Clinicopathological Features Of Renal Tubulo-interstitial Diseases Induced By Drugs

Because of the fast development and wide usage of new drugs,a large amount of drugs are known to cause acute interstitial nephritis.Drug-induced acute interstitial nephritis(DAIN)is currently the most common etiology of acute interstitial nephritis,with antimicrobials and nonsteroid anti-inflammation drugs(NSAIDs)being the most frequent culprit agents.Acute interstitial nephritis is considered a cause of reversible acute kidney injury.However,DIAIN may result in delayed function recovery or chronic kidney disease.To study the underlying mechanisms,clinical and pathological features of DIAIN with delayed renal function recovery were investigated.Aristolochic acid nephropathy(AAN)was tubular-interstitial damage caused by the intake of aristolochic acid(AA)containing materials.There were lots of reports about the isolated aristolochic acid nephropathy(iAAN).In the clinical practice,however,acute kidney injury induced by AA might occur in patients with chronic kidney disease(CKD).Here,we explored the clinical and pathological characteristics of patients with acute AAN superimposing CKD.Part 1.Clinical and pathological features of drug-induced acute interstitial nephritisObjective:To investigate the clinical and pathological features of patients with drug-induced acute interstitial nephritis(DAIN).Methods:Patients with DAIN from January 2003 to December 2009 were included in this retrospective study.Clinical and pathological datas were analysed.Results:A total of 72 patients were diagnosed as drug-induced acute interstitial nephritis,including 41 male and 31 female,with a average age of 42.7±11.7y(from 18 to 68 years old).Antibiotics were the main offending drugs causing DAIN.43.1%patients presented with gastro-intestinal symptom,and 15.3%patients were asymptomatic.Anemia was found in 37 patients,accounting for 51.3%.Abnormal urine NAG and retinol binding protein(RBP)were observed in 86.1%and 70.8%patients,respectively.Proteinuria and hematuria were found in 52.7%and 12.5%patients.The pathological changes were characterized by different stages of tubular destruction in the renal interstitium,including brush border dropping,tubulitis,and regeneration.Eosinophils infiltrations were observed in 32 patients(44.4%).Conclusion:Antibiotics were the most common incriminated drugs in DAIN.Most patients complained with gastro-intestinal symptom.The pathological changes were accompanied by different stages of tubular destruction.Part 2.Delayed renal function recovery from drug-induced acute interstitial nephritisObjective:Acute interstitial nephritis,considered one of the major causes of reversible acute kidney injury,was frequently encountered as drug-treatment complication in the early stage of infection control.In some cases,drug-induced acute interstitial nephritis(DAIN)resulted in delayed function recovery or chronic kidney disease.To study the underlying mechanism,the authors investigated the clinical and pathological features of DAIN patients with delayed renal function recovery.The delayed recovery group consisted of patients with reduced renal function for more than 3 months after diagnosis.Methods:In this retrospective study,18 patients with DAIN from January 2003 to December 2009 were identified as the delayed recovery group,whereas 54 patients with DAIN who recovered completely within 3 months were treated as the control group.Clinical and pathological features were compared between the 2 groups.Results:In the delayed recovery group,the average age at onset was 48.8 years,antibiotics and herbs were the 2 main causative drugs and the dominant extra-renal manifestation was gastrointestinal symptomatology.In comparison with patients in the control group,patients in the delayed recovery group had longer interval time from disease onset to hospitalization(34.13±30.4vs14.5±15.3d,P<0.001),and they presented with less oliguria.Moreover,these patients had higher levels of urine retinol binding protein(RBP)(32.2±19.6 vs 17.1±14.9mg/1,P=0.004),and more renal interstitial inflammatory cell infiltrations were observed in their renal histology.In logistic regression,it showed that uric acid(OR=0.992,95%CI:0.987?0.998,P=0.012),urine RBP(OR=0.952,95%CI:0.907?0.998,P=0.041),and interstitial eosinophils infiltration(OR=0.173,95%CI:0.032?0.928,P=0.041)were risk factors for delayed renal function recovery.Conclusion:Uric acid,urine RBP,and interstitial eosinophils infiltration were related to delayed renal function recovery in patients with drug-induced acute interstitial nephritis.Part 3.Clinical and pathological features of arisotolochic acid nephropathyObjective:To investigate the clinical and pathological features of aristolochic acid nephropathy.Methods:A total of 79 patients of AAN were enrolled in this retrospective study.The clinical and pathological features were summarized.Factors related to the decreasing rate of e-GFR were analyzed.Results:There were 39 male patients and 40 female patients,aging from 18 to 69y,including 9 acute AAN and 70 chronic AAN.In chronic patients,hypertension,nocturia and fatigue were the main clinical symptoms,accounting for 47.1%,30%and 24.3%,respectively.While among the acute patients,gastrointestinal abnormalities were major complaints.The laboratory examinations showed that anemia was accounting for 80%,86%for abnormal urine NAG,65.2%for abnormal RBP in the chronic group.However,in the acute group,hypouricemia and RTA were more obvious,accounting for 33.3%and 44.4%.Pathologically,chronic AAN presented with prominent thickness of tubular basement membranes(84.6%)and vascular lesions(73.1%).On the contrast,tubular brush border ablating and denuded tubular basement membranes were the main findings.38 chronic AAN patients were followed-up more than 6 months,the gender(r=-0.36,P=0.013),urine protein excretion(r=0.420,P=0.013),the urine RPP(r=0.456,P=0.009),and the glucosuria(r=-0.376,P=0.024)were found out to be factors correlated with the decrease rate of e-GFR.Only 5 acute AAN patients were followed-up in the out-patient department,but 4 of them got improvement with the renal function.Conclusion:Acute AAN patients complained more gastrointestinal symptoms,and presented mainly with tubular brush border ablating and denuded tubular basement membranes.In chronic AAN,hypertension,nocturia,and fatigue were the major complaints,while TBM thickness and vascular lesions were the main findings.The renal function had been restored in acute AAN,however,the chronic AAN had unsatisfied prognosis which was correlated to the gender,proteinuria,RBP and glucosuria.Part 4.Acute kidney injury induced by aristolochic acid in patients with primary glomerular nephritisObjective:Aristolochic acid nephropathy(AAN)was tubular-interstitial damage caused by the intake of aristolochic acid(AA)containing materials.There were lots of papers about the isolated aristolochic acid nephropathy.In the clinical practice,however,acute kidney injury induced by AA might occur in patients with chronic glomerular nephritis(CGN).Here,we explored the clinical and pathological characteristics of patients with acute AAN superimposing CGN(AAN-CGN).Methods:18 patients with acute AAN were included in this retrospective study,from January 2000 to December 2009.According to the pre-existing CGN,13 patients were identified as the AAN-CGN group,and 5 isolated AAN patients as the control group.Clinical and pathological features were compared between the two groups.Results:In the AAN-CGN group,6 patients complained with gastrointestinal symptoms,such as nausea,vomiting or loss of appetite.The rest of 7 cases were asymptomatic or minimally uncomfortable,who were found with elevated serum creatinine(Scr)in the follow up of CGN.No patients presented with oliguria.For the laboratory data,there was no difference found in the levels of Scr,urine retinol binding protein,and urine osmole between the two groups.And incidences of anemia,hypertension,and glucosuria were similar in the two groups.Furthermore,patients in AAN-CGN group had higher levels of serum uric acid,urine n-acetyl-?-d-glucosaminidasae,and urine protein excretion(366.2±122.8 vs 218.0±125.8umol/l,P=0.037;9.74±4.4 vs 1.38±1.01g/d,P=0.001;61.2±21.9vs 27.4±15.8 u/g.cr,P=0.007,respectively).Compared with the control group,the AAN-CGN patients had a absolutely prominent percentage of macromolecule substance in the urine protein electrophoresis(25.0±6.32 vs 15.8±7.8%,P=0.029).The occurrence of hypokalemia and excretion of aminoaciduria were lower than that in the control group.Pathologically,92.3%of patients were found with tubular brush border dropping,30.8%with naked tubular basement membrane,and 15.4%with different stages of vascular lesion.There were no statistical differences in the above mentioned pathological parameters between the two groups.In the follow-up,10 patients with AAN-CGN recovered with normal Scr,accounting for 76.9%,which was better than the recovery in the control group(40.0%),though it did not reach the statistical difference.Conclusion:Patients with acute AAN superimposing CGN manifested with a great mass of urine protein excretion and a large percent of macromolecule substance in the urine.Compared to the isolated acute AAN,the hypokalemia and the extent of aminoaciduria were less obvious.Furthermore,the tubular-interstitial lesions were similar to the isolated AAN.As a result,for acute kidney injury in patients with CGN,more attention should be paid to the medication history,especially for the AA containing drugs,and renal biopsy should be performed if possible,avoiding the ignorance of renal damage caused by AA.