PATHOPHYSIOLOGY of the RENAL BIOPSY www.jasn.org

Acute Tubular Necrosis Is a Syndrome of Physiologic and Pathologic Dissociation

Seymour Rosen* and Isaac E. Stillman†

*Department of Pathology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts; and †Department of Pathology and Renal Division, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts

ABSTRACT Acute tubular necrosis (ATN) is a syndrome of intrinsic renal failure secondary to edema and mononuclear inflammation ischemic or toxic insults. The histopathologic findings of ATN are inconstant. When (Figure 1A). Casts, pigmented or other- present, they are limited to the tubulo-interstitium and often subtle despite pro- wise, were inconspicuous. SCr peaked at found dysfunction. Experimental models of ATN in healthy animals commonly use 8.5 mg/dl and on day 4 he spontaneously single insults that result in extensive injury, circumstances that do not parallel the converted to a nonoliguric state. The pa- human situation. Recently, there has been a shift to more clinically relevant models tient never required dialysis, was dis- using an acute insult superimposed on predisposing factors. This review discusses charged (SCr 5.2 mg/dl), and did not re- the complex hemodynamic interrelationships of hypoxia, tubular injury, and altered turn for follow-up. glomerular filtration, suggesting new ways to understand the pathophysiology of ATN. RENAL INJURY OF ATN J Am Soc Nephrol 19: 871–875, 2008. doi: 10.1681/ASN.2007080913 Background In the past, acute renal failure was often The syndrome of acute renal failure overt tubular necrosis will be juxtaposed, trauma related, and both World Wars (ARF) is common, particularly in hospi- as we focus on the complex interrelation- were stimuli to identify and investigate talized patients. Its two most frequent ships of hypoxia, altered intrarenal mi- this condition. Most studies were au- causes are prerenal failure, reflecting re- crocirculation, tubular injury, and di- topsy based and, thus, inherently limited. nal adaptation to volume depletion, minished glomerular filtration rate The modern era of investigation began without parenchymal injury, and what (GFR) in an attempt to understand the with the widespread adoption of the re- has been historically known as acute tu- dissociation between function and struc- nal biopsy and the study of non–trauma- bular necrosis (ATN). By this we mean a ture seen in ATN. related acute renal failure. Brun and clinicopathologic syndrome of intrinsic Munk were one of the first to note the acute renal injury that is secondary to contrast between the limited pathologic ischemic or toxic insults. As we will see, CASE REPORT changes seen on biopsy and the pro- necrosis is not a defining feature of this found acute renal failure.1 Autopsy stud- entity and the recent proposal to substi- A 25-yr-old man presented with malaise ies also documented subtle changes, par- tute the term “acute tubular injury” 3 to 4 d following cocaine use. On admis- ticularly involving the distal . (ATI) reflects this reality. In this article, sion, the patient was found to be volume- Some correlations were found, such as an we will use the terms interchangeably. depleted and in oliguric ARF (SCr 3.2 Furthermore, these two entities are re- mg/dl). Other laboratory values included lated pathogenetically. We will present a a CPK of 304 (CK-MB and troponin in Published online ahead of print. Publication date case that exemplifies the most common normal range) and a positive urine toxi- available at www.jasn.org. histopathologic findings in ATN (lim- cology screen for cocaine. The patient Correspondence: Dr. Isaac E. Stillman, Department ited tubular alterations) and highlights was volume expanded without improve- of Pathology, Beth Israel Deaconess Medical Cen- ter, 330 Brookline Avenue, Boston, MA 02215. the paradox that typically characterizes ment and underwent biopsy on day 2 Phone: 617-667-4344; Fax: 617-667-7120; E-mail: this entity: profound renal failure with- (SCr 7.4 mg/dl). Relevant biopsy find- [email protected] out a morphologic equivalent (ATN ings were limited to some brush border Copyright ᮊ 2008 by the American Society of without any “N”). An unusual case of diminishment and mild interstitial

J Am Soc Nephrol 19: 871–875, 2008 ISSN : 1046-6673/1905-871 871 PATHOPHYSIOLOGY of the RENAL BIOPSY www.jasn.org

Figure 1. Renal findings in acute renal failure. (A) Renal biopsy in a case of ATN following cocaine. Cortical tubules are dilated, with some diminishment of their brush border, but no necrosis is noted (periodic acid-Schiff). (B) Renal autopsy findings of a different patient, 13 d following cardiac arrest. Proximal tubules are lined by flattened regenerating epithelium; their lumens contain necrotic cellular debris (hematoxylin and eosin). (C) Immunoperoxidase for cytokeratins (AE1/AE3; CAM 5.2) highlights the attenuated proximal tubular epithelium, which contrasts with the smaller intact distal tubules that show intense staining. A-C: original magnification, ϫ200. inverse relationship between distal tubu- and mild. Indeed, recent proposals to emia and nephrotoxins is simplistic. lar necrosis and urine volume.2 update the nomenclature reflect this. Some nephrotoxins (cyclosporine and A more recent biopsy study con- The term acute injury (AKI) has amphotericin) might be more accurately firmed the limited nature of the findings been suggested in place of acute renal considered hypoxia-inducing agents, as and identified two tubular lesions signif- failure, reflecting the spectrum of declin- they diminish renal perfusion, causing icantly less severe in recovering versus ing GFR short of total “failure.” Simi- injury to zones (medullary ray and inner sustained ATN: single cell necrosis and larly, given the variable degree of necro- stripe) known to have limited oxygen brush border loss.3 The presence of nu- sis in ATN, the replacement term acute availability.10 Furthermore, the hypoxia- cleated cells within the vasa recta (possi- tubular “injury” may indeed be more ap- mediated renal injury induced by some bly representing hematopoiesis or hom- propriate. nephrotoxins (amphotericin, heme pig- ing mesenchymal cells) has been ments, and possibly radiocontrast regarded as a characteristic feature.4 Ul- Failure of Animal Models agents) is likely also associated with di- trastructural studies confirmed only lim- Although human ATN has a multifacto- rect tubulotoxicity. ited tubular injury, finding little necrosis rial basis, for the purposes of research Most cases of ATN occur in patients and observing discrete cell loss mostly af- and conceptualization, etiological agents with predisposing comorbidities, in fecting the (pars recta), have been grouped into two major cate- sharp contrast to the healthy animals collecting duct and the medullary thick gories: and nephrotoxins.8 An- used in most models of ATN. Conse- ascending limb (mTAL).5 Biopsies of imal models have been developed using quently, intense insults, such as pro- ATN in the transplant setting have both ischemia (primarily warm ischemia longed ischemia or mega-doses of neph- shown similar findings; that is, very lim- with reperfusion) and drugs. However, rotoxins, are required to achieve ited tubular necrosis, which often stands the insults used have been, for the most reproducible experimental renal failure, in sharp contrast to the marked and pro- part, too extreme, as evidenced by the ex- which in turn is associated with tubular longed acute renal failure.6 Another ex- tensive necrosis typically produced. pathology that is far more extensive than ample of structural and functional dys- Those models therefore have at best very is seen in humans. Unfortunately, such synchrony is seen in some cases (Type I) limited clinical, pathophysiologic, and animal studies have become the refer- of acute humoral rejection. Given the morphologic relevance to the human sit- ence point for analysis and interpreta- minimal histologic alterations, it is not uation.8 tion of human ATN. For example, the surprising that they are considered Indeed, many of the nephrotoxins model of renal artery obstruction with “ATN like.”7 which are directly tubulotoxic in animal subsequent reflow (warm ischemia In summary, the histopathologic studies (such as cisplatin, gentamicin, reperfusion) produces extensive necrosis findings of ATN are inconstant. When and ) produce minimal of proximal tubules, lesions far beyond present, they are essentially limited to the histologic changes in the human.9 Fur- what is typical for humans.11 Indeed, tubulo-interstitium, and often subtle thermore, the distinction between isch- multiple clinical trials, based on success-

872 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 871–875, 2008 www.jasn.org PATHOPHYSIOLOGY of the RENAL BIOPSY ful interventions in rats, have failed in al. have used high amplification HIF-1␣ prerenal failure. When they are over- humans.9 Gentamicin is an example in immunohistochemistry to study human whelmed, as in ATN, tubular dysfunc- which suprapharmacologic doses are allograft ATN. Elevated HIF-1␣ expres- tion, as reflected by diminished urine necessary to cause tubular necrosis and sion was seen in immediate graft func- concentrating capacity and sodium reab- renal failure in healthy animals.10 Its dis- tion, as opposed to the low levels noted in sorption, ensues. tinctive lesion (intracellular laminar my- primary nonfunction.16 Although coun- Furthermore, activation of tubulo- elin type whorls) shows no correlation terintuitive, these findings likely reflect glomerular feedback may alter glomeru- with renal in humans. However, higher renal oxygen tensions that are a lar hemodynamics and reduce filtration when combined with additional insults function of diminished tubular oxygen rate to an extent out of proportion to tu- (such as ischemia, volume depletion, ob- demand secondary to reduced GFR. bulointerstitial injury, hence reducing struction, or organ necrosis), animals do Taken together, these studies document tubular transport and improving medul- develop renal failure with clinically rele- acute renal failure with only limited lary oxygenation, a process Thurau and vant doses.10 The combination of other- morphologic alterations and suggest Boylan cleverly called acute renal suc- wise nontoxic doses of cisplatin and lipo- novel therapeutic approaches using cess.26 Recently developed noninvasive polysaccharides results in severe renal drugs that upregulate HIF and target techniques may help document the evo- failure and mortality in rats.12 Myoglo- genes, such as erythropoietin.17 These lution of these changes over time. BOLD bin per se is relatively nonrenotoxic un- strategies have been shown to both pro- (blood oxygen level detection) MRI less combined with other insults (vol- mote cell survival in isolated perfused studies based on the magnetic resonance ume depletion or prostaglandin kidneys18 and ameliorate renal failure af- of deoxyhemoglobin have demonstrated synthesis inhibition). Under those cir- ter warm-ischemia reflow.19 limited oxygen availability in the human cumstances, renal retention of the tubu- medulla as well as the expected increase lotoxic agent may increase, and casts may Dynamic Changes in Intrarenal in pO2 when transport activity is inhib- form, leading to intrarenal obstruction, Microcirculation ited by loop diuretics.27 BOLD MRI con- 13 another possible mechanism for ATN. Changes in renal microcirculation and firms diminished medullary pO2 in ani- Casts were inconspicuous in our biopsy, oxygenation are likely to occur following mal models of contrast nephropathy.28 and the CPK was not markedly elevated, use of prostaglandin inhibitors, radio- Interestingly, renal sodium MRI can de- suggesting that this mechanism was not contrast administration, or strenuous tect early loss of tubular function (di- relevant in our case. exercise, such as marathon running. minished sodium concentration gradi- In summary, with the possible excep- Compensatory mechanisms in healthy ent) in this model when there is still very tion of calcineurin inhibitors, there is lit- individuals maintain renal function. limited tubular injury.29 tle correlation between the histology ob- With increasing intensity of renal insults, The recent introduction of extended served in many animal studies of ATN and importantly, as they are multiplied, sepsis models more analogous to the hu- and the human situation.10 tubular injury develops, as has been doc- man situation (with the use of fluid re- umented by urinary detection of bi- suscitation, antibiotics, and inotropes), A New Approach omarkers such as cytokines (IL-6, IL-8, and the finding of primary toll-like re- It seems clear that an appropriate model IL-18),20,21 NGAL,22 NAG, and KIM-1.23 ceptors for Gram-negative toxins, such for ATN would be one of acute renal fail- Interestingly, IL-6 RNA was upregulated as TLR4 and their effector proteins, such ure accompanied by limited changes by in renal allograft donor biopsies after as MyD88, have also led to a deeper un- light microscopy, recapitulating the cold ischemia and reperfusion and was derstanding of acute renal failure in sep- physiologic and pathologic dissociation. correlated with longer cold ischemia sis.30 The minimal morphologic lesions Indeed, recent studies in the isolated per- times.24 present underscore their clinical rele- fused rat kidney and in in vivo models of Numerous studies over the past two vance. Indeed, studies of autopsies in pa- prostaglandin inhibitors and contrast decades have focused on the limited ox- tients with sepsis have found apoptotic nephropapthy seem to fit that goal, as in ygen availability (pO2) of the medulla, in changes primarily limited to the gastro- some protocols there is documented tis- both animals and humans.25 This “hy- intestinal tract and the spleen.30 There sue hypoxia and adaptive responses in poxic condition” is a function of both the seems to be agreement, certainly in ani- the setting of relatively intact tubular renal microanatomy that enables urinary mals and likely in humans, that both sys- morphology. Upregulation of hypoxia concentration and the energy demands temic and renal blood flow dynamics are inducible factors (HIF) with their multi- of tubular reabsorption. Multiple mech- severely altered in sepsis.30 ple cell survival target genes have been anisms, such as prostaglandins, nitric ox- localized to hypoxic cells. Experiments in ide, adenosine enable the preservation of Vasomotor Hypoxic Nephropathy 14 15 isolated perfused kidneys and in vivo pO2 by balancing regional oxygen supply As we have seen, the pathophysiologic illustrate that failure to generate HIF and with transport activity. When the insults basis for acute renal failure likely relates HIF-mediated responses is associated are limited, these adaptive responses pre- to alterations in renal blood flow and ox- with lethal tubular injury. Rosenberger et serve tubular function and integrity, as in ygenation. In our case, acute renal failure

J Am Soc Nephrol 19: 871–875, 2008 Acute Tubular “Necrosis” 873 PATHOPHYSIOLOGY of the RENAL BIOPSY www.jasn.org was secondary to the action of cocaine, all cases, efferent arteriolar perfusion is suf- in increased tubular oxygen demand, known to induce marked vasoconstric- ficient to maintain tubular integrity, as may be counterproductive unless ac- tion.31 Blood flow, sufficient to prevent demonstrated in our biopsy, and the re- companied by reconstitution of the peri- necrosis, but not enough to maintain duction in GFR may serve to preserve tu- tubular microcirculation/oxygenation. GFR, is the likely explanation for the pa- bular integrity by decreasing tubular trans- Important questions remain as to renchymal preservation. This is likely ac- port work and oxygen consumption. In the how this aberration of flow develops and complished by “corticomedullary blood contrasting autopsy case, there likely was a is maintained. Vascular tone is a function redistribution,” and tubuloglomerular period of no renal perfusion, a scenario of endothelial and smooth muscle cell in- feedback (diminishing filtration), lead- that is not typical of ATN. This extreme teraction. Endothelial cells release many ing to acute renal success, and preserving insult, as used in many animal models, led vasoactive factors, some potent vasodila- medullary pO2. Comparison of our case to a similar pattern of widespread tubular tors (such as nitric oxide, prostaglandin with another, showing the unusual find- necrosis. E2, and prostacyclin) and others vaso- ing of extensive tubular necrosis is useful Furthermore, it appears that tubular constrictors (such as endothelin, prosta- in exploring their differing pathophysi- segments respond differently to hypoxia. noids, and components of the renin-an- ologies. Proximal tubules normally reside in a high giotensin system). Some agents, such as

Case 2 was a 71-yr-old man with a pO2 region and have a more constant endothelin, angiotensin-II, and adeno- hospital course complicated by cardio- workload and therefore oxygen require- sine, have diverse effects on cortical va- pulmonary arrest with postresuscitation ment. Their injury, at least in warm isch- soconstriction and medullary microcir- hemodynamic instability, respiratory emia reflow, seems to be more related to culation vasodilation, depending on the compromise, and oliguric renal failure, diminished pO2 than increased demand. type and density of their various recep- requiring ventilation and dialysis until This is the type of injury evident in the ex- tors. Reactive oxygen species signaling his death 13 d later. Postmortem exami- tensive necrosis present at autopsy and may be relevant to the control of vascular nation of the kidneys revealed marked only minimally present in our biopsy case. dynamics. Elaborated by the mTAL and necrosis of proximal tubules with regen- Distal tubules, in contrast, reside in a hy- governing HIF-1 activation, reactive ox- erative changes. Distal tubules appeared poxic environment and their workload is ygen species are crucially poised to regu- spared (Figure 1, B and C). This case par- more variable, a function of the GFR and late or dysregulate vascular function and allels the warm ischemia reflow animal proximal solute reabsorption. mTAL in- integrity.32 Cytokines have also been sug- model (cardiac arrest followed by reper- jury thus reflects an imbalance between re- gested as early markers for ATN and are fusion) and indeed showed widespread gional pO2 and tubular oxygen demand known to have a profound effect on vas- tubular necrosis and regeneration at au- and can occur both initially, and during re- cular tone, both inducing the expression topsy, findings almost never seen in clin- covery from ATN, as filtration rate in- of cytokine receptors and other media- ical ATN. creases. Adaptive responses as discussed tors of vasoconstriction as well the ex- Inasmuch as tubular necrosis is not a above may limit these changes, a process pression of enzymes such as inducible necessary prerequisite for ATN, what these that may account for the tubular preserva- NO synthase and cyclooxygenase-2.33 two cases share is an important element of tion seen in our biopsy. In summary, the physiologic derange- hemodynamic dysregulation. This spec- ATN may therefore be understood as ments of ATN are far more striking than trum of changes is detailed in Table 1. How a (mal)adaptive response of the kidney- the morphologic changes that accom- then can we explain the difference in mor- trading away GFR for the preservation of pany them. Noninvasive techniques and phologic patterns? Parenchymal preserva- medullary pO2 and tubular integrity. If recently developed experimental models tion results when intrarenal blood flow so, the effect of therapeutic agents in have begun to unravel this paradox. dysregulation is associated with sufficient ATN may be more of a function of their pO2. Renal failure results when that flow ability to restore normal intrarenal he- does not maintain glomerular filtration modynamics and tubular integrity. In- ACKNOWLEDGMENTS and tubular function. However, in almost deed, restoration of GFR alone, resulting The authors thank John Conrey who graciously Table 1. Hypothetical schema of hemodynamic dysregulation in acute kidney supplied information on the biopsy case and injury Von Samedi who performed the postmortem Hemodynamic Total Cessation of examination on the contrasting case as well as Compensated Dysregulation State Blood Flow Samuel Heyman and Christian Rosenberger for reviewing this manuscript and collaborating on Clinical scenario Prerenal Acute tubular necrosis Vascular catastrophe Tubular injury 0 Rare-1, focal 111 many related studies, and Mayer Brezis who Biomarkers 0-limited 1-11 111 helped form the foundation for these ideas. Fi- GFR 2-22 2-222 222-0 nally, we all owe Franklin Epstein special recog- Clinical frequency Common Less common Rare nition as a pioneer in this field, and gratitude for 1, increase; 2, decrease. being our mentor.

874 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 871–875, 2008 www.jasn.org PATHOPHYSIOLOGY of the RENAL BIOPSY

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