[contributions to nephrology] nephrology grand rounds. clinical issues in nephrology volume 124 ||...

HABE:L01:ZNEPH328XA.70 FF: W1FP E1: CN12 $$$ ((W1: Bund + Kopf: 5 Cic.; Z1: Bund 5 Cic. / Kopf 6 Cic.)) 1.10.1998

Ritz E, Zeier M (eds): Nephrology Grand Rounds. Clinical Issues in Nephrology.Contrib Nephrol. Basel, Karger, 1998, vol 124, pp 43–63

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Pathogenesis of Acute Renal Failure:New Aspects1

H. Andreas Bock

Division of Nephrology, Kantonsspital, Basel, Switzerland

Key Words. Acute renal failure W Tubular obstruction W Glomerular hemodynamics W

Growth factors W Endothelin receptor antagonists W Atriopeptin W Cast nephropathy W

Myeloma W Angiotensin-converting enzyme inhibitors W Renal artery stenosis

Case Presentations

Patient 1This 65-year-old female had been in good health except for chronic mild

depression and slight hypercholesterolemia for which she was treated with mapro-tilin (Ludiomil®, 75 mg/day) and simvastatin (Zocor®, 10 mg/day). She hadundergone hysterectomy for uterine myoma at the age of 48 years.

Four months before admission, she noted gradual onset of chronic pain inboth arms and knees which increased over the next few months. Her serum creat-inine level had been 90 Ìmol/l in January 1994. When she consulted her familydoctor on March 1, the initial laboratory screening revealed a serum creatininelevel of 539 Ìmol/l. She was sent to the hospital for workup.

On admission on March 3, she was in good general and nutritional status(70.7 kg). Her only complaint was motion-induced pain of her right shoulder.Heart, lungs and abdomen were normal on physical examination; she had normaljugular vein filling and minimal ankle edema. There was no skeletal pain, neitherspontaneous nor induced. Her blood pressure was 205/110 mm Hg, and the neu-rological examination was unremarkable.

Admission laboratory results included Na+ 138 mmol/l, K+ 4.1 mmol/l,serum creatinine 544 Ìmol/l, urea 30.4 mmol/l, calcium 2.86 mmol/l, phosphorus

1 Published in Nephron 1997;76:130–142.

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2.39 mmol/l, total protein 96 g/l, albumin 39 g/l, Hb 8.5 g/dl, white blood cells6,340/mm3, platelets 247,000/mm3. The urine sediment showed pH 5, ++ pro-teinuria, 0–2 white blood cells, 0–1 nondysmorphic red blood cells and no otherpathology. Serum immunoelectrophoresis revealed marked monoclonal gammo-pathy of type IgG kappa and free kappa light chains. 24-hour creatinine clearancewas 8.3 ml/min. 24-hour proteinuria was 6.8 g with the biuret method and 2.9 gwith the pyrogallol method; there was abundant Bence Jones protein (BJP) of typekappa (6.0 g/day). Bone marrow aspiration biopsy on March 4 disclosed 180%atypical plasma cells, consistent with multiple myeloma.

Bone radiographs showed multiple small osteolytic foci in both humeri and inthe distal thirds of both femora; there were some small foci in the skull, but noosteolysis in the vertebral column. Abdominal ultrasound gave symmetricallyenlarged kidneys (5.1 ! 6.2 ! 12.4 cm right; 5.1 ! 5.3 ! 12.4 cm left) with slightlyincreased echogenicity and no other pathology, particularly no lymphoma.

She was ordered to drink at least 2,500 ml/day and to take 1.5 g of sodiumbicarbonate three times daily. A chemotherapy consisting of six monthly cycles ofmelphalan 10 mg/day for 4 days and prednisone 100 mg/day for 5 days wasinitiated on March 7.

Serum creatinine did not increase any further. The hyperphosphatemiaresponded well to phosphate binders. The patient was discharged from the hospi-tal on March 21 with a creatinine level of 465 Ìmol/l. The renal function contin-ued to improve, and the serum creatinine level was 260 Ìmol/l on June 6. Phos-phate binders were discontinued, and the articular pain subsided.

This case illustrates an ‘obstructive’ type of acute renal failure (ARF), namelymyeloma kidney. It is obviously important to consider this diagnosis in any elder-ly patient with otherwise unexplained ARF, particularly if associated symptomsinclude skeletal pain, hypercalcemia, or hyperproteinemia, as in the present case.This particular patient was spared a renal biopsy, because the situation becamequickly obvious; in less obvious cases, biopsy would be mandatory to investigatethe precise cause of renal failure [1].

Once the diagnosis is established, the cornerstones of therapy in this type ofARF are to start alkaline diuresis [2], to initiate chemotherapy, and to avoidunnecessary investigations, especially including radiocontrast, which may put thepatient on hemodialysis once and for ever. With proper management, hemodialy-sis may be avoided in many patients.

Patient 2This 67-year-old male had been on hemodialysis since 1990 because of

chronic glomerulonephritis. Pretransplantation workup showed hypertensive car-diopathy with normal coronary arteries. On February 11, 1994, he received acadaver kidney graft (64-year-old donor, one match on HLA-A, four mismatches

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Pathogenesis of Acute Renal Failure:New Aspects

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on B/DR) which immediately took up function, so that his serum creatinine was79 Ìmol/l on day 7 and remained below 90 until April 1994. Immunosuppressioninitially consisted of ciclosporin A, azathioprine and prednisone. Because of acompletely rejection-free course, the latter two were tapered to zero, so that hewas on ciclosporin as the only immunosuppressant since the end of June 1994.

His blood pressure was initially normal without medication. In April, thesystolic pressures occasionally increased to 1160 mm Hg (diastolic pressurealways !90), prompting treatment with a calcium channel blocker (amlodipine,Norvasc®). In May, this was replaced by a diuretic (hydrochlorothiazide plus ami-loride, Moduretic®) because of ankle edema, but the blood pressure remainedelevated. At the same time, his creatinine level gradually began to increase whichprompted a transplant biopsy on June 27 at a creatinine concentration of125 Ìmol/l. The biopsy specimen revealed only minimal arteriolosclerosis, withno relevant changes when compared with the graft’s ‘zero hour’ biopsy. The situa-tion was, therefore, interpreted as functional ciclosporin toxicity, and the ciclo-sporin dose was reduced by 20%.

On July 15, the patient was hospitalized with pulmonary edema with a bloodpressure of 178/92 mm Hg. Since there was no evidence of myocardial ischemia,this complication was interpreted as decompensated hypertension. Diuretic ther-apy was initiated with furosemide (Lasix®) in addition to Moduretic. The serumcreatinine level increased to 144 Ìmol/l, the patient still complained of orthop-nea, and the blood pressure was 160/90 mm Hg. Diuretic therapy was, therefore,replaced by enalapril 20 mg plus hydrochlorothiazide 12.5 mg (Co-Reniten®) onJuly 19.

Within an hour of taking the first tablet, the patient experienced a dramaticimprovement of dyspnea, and his blood pressure decreased to 120/80 mm Hg.However, he stopped passing urine from that moment on and remained in abso-lute anuria for 3 days. Serum creatinine increased to 453 Ìmol/l on July 21. Color-coded duplex sonography revealed an 80% stenosis of the transplant artery closeto the anastomosis. On July 21, the stenosis was dilated by percutaneous translu-minal angioplasty, followed by prompt onset of diuresis within half an hour. Theserum creatinine values decreased below 100, and the angiotensin-convertingenzyme (ACE) inhibitor was now well tolerated.

This case of a ‘hemodynamic’ type of ARF demonstrates that even pro-tracted, absolute anuria is not necessarily followed by the syndrome of ARFwhich is characterized by failure to recover despite restoration of perfusion pres-sure. In the present case, the renal function immediately returned after restoringthe perfusion pressure which would usually be considered a typical feature of‘prerenal’ failure. In this case, the triggering event was really ‘postglomerular’,namely efferent arteriolar dilatation by the ACE inhibitor in a situation whereglomerular filtration critically depended on the efferent arteriolar tone.

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This patient also illustrates one of the more important hemodynamic lesionsin ARF: efferent dilatation which will be discussed below. Lastly, this patientraises another important question: why is a 3-day complete anuria immediatelyreversible upon percutaneous transluminal angioplasty, whereas it often takesmerely hours for ‘prerenal’ anuria to progress to full-blown ARF?

Taken together, these cases illustrate the bandwidth of the syndrome of‘ARF’. Although a comprehensive pathophysiological concept of ARF is still outof sight, our understanding has been advanced by recent research at least in someaspects which I will now review. For practical purposes, the course of ARF is bestdivided into the three phases of initiation, maintenance, and recovery, each ofwhich will be discussed separately.

Pathophysiology of ARF

One of the major problems hampering the investigation of ARF is the ques-tionable relevance of experimental models. This is less of a problem in nephro-toxic ARF than in models of renal ischemia. Clamping one or both renal arteries,with or without contralateral nephrectomy, has long been the paradigm experi-ment in the investigation of ARF. This model has, however, been challenged inmore recent years, because it creates a peculiar situation in which not only thekidney’s oxygen supply is reduced to zero (which would favor ischemic damage),but also the kidney’s work is significantly reduced by the cessation of glomerularfiltration (which would counteract ischemic damage). This particular balance ofsupply and demand may not be representative of clinical ischemic ARF [3]. Alter-native models, such as norepinephrine-induced ARF or ischemic damage in theisolated perfused kidney are, however, limited in other respects. Pathophysiologi-cal concepts of ARF, therefore, need to integrate the data obtained in differentmodels.

Initiation Phase

In reality, the interaction between vascular factors – decrease of renal bloodflow and glomerular filtration rate – and tubular factors in early ARF is quitecomplex. There are several loops which are potentially self-perpetuating (seefig. 1). The decrease of the renal blood flow may either be the cause of glomerularfiltration rate decrease and tubular damage, or it may itself result from tubulardamage via mechanisms such as tubular obstruction, medullary capillary conges-tion, or even tubuloglomerular feedback. It is worth recalling that the term ‘acutetubular necrosis’, widely used as a synonym for ARF, clearly is a misnomer, since

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Fig. 1. Synopsis of factors thought to be relevant in the pathophysiology of acute renalfailure. RBF = Renal blood flow; ATP = adenosine triphosphate; THP = Tamm-Horsfallprotein; TGF = tubuloglomerular feedback.

frank tubular necrosis is unusual in human ARF, except in its nephrotoxicvarieties [4].

Depression of the Glomerular Filtration RateLow Blood Pressure and Renal Vasoconstriction. The initial decrease of renal

blood flow may result either from a decrease of the arterial pressure below theautoregulatory limit or from increased renal vascular resistance as a consequenceof local vasoconstriction. Several vasoconstrictors, including endothelin 1 [5],adenosine [6], and angiotensin [7], have been implicated in mediating ischemicrenal failure. Endothelin appears to be particularly important in radiocontrast-induced renal failure [8].

Mesangial Contraction. With the possible exception of norepinephrine,mesangial cells appear to contract to essentially the same agents as vascularsmooth muscle cells. Mesangial cell contraction is, therefore, likely to occur when-ever there is renal vasoconstriction. In addition, data obtained in our laboratoryin isolated perfused glomeruli indicate that endotoxin perfusion increases the

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intraglomerular resistance by a novel pathway which involves platelet-activatingfactor, thromboxane A2, and endothelin. The most likely mechanism of this intra-glomerular resistance increase is mesangial contraction [9]. Mesangial contrac-tion is also expected to reduce the glomerular filtering area and – by this – also theglomerular ultrafiltration coefficient Kf. These data are, therefore, consistent withnumerous reports describing a decreased Kf, in early ischemic renal failure indogs [10, 11], in gentamicin or uranyl nitrate induced renal failure in rats [12, 13],and in gentamicin nephrotoxicity in the rabbit [14]. The change of Kf in thesestudies was large enough to fully explain the observed decrease in glomerularfiltration rate. In the uranyl nitrate rat model, the decrease of the Kf was found tobe largely preventable by ACE inhibition and/or volume expansion, suggestingthat angiotensin II is involved [13].

Tubuloglomerular Feedback. In addition to hormone-induced vascular andmesangial contraction, tubuloglomerular feedback has been suspected to mediatepart of the decrease of the glomerular filtration rate in early ARF, at least in somemodels [15]. The relevance of this component has, however, been difficult toassess, since maneuvers which inhibit the tubuloglomerular feedback, such as theadministration of furosemide, have surprisingly little protective effect [16].

Tubular Cell DamageTubular damage is one of the central events during the initiation phase.

Using the newer tools of cell biology, it has been extensively investigated in recentyears. Susceptibility to damage is clearly related to oxygen requirements. Sincethe pO2 is normally lower in the medulla, it has been postulated that renal damagebegins in the thick ascending limb of Henle’s loop, the high energy requirement ofwhich contrasts with a relatively poor and critical oxygen supply [3]. The samearea of the kidney also contains the S3 segment of the proximal tubule which inmany models of ARF is the main area of tubular damage. It is, however, impor-tant to realize that under conditions of salt depletion, which are known to predis-pose to ARF, the normal cortico-medullary gradient reverses, i.e., there appears tobe ample oxygen available in the medulla. In the same setting, the cortical pO2

appears to be decreased due to the enormous increase of proximal tubular saltreabsorption which takes place under these conditions [17].

With the initial decrease of cellular energy stores, a calcium influx into thecell ensues which in itself has deleterious effects by triggering a number of Ca2+-dependent proteases and lipases. The increase in calcium, however, does notappear to be a sufficient condition per se, since maneuvers such as acid pH orglycine are in vitro protective without interfering with the increase of intracellularcalcium [18, 19]. It also has become clear that there are calcium-independentphospholipases which are activated by hypoxia [20].

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One of the earliest demonstrable events in isolated perfused proximaltubules, which occurs within minutes after hypoxia, is a decrease of the transepi-thelial potential. This can be shown to be due to a leakiness of cell-to-cell junc-tions as opposed to a decrease in transcellular transport rate [21]. A similarly earlystep is the disruption of the proximal tubular microfilament network which canbe traced back to the first 5 min of ischemia [22]. Later, from about 10 min on,cells begin to lose their polar differentiation: the ubiquitous Na-K-ATPase startsto dissociate from its basolateral position and redistributes towards the apicalmembrane. At the same time, F actin is redistributed within the cells [23]. Theprocesses clearly are not to be equated with cell death, because they are entirelyreversible upon addition of exogenous adenosine triphosphate [24].

Energy depletion is a key step in these early changes. A particularly impor-tant role appears to be played by the enzyme 5)-nucleotidase which catalyzes thebreakdown of adenosine monophosphate to adenosine which – unlike adenosinemonophosphate – is free to cross the cell membrane. Conversely, exogenous aden-osine triphosphate reaches the cytoplasm only after being broken down to adeno-sine monophosphate and further to adenosine [25]. Consistent with this, maneuv-ers designed to minimize the loss of energy substrates (such as the inhibition of5)-nucleotidase) [26] or to replenish them (such as the administration of inosine)[27] have been shown to afford some protection from ARF.

Oxygen free radical injury has been implied in causing additional cell dam-age after ischemic injury. Oxygen free radicals are mainly generated in the phaseof reperfusion after ischemia, e.g., by xanthine oxidase, which converts accumu-lated hypoxanthine back to xanthine in the presence of oxygen [28]. An additionalmechanism may operate in rhabdomyolysis where iron released from degradedmyoglobin helps to catalyze the conversion from superoxide anion or hydrogenperoxide to hydroxyl radical. Oxygen radicals not only damage cells directly, butalso may indirectly promote renal vasoconstriction by enhancing degradation ofendothelial derived nitric oxide [29]. Overall, however, the relative contributionof oxidant injury has been difficult to assess, because maneuvers designed toreduce free oxygen radicals (such as allopurinol, superoxide dismutase, and cata-lase) do not have very consistent protective effects [30].

It has recently been recognized that a substantial percentage (30–100%) ofthe tubular cells excreted in the urine of patients with ARF are viable, at leastas judged by trypan blue exclusion [31, 32]. Thus there is the possibility thatdamage to cell-cell adhesion molecules (integrins) and the cytoskeleton (F actin)leads to the detachment of viable cells followed by (a) backleak of glomerularfiltrate across the damaged tubular epithelium and (b) the potential formationof cell-to-cell aggregates via integrin receptors and downstream tubular obstruc-tion by cellular casts. Since these processes could be receptor mediated, theircharacterization might yield new targets for specific intervention such as the

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administration of integrin receptor blockers to interfere with cell-to-cell adhe-sion [33].

Riding on the recent enthusiasm for ‘programmed cell death’ or apoptosis,evidence has been presented to suggest that apoptosis of proximal tubular cells is acofactor in the pathogenesis of ARF [34, 35]. At present, however, it is unclear towhat extent apoptosis – as opposed to the mere ‘degenerative’ changes – is impor-tant. A regulated process such as apoptosis would, of course, also offer new oppor-tunities for targeted intervention.

Tubular ObstructionProximal Tubular Casts. Examples of mainly proximal tubular cell damage

include most nephrotoxic models of ARF and even some cases of myeloma kid-ney where BJP have been shown to specifically damage the proximal tubule [36].In addition, the fact that pressures in the proximal tubule are high during the first1–6 h after experimental renal ischemia can hardly be explained by anything butobstruction; later, however, pressures decrease to the lower values typical of themaintenance phase [27]. High tubular pressures are correlated with the occur-rence of medullary capillary congestion (see below). Overall, there is marked het-erogeneity among nephrons both during this early phase and even more duringthe maintenance phase [27].

Tubular casts are much less common in human ARF (except for cases ofmyeloma kidney and similar conditions) than in the various animal models ofARF [4, 37]. However, the fact that the tubular segments proximal to casts appearcollapsed rather than dilated in biopsy specimens from human ARF cases shouldnot be taken as evidence that obstruction is irrelevant, since the increase of theproximal tubular pressure is clearly restricted to the first few hours of ARF [27].Biopsy specimens of myeloma kidney illustrate the limitations of deducing patho-genetic mechanisms from histology, since one may find collapsed proximaltubules and glomerular tufts filling Bowman’s space even in these clearly obstruc-tive forms of ARF [4].

Distal Tubular Casts. While proximal obstruction is mostly caused by aggre-gates of tubular cells and blebs, distal nephron casts usually contain a matrix ofTamm-Horsfall protein (THP). It is noteworthy that THP aggregation is en-hanced by increasing the NaCl concentration from the hypotonic values typical ofthe late thick ascending limb of Henle to isotonic values [38]. Since furosemideincreases the NaCl concentration in the thick ascending limb and the distal neph-ron, this would lead to predict a proaggregatory effect of furosemide. Administra-tion of furosemide has indeed been found to enhance cast formation in a ratmyeloma kidney model [39].

It is interesting that some BJP themselves appear to create a milieu favorablefor tubular obstruction by inhibiting loop of Henle chloride absorption [38]. In

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addition, the isoelectric point of the BJP appears to play a role, since BJP with avalue !7.4 appear to precipitate more easily in the distal nephron which is proba-bly related to the progressive pH drop of renal tubular fluid along the distal neph-ron [36]. Consistent with this, urine acidification has been clearly shown to pro-mote BJP aggregation [2]. Lastly, it has recently been found that BJP bind to aspecific site on THP and that this binding interaction can be inhibited by either amonoclonal anti-THP antibody or by reducing agents such as penicillamine ordithiothreitol [40].

In theory, increasing tubular fluid flow should have a protective effect inobstructive forms of ARF. But although volume repletion and hydration appearto be protective in certain nephrotoxic forms of ARF in humans (such as cis-platinum) [41] and (combined with alkalinization) in myeloma or heme pigmentinduced ARF [42], evidence for protective effects of furosemide (and mannitol) isrestricted to animal studies [16, 27]. One of the reasons may be furosemide’sproaggregatory effect on THP.

Medullary Capillary CongestionCongestion of blood in the capillaries of the inner stripe of the outer medulla

is a common feature of established ARF and may impair both circulation andtubular flow in this critical region [43]. Its pathogenesis has remained speculative.One hypothesis would propose that free oxygen radical damage causes a dramaticincrease in capillary permeability in this area, leading to leak of fluid out of thecapillaries, whereas erythrocytes would remain trapped, accumulate, and ulti-mately plug the capillary system [44]. Consistent with this, interstitial edema is acommon finding in human biopsy specimens of ARF [4]. Alternatively, tubularobstruction might, during the first hours of ARF, when the intratubular pressureis still high, cause dilatation of the proximal tubule which then could impede thealready narrow passage of erythrocytes out of the medulla back up to the cortex,initiating the same vicious cycle. Medullary capillary congestion does not involvethe coagulation system, since both acetylsalicylic acid and heparin are ineffectivein ameliorating either renal failure or medullary congestion [43]. In contrast,hemodilution has been shown to protect from and hemoconcentration to enhancethe severity of ARF in rat models of ischemia, which is consistent with an impor-tant role of medullary capillary congestion in the pathogenesis of ARF [43, 45].

Maintenance Phase

This is defined as the phase where the triggering factors of ARF have ceasedto exist, but renal failure continues. It usually extends from 6–8 h after the trigger-ing event(s) to several days or weeks. Again, both hemodynamic and tubular fac-

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tors contribute to the maintenance of renal failure. Besides persisting tubularobstruction and medullary capillary congestion, there are typical hemodynamicand tubular alterations.

Hemodynamic AlterationsThe glomerular capillary pressure is uniformly low during the maintenance

phase, even in ‘obstructive’ forms of ARF, reflecting at the same time an increaseof afferent resistance and a decrease of efferent resistance [46]. Despite persistentanuria, the renal blood flow is usually decreased to only 50% in humans withestablished renal failure [47].

Persistence of afferent vasoconstriction has been attributed to a number ofvasoconstrictors, the most recent of which is endothelin. In fact, 25 or 45 min ofrenal ischemia have been found to at least double the renal levels of ET-1 mRNAfor several days [48] and interfering with endothelin vasoconstriction has provenprotection in some models of ARF (see below).

Adenosine has also been implicated in the pathogenesis of the persistentvasoconstriction of the maintenance phase. Adenosine would appear to be a suit-able candidate, since it becomes available in ample amounts from adenosine tri-phosphate breakdown once the energy balance of the renal tubules is disturbed.Although the adenosine-induced constriction of the afferent arteriole (via A1-typepurinergic receptors) is usually short-lived and followed by vasodilatation, adeno-sine-induced constriction might be more sustained in the presence of high angio-tensin II levels such as often exist in ischemic renal failure [49, 50]. Consistentwith the concept of efferent dilatation in established renal failure, adenosinemight also dilate the efferent arteriole (as it does in most vessels of the generalcirculation). However, the evidence for this is indirect [51], and some availabledirect evidence appears to indicate that the efferent arteriole does not respond toadenosine [52].

Overall, the significance of the vasoconstrictors during the maintenancephase is far from certain, because the renal blood flow may rather easily berestored to normal or even supernormal values by vasodilators without any effecton the glomerular filtration [53]. This puzzling finding may support a role forefferent vasodilatation which could well explain both the decreased glomerularcapillary pressure and the failure to respond to vasodilator therapy.

Tubular BackleakWhereas tubular obstruction appears to be an early mechanism, which con-

tinues into the maintenance phase, tubular backleak across damaged tubular epi-thelia appears to become relevant slightly later. Backleak has been shown to besignificant in protracted human ARF: as much as 50% of the already low glomer-ular filtration rate may leak back to the interstitium [54, 55].

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Recovery Phase: Role of Growth Factors

This phase is characterized by the gradual recovery of renal function whichgoes hand in hand with the normalization of renal hemodynamics, resolution oftubular obstruction and tubular cell regeneration. Using the tools of molecularbiology, cell regeneration can be demonstrated at surprisingly early time points:induction of cfos and Egr-1 mRNA is detectable within 30 min after a 50-minischemia [56]. DNA synthesis increases within 24 h of ischemia and is significant-ly enhanced by administration of growth factors such as epidermal growth factor(EGF) [57]; the same has been shown in a model of HgCl2-induced ARF [58].EGF is mitogenic for proximal tubular cells [59], and the EGF receptor number isincreased after ischemia [56]. In one study [60], proximal tubular cells, whichusually are EGF negative, showed increased EGF staining after a 10-day treat-ment with the aminoglycoside amikacin which was accompanied by an almostfive-fold increase of DNA synthesis. Insulinlike growth factor 1 (IGF-1) bindingincreases approximately twofold after ischemia and remains elevated for approxi-mately 1 week [61]. Regenerating cells appear to actively synthesizeIGF-1, since they are positive for IGF-1 by immunofluorescence and for IGF-1mRNA by in situ hybridization [61]. Some authors have failed to find evidencefor IGF-1 or EGF synthesis in regenerating proximal tubules after gentamicin-induced renal failure [62]. Taken together, however, these data suggest that renaltubular regeneration begins very early after the initial insult, is an important stepin recovering normal renal function, and may be strongly enhanced by growthfactors.

Therapeutic Maneuvers

The prognosis of clinical ARF is dismal. In a Basel series of 90 patients, theoverall mortality was 62%, rising to 82% in a subgroup of patients with septicshock [63]. Although this figure mainly reflects the severity of the disease whichleads to ARF, ARF itself certainly complicates the management by requiringrenal replacement therapy, antibiotic dose adjustments, differentiated fluid man-agement, additional intravascular catheters, etc. Hence, there is substantial inter-est in therapeutic modalities which might shorten or prevent ARF. Among themyriad of agents found protective, some of the more promising ones will be brief-ly reviewed.

GlycineGlycine has a cellular protective effect in in vitro models of renal tubular

damage [64], the mechanism of which, however, is not entirely clear. It appears to

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be independent of the rise of intracellular calcium [19]. Potential protectiveeffects of glycine in vivo could additionally be mediated by renal vasodilatation[65]. The evidence for a protective effect of glycine in intact animals is, however,not overwhelming, and detrimental effects of glycine infusion have been found insome models [66].

Atrial Natriuretic Peptide (ANP)Since ANP increases the glomerular filtration rate by increasing Kf and effer-

ent resistance, it appears to be a logical choice for counteracting some of thehemodynamic abnormalities in ARF. ANP has in fact been shown to afford par-tial protection even with posttreatment in a model of ischemic renal failure in therat [67]. Also, a recent study has for the first time provided evidence for a benefi-cial effect of ANP in established human ARF [68]. Due to some methodologicalproblems, however, the latter data await further confirmation.

Growth FactorsIn a rat model of 30 min bilateral ischemia, EGF was shown to increase renal

thymidine incorporation (as an index of renal cell regeneration), to attenuate theseverity of the ensuing renal failure, and to accelerate the recovery of renal func-tion [57]. Similar effects have been shown in a model of HgCl2-induced nephro-toxicity [58]. Furthermore, IGF-1 was also found to dramatically improve thecourse of ischemic renal failure in rats [69]. As an added ‘side effect’, the use ofgrowth factors tends to reverse the catabolic metabolic state which usually accom-panies ARF. Thus far, however, there have been no published studies inhumans.

NO Synthase InhibitorsDespite the encouraging results recently obtained with the administration of

NO synthase inhibitors in septic shock [70], the available evidence leads to theprediction that these inhibitors may sacrifice the kidney for the sake of maintain-ing the systemic pressure. In other words, inhibition of the NO system may inten-sify renal vasoconstriction beyond the point of no return.

Endothelin Receptor AntagonistsThe endothelin-A receptor antagonist BQ123 has recently been shown to

dramatically improve the course of postischemic renal failure when given – as atrue ‘post-treatment’ – intravenously 1 day after a 45-min ischemia in awake,uninephrectomized rats [71]. Another endothelin A receptor antagonist,CP170687, was shown to revert radiocontrast-induced plus nonsteroidal anti-inflammatory drug-induced renal vasoconstriction in rats [8]. These findingsraise high hopes which await confirmation in human studies.

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Concluding Remarks

We are still far from a unifying concept for understanding the multifacetedsyndrome of ARF. In particular, the intricate interplay between tubular and glo-merular alterations, which is inappropriately described by the term ‘tubularnecrosis’, is only incompletely understood, although it probably holds the key tothe pathophysiology of ARF. Some progress has, however, been made duringrecent years. Some of these newer insights will most likely translate into clinicallyapplicable strategies in the years to come.

Discussion

Ritz: If one looks at the original data by Stillman et al. [17] you just showed,there is an interesting paradox. There appear to be areas in the renal cortex in whichthe PO2 is only 5–10 mm Hg. If indeed the cellular insult is caused by depletion ofenergy-rich nucleotides – as believed by many – the normal kidney would containmany areas where ARF is going on. Why is this not actually happening?

Bock: One aspect may be that tolerance to ischemia can be conditioned.Shortly after an ischemic insult, rats are fairly resistant to oxygen depletion [72].One could imagine that these hypoxic zones have adapted to these conditions. Ofcourse, it is also conceivable that the preparation for these measurements mightcause focal cortical ischemia, i.e., that these measurements are an artifact of themethod.

Ritz: As you know, there is an in vivo sensor which tells us which PO2 thekidney sees in vivo, namely erythropoietin (EPO). Are there any good studiestelling us what EPO does in the induction phase? Does it increase?

Bock: One might expect this, but I do not know of any pertinent data. Theearliest measurements known to me are in the maintenance phase of ARF, whereEPO is clearly depressed relative to the degree of anemia [73]. At this time at leastthe physiological relation between PO2 and EPO production appears to be dis-turbed.

Zeier: A question regarding the prophylaxis of ARF after kidney transplanta-tion. Do you use calcium channel blockers in the perfusion solution?

Bock: No. We may be prejudiced because we performed some studies on theprotective effects of calcium channel blockers and did not find any protection [9].I appreciate that there are data, particularly from Germany, which show a certainprotective effect in this setting [74, 75]. However, due to the small size of ourcountry, cadaver kidneys in Switzerland tend to have shorter ischemia times thanin the Eurotransplant area: ischemia rarely exceeds 24 h, and we, therefore, thinkthat we can do without calcium channel blockers.

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Andrassy: What is your opinion about the prophylactic use of catechol-amines? We frequently use dopamine and diuretics for the prophylaxis of ARF.This is mainly done in intensive care units and is questioned more and more, alsobecause dopamine is given at pharmacological doses and, therefore, needs to begiven at higher doses than norepinephrine. Norepinephrine would perhaps bemore renoprotective and more economical. What is your opinion?

Bock: We have never used dopamine for the prophylaxis of ARF, although ourintensive care unit doctors use it at the so-called ‘renal dose’ which is 100–200Ìg/min. To my knowledge, there is not a single study which documents the efficacyof dopamine for the prophylaxis of ARF. Neither the ‘renal dose’ of dopamine nor ahigher dose which seemingly normalizes blood pressure but vasoconstricts the kid-ney can substitute for a good, stable circulation. Furosemide also may be a two-sided sword. We do not use furosemide as a prophylaxis, but merely for maintain-ing fluid balance in oliguric patients. I am of course concerned about the potentialnegative effects of furosemide which can be derived from the data on THP aggrega-tion promoted by furosemide [38]. Certainly, no effective protection may beexpected from it. A good tubular flow rate, achieved by whatever means, is proba-bly one of the better means of preventing ARF. But as long as the state of thecirculation permits, it is probably better to reach this by volume expansion – there-by making use of endogenous ANP – than to put your hopes into furosemide.

Gretz: From prophylaxis to therapy: The papers by Hakim et al. [90] in KIseem to suggest that choice of the dialysis membrane is a decisive factor. What isyour opinion on this?

Bock: Personally I do not believe that this has any prognostic impact, becausethe prognosis of ARF is much more determined by its underlying cause, whereasdialysis is a means of supportive therapy.

Ritz: You were very cautious with respect to the study on the protective effectof ANP in humans [68]. Following the publications by Schafferhans et al. [76] andShaw et al. [77], who to my knowledge were the first to suggest a prophylactic rolein a rat model of ischemic ARF in the rat, there was a study in a German universi-ty whose final publication I have never seen. In this study, the hypothesis wassubjected to the most stringent condition: ANP was given at the time of transplan-tation, but there was no effect whatsoever on outcome. I am, therefore, quiteskeptical with respect to this less stringent study from Denver [68]. RegardingIGF-1: How could one avoid one severe side effect of IGF-1, namely hypoglyce-mia? Using high doses of IGF-1 in animal experiments, we have lost a large num-ber of our animals due to hypoglycemia.

Bock: I was not aware of this problem, since I have not personally workedwith IGF-1. Could this effect be dose dependent and is there a renoprotectivedose without this side effect? Could the problem be solved by glucose administra-tion?

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Ritz: Experimentally, it is very difficult to titrate the effect exactly. The sameproblem will of course also be substantial in clinical use.

Bock: Despite this, I think that there is a lot of potential in growth factortherapy. EGF, for example, would not have the side effect of hypoglycemia. Cer-tainly, cost-benefit considerations need to be taken into account as well.

Gretz: An additional interesting field would be the prophylactic use of urodi-latin which is currently discussed in heart surgery and liver transplantation.

Bock: As far as I know, the effects of urodilatin are very similar to the ones ofANP. There is no fundamental difference in its effect on renal hemodynamics.The main difference is its site of synthesis, namely the distal nephron.

Zeier: In this indication, however, ARF may be anticipated, and the prophy-lactic use of ANP or urodilatin may make sense.

Bock: I agree.Ritz: You pointed out, probably correctly, that the role of adenosine is fairly

unclear, although Osswald et al. [49] and Spielman and Osswald [78] have pre-sented very interesting studies on the subject. There is now a recent study by Erleyet al. [79] in which theophyllin attenuated radiocontrast-induced ARF. Of course,theophylline needs to be used with caution in patients with an unstable circula-tion. What is experimentally known in this regard?

Bock: I am not sure how well radiocontrast-induced ARF fits the typical pic-ture of ARF as I have described. Radiocontrast ARF essentially appears to be arenal vasoconstriction of long duration, perhaps mediated by endothelin, and itmay, therefore, be a much easier target than situations where the whole cascade oftubular damage, obstruction, backleak, etc., has been triggered. In our experience,contrast-induced ARF rarely lasts for more than 2 days, and it is a long time sincewe had to dialyze a patient for contrast-induced ARF. Adenosine is a compoundwhich behaves somewhat chimerical. Whether it causes renal vasoconstriction orvasodilatation appears to greatly depend on the circumstances. Many of the con-cepts about adenosine’s presumptive action are contradictory.

Ritz: A short comment about contrast-induced ARF being essentially vaso-constriction without true renal failure. I believe that it is correct to criticize that a15- to 20-ml/min decrease of the glomerular filtration rate – as shown in the paperby Erley et al. [79] – is not ARF in the term’s proper sense. On the other hand,there are the interesting findings by Gross et al. [91] who found a massive increasein endothelin message after exposing renal tubular and collecting duct cells toradiocontrast media. A further interesting aspect is that all states in which radio-contrast is known to trigger ARF are states characterized by substantial protein-uria such as diabetes mellitus, myeloma, or advanced renal failure. At the sametime, these states usually show pronounced increases of endothelin message. Thismight be an additional ‘missing link’ to a pathogenetic mechanism.

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Bock: These findings certainly point to an important role of endothelin. Inour own studies on urinary endothelin excretion in humans, we found it to belargely dependent on urine flow. In my view, it is an unresolved issue whetherrenal endothelin, the RNA of which is mainly found in the collecting duct, hasanything to do with renal hemodynamics, is just another peptide which the col-lecting duct synthesizes for phylogenetic reasons, or whether it has a true role asan autacoid in this tubular segment.

Huber: What is your experience with the use of bicarbonate for the prophy-laxis of ARF?

Bock: We use bicarbonate, i.e., urine alkalinization, only in rhabdomyolysisand myeloma kidney, because data supporting a beneficial effect are availablehere. Other than that, there seems to be no reason for the prophylactic use ofbicarbonate.

Ritz: There are data published by Zager [92] some years ago with which hewas able to show that the susceptibility to ARF can be modulated by administra-tion of amino acids. Could you comment on a possible mechanism operating viaL-arginine and NO synthase? There also was an interesting paper in the Lancet[80] showing that, depending on the dose of NO synthase inhibitor given, theremay be either improved organ perfusion and a rise in blood pressure or impairedperfusion of peripheral end organs with consecutive organ failure. What is knownwith respect to ARF in this context? Can the course or ARF be altered by modu-lating NO synthase, either during the induction phase or – more likely – in themaintenance phase?

Bock: There are at least two papers [81, 82] showing that NO synthase inhibi-tion favors ARF. This is to be expected to a certain degree, because unlike otherorgans, the kidney is vasoconstricted in septicemia, and this is enhanced by inhib-iting NO synthase. The often cited clinical paper in the Lancet [70] showing abenefit on blood pressure in 2 patients, should be viewed with caution. Essential-ly, it is an attempt to save blood pressure by sacrificing the kidney. PersonallyI set much more hope on endothelin receptor antagonists than on NO synthaseblockers.

Ritz: One further aspect: states in which the concentration of L-arginine isdecreased, for example pregnancy, are also states which are particularly prone toARF. For this, a change by a factor of two is sufficient, as was shown in theexample of hemolytic-uremic syndrome in pregnancy [83] and in an additionalpaper by Podjarny et al. [84] on eclampsia. Intensive care patients are frequentlymalnourished. The question is: do changes of amino acid metabolism in this orderof magnitude play a role for the risk of ARF? Is there a possibility to change therisk of ARF along this track?

Bock: Although this seems a plausible argument, I am afraid it is not current-ly supported by data. Changes of plasma arginine levels may not necessarily imply

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NO deficiency, because plasma arginine levels are usually 50–100 times higherthan the Km of the constitutive (endothelial) NO synthase [85]. In other words,extremely low levels of L-arginine would be required to explain any NO deficien-cy on this basis. I, therefore, doubt that administration of L-arginine is able tosubstantially change the risk of ARF.

Dieker: Earlier, thyroid hormones were given in ARF to improve tubularregeneration. In older and multimorbid patients with ARF, we frequently see lowlevels of thyroid hormone. Are there any newer data?

Bock: Most of these patients probably belong to the category called ‘euthy-roid sick’ syndrome [86], i.e., they are not truly hypothyroid. There are two orthree papers describing the prophylactic value of L-thyroxine in ARF [87–89].Like several other maneuvers experimentally shown to be of some prophylacticuse, thyroxine administration has not been generally adopted for clinical use,probably because the reported benefits were relatively small.

Dieker: In a paper published in the Deutsche Medizinische Wochenschrift, itwas actually shown that there is no favorable effect on ARF.

Ritz: It is much more common for septic shock to be followed by ARF thanfor nonseptic shock. During the last 2 years a number of new interventions wereproposed, e.g., cytokine antagonists, monoclonal antibodies, etc., and there is aseries of experimental studies in septic shock which in part look quite promising.Are there, beyond this, any data suggesting that the course of septicemic ARF maybe altered favorably?

Bock: I only know of an ‘on-dit’ of the Institute Henri-Beaufour which claimsthat one of their platelet-activating factor antagonists has been able to improvethe prognosis of ARF in septicemic patients in France in a double-blind study.Other than that, there seem to be no clinical studies showing an improvement ofprognosis.

Zeier: Are there differences between verapamil and diltiazem when used inthe perfusion solution at the time of harvesting the organ?

Bock: I do not know of any.Ritz: An Australian paper has shown that Ca channel blockers of the dihydro-

pyridine type may be effective after transplantation, suggesting a class-specific,not a substance-specific effect. It should be pointed out, however, that calciumchannel blockers of the dihydropyridine type may cause coronary side effects upto myocardial infarction which were also reported.

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76 Schafferhans K, Heidbreder E, Grimm D, Heidland A: Norepinephrine-induced acute renal failure:Beneficial effects of atrial natriuretic factor. Nephron 1986;44:240–244.

77 Shaw SG, Weidmann P, Hodler J, Zimmermann A, Paternostro A: Atrial natriuretic peptide pro-tects against acute ischemic renal failure in the rat. J Clin Invest 1987;80:1232–1237.

78 Spielman WS, Osswald H: Blockade of postocclusive renal vasoconstriction by an angiotensin IIantagonist: Evidence for an angiotensin-adenosine interaction. Am J Physiol 1979;237:F463–F467.

79 Erley CM, Duda SH, Schlepckow S, Koehler J, Huppert PE, Strohmaier WL, Bohle A, Risler T,Osswald H: Adenosine antagonist theophylline prevents the reduction of glomerular filtration rateafter contrast media application. Kidney Int 1994;45:1425–1431.

80 Nava E, Palmer RM, Moncada S: Inhibition of nitric oxide synthesis in septic shock: How much isbeneficial? Lancet 1991;338:1555–1557.

81 Chintala MS, Chiu PJ, Vemulapalli S, Watkins RW, Sybertz EJ: Inhibition of endothelial derivedrelaxing factor (EDRF) aggravates ischemic acute renal failure in anesthetized rats. NaunynSchmiedebergs Arch Pharmacol 1993;348:305–310.

82 Maree A, Peer G, Schwartz D, Serban I, Blum M, Wollman Y, Cabili S, Iaina A: Role of nitric oxidein glycerol-induced acute renal failure in rats. Nephrol Dial Transplant 1994;9:78–81.

83 Raij L: Glomerular thrombosis in pregnancy: Role of the L-arginine-nitric oxide pathway. KidneyInt 1994;45:775–781.

84 Podjarny E, Mandelbaum A, Bernheim J: Does nitric oxide play a role in normal pregnancy andpregnancy-induced hypertension? Nephrol Dial Transplant 1994;9:1527–1529.

85 Stuehr DJ, Griffith OW: Mammalian nitric oxide synthases. Adv Enzymol Relat Areas Mol Biol1992;65:287–346.

86 Vermaak WJ, Kalk WJ, Zakolski WJ: Frequency of euthyroid sick syndrome as assessed by freethyroxine index and a direct free thyroxine assay. A limitation of FT4 assays. Lancet 1983;1:1373–1375.

87 Siegel NJ, Gaudio KM, Katz LA, Reilly HF, Ardito TA, Hendler FG, Kashgarian M: Beneficialeffect of thyroxine on recovery from toxic acute renal failure. Kidney Int 1984;25:906–911.

88 Cronin RE, Brown DM, Simonsen R: Protection by thyroxine in nephrotoxic acute renal failure.Am J Physiol 1986;251:F408–F416.

89 Michael UF, Logan JL, Meeks LA: The beneficial effects of thyroxine on nephrotoxic acute renalfailure in the rat. J Am Soc Nephrol 1991;1:1236–1240.

90 Hakim RM, Wingard RL, Parker RA: Effect of the dialysis membrane in the treatment of patientswith acute renal failure. N Engl J Med 1994;331:1338–1342.

91 Gross P, Büssemaker E, Kapturczak M, Distler A: Radiocontrast agents stimulate endothelin to acomparable degree. Nieren-Hochdruckkrankh 1994;9:423.

92 Zager RA, Venkatachalam MA: Potentiation of ischemic injury by amino acid infusion. Kidney Int1983;24:620–625.

Dr. H. Andreas Bock, Division of Nephrology,Kantonsspital, 5001 Aarau (Switzerland)

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[contributions to nephrology] nephrology grand rounds. clinical issues in nephrology volume 124 ||...

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