Nephrol. Dial. Transplant. 2008 Lankisch 1401 5

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Nephrol Dial Transplant (2008) 23: 14 011405

doi: 10.1093/ndt/gfm769

Advance Access publication 9 December 2007

Original Article

Frequency and severity of acute pancreatitis in chronic dialysis

patients

Paul G. Lankisch1, Bettina Weber-Dany1, Patrick Maisonneuve2 and Albert B. Lowenfels3

1Clinic for General Internal Medicine, Medical Centre, Municipal Clinic of L uneburg, Luneburg, Germany, 2 European Institute of

Oncology, Milan, Italy and3 Medical College, Valhalla, NY, USA

Abstract

Background.The incidence and severity of acute pancre-atitisin patients undergoingdialysis treatment are unknown.Methods. A questionnaire asking for the incidence and

the severity of a first attack of acute pancreatitis in chronicdialysis patientsin the year 2002 was sent to the members ofQuaSi-Niere gGmbH, an organization representing almostall dialysis centres in Germany. A second questionnaire wassent to those who reported such patients.Results. Response rates for the first and secondquestionnaire were 72%(832 outof 1150 centres) and100%(72 out of 72 centres), respectively. After the exclusion ofpatients with invalid data, 55 patients with acute pancreatitisremained: 46 patients out of 68 715 haemodialysis (HD)patients (incidence rate 67/100 000/year; 95% confidenceinterval, 49 to 89/100000/year) and9 out of 3386 peritonealdialysis (PD) patients (incidence rate 266/100 000/year;95% confidence interval, 122 to 504/100 000/year; Fishers

exact test: P= 0.002). Twenty-eight patients (51%) hada known risk factor for acute pancreatitis. When thesewere excluded, the incidence of pancreatitis of unknownaetiology was 32/100 000/year (2048) for HD patients(n, 22) and 148/100 000/year (48345) for PD patients(n, 3; Fishers exact test: P= 0.016). PD patients requiredhospital admission more frequently than HD patients (100%versus 76%) and suffered more frequently from necrotizingpancreatitis (50% versus 19%).Conclusions. Dialysisespecially PDis another riskfactor that increases the susceptibility of the pancreas toacute pancreatitis. Acute pancreatitis in patients undergo-ing PD is more frequent and seems to be more severe thanin those receiving HD treatment.

Keywords: acute pancreatitis; dialysis; haemodialysis;peritoneal dialysis

Correspondence and offprint requests to: P. G. Lankisch, Reiherstieg23, D-21337 Luneburg, Germany. Tel: +49-4131-403503; +49-4131-249495; E-mail: [email protected]

Introduction

Several postmortem studies have shown that the pancreasis affected by uraemia [13]. Some case reports and small

studies suggest that the risk of acute pancreatitis is in-creased in patients with end-stage renal disease undergoingperitoneal dialysis (PD) as compared to those undergoinghaemodialysis (HD) treatment [49], whereas others couldnot confirm this connection [10].

Recently, twointerestingstudies on this subject have beenpublished. In one retrospective single-centre cohort studyfrom the Netherlands, patients on long-term PD (but notHD) were found to have a higher incidence of acute pan-creatitis than the general population [11]. Another retro-spective case-control study from the United States reportedthat PD is a risk factor for acute pancreatitis in the blackpopulation and that there are no statistical differences inacute pancreatitis-related mortality and morbidity between

both dialysis procedures [12].Since the number of dialysis patients waiting for kidney

transplants is increasing, the conclusions of both studieshave a substantial clinical impact on the care of these pa-tients and were therefore questioned. The aim of our studywas to determine the incidence and severity of acute pan-creatitis in a substantially larger patient population.

Patients and methods

In the year 2003, we sent out a questionnaire to the membersof the QuaSi-Niere gGmbH asking for the incidence and

the severity of a first attack of acute pancreatitis in chronicdialysis patients in 2002. This organization represents al-most all dialysis centres in Germany (n, 1150; response rate:832 or 72%). There were no obvious differences betweenreporting and non-reporting centres concerning the sizeand the geographical distribution of the centres. Chronicdialysis was defined as a total dialysis period longer than6 weeks [11].

Acute pancreatitis is usually defined as acute abdominalpain with an increase in serum levels of pancreatic enzymes.Serum amylase and lipase are frequently elevated in chronic

C The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please e-mail: [email protected]


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Table 1. Frequency of acute pancreatitis (AP) in chronic dialysis patients with and without known risk factors (CI, confidence inter val)

Haemodialysis patients(n, 68 715)

Peritoneal dialysis patients(n, 3386)

All dialysis patients(n, 72 101)

Incidence rate/ Incidence rate/ Incidence rate/Number of AP 100 000/year Number of AP 100 000/year Number of AP 100 000/yearpatients (%) (95% CI) patients (%) (95% CI) patients (%) (95% CI)

Acute pancreatitis (AP) 46 67 (4989) 9 266 (122504) 55 76 (5799)

AP with known risk factor 24 (52) 35 (2252) 4 (44) 118 (32302) 28 (51) 39 (2656) Biliary 14 (30) 20 (1134) 3 (33) 89 (18259) 17 (31) 24 (1438) Alcoholic 7 (15) 10 (421) 1 (11) 30 (1165) 8 (15) 11 (522) Other aetiology 3 (7) 4 (113) 0 3 (5) 4 (112)

Idiopathic 22 (48) 32 (2048) 5 (56) 148 (48345) 27 (49) 37 (2554)

Fishers exact test for haemodialysis versus peritoneal dialysis: P= 0.002; P= 0.016.

renal failure and may exceed three times the upper limit ofnormal even in the absence of acute pancreatitis [13]. Sincethe severity of acute pancreatitis is not dependent on thedegree of pancreatic enzyme elevation, a severe attack mayoccur in a substantial number of patients where the enzyme

elevation is less than three times the upper limit of normal[14]. In our study, the diagnosis of acute pancreatitis wasmade when, in addition to acute abdominal pain, enzymeelevation was present. When this elevation was less thanthree timesthe upper limit of normal, thediagnosis had to besupported by an abnormal imaging procedure [ultrasound(US) or contrast-enhanced computed tomography (CT); seeTable 3].

Alcohol abuse was assumed to be the cause of acutepancreatitis in patients reporting >60 g pure alcohol/day aswas biliary disease in patients who demonstrated stonesin the gallbladder or common bile duct upon differentimaging procedures. Many patients (26/55; in HD patients19 out of 27 and in PD patients 7 out of 9; differences not

significant) received drugs that, in rare cases, have beenthought to cause acute pancreatitis [15]. Because none ofthese patients discontinued this medication after the onsetof acute pancreatitis and no relapse of pancreatitis occurred,however, drug-induced pancreatitis seemed unlikely here.Other factors were considered to be responsible in patientswho had undergone interventional or surgical procedures,suffered from immunological disorders, experienceddialysis-related complications, or had systemic shock,hypercalcaemia (>12 mg/dl), hypertriglyceridaemia(>500 mg/dl) or posttraumatic pancreatitis. In theremaining patients, acute idiopathic pancreatitis wasdiagnosed.

Acute pancreatitis was staged as either mild (abdominal

pain, elevated pancreatic enzymes; no imaging proceduresdeemed necessary by the members of the centre), moderate(mild plus an abnormal US or CT, no necrosis) or severe(moderate plus evidence of necrosis on contrast-enhancedCT).

Centres which reported patients with acute pancreatitis(72 centres; 77 HD and 17 PD patients) received a secondquestionnaire and were asked to send in anonymously themedical charts of these patients for re-evaluation of the di-agnosis with consideration of age, gender, aetiology, medi-cation, onset of symptoms (during dialysis/independent of

the procedure), initiation of dialysis, pain intensity, signs ofperitonitis, amylase and lipase elevation, results of imag-ing procedures, necessity for hospital admission, relapse ofacute pancreatitis and mortality. Altogether, 31 HD and 8PD patients with initially reported acute pancreatitis were

excluded for the following reasons: occurrence of acutepancreatitis in a year other than 2002 (6 HD patients, 1 PDpatient), occurrence prior to the initiation of dialysis (5; 0)or the misdiagnosis of an acute attack of already provenchronic pancreatitis (13; 3). In 11 patients, the diagnosisof acute pancreatitis could not be verified on the basis ofmedical reports (7; 4).

Statistical methods

The incidence rate of acute pancreatitis during dialysis wascalculated dividing the number of events during the year2002 by the number of patients at risk. Ninety-five percent

confidence intervals were calculated using the Fishersexact test. Comparison of the rate of pancreatitis inpatients receiving PD and HD was assessed by the Fishersexact binomial test. The Wilcoxon two-sample test wasused to compare the time interval from first dialysis to thedevelopment of pancreatitis and the Fishers exact test tocompare the proportion of other patients characteristics inthe two dialysis groups. AllP-values were two-sided.

This study was approved by the Ethical Committee of theGeorg-August-University of Gottingen, no. 25/1/03.

Results

The incidence of first-time acute pancreatitis in thesedialysis patients was 75/100 000/year for both procedures,67/100 000/year for HD and 266/100 000/year for PD.

Altogether, 46 cases of acute pancreatitis were foundin 45 centres out of 68 715 HD patients (incidencerate 67/100 000/year, 95% confidence interval, 49 to89/100 000/year) and in 9 patients with acute pancreatitisout of 3386 PD patients [incidence rate 266/100 000/year,95% confidence interval, 122 to 504/100 000/year, Fishersexact test:P= 0.002 (Table 1)].


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Frequency and severity of acute pancreatitis in chronic dialysis patients 1403

Table 2. Characteristics of and parameters of severity of acute pancreatitis in the 55 patients who developed this condition under different dialysisprocedures for chronic renal failure (data not available for all patients)

All dialysis procedures

Patients characteristics and parameters Peritoneal dialysis (n, 9) Haemodialysis (n, 46) P-value

Gender Male 5 25Female 4 21 1.00

Onset of symptoms During dialysis 5 7

Between dialyses 4 39 0.017Severe abdominal pain No 0 1

Yes 9 45 1.00Signs of peritonitis No 5 29

Yes 3 14 1.00Serum amylase 3 times ULNa 2 19 0.41Serum lipase 3 times ULNa 8 30 0.096Ultrasound findings Normal 3 17

Abnormal 5 21 1.00Computed tomography findings Normal 2 9

Abnormal 6 18 1.00Necrotizing pancreatitis (Balthazar score 5 points) No 4 22

Yes 4 5 0.16Hospital admission No 0 11

Yes 9 35 0.18

aUpper limit of normal.

The age of the patients did not differ significantly be-tween the groups [59.5 years in HD patients and 59.0 yearsin PD patients (median values;P= 0.90)]. There were alsono significant differences in ages among the aetiologicalsubgroups.

The two most common aetiological factors were alcoholabuse in 7 HD patients and 1 PD patient, and biliary diseasein 14 HD patients and 3 PD patients. Acute pancreatitiswas related to other defined causes in three HD patients

(immune vasculitis, haemolysis after HD and prior coro-nary bypass surgery). When these patients with a knowncause of acute pancreatitis [28 (51%) out of 55 patients]were excluded, the incidence rate was 32/100 000/year,95% confidence interval, 20 to 48/100 000/year in HDpatients and 148/100 000/year, 95% confidence interval,48 to 345/100 000/year in PD patients, P = 0.016(Table 1).

There was a minimal difference in the time intervalbetween first dialysis and onset of acute pancreatitis:21 months in HD patients and 19 months in PD patients(median values;P= 0.78). No differences concerning thistime interval existed among the different aetiological sub-groups. Finally, no differences were found between PD and

HD patients regarding gender, onset of symptoms, intensityof pain, signs of peritonitis, pancreatic enzyme elevation,abnormal imaging procedures, necessity for hospitalizationand mortality (Table 2).

Acute pancreatitis during dialysis treatment occurredmore frequently in PD patients than in HD patients: 5 (56%)out of 9 PD patients and 7 (15%) out of 46 HD patients.Among patients who had a CT within 72 h from admission,necrotizing pancreatitis was also more frequent in PD pa-tients than in HD patients: 4 (50%) out of 8 PD patients and5 (19%) out of 27 HD patients (Table 2).

Table 3. Staging of acute pancreatitis in the 46 haemodialysis (HD)patients and 9 peritoneal dialysis (PD) patients with acute pancreatitis; allhad acute abdominal pain

Known riskfactor(s)

Unknown riskfactor(s) (idiopathic)

Staging of acutepancreatitis HD PD HD PD All (%)

Milda 11 9 1 21 (38)Moderateb 11 2 10 2 25 (45)

Severec 2 2 3 2 9 (16)

aMild: elevation of amylase/lipase >3 times the upper limit of normal(ULN): 15 patients; elevationof amylase/lipase3 times ULN: 16 patients,abnormal US: 10, abnormal CT: 5, abnormal US and CT: 10 patients.cSevere: elevation of amylase/lipase >3 times ULN: 8 patients, abnormalCT (necrosis): 4, abnormal CT (necrosis) and abnormal US: 5 patients.

In general, acute pancreatitis was mild or moderate inthe majority of patients (84%) and severe only in 16%(Table 3). None of the patients died of acute pancreatitis.

Follow-up of the patients with acute pancreatitis showedthat only 5 (9%) of the 55 patients had a second attackand that they were all from the HD group. Of these, onepatient had continued alcohol abuse, another patient had asecond relapse of acute pancreatitis due to biliary diseaseafter refusing cholecystectomy and the patient whose initialacute pancreatitis had been due to immune vasculitis hadseveral other attacks including one also after successfulkidney transplantation. Furthermore, the two patients withidiopathicpancreatitis hadanother attackof thedisease.Thedialysis procedure had not been changed in these cases.


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Discussion

Theincidence of acute pancreatitis among thegeneral popu-lation of Germany is 19.7/100 000/year [16]. The number ofincidences calculated in our study among dialysis patientsfor both procedures (HD and especially PD) is consider-ably higher. This stands in contrast to the study from theNetherlands that reported that the risk of acute pancreatitis

in patients on PDbut not on HDwas higher than in thegeneral population.Since our study (and probably the Dutch study as well

[11]) was performed in Caucasian patients, we cannot con-firm the observation of the American group that acute pan-creatitis in patients undergoing chronic PD occurs only inthe black population [12].

The proportion of patients with identified risk factorsfor acute pancreatitis was higher in our study (55%) ascompared to the American study (29%) [12]. In the Dutchstudy, no known risk factors were reported in the sevenpatients with acute pancreatitis under PD [11].

The median age at the first attack of acute pancreatitisin dialysis patients did not differ from the median age at

the first attack of acute pancreatitis in all patients at ourhospital, which is 58 years.Most of the patients in our study had mild to moder-

ate pancreatitis (Table 3) when using clinical parametersand imaging procedures for staging. There were no sig-nificant differences between the groups concerning theseverity of abdominal pain, signs of peritonitis and thedegree of pancreatic enzyme elevation. However, some pa-rameters showed that acute pancreatitis in the PD groupwas more severe than in the HD group: all patients of thefirst but only 67% of the second group required hospital-ization for the treatment of the disease, and necrotizingpancreatitis occurred in 50% of the first and in only 19%of the second group. However, the disease had no impact

on patients survival. In contrast, all patients with acutepancreatitis in the American study in whom a contrast-enhanced CT was performed had interstitial pancreatitisand thus the mild form of the disease [12]. In the Dutchstudy, however, two out of seven patients had necrotizingpancreatitis [11]. Similar to our study, mortality was low inthe two other reports: none of the American patients andonly one of the Dutch patients died [11,12]. In our study,the relapse rate of acute pancreatitis in patients on dialysiswas 9%. The two other reports do not have any comparativedata.

Our study has two disadvantages: first, its design,which is retrospective and not prospective. Second, thecontrast-enhanced CT, the gold standard for morphological

evaluation of the pancreas, was performed only in 23 (50%)patients. However, this procedure is frequently impossibleif there is renal insufficiency. Third, there may be a possiblebias due to the over- or under-reporting of acute pancreati-tis. As the usual response rate for medical questionnairesdoes not exceed 58% [17],our response rates of 72% for thefirst and 100% for the second questionnaire may be con-sidered fairly representative. However, 28% of the centresdid not respond to our first questionnaire, which rendersour results less representative than we would have desired.As it is more troublesome to search archives for the medi-

cal records of patients with acute pancreatitis than simplyreport that no such patient was seen, the incidence of acutepancreatitis in chronic dialysis patients may in truth be evenhigher than was reflected in our study.

Idiopathic pancreatitis in this special population maypossibly be due to the cumulative effect of separatepathogenic factors: the risk of the general population;the risk related to renal insufficiency, uraemia, secondary

hyperparathyroidism with hypercalcaemia, hypertriglyceri-daemia and drug abuse [11] plus the risk of dialysis itself. Inthe group of patients with alcohol abuse and biliary disease,dialysis may render the pancreas especially susceptible topancreatitis.

In both groups, the time between the first dialysis proce-dure and the first attack of acute pancreatitis corresponded.However, the occurrence of acute pancreatitis during thedialysis procedure, which was much higher in the PD groupthan in the HD group, suggests that within the dialysisprocess itself there yet exist unidentified risk factors. Thesemay be the composition and amount of fluid given anddialysate through the peritoneum of the lesser sac to the an-terior surface of the pancreas, causing chemical irritation.

Finally, another potential mechanism could be linked to thecalcium in the peritoneal dialysate. Calcium could diffusethrough the peritoneum, causing local hypercalcaemia ofthe pancreas, even though the systemic calcium levels maynot be elevated [12].

In summary, our nationwide study including >70 000dialysis patients establishes that dialysisespeciallyPDis another risk factor that increases the susceptibil-ity of the pancreas to acute pancreatitis, a possibly fataldisease. Furthermore, acute pancreatitis is four times morefrequent and generally more severe in PD than in HD pa-tients. A prospective study would be of interest, especiallyto investigate the specific causes of acute pancreatitis indialysis patients.

Conclusions

Cliniciansshould be aware that acute abdominalpain and/orelevation of pancreatic enzymes in dialysis patients may becaused by acute pancreatitis rather than by uraemic gas-tritis or an insufficient renal clearance of these enzymes.Earlier diagnosis and treatment may be helpful in suchpatients.

Conflict of interest statement. None declared.

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Received for publication: 12.7.07Accepted in revised form: 2.10.07

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