28: Renal Principles

The kidneys lie in the paravertebral grooves at the level of the T12 to L3 ­vertebrae. The medial margin of each is concave, whereas the lateral margins are convex, giving the organ a bean-shaped appearance. In the adult, each kidney measures 10 to 12 cm in length, 5 to 7.5 cm in width, and 2.5 to 3.0 cm in thickness. In an adult man, each kidney weighs 125 to 170 g; in an adult woman, each kidney weighs 115 to 155 g.

On the medial surface of the kidney is the hilum, through which the renal artery, vein, renal pelvis, a nerve plexus, and lymphatics pass. On the convex surface, the kidney is surrounded by a fibrous capsule, which protects it, and a fatty capsule with a fibroareolar capsule called the renal fascia, which offers further protection and serves to anchor it in place.

The arterial supply begins with the renal arteries, which are direct branches of the aorta. On entering the hilum, the arteries subdivide into branches supplying the five major segments of each kidney: the apical pole, the anterosuperior segment, the anteroinferior segment, the posterior segment, and the inferior pole. These arteries subsequently divide within each segment to become lobar arteries. In turn, these vessels give rise to arcuate arteries that diverge into the sharply branching interlobular arteries, which directly supply the glomerular tufts.

The cut surface of the kidney reveals a pale outer rim and a dark inner region corresponding to the cortex and medulla, respectively. The cortex is 1 cm thick and surrounds the base of each medullary pyramid. The medulla consists of between 8 and 18 cone-shaped areas called medullary pyramids; the apex of each area forms a papilla containing the ends of the collecting ducts. Urine empties from each papilla into a calyx and the calyces join together to form the renal pelvis. Urine is drained from the pelvis into the ureters, and, subsequently, into the urinary bladder.

The kidneys serve three major functions: (1) homeostasis of fluids, acid-base balance, and electrolytes, (2) excretion of nitrogen, as urea, and other waste products, and (3) endocrine production (eg, 1,25-dihydroxy vitamin D, renin, erythropoietin).

The kidneys maintain the constancy of the extracellular fluid by creating an ultrafiltrate of the plasma that is virtually free of cells and larger macromolecules, and then processing that filtrate, reclaiming what the body needs and letting the rest escape as urine. Every 24 hours, an adult’s glomeruli filter nearly 180 L of water (total body water is ∼ 25–60 L) and 25,000 mEq of sodium (total body Na⁺ content is 1200–2800 mEq). Under normal circumstances, the kidneys regulate salt and water excretion, depending on intake and extrarenal losses. Approximately 1% of the filtered water and 0.5% to 1% of the filtered Na⁺ are excreted.

Renal function begins with filtration at the glomerulus, a highly permeable capillary network connecting two arterioles in series. The relative constriction or dilation of these vessels normally controls the glomerular filtration rate (GFR). Under healthy circumstances, the filtration fraction, the proportion of renal plasma that is filtered, is approximately 20%. Plasma water crosses the filter, along with electrolytes, small solutes such as glucose, amino acids, lactate, and urea; blood cells and most of the larger proteins, including albumin and globulins do not typically cross the filter, although recent observations suggest that more plasma proteins than previously thought are filtered and reclaimed by the proximal tubule. The filtrate then enters the tubules, the serial segments of which have varying roles to metabolize, reabsorb, and secrete various solutes.

The proximal tubule performs the bulk of reabsorption, isotonically reclaiming 65% to 70% of the filtrate. Distal to the proximal tubule is the loop of Henle, which controls concentration and dilution of the urine and plays an important role in the balance of Na⁺, Ca²⁺ and Mg²⁺. The distal convoluted tubules also reabsorb Na⁺ and Ca²⁺ and are joined by the connecting tubules to form the collecting ducts, which do the fine-tuning in the balance between excretion and reclamation of water, urea, K⁺, and H⁺. Paracellular reabsorption of sodium is controlled proximally by hydrostatic and oncotic pressures between the peritubular capillaries and the tubule while transcellular reabsorption is stimulated by angiotensin II. In the distal tubule, hormones such as aldosterone, and a variety of kinases control sodium transport. Control of water balance, dilution, and concentration depends first on function of the ascending limb of the loop of Henle, which absorbs solute without water. This produces a dilute tubular fluid and at the same time makes the medullary interstitium hypertonic. Final regulation of water reabsorption is related to the concentration of antidiuretic hormone (ADH; or vasopressin), which moves water-reabsorbing channels (aquaporins) into the membranes of the collecting ducts. The kidneys also regulate the balance of potassium and hydrogen ions (which are influenced by the effect of aldosterone on the distal nephron), and calcium and phosphate via circulating parathyroid hormone, activated vitamin D, and fibroblast growth factor 23.

Xenobiotics may affect kidney function in various ways and, conversely, renal disease may influence drug pharmacokinetics and lead to dangerous underdosing or overdosing. In the latter case, renal failure, whether acute or chronic, reduces the clearance of drugs eliminated by the kidneys. This may lead to drug accumulation and potential toxicity. The ideal dosing of drugs such as gabapentin, digoxin, baclofen, and vancomycin can vary several fold in patients with kidney failure compared to those with intact renal function. Some non-therapeutic xenobiotics may be potentially toxic in patients with kidney impairment while being relatively benign in patients with normal GFR. This is the case for gadolinium-based contrast used for magnetic resonance imaging, which carries the risk of nephrogenic systemic fibrosis.⁴⁶

Drug dosing in patients dependent on hemodialysis or peritoneal dialysis further complicates pharmacokinetics; in particular, the behavior of many antimicrobials can be severely altered in critically ill patients with kidney failure, whether acute or chronic. In this setting, the risk of underdosing with subsequent therapeutic failure and breakthrough resistance acquired by microorganisms may surpass that of drug accumulation. A notable example is fluconazole: the required dosage in patients undergoing continuous renal replacement therapy may surpass drug requirement in patients with intact renal function.⁵¹ For those drugs of which a substantial fraction is removed by hemodialysis, drug dosing after dialysis is often ­recommended. The use of therapeutic guides is encouraged to ensure proper drug prescription in patients with a history of kidney disease.³

Many xenobiotics cause or aggravate renal dysfunction. The ­kidneys are particularly susceptible to toxic injury for four reasons²⁶: (1) they receive 20% to 25% of cardiac output, yet make up less than 1% of total body mass implying a relatively large exposure to circulating xenobiotics, (2) they are metabolically active, and thus vulnerable to xenobiotics that disrupt metabolism or are activated by metabolism, such as acetaminophen (APAP), (3) they remove water from the filtrate which increases tubular concentration of xenobiotics, and (4) the glomeruli and interstitium are susceptible to attack by the immune system. Many factors, such as renal perfusion, can affect an individual’s reaction to a particular nephrotoxin.⁴ Clinicians should be aware of these factors and, when possible, alter them to minimize the adverse effect after a toxic exposure.

Xenobiotics can affect any part of the nephron (Fig. 28–1), although not every type of toxic renal exposure will result in loss of GFR. The following will be described: (1) acute kidney injury, (2) chronic kidney ­disease, and (3) functional kidney disorders.

Acute Kidney Injury

Acute kidney injury (AKI; formerly called “acute renal failure”) relates to an abrupt decline in renal function that impairs the capacity of the kidney to maintain metabolic balance.

Several recent definitions of AKI have now been proposed, although they will likely be revised with the advent of newer and more specific biomarkers of kidney injury. The Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines introduced staging criteria for AKI, based on prior work from Acute Dialysis Quality Initiative (ADQI) and Acute Kidney Injury Network (AKIN) (Table 28–1).

The three main categories of acute kidney injury are prerenal, postrenal, and intrinsic AKI.

Prerenal AKI.

Prerenal AKI implies impaired renal perfusion, which can occur with volume depletion, systemic vasodilation, heart failure, or preglomerular vasoconstriction. Renal hypoperfusion initiates a sequence of events leading to renal salt and water reabsorption.⁴ Renin is released, causing production of angiotensin II, which enhances proximal tubular sodium reabsorption and stimulates adrenal aldosterone release, thus increasing distal sodium reabsorption. Therefore, prerenal AKI is usually accompanied by low urinary sodium excretion. Release of ADH increases water and urea retention. Histologically, the kidney appears normal. However, recent data showing elevated urinary content of molecules thought to represent kidney injury suggest a less benign course.

Any toxic exposure that compromises renal perfusion may contribute to prerenal AKI including bleeding (eg, overdose of anticoagulants), volume depletion (diuretics, cathartics, or emetics), cardiac dysfunction (β-adrenergic antagonists), or hypotension from any cause can lead to acute prerenal AKI.⁹ Nonsteroidal antiinflammatory drugs (NSAIDs) lower filtration rate by inhibiting production of vasodilatory prostaglandins in the afferent arteriole. Finally, cardiotoxins, such as doxorubicin, can cause severe heart failure (Fig. 28–1). Calcineurin inhibitors (cyclosporine, tacrolimus) may cause prerenal vasoconstriction by their effect on both afferent and efferent arterioles, possibly induced by endothelin. Calcineurin nephrotoxicity is usually dose-dependent and especially occurs when trough concentrations remain supratherapeutic for an extended period of time. Nephrotoxicity is often reversible after temporary discontinuation or decrease in the calcineurin dose if identified relatively quickly.

Prerenal AKI can also be caused by the hepatorenal syndrome, which is characterized by progressive renal hypoperfusion in the context of severe acute or chronic liver failure, marked constriction of the renal arterial vasculature and systemic hypotension. Circulating mediators of vasoconstriction that are subsequently increased include angiotensin, norepinephrine, vasopressin, endothelin, and isoprostane F₂ all contribute to an extreme cortical vasoconstriction. That the cause of AKI is extrarenal is best illustrated by the fact that when a kidney from a patient with hepatorenal syndrome is transplanted into a uremic patient, the function of the graft promptly returns to normal.

Finally, the entity known as the abdominal compartment syndrome is becoming increasingly recognized as a potential cause of renal hypoperfusion.Abdominal compartment syndrome is usually defined as new organ dysfunction induced by intraabdominal hypertension. Abdominal compartment syndrome may be observed when the intraabdominal pressure exceeds 20 mm Hg, especially if sustained. This abdominal hypertension may then induce renal artery vasoconstriction and impede venous drainage. Abdominal compartment syndrome can be caused by several entities, but usually requires some abdominal event, especially with concomitant aggressive fluid resuscitation. Surgical decompression is life-saving in this context.

Renal AKI.

Renal AKI implies intrinsic damage to the renal parenchyma, which can be divided into vascular, glomerular, and tubulointerstitial etiologies.

Vascular etiologies of AKI includes vasculitis, malignant hypertension, atheroemboli, scleroderma, and hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura (HUS/TTP), the latter of which can sometimes be associated with use of certain xenobiotics (Table 28–2).

Glomerular diseases infrequently cause acute AKI, but more commonly either chronic or subacute decline in kidney function. Glomerular lesions can present with the nephrotic or nephritic syndrome. A nephritic pattern is associated with histological inflammation, an active urine sediment with proteinuria and hematuria, and impaired kidney function. Hypertension is common. Nephrotic syndrome is characterized by massive proteinuria (>3.5 g/day), hypoalbuminemia, hyperlipidemia, and pitting pedal edema that usually prompts the patient to seek medical attention. Although the relationships among these findings are not completely understood, the underlying event is injury to the glomerular barrier that normally prevents macromolecules from passing from the capillary lumen into the urinary space. Xenobiotics induce nephrotic syndrome (Table 28–3) in two ways. First, they may release hidden antigens into the blood, which leads to antigen–antibody complex formation after the immune response is elicited. These complexes subsequently deposit in the glomerular basement membrane, thereby changing its properties (eg, gold)¹⁶ (Fig. 28–2). Second, they can upset the immunoregulatory balance.

Kidney biopsy will permit identification of the characteristic pathologic pattern, either minimal glomerular change disease, membranous glomerulopathy, or focal segmental glomerulosclerosis. Hypoalbuminemia usually is worse than urinary excretion of albumin would suggest, as a result of renal tubular catabolism of filtered protein. The tubules also retain sodium, causing expansion of the extracellular space and edema. The glomerular lesion may progress to end-stage renal disease (ESRD) if the pathologic process continues.

The major causes of acute tubulointerstitial diseases include acute ­tubular necrosis (ATN), acute interstitial nephritis (AIN), and tumor lysis syndrome. Although there is controversy about how a tubular lesion leads to glomerular shutdown, it is generally felt that tubular obstruction, back-leak of filtrate across injured epithelium, renal hypoperfusion, and decreased glomerular filtering surface combine to impair glomerular filtration.⁴⁴ Additionally, filtration pressure is diminished by neutrophil infiltration into the interstitium and vasa recta.⁴⁸ Evidence also suggests that prolonged medullary ischemia, perhaps caused by an imbalance in the production of vasoconstrictors such as endothelin and vasodilators such as nitric oxide, is important in prolonging the renal dysfunction after the tubular injury develops.²³

ATN is the most common cause of AKI in hospitalized patients (Table 28–4).²⁷ ATN is manifested pathologically by patchy necrosis of the tubular epithelium and occlusion of the lumen by casts and cellular debris (Fig. 28–3). Clinically, ATN presents as a rapid deterioration of renal function. Muddy brown casts or renal tubular cells may be seen in the ­urinary sediment, but hematuria and leukocyturia are unusual. Disorders of metabolic balance, such as hyperkalemia and metabolic acidosis, are also common. The abrupt fall in GFR usually leads to positive sodium and water balance.³⁰

ATN occurs following an ischemic or toxic injury.³⁵ Direct toxicity accounts for approximately 35% of all cases of ATN.⁴⁵ Xenobiotics can affect different segments of the renal tubules; for example, uranium attacks the proximal tubule and amphotericin the distal tubule⁴⁰ (Fig. 28–1). Certain xenobiotics cause a sudden or progressive decrease in GFR with concomitant prominent tubular wasting for electrolytes, though mechanisms of injury vary; this is the case of ifosfamide,¹⁷ amphotericin B,⁴⁰ aminoglycosides,³⁹ pentamidine,²⁹ and cisplatin.² Poisoning may also lead to ischemic tubular necrosis if hypotension or cardiac failure causes prolonged ischemia of nephron segments (proximal straight tubule and inner medullary collecting duct) that are particularly vulnerable to hypoxia. Patients who receive significant amounts of colloids (specifically mannitol, dextran, or hydroxyethyl starch)¹⁴ can occasionally develop AKI, characterized by tubular vacuolization or “osmotic nephrosis.” Iodinated contrast can cause AKI by mediating medullary vasoconstriction and inducing reactive oxygen species in tubules. Whatever the clinical pattern of rapidly declining renal function, all forms of ATN usually present with oliguria. Aminoglycosides are one exception: kidney failure, which may appear after several days of exposure, is nonoliguric.²⁵

Pigmenturia (myoglobinuria following rhabdomyolysis or hemoglobinuria from massive hemolysis) may also cause tubular injury and necrosis by precipitating in the tubular lumen.^11,35 Myoglobin is normally excreted without causing toxicity. A study of patients with rhabdomyolysis suggests that the concentration of myoglobin in the urine may affect the development of AKI.¹¹ If myoglobin inspissates in the tubular lumen because of renal hypoperfusion and high urinary concentration, it dissociates in the relatively acidic environment as H⁺ is secreted, releasing tubulotoxic hematin. This toxicity may stem from the iron-catalyzing production of oxygen free radicals.

Rhabdomyolysis is most often caused by direct muscle injury following trauma or prolonged immobilization (Table 28–5). Any poisoning causing extended unconsciousness (eg, opioids and sedative-hypnotics), hyperthermia (neuroleptic malignant syndrome), excessive muscle contraction (cocaine, amphetamines),^24,33 or tonic-clonic seizures (alcohol withdrawal, theophylline, isoniazid) may therefore lead to muscle breakdown.¹³ Other xenobiotics are directly myotoxic in some individuals, such as ­alcohol,²⁰ HMG-CoA reductase inhibitors (statins),¹⁸ carbon monoxide, copper sulfate, and zinc phosphate.^28,50 Rhabdomyolysis can also occur after extensive bee or wasp stings¹⁹ or fire ant bites.²² Hypokalemia and hypophosphatemia (which may follow diuretics and laxatives abuse) can also induce rhabdomyolysis.

Hemoglobinuria follows hemolysis, which can be caused by a number of xenobiotics, including snake and spider venoms, cresol, dapsone, phenol, aniline, arsine, stibine, naphthalene, dichromate, and methylene chloride. Sensitivity reactions to drugs (hydralazine, quinine) can also cause hemolysis.²¹ The pathophysiology of hemoglobinuric ATN resembles that of myoglobinuria. The pigment deposits in the tubules and dissociates, causing necrosis to occur.³⁵ Volume depletion and acidosis precipitate the disorder; therefore, volume expansion and alkalinization may help prevent kidney injury.

Differentiation of ATN and prerenal AKI may be difficult clinically especially in critically ill patients; Table 28–6 illustrates empiric criteria to separate them, although there are numerous exceptions to these. These exceptions should always be considered and correlated with clinical status. For example, fractional sodium excretion (the proportion of filtered sodium that appears in the urine, FE_Na) can be paradoxically high in prerenal AKI associated with metabolic alkalosis, diuretics, or adrenal insufficiency (Table 28–7). FE_Na can also be low in renal AKI secondary to rhabdomyolysis or contrast-induced AKI. Furthermore, distinction between both entities is difficult when there is exposure to xenobiotics capable of affecting the kidneys in various ways. NSAIDs, for example, can cause prerenal AKI, ATN, acute interstitial nephritis, analgesic nephropathy, or membranous nephropathy.

The other major tubulointerstitial cause of AKI is AIN (Table 28–8), which is characteristically distinguished from ATN by a dense cellular infiltrate separating tubular structures on renal biopsy (Fig. 28–4). Nearly all cases of acute interstitial nephritis are caused by hypersensitivity.⁴⁷ The diagnosis may be clear and kidney biopsy not necessary if kidney failure follows exposure to culpable drugs and is accompanied by classic manifestations of systemic allergy such as fever, rash, or eosinophilia, although only 10% of patients typically present with this classic triad.⁵ Flank pain or arthralgia may also be present. Unlike those with ATN, most patients with AIN have hematuria and leukocyturia,¹ particularly eosinophiluria, which is specific to this disorder.³⁴ The development of AIN is not dose-dependent and usually improves after cessation of the offending xenobiotic, although corticosteroids may hasten recovery in severe cases.

Tumor lysis syndrome also affects the tubulointerstitium and usually occurs following chemotherapy for large bulk tumors. The incidence of tumor lysis has decreased with better procedural hydration and premedication with allopurinol or rasburicase.

Postrenal AKI.

Postrenal AKI implies obstruction of urine flow anywhere from the renal pelvis to the urethra. Regardless of the cause of urinary tract obstruction, there are characteristic histologic and pathophysiologic alterations in the kidney: tubular dilation, predominantly in the distal tubule and collecting ducts, occurs initially and glomerular structure is preserved; subsequently dilation of the Bowman space occurs, and finally periglomerular fibrosis develops. Tubular function is impaired such that concentrating ability, potassium secretory function, and urinary acidification mechanisms are all altered.

Urinary tract obstruction should always be considered when the ­kidneys fail rapidly. Other risk factors include having a solitary kidney or a history of abdominal or genitourinary malignancy. Sudden anuria is a classical but rare feature of obstructive nephropathy; alternating phases of oliguria and polyuria are more common. Continued production of urine in the presence of obstruction leads to distension of the urinary tract above the blockage. Calyceal dilation is common. Obstruction of the bladder outlet or urethra may distend the bladder.

Obstruction may be caused by xenobiotics (Table 28–9). Most do so by impairing contraction of the bladder through anticholinergic action (atropine, antidepressants). Rarely, certain xenobiotics, particularly methysergide,⁴³ cause retroperitoneal fibrosis and ureteral constriction. Finally, a few xenobiotics lead to crystalluria and intratubular obstruction (eg, oxalosis in ethylene glycol poisoning³⁷). Sometimes the xenobiotic itself forms precipitates (sulfonamides, atazanavir, or methotrexate).^7,42,49

Patients who present with acutely deteriorating kidney function often represent a difficult diagnostic challenge. Not only are there three major etiologic categories, each category has several subdivisions; and more than one factor may be present. For example, a patient with an opioid overdose may have neurogenic hypotension (prerenal), together with muscle necrosis causing myoglobinuric renal failure (intrinsic renal), and opioid-induced urinary retention (postrenal). Because renal, prerenal, and postrenal processes are not mutually exclusive and require different interventions, all three should always be considered, even when one appears to be the most obvious cause of the kidney failure.

Chronic Kidney Disease

Chronic kidney disease (CKD) refers to a disease process of a minimum duration of 3 months that often causes progressive decline of renal function. There is usually a gradual rise in blood urea nitrogen (BUN) and serum creatinine concentration as the GFR falls; unless advanced, there are often no clinical manifestations other than hypertension and nocturia (indicating loss of urinary concentrating ability). Classification of various stages of CKD, presently endorsed by KDIGO, is presented in Table 28–10.

In industrialized countries, most of the cases of CKD are caused by diabetes, hypertension, or glomerulonephritis. Nevertheless, many xenobiotics are implicated as nephrotoxins in long-term exposures. The most common lesion of nephrotoxic CKD is chronic interstitial nephritis (Fig. 28–5), which involves destruction of tubules over a prolonged period,¹² with tubular atrophy, fibrosis, and a variable cellular infiltrate (Fig. 28–5), sometimes accompanied by papillary necrosis. This then leads to ureteral colic via papillary sloughing. Acute interstitial nephritis may progress to chronic interstitial nephritis, if exposure is prolonged.⁴¹ Analgesic nephropathy was a common etiology of CKD until certain analgesics (such as phenacetin) were discontinued.³⁶ Chronic interstitial nephritis presents with mild to moderate proteinuria that remains well under the nephrotic range. Unlike other chronic renal disorders, it is characterized by failure of the diseased tubules to adapt to the renal impairment, resulting in metabolic imbalances such as hyperchloremic metabolic acidosis, sodium wasting, and hyperkalemia early in the disease course.¹⁰ Injury to erythropoietin-secreting cells may produce a disproportionate anemia.

Functional Toxic Renal Disorders

Although most toxic renal injury results in decreased renal function, certain functional disorders can also upset systemic balance despite normal GFR in anatomically normal kidneys. Three examples are presented here: renal tubular acidosis (RTA), syndrome of inappropriate secretion of ADH (SIADH), and diabetes insipidus.

RTA is a loss of ability to reclaim the filtered bicarbonate (proximal type 2 RTA) or a decreased ability to secrete protons and generate new bicarbonate to replace that lost in buffering the daily acid load (distal type I RTA). In either case, there is a nonanion gap hyperchloremic metabolic acidosis (Chap. 19).

The primary defect in distal RTA (also called type 1 RTA) involves the decreased secretion of protons (H⁺) from the intercalated cells of the distal tubule. This defect is most frequently the result of a defect in the H⁺-translocating adenosine triphosphatase (ATPase) on the luminal surface of these cells. Less frequently occurring mechanisms include abnormalities of the chloride-bicarbonate exchanger, which is responsible for returning bicarbonate generated within the cell to the systemic circulation. Also, given the voltage dependence of proton secretion, a decrease in the luminal electronegative charge will cause a decrease in its secretion. Most of this voltage is created by the activity of the Na⁺-K⁺-ATPase on the peritubular capillary side of the adjacent cell. (Note: Cells adjacent to the intercalated cells are called principal cells and primarily control water absorption and K⁺­secretion.) As this pump malfunctions, less sodium is returned to the capillaries, creating a decreased gradient from the lumen to the cell. Thus, the lumen becomes more electropositive, diminishing the transmembrane potential. Amphotericin B and some analgesics can cause distal RTA by allowing secreted H⁺ to leak back into the tubular cells.⁶

The primary defect in proximal type 2 RTA is incompletely understood. Normally, the Na⁺-H⁺ exchanger in the luminal membrane, the Na⁺-K⁺-ATPase in the basolateral membrane, and the enzyme carbonic anhydrase are the key systems necessary for proximal tubular bicarbonate reabsorption. If one or more of these mechanisms becomes disordered, then the resorptive capacity of the proximal tubule is diminished. Proximal RTA often occurs as part of the Fanconi syndrome, a generalized failure of proximal tubular transport (proximal RTA plus amino­aciduria, glycosuria, and hyperphosphaturia). Xenobiotics associated with type 2 RTA include aminoglycosides, lead, ifosfamide, mercury, and acetazolamide.

What was once known as type 3 RTA is recognized to be a combination of features of both distal and proximal RTA and affects infants as part of an autosomal recessive syndrome. Type 4 RTA is caused by a deficiency of aldosterone or by tubular resistance to its action. It most often occurs in adult patients with both diabetes and CKD who have hyporeninemic hypoaldosteronism. Hyperkalemia is the most prominent electrolyte disturbance while the metabolic acidosis itself is usually mild.

SIADH occurs when the posterior pituitary gland or abnormal, unregulated sources such as lungs or tumors, secrete ADH despite the absence of physiological conditions that normally stimulate ADH secretion. The two usual stimuli for ADH release are elevated plasma osmolality and contraction of the effective arterial blood volume (eg, volume depletion, congestive heart failure, cirrhosis). ADH primarily affects the collecting tubule and causes increased water reabsorption by increasing the permeability of the collecting duct by causing movement of aquaporins from intracellular lysosomes to the apical membranes. The hormonal effect of ADH augments normal free water retention, which subsequently leads to the main clinical manifestations of SIADH, namely, inappropriately concentrated urine (as reflected in a failure to decrease urine osmolality to 50–100 mOsm/kg) and hyponatremia in the setting of euvolemia. Although this manifestation most often occurs as a complication of intracranial lesions or from ectopic ADH production by a tumor or a diseased lung, many xenobiotics (eg, carbamazepine, chlorpropamide, antidepressants, vincristine, opioids, methylenedioxymethamphetamine {MDMA or Ecstasy}) can also cause inappropriate ADH release (Chap. 19).

Diabetes insipidus (DI) is the inability of the kidneys to maximally ­concentrate the urine and retain water leading to inappropriate loss of urine. Its two causes are the absence of pituitary ADH secretion (central DI) or by the absence of an appropriate renal response to ADH stimulation (nephrogenic DI). DI will typically present with polyuria or hypernatremia if water intake is limited, in the presence of inappropriately dilute urine. Central DI can be due to autoimmune destruction of the pituitary or trauma but often is the result of a space-occupying lesion affecting the posterior hypophysis. NDI can be caused by a variety of factors, including genetic disorders, kidney failure, disease states, or electrolyte perturbations, but xenobiotics are often implicated. Lithium, demeclocycline, foscarnet, and clozapine are drugs that can cause this syndrome (Chap. 19). NDI from lithium toxicity is thought to result from impaired aquaporin-2 synthesis and transport despite normal ADH binding to vasopressin type 2 receptors at the basolateral membranes of the collecting ducts.³⁸

Evaluation of a patient with suspected toxic renal injury should include consideration of extrarenal as well as renal factors. The kidney’s response to xenobiotics is affected by baseline renal function, renal blood flow, and the presence of urinary tract obstruction, all of which must be considered.

History

A past history of renal disease or conditions that can affect the kidney (eg, diabetes, hypertension, cardiovascular disease, stones, urinary tract infection, prior chemotherapy) should be noted. Pertinent family history of kidney disease, glomerulopathy, kidney stones, and polycystic kidney disease needs to be recorded. Flank pain, hematuria, urine discoloration, or an abnormal pattern of urine output are important findings. Acute loss of kidney function may be suspected if urine output decreases, but oliguria is not universal. The patient’s intravascular volume status affects renal perfusion. Thus, a recent history of heart disease, vomiting, or diarrhea is important. Symptoms of kidney failure are usually only present when severe but include anorexia, nausea and vomiting, leg cramps, fatigue, edema, and mental status changes. Systemic symptoms such as arthralgias, weight loss, and fever may suggest vasculitis.

All current xenobiotics should be evaluated for potential renal effects.¹⁵ The patient’s intake of alcohol and drugs of abuse, as well intake of natural products and medicinal herbs, should be explored. A careful occupational history and assessment of hobbies and lifestyle are crucial, with emphasis on exposure to nephrotoxic xenobiotics.

Physical Examination

The patient’s hemodynamic status should be carefully assessed. Postural changes in pulse and blood pressure, and either engorgement or decreased filling of the neck veins, give important information about the intravascular volume. The skin should be examined for lesions. Funduscopy may reveal evidence of chronic hypertension or diabetes. All aspects of cardiac function should be noted, including presence or absence of edema. Bluish discoloration of toes can suggest recent cholesterol emboli. Injuries or scars in the suprapubic area or evidence of past urologic or retroperitoneal surgery may suggest obstruction, as may a palpable or percussible bladder.

Laboratory Evaluation

Although history and physical examination may suggest nephrotoxic injury, laboratory testing is indispensable to confirm the degree of renal dysfunction. The approach to a patient with renal disease usually combines both assessment of GFR and urinalysis. Both are noninvasive, inexpensive, and have considerable predictive value for patients with renal disease.

Because creatinine is freely filtered by the glomerulus and not significantly reabsorbed or metabolized in the tubule, serum creatinine concentration is used as the preeminent marker of overall kidney function; because a small proportion of total excreted creatinine in urine appears as the result of tubular secretion, creatinine clearance always overestimates GFR. As the kidneys fail, creatinine concentration increases. However, the relationship between its concentration and GFR is hyperbolic, not linear; therefore, a small initial elevation in serum concentration denotes a large decrease in kidney function. By the time the serum creatinine concentration exceeds the upper limit of normal, GFR is reduced by up to 50%. Furthermore, creatinine secretion becomes a significantly greater proportion of creatinine excretion as GFR fails. Renal hypoperfusion and prerenal states are associated with a disproportionate rise in urea in comparison with the rise in creatinine, because urea is partially reabsorbed in the proximal tubule along with salt and water. However, this often cited increase in the BUN–creatinine ratio may fail to occur in patients with chronic kidney disease, including the elderly. There are other limitations of their use as markers of renal injury; decreased production of urea (starvation or liver failure) or creatinine (amputation, muscle wasting) may result in a normal BUN or ­creatinine in the presence of significant renal impairment. Certain xenobiotics alter measured concentrations of urea and creatinine in the absence of any change in renal function.³² The most obvious is exogenous creatine taken to build muscle mass. Drugs that block renal creatinine secretion, such as cimetidine and trimethoprim, may also increase serum creatinine. BUN may be raised independently of renal function by corticosteroids (increased protein catabolism), tetracycline and by gastrointestinal bleeding due to digestion of hemoglobin.

Recently, more sensitive serum or urine markers of early AKI have been proposed, such as serum cystatin C, urinary kidney injury ­molecule-1, neutrophil gelatinase-associated lipocalin (NGAL), and N-acetyl-β-­glucosaminidase. Early studies suggest they may help discriminate between ATN and prerenal AKI although they are costly and unavailable in most centers. Renal function can also be estimated by nuclear medicine and inulin clearance but these tests are impractical.

In patients with stable chronic kidney disease, a more precise estimation of the glomerular filtration rate is available. The Cockroft-Gault formula and 24-hour urine collection for creatinine clearance are commonly used to assess renal function. More recently, the estimated GFR (eGFR) has been validated in several populations of kidney disease populations (Table 28–10). Using these measurements in AKI is not helpful, as the accuracy of the measurement of clearance implies a steady state. Changing GFR during a clearance time period distorts the resulting estimation. There is also a lag period between changes in kidney function and changes in BUN or creatinine concentrations. An extreme example would be a patient undergoing bilateral nephrectomy: although GFR immediately postoperatively equals 0 mL/min, the increase in serum creatinine will only be evident after a few hours. Any clearance calculation would yield an estimated GFR very different from true GFR. In general, a patient with AKI and rapidly changing creatinine concentration should be managed as if GFR were less than 10 mL/min until serum creatinine concentration ­stabilizes and GFR can more accurately be estimated. Estimation of GFR is most important in prescribing drugs. Since much of the relevant pharmacology literature predates the current equations used to estimate GFR, many recommendations for drug dosing are still based on the Cockcroft-Gault formula, which estimates creatinine clearance.

Most patients presenting with AKI should have their urine examined. Standard automated dipsticks will detect albumin and glucose. The presence of a positive dipstick for blood when the urine contains no or few RBCs suggests either rhabdomyolysis or hemolysis. A simple urine spot test may help discriminate prerenal azotemia from ATN (Table 28–6); this is suggested by a fractional sodium excretion below 1% and urine osmolality above 400 mOsm/kg. Direct microscopic examination of the urine sediment also provides useful clues. Dysmorphic red cells suggest glomerular hematuria but are neither sensitive nor specific. If acute interstitial nephritis is a consideration, a fresh urine sample should be stained for eosinophils.³¹ Crystalluria may suggest an obstructive cause to AKI and may reveal exposure to xenobiotics such as ethylene glycol.

Measurement of postvoiding residual urine volume, preferably by suprapubic ultrasonography or by passage of a urinary catheter with complete bladder emptying, can demonstrate lower urinary tract obstruction; if the volume is in excess of 75 to 100 mL, then bladder dysfunction or obstruction should be suspected. Among the many radiologic studies used in patients with kidney diseases, renal ultrasonography is the most useful and is indicated in all patients with AKI or CKD of unknown etiology; postrenal AKI is suggested by obstruction of the urinary tree, characteristically by swelling of one or two kidneys (hydronephrosis). Asymmetry between kidney diameters may suggest vascular stenosis. Cortex thinning and poorly differentiated corticomedullary junction are consistent with long-standing kidney failure of any etiology. When the etiology of kidney disease remains elusive, a percutaneous renal biopsy can establish the final diagnosis. Table 28–11 summarizes the nephrotoxic effect of various metals to demonstrate some of the complexities of the issue.

• The kidneys are exposed to exogenous or endogenous xenobiotics in their role as primary defenders against harmful xenobiotics entering the bloodstream.

• The environment, the workplace, and, especially, the administration of medications represent potential sources of nephrotoxicity. Consequently, it is important to determine, by history and observation, to which xenobiotics a patient may have been exposed and to be aware of their potential to harm the kidneys.

• It is equally crucial to work the other way when a patient presents with renal dysfunction: review all xenobiotics, both conventional and complementary, all xenobiotic exposures, and any conditions that can adversely affect the kidneys.

Acknowledgment

Donald A. Feinfeld, MD (deceased), Nikolas B. Harbord, MD, and Vincent L. Anthony, MD, contributed to this chapter in previous editions.

References