associated with kidney disease. The two main mechanisms by which kidney disease leads to hypertension, especially accelerated hypertension, are (1) plasma volume expansion caused by the failure to excrete sodium chloride and water and (2) hyperreninemia associated with decreased kidney perfusion.

Plasma and Extracellular Volume Expansion

Plasma and extracellular volume expansion are associated with kidney failure. With an abrupt decline in GFR, even “normal” amounts of sodium and water intake expand the extracellular and plasma volumes. Depending on the cardiac status of the patient, the serum albumin level, and the degree of capillary permeability, this extracellular and plasma volume expansion may be manifest as peripheral edema, hypertension, or congestive heart failure and pulmonary edema. In situations of hypertension or congestive heart failure, the treatment involves two principles. The first is to reduce to as low a level as possible the amount of sodium and fluid the patient receives. This requires attention to diet, intravenous or hyperalimentation solutions, and drugs. The second principle is to remove extracellular fluid. If the patient’s kidney function permits (glomerular filtration of approximately 15 mL/min or higher), then diuretics, especially loop diuretics such as furosemide, bumetanide, or ethacrynic acid, will help to stimulate a diuresis that should improve the blood pressure or the congestive heart failure. The addition of thiazide diuretics prior to the use of loop diuretics may potentiate the effectiveness of loop diuretics allowing for a greater diuresis.⁷² In children with more severe kidney disease, diuretic therapy does not result in diuresis, and dialysis will be necessary.

Severe Metabolic Acidosis

The kidney is responsible for the excretion of hydrogen ion and the regeneration of bicarbonate. When kidney function rapidly deteriorates, then the extracellular concentration of hydrogen ion increases, and this increase leads to acidosis and low serum bicarbonate concentrations. This problem is exacerbated by conditions that increase the production of hydrogen ion and its release into the extracellular fluid. Conditions such as sepsis, severe trauma, burns, extensive abdominal disease or surgery, high chloride-containing intravenous fluids, and hemolysis are all examples in which hypoxia, high hydrogen ion production and/or release into the extracellular space, and a decline in RBF and the GFR are combined. The result is severe metabolic acidosis.

Hypocalcemia/Hyperphosphatemia

Hypocalcemia arises from hyperphosphatemia as a result of dietary load, cellular breakdown, and reduced kidney phosphate excretion; reduced synthesis of calcitriol; downregulation of skeletal cell receptors for PTH; and acidosis.⁷³

Hyperphosphatemia may not be recognized, for the plasma phosphorus level is not contained on any of the classic “lab panels” as directed by Medicare; it therefore needs to be thought of and sought out for identification.

Uremia

The symptoms of uremia are frequently vague and difficult to quantitate. They include central nervous system (CNS) manifestations such as lethargy, confusion, seizures, and obtundation and also gastrointestinal manifestations such as anorexia, nausea, and vomiting. These symptoms plus metabolic derangements often lead to the initiation of dialysis.