FIGURE 16.1 Nephron, the functional unit of the kidney.
- Tubuloglomerular feedback: Situations associated with an increased delivery of sodium chloride to the macula densa result in vasoconstrictive response of the afferent arteriole. The increased uptake of chloride ions by the macula densa cells leads to adenosine triphosphate (ATP) release into the surrounding extracellular space. ATP is then converted to adenosine, which binds to adenosine A1 receptors causing afferent arteriolar vasoconstriction.
Basic Principles of Tubular Transport
The kidneys filter about 180 L of plasma per day, and all but 2 L are reabsorbed. This massive reabsorption is accomplished through several modifications of the glomerular ultrafiltrate, consisting of absorption and secretion of water and solutes before becoming the final urine. In general, three different tubular segments are involved in this process and can be recognized based on the differences in the function of their cells.
- The proximal tubule reabsorbs most of the filtered glucose, amino acids, low–molecular-weight proteins, and water (approximately 65%). Other solutes, such as sodium (Na+), potassium (K+), chloride (Cl−), bicarbonate (HCO3−), phosphate (PO4−), and urea are also absorbed in this nephron segment. The terminal segment of the proximal tubule—the pars recta or S3—is responsible for the secretion of numerous drugs and toxins.
- The straight portion of the proximal tubule, the thin ascending and descending limbs, and the thick ascending limb constitute the region known as the loop of Henle. This region is responsible for the continuing reabsorption of the solutes that escaped the proximal tubules (sodium, potassium, chloride, calcium, magnesium ions). It is the major area responsible for the ability of the kidneys to concentrate or dilute the final urine. The principal luminal transporter expressed in the thick ascending limb is the sodium-potasium-2chloride cotransporter (NKCC2), which is the target of diuretics such as furosemide.
- The distal nephron is responsible for the final adjustments in the urine. Critical regulatory hormones such as vasopressin and aldosterone regulate the acid and potassium excretion and the urinary concentration at this segment. Thiazide diuretics act at the distal convoluted tubule through a thiazide-sensitive Na+ −Cl−cotransporter on the apical membrane.
The Glomerulotubular Balance
The fact that the tubules tend to reabsorb a constant proportion of a glomerular filtrate rather than a constant amount is called glomerular balance. As an example, if the filtered load of Na+ were increased by 10%, total Na+ reabsorption in the tubules would also increase by 10%, keeping the final amount of Na+ in the urine stable at 100 to 250 mEq/day. In the absence of this mechanism, even small changes in the GFR would cause major changes in the final amount excreted of any solute. The mechanisms responsible for this balance are not fully understood, but changes in the oncotic pressure in the peritubular capillaries and in the delivery of certain solutes (glucose and amino acids) to the proximal tubule are probably involved.
Control of Effective Circulating Volume via Integrated Mechanisms
Most volume-regulatory mechanisms in the kidney use the effective circulating volume (ECV), or the degree of fullness of the vasculature, as the final target. Under normal conditions, the ECV varies in direct proportion to the extracellular fluid volume. As Na+ is the most abundant extracellular solute, the kidney excretion or retention of Na+ is a crucial step to control ECV. Osmoregulation is under the control of a single hormonal system, antidiuretic hormone (ADH), but volume regulation requires a complex set of redundant and overlapping mechanisms.
The kidneys are able to conserve water by excreting the solute load in concentrated urine in conditions of excess water loss. Similarly, in high water intake states, the urinary volume may increase to as high as 14 L/day, with an osmolality significantly lower than that of the plasma. Vasopressin or ADH regulates the water permeability in the distal nephron and is the principal hormone responsible for the determination of the urinary concentration and volume. Normally, the major stimulus to secretion of ADH is the plasma osmolality, but in situations of extracellular volume depletion, the set point to release ADH is shifted, and higher levels of this hormone are common even in hypotonic states.
The renin–angiotensin system plays a central role in the control of ECV. The afferent arteriolar cells that form part of the juxtaglomerular apparatus release renin in response to increased sympathetic nervous stimulation, reduced arterial blood pressure, or reduced delivery of sodium chloride (NaCl) to the macula densa region. Renin cleaves angiotensinogen into angiotensin I and is then converted to angiotensin II by the angiotensin-converting enzyme. Angiotensin plays important roles in the control of blood pressure and the effective circulatory fluid volume.
- Angiotensin II has the direct effect of increasing the sodium reabsorption in the proximal tubule (stimulation of Na+/H+ exchange).
- The aldosterone secreted by the adrenal glands in response to the angiotensin II stimulates sodium reabsorption in the distal nephron.
- Angiotensin II causes general arteriolar vasoconstriction, thereby increasing arterial pressure.
Increased renal sympathetic tone enhances renal salt reabsorption and often decreases RBF. In addition to its direct effects on renal function, increased sympathetic outflow promotes the activation of the renin–angiotensin system.
IMPACT OF ALTERED RENAL PHYSIOLOGY
Altered renal physiology can manifest as mild abnormalities in electrolyte and acid–base homeostasis or solute clearance to full-blown AKI that can progress to chronic kidney disease. The impacts of perturbed renal physiology and proposed pathogenesis are discussed.
Consequences of Aberrant Renal Blood Flow Autoregulation
RBF is dependent on systemic blood pressure and intrarenal vascular resistance. The autoregulatory mechanisms, through changes in vascular resistance, ensure that over a wide range of perfusion pressures RBF remains stable and glomerular filtration can be maintained. However, a substantial loss of renovascular response to neurohormonal stimuli follows ischemic AKI (6), related to increased renal vasoconstriction (7). Clinically this manifests as ischemic AKI, a syndrome that develops following a sudden transient drop in total or regional blood flow to the kidney resulting in tissue hypoxia, tubular and vascular injury, and loss of renal structure and function (Fig. 16.2). The severe form of this entity is known as acute tubular necrosis. An aberrant RBF autoregulation is also implicated in normotensive ischemic AKI. Whereas normal GFR is maintained until MAP falls below 50 mmHg, in normotensive ischemic AKI RBF and GFR can decrease by as much as 50% despite the maintenance of MAP within the autoregulatory range (8), suggesting the presence of heightened renal vasoconstriction.
The paradoxical rise in renovascular resistance seen with decreasing renal perfusion in ischemic AKI is due to the loss of the usual balance of vasoconstrictors and the vasodilators required to maintain the normal tone of the renal vasculature. The downstream consequence of aberrant responses to neurohormonal stimuli and the persistent vasoconstriction is that it worsens renal perfusion and impairs oxygen and nutrient delivery to the areas supplied by the postglomerular vessels.
The PO2 in the outer medulla is about 10 to 15 mmHg; even a mild decrease in renal perfusion can lead to a hypoxic insult (oxidative stress) to the vulnerable medullary nephron segments. Tissue hypoxia can result in depletion of cellular ATP stores, increased intracellular calcium, and subsequent disruption of actin cytoskeleton in the endothelial and vascular smooth muscle cells, with resultant hemodynamic impairment and tubular injury. Adenosine nucleotide metabolic products are not reused for the regeneration of ATP and are, instead, diverted through the degradatory pathways to generate xanthine and uric acid. Accumulation of adenosine and uric acid worsens vasoconstriction and renal perfusion via their effects on adenosine receptors and afferent arterioles, respectively. Cellular activation also leads to reactive oxygen species generation, phospholipase activation, and membrane lipid alterations (9).
FIGURE 16.2 Schematic representation of the mechanisms of ischemic acute kidney injury. RAS, renin–angiotensin system; SNS, sympathetic nervous system; ET-1, endothelin-1; ROS, reactive oxygen species; TXA2, thromboxane A2; NO, nitric oxide; PGI2, prostaglandin I2; EDHF, endothelium-derived hyperpolarizing factor; ATP, adenosine triphosphate; Ca2+, calcium.
Hypoxia, with subsequent reperfusion, leads to acute inflammatory changes. Inflammation is one of the major pathophysiologic pathways contributing to ischemic AKI. Ischemic injury to the vasa recta results in enhanced adherence of leukocytes to the vascular endothelial cells, sequestration of leukocytes, vascular congestion—that is, a no-flow phenomenon—cellular infiltration, production of inflammatory mediators, and generation of reactive oxygen species. Cytokines and chemokines, released from the injured cells, attract inflammatory cells to the site of injury and potentiate the inflammatory cascade. A similar inflammatory response is also seen in tubular cell injury, which is also capable of producing chemokines and inflammatory mediators. The inflammatory changes are most pronounced in the outer medullary stripe, the region that is most susceptible to hypoxic insult.
Numerous stress response mechanisms are rapidly activated in response to oxidative insults. Some of the pathways are preferentially linked to cell survival whereas others are proapoptotic; these pathways intersect and modulate each other’s activities. Whether a particular insult leads to cell repair and survival—or death—depends on the nature and severity of the insult, the balance between the proapoptotic and antiapoptotic signals, and the basal state of the cells. Ongoing efforts to elucidate factors that play a role in microvascular endothelial injury and dysfunction, the role of immune system, the expression of adhesion molecules that facilitate leukocyte–endothelial interactions, the cytokine network, the cellular response to oxidative stress, and the gene activation patterns that regulate tissue injury and repair will result in a better understanding of the complex mechanisms involved in the pathogenesis of ischemic AKI.
Effect of Baseline Renal Function on New-Onset Acute Kidney Injury
RBF autoregulation is often impaired in the setting of chronic disease conditions such as hypertension, diabetes, and atherosclerosis. Additionally, endothelial dysfunction, chronic hypoxia, tubulointerstitial fibrosis, and vascular dropout may predispose the renal parenchyma to further damage. Consistent with these hypotheses, retrospective data suggests an increase in the risk of AKI from 1.95 to 40 times with increasing severity of renal dysfunction—for chronic kidney disease stage 3 through stage 5 patients compared to patients with estimated GFR in the stage 1 and 2 range (10). Nevertheless, the causal relationship between renal dysfunction and risk for AKI is uncertain despite assessments based on epidemiologic and outcome data that the two entities may be interconnected (11).
Effect on Fluid Balance
It is evident from the above discussion that acute deterioration in renal physiologic functions is synonymous with the entity of AKI in most clinical situations. A major complication of AKI is decrease in urine output and, hence, inability to maintain fluid balance. AKI complicates the implementation of fluid resuscitation strategies that are often utilized to optimize systemic hemodynamics in the critically ill patients. Fluid accumulation can contribute to tissue edema, impaired oxygenation and metabolite diffusion, disturbed cell–cell integrity, infections, delayed wound healing, and organ dysfunction. Indeed, positive fluid balance is a predictor of adverse outcomes in the critically ill patients (12–15). A 10% increase in body weight relative to baseline was reported to increase mortality and decrease the likelihood of renal recovery in critically ill patients (16). Fluid overload at dialysis initiation can double the adjusted odds ratio for death. In nondialyzed patients, less fluid accumulation at the peak of their serum creatinine was associated with better survival. Fluid balance can be particularly problematic in major surgery where a 3 to 6 kg increase in postoperative weight is not uncommon. It should be also noted that fluid overload may prevent or delay the diagnosis of AKI. Although dialysis is effective at volume removal, mortality has been shown to increase in relation to the proportion of dialysis days with fluid overload (16). An intriguing question is the causal relationship between fluid balance and AKI. Data from cardiac surgery suggests that positive fluid balance develops early in the intraoperative period (17) due to intravenous fluid bolus administered to treat hypotension (18). In pediatric surgery, fluid overload was associated with the development of AKI and more often preceded it than followed it (19). Moreover, the predictive power of positive fluid balance to diagnose AKI has been reported to be comparable to preoperative conventional (serum creatinine, GFR) and postoperative 24-hour novel biomarkers (urine neutrophil gelatinase–associated lipocalin, IL-18, and serum tumor necrosis factor-alpha [TNF-α] and monocyte chemoattractant factor-1) (15). Angiopoietin-2, a mediator of vascular permeability, was reported to positively correlate with fluid balance, pulmonary dysfunction, and death in sepsis patients (20). Despite these provocative data, the causative association between fluid balance and AKI has yet to be established.
Effect on Pulmonary Function
AKI negatively affects lung physiology significantly by altering the homeostasis of fluid balance, acid–base balance, and vascular tone (21). Most patients with acute respiratory failure receiving mechanical ventilation (MV) require some form of renal replacement therapy. Conversely, alterations in respiratory drive, mechanics, muscle function, and gas exchange are frequent consequences of uremia. The development of AKI predisposes patients to overall fluid overload, decreased plasma oncotic pressure, and leakage of fluid from pulmonary capillaries. The restrictive effects of pulmonary interstitial and alveolar edema, pleural effusion, and chest wall edema increase the work of spontaneous breathing and may contribute to the development of acute ventilatory failure. Additionally, the metabolic acidosis present in most instances of AKI increases the demand for ventilation through compensatory respiratory alkalosis, further disrupting the relationship between the patient’s ventilatory needs and capabilities. Pulmonary edema and ventilation at low lung volumes can cause or worsen hypoxemia. Bidirectional kidney–lung cross-talk occurs in acute lung injury (ALI) and is deleterious for both organs. As previously mentioned, the renal medulla is sensitive to hypoxic injury and its presence results in activation of downstream inflammatory pathways and resultant AKI. Further, sympathetic overactivation, decreased cardiac output due to altered cardiopulmonary interaction, and release of proinflammatory mediators in ALI can affect renal vascular tone and renal cell viability (21).
AKI can necessitate several modifications in the management of MV. Higher airway pressure is required to maintain the same level of ventilation in the presence of pulmonary edema, pleural effusion, or total-body fluid overload. Airway mucosal edema can reduce effective airway diameter, predisposing to air trapping and intrinsic positive end-expiratory pressure, which can reduce venous return, further compromising cardiac function and increasing the risk of alveolar rupture. The management of ALI and acute respiratory distress syndrome (ARDS) using lung-protective ventilation strategies is made more difficult in the presence of metabolic acidosis, which increases ventilatory drive and worsens acidemia related to permissive hypercapnia. AKI has been reported to reduce ventilator-free days in cardiac surgery patients (22).
It is estimated that 8% to 10% of lung transplant patients who develop AKI require renal replacement therapy (23). Those with AKI following lung transplant surgery are noted to have reduced 5-year survival rates (30%) compared to patients without AKI (48.8%) (24). Patients with an episode of AKI are also at increased risk for chronic kidney disease and the risk appears to be similar irrespective of whether the patients had a complete or nonrecovery of the insult (25). AKI after lung transplantation is associated with longer duration of MV, increased hospital stay, and increased early mortality (26). As in other disease states, pre-existing renal disease also adversely affects clinical outcomes in this cohort. Those with pretransplant GFR less than 50 mL/min/1.73 m2 have been shown to have a twofold increased risk for adverse outcomes compared to those with GFR above 50 mL/min/1.73 m2 (27).
Effect on Neurobehavioral Function
Executive functions may be impaired in severe AKI due to accumulation of uremic toxins that impair cellular function. Although there is credible evidence for an association between functional and cognitive impairment and hyponatremia (28), the dose-response correlation of uremia with neurobehavioral changes in AKI are not available. This is confounded by the fact that although many solutes have been implicated, very few of them were actually investigated in clinical medicine for this purpose. Plasma concentrations of urea do not correlate with mental status changes (29), but several compounds including guanidine, uric acid, indoxyl sulfate, p-cresyl sulfate, IL-1-β, IL-6, TNF-α, and PTH appear to affect the cerebrorenal interaction (30). In dialysis patients, cognitive impairment is not uncommon and improves with dialysis therapy. In AKI, the effect of uremia, if any, is often complicated by concomitant metabolic derangements, medications, and underlying disease process. Although a trial and error approach to treatment is often utilized, causal relationship between them remains elusive in humans.
Effect on Drug Dosing
The pharmacokinetics of most drugs are altered in AKI; clearances of drugs are impaired, the half-lives are prolonged, or they accumulate in tissues and continue to exert their effects long after their administration. Some of the drugs are broken down into their metabolites with deleterious consequences; most of the drugs are not completely removable by dialysis due to their high protein binding. Many effective drug therapies cannot be used because of the risk of accumulation and toxicity; some drugs are removed by dialysis and require postdialysis supplementation. However, the varying clearances of the different continuous renal replacement therapies mandate the knowledge of the clearance of the particular modality used to effectively dose a particular drug. The minimum inhibitory concentration of antibiotics to treat severe infection may not be attained at their usual doses if the clearance of the drug is enhanced by renal replacement therapies and higher dosing regimens maybe required. Patients with acute or chronic kidney diseases, not on dialysis, also require careful consideration of drug dosing. The half-life of the drug, once-daily versus intermittent dosing regimens, bioavailability and volume of distribution between plasma and tissue compartments, acid–base dissociation constant of the drug, plasma protein binding, pharmacokinetics, and clearance are important considerations for drug dosing in these patients.
Implications of Altered Tubulointerstitial Function
Renal tubules are involved in electrolyte, acid–base, and fluid homeostasis and, therefore, alterations in their function may result in various disorders. Renal tubular dysfunction can be a consequence of medications, infections, crystalluria, rhabdomyolysis, acute and chronic inflammatory diseases, underlying diseases, and genetic causes. Alterations in tubular function in acute or chronic tubulointerstitial nephritis, for example, can be associated with imbalances of potassium, metabolic acidosis, and impaired urinary concentrating capacity. In critically ill patients, ischemia and non–ischemia-derived lactic acidosis can complicate chronic acidemia with resultant decrease in myocardial contractility, shift of oxyhemoglobin curve to the right, and interference of epinephrine binding to its receptor (31). An underlying renal tubular acidosis—for example, acquired or due to mutations in basolateral sodium bicarbonate cotransporter, NBCe1—may worsen after with treatment with ifosfamide or other medications that are toxic to the tubules. Nephrogenic diabetes insipidus is often due to acquired tubular structural damage, but may be complicated by mutations in the arginine vasopressin receptor 2 and vasopressin-sensitive water channel (aquaporin 2) gene that is associated with loss of water but normal conservation of sodium, potassium, chloride, and calcium. However, inactivating mutations in genes—SLC12A1, KCNJ1, CLCNKB, CLCNKA and CLCNKB in combination, or BSND—that encode the membrane proteins of the thick ascending limb of the loop of Henle have a complex polyuropolydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium, and treatment is difficult (32). Disturbances in sodium and potassium balance may also be due to loss—pseudohypoaldosteronism, Bartter and Gitelman syndromes—or gain of function gene mutations—Liddle syndrome (33). Careful attention to renal tubular functions is essential to avoid pitfalls in the critical care settings.
Effect of Acute Kidney Injury on the Progression to Chronic Kidney Disease
Several studies have advocated that AKI is a risk factor for progression to chronic kidney disease (CKD). In elderly patients, AKI without previous CKD, CKD without AKI, and AKI with CKD were associated with a 13-, 8.4-, and 41.2-fold increased risk for developing end-stage renal disease (ESRD) relative to those without kidney disease (34). Hematopoietic stem cell transplant patients who developed AKI within the first 100 days of stem cell transplant were reported to have an increased cumulative incidence of ESRD over time that reached 34% at 10 years (35). Additionally, dialysis requiring ARF was independently associated with a 28-fold increase in the risk of developing stage 4 or 5 CKD and more than a twofold increased risk of death (36). It however remains controversial whether an episode of AKI is itself responsible for the long-term poor prognosis rather than the progression of the underlying renal disease. Despite the notion of interconnectedness of the entities, the drivers of progression to CKD may include failed differentiation and atrophy during tubular regeneration and maybe independent of the processes that initiated them (37).
Clinical Outcomes Following Acute Kidney Injury
The outcome of AKI during a critical illness is of immense importance. The mean duration of inhospital AKI is 14 days. Most episodes resolve in the first month of evolution (38), and 11% of the patients require renal replacement therapy (39). However, the requirement for renal replacement therapy increases to over 70% when AKI is severe, that is, when associated with oliguria or severe azotemia (40,41). The usual ICU mortality approximates 5% without AKI, 23% with AKI, and over 60% with AKI requiring renal replacement therapy. Of the patients with AKI who expire, 78% do so within 2 weeks after the renal insult. The 90-day and 1-year survival of those who are discharged from the hospital are 64% and 50%, respectively (41). Interestingly, the ICU mortality of patients with ESRD is 11%, much lower than for AKI patients who do not need dialysis support (39). The increased mortality associated with the acute decline in renal function is not explained simply by loss of organ function. Recent data from a propensity-matched cohort study has shown that dialysis was associated with increased survival when initiated in patients with AKI who have a more elevated creatinine level (≥3.8 mg/dL) but was associated with increased mortality when initiated in patients with lower creatinine concentrations (42).
The recovery of renal function is influenced by many factors, including pre-existing chronic illness. In one review, only 41% of the patients were reported to be in good health 3 months before entry into the ICU (43); CKD has been reported in 30% of all patients admitted to the ICU (40,41,43). Most survivors of AKI recover renal function within 2 weeks, and 65% to 94% of them have independent renal function at discharge from the hospital (40,41,44). In 43.9 months of follow-up of patients from the Randomised Evaluation of Normal versus Augmented Levels of RRT (RENAL) study, patients with AKI had high long-term mortality (62% to 63%), but few required maintenance dialysis (5.1% to 5.8%) (5).
CHRONICALLY ALTERED RENAL PHYSIOLOGY
Chronic Kidney Disease
The injured kidney can repair itself and regain its structural and functional integrity quickly if the damage is mild. However with severe injury, parenchymal injury may lead to tissue fibrosis and progression to CKD. AKI increases the risk for ESRD; it has been postulated that the surviving renal tubular epithelial cells may have a role in fibrosis due to failure of differentiation and persistently high signaling activity that drives downstream events in the interstitium: inflammation, capillary rarefaction, and fibroblast proliferation (37).
Epidemiology of Chronic Kidney Disease
An increasingly elderly population with pre-existing renal dysfunction is treated in the ICU. The presence of CKD on admission to the ICU is associated with an increase in long-term mortality in survivors of AKI. Furthermore, recovery from AKI is often accompanied by residual renal dysfunction and the perils associated with CKD, which affects 10% of the US population (45).
In 2011, 113,136 patients in the United States started treatment for ESRD. The number of new cases of ESRD in people with diabetes or high blood pressure declined by about 2% in 2011 compared with 2010—the first decrease in more than 30 years; the projected ESRD incident count through 2020 is 150,722 patients, with a projected prevalent count of 784,613 (46). One reason for the discrepancy between the size of the CKD pool and the incidence of ESRD may be the premature cardiovascular death in many patients before progression to renal end stage. An independent, graded association was observed in a large, community based-population between reduced estimated GFR and the risk of death, cardiovascular events, and hospitalization (47). The 5-year mortality of patients with CKD stages 2, 3, and 4 are 19.5%, 24.3%, and 45.7%, respectively; 1.1%, 1.3%, and 19.9% progress to renal replacement therapy, respectively (48). The above data underscore the impact of pre-existing organ dysfunction on the prognosis of critically ill patients.
Chronic Kidney Disease as A Final Common Pathway
The U.S. National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative classification of CKD (Table 16.2) facilitates the development of appropriate management plans but does not provide information on the future risk of decline in renal function. Once renal damage reaches a certain threshold, the progression of renal damage is consistent, irreversible, and independent of initial insult. The characteristic histologic findings of tubular atrophy, interstitial fibrosis, and glomerulosclerosis in CKD of diverse causes suggest that multifactorial and complex interactions between numerous pathways of cellular damage by both cellular and humoral pathways contribute to their progression to a common final pathway. Brief overviews of the proposed mechanisms that are involved in the progression of CKD are provided in the following paragraphs.
| TABLE 16.2 Definition and Classification of Chronic Kidney Disease (CKD) | ||
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