Abstract
Background and objectives: The objective of this study was to describe the characteristics of patients with HIV infection and biopsy-proven acute interstitial nephritis (AIN).
Design, setting, participants, & measurements: Pathology reports were reviewed for patients who had HIV infection and underwent renal biopsy at Johns Hopkins Hospital from January 1, 1995, through January 1, 2008. Patients who received a diagnosis of AIN without evidence of HIV-associated nephropathy were identified, and their clinical course was reviewed up to 18 months after biopsy.
Results: Of 262 biopsies, 29 (11%) patients who had AIN without evidence of HIV-associated nephropathy were identified. The mean age at the time of biopsy was 47.5 years (range 28 to 71 years), 17 (59%) were men, and 23 (79%) were black. The majority (62%) of patients were on antiretroviral therapy, 59% were current or former intravenous drug users, and 62% had hepatitis C co-infection. Drugs were identified as the cause of AIN in the majority (72%) of cases. Nonsteroidal anti-inflammatory drugs were most commonly implicated, followed by sulfamethoxazole/trimethoprim. Antiretroviral therapy was identified as the cause in only three cases. None of the patients presented with the classic triad of fever, rash, and pyuria, and only seven (24%) patients presented with <1 g/d proteinuria.
Conclusions: In our series, AIN was prevalent (11%) and was often drug induced. AIN should not be excluded from the differential diagnosis on the basis of absence of the classic clinical triad of fever, rash, and pyuria.
Patients with HIV infection are afflicted with many renal diseases other than HIV-associated nephropathy (HIVAN) (1). In a report of 152 consecutive renal biopsies in patients with HIV infection at our institution, HIVAN was indeed the most common diagnosis, seen in 34.9% of specimens (2). The third most common diagnosis in this series was acute interstitial nephritis (AIN; 7.9%). In a 2007 Swiss case series, Schmid et al. (3) reported AIN in six (20%) of 30 for-cause biopsies in individuals with HIV infection.
Patients who have HIV infection and acute kidney injury require particularly special attention for the increased possibility of AIN compared with individuals without HIV infection. Potential risks include (1) frequent exposure to drugs linked to hypersensitivity reactions in the renal parenchyma, including some antibiotics and antiretroviral medications (4) (Table 1); (2) increased risk for disseminated or severe infections linked to interstitial nephritis; (3) immunologic syndromes associated with HIV disease and AIN, including immune reconstitution inflammatory syndrome (IRIS) and diffuse infiltrative lymphocytosis syndrome (DILS); and (4) interstitial inflammation caused by the HIV itself, as suggested by the pathologic changes seen in HIVAN.
Table 1.
Causative agents associated with AIN in patients with HIV infection
| Drugs |
| ARVs |
| indinavir |
| abacavir |
| atanazavir |
| antibiotics |
| β lactams |
| sulfonamides |
| quinolones |
| rifampin |
| proton pump inhibitors |
| NSAIDs |
| furosemide |
| foscarnet |
| allopurinol |
| Infections |
| Cryptococcus |
| tuberculosis |
| adenovirus |
| Epstein-Barr virus |
| polyomavirus |
| cytomegalovirus |
| Candida |
| Immunologic |
| DILS |
| immune reconstitution |
The vast majority of AIN cases in the general population are associated with a drug hypersensitivity reaction (5). In addition to common causative agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and antibacterial antibiotics, patients with HIV infection are commonly exposed to antiretroviral (ARV) and antituberculosis drugs that are known to cause AIN. Furthermore, a variety of ARV drugs such as indinavir, abacavir, and atanazavir have been implicated in the cause of biopsy-proven AIN (4,6,7).
Infection-induced AIN is not unique to the HIV population; however, in light of their immunocompromised state in the context of AIDS, patients with HIV infection are at increased risk for severe or disseminated infections that are known to cause AIN. In a prospective study carried out in Thailand, ARV-naive patients with HIV and >1.5 g/d proteinuria were offered renal biopsy (8). Three of 26 patients had AIN, and all cases were attributed to infection (one to tuberculosis and two to Cryptococcus). Similarly, Epstein-Barr virus, adenovirus, and polyomavirus have been reported as causes of AIN in patients with HIV infection (9–11).
Pathologic, oligoclonal CD8+ cell expansion and immune restoration inflammatory syndrome both are associated with HIV disease and have been implicated in AIN (12,13). DILS is characterized by an oligoclonal expansion of CD8+ lymphocytes in patients with HIV infection. DILS typically presents as a diffuse inflammatory process that often mimics infectious or rheumatologic disease and can present with AIN (12), often in patients with uncontrolled HIV infection despite long-term highly active ARV therapy (13). IRIS is associated with initiation of ARV therapy in severely immunosuppressed patients with HIV infection and can present with AIN (13). Both syndromes can present with granulomatous interstitial nephritis in the absence of active mycobacterial infection. IRIS-associated AIN may be difficult to differentiate from drug-induced AIN (from ARV therapy) because both present days to weeks after the initiation of ARV therapy. In this study, we set out to characterize features of AIN in patients with biopsy-proven disease in the setting of HIV infection.
Materials and Methods
All renal biopsies done on patients with HIV infection at Johns Hopkins Hospital between January 1, 1995, and January 1, 2008, were evaluated for the diagnosis of AIN. Cases were identified by their original (archived) pathologic diagnosis. A total of three attending pathologists signed out the reports. All are specialized in renal pathology. Because interstitial nephritis is an integral component of the morphologic findings of HIVAN, patients with biopsy-proven HIVAN were excluded from study. Approval of the study was obtained from the Johns Hopkins Hospital institutional review board.
Baseline serum creatinine was defined as the lowest reported value within the 3 months before biopsy. In two cases, previous renal function was reported qualitatively as “normal.” These patients were assigned a baseline serum creatinine of 1.0 mg/dl. Proteinuria was determined by 24-hour collections in the majority of cases, although a few were determined by spot protein-to-creatinine ratio measurement. Specific drugs implicated as the cause of the AIN were identified on the basis of the treating clinician's assessment at the time of the biopsy. Assessment of the implicated agent was evaluated by authors (S.M.P. and D.M.F.) to confirm appropriate timing of exposure or recovery after withdrawal of proposed culprit agent.
Follow-up laboratory data were assessed in the 3- to 6-month, 6- to 12-month, and 12- to 18-month periods after biopsy. The first data point in each date range was used in analysis. Renal recovery was defined as serum creatinine within 0.2 mg/dl of baseline.
Results
Of 262 renal biopsies performed on patients with HIV infection at Johns Hopkins Hospital between January 1, 1995, and January 1, 2008, 30 (11.4%) biopsies that corresponded to discrete patients had AIN. One patient had no follow-up data after biopsy and was thus excluded from analysis.
Baseline characteristics of the studied patients are presented in Table 2. The population was predominately black (79%), and the majority (62%) had co-infection with hepatitis C and history of injection drug use (59%). Mean CD4 count at presentation was 284 cells/ml (SD 197).
Table 2.
Baseline characteristics of 29 patients with HIV infection and biopsy-proven interstitial nephritis
| Characteristic | Value |
|---|---|
| Age (years; mean [range]) | 47.5 (38 to 71) |
| Female gender (n [%]) | 12 (41) |
| Black race (n [%]) | 23 (79) |
| Hypertension (n [%]) | 15 (52) |
| Hepatitis C (n [%]) | 18 (62) |
| Injection drug use (n [%]) | 17 (58) |
| CD4 count (cells/mm3; mean) (n = 28) | 278 |
| <200 (n [%]) | 12 (41) |
| 200 to 500 (n [%]) | 14 (48) |
| >500 (n [%]) | 3 (10) |
| HIV viral load (copies/ml; mean) | 64,300 |
| Proteinuria (g/d) | |
| mean | 2.9 |
| <1 g/d (n [%]) | 8 (28) |
| 1.0 to 3.5 (n [%]) | 12 (41) |
| >3.5 (n [%]) | 9 (31) |
| Serum creatinine (mg/dl; mean)a | |
| baseline (n = 23) | 1.4 |
| peak | 5.6 |
Baseline serum creatinine was defined as the best serum creatinine in the 3 months before biopsy. Baseline serum creatinine was not known for five patients. Peak serum creatinine was defined as the highest serum creatinine observed within 18 months after biopsy.
Detailed characteristics of all 29 patients are shown in Table 3. None of those patients presented with the classic clinical triad of hypersensitivity that includes fever, rash, and peripheral eosinophilia. Pyuria and hematuria were the most common clinical features in these patients. The mean baseline serum creatinine was 1.36 mg/dl (n = 26) at the time of renal biopsy. The degree of proteinuria at presentation varied widely and was, on average, 2.8 g/d (SD 2.9). Only seven patients had <1 g/d proteinuria. Coexisting noncollapsing focal and segmental glomerulosclerosis (FSGS) was found in eight patients; six were on ARV therapy at presentation, and five had an undetectable HIV viral load.
Table 3.
Selected characteristics of 29 patients with HIV and biopsy-proven AIN
| Characteristic | Value |
|---|---|
| Presentation | |
| fever (n [%]) | 1 (3) |
| rash (n [%]) | 0 (0) |
| peripheral eosinophilia (n [%]) | 13 (45) |
| pyuria (>5 cells/hpf; n [%]) | 16 (55) |
| hematuria (>3 cells/hpf; n [%]) | 15 (52) |
| proteinuria (g/d; mean [SD]) | 2.8 (2.9) |
| Culprit drugsa | |
| NSAIDs | 6 |
| SMZ/TMP | 3 |
| dapsone | 1 |
| ciprofloxacin | 1 |
| atanazavir | 1 |
| abacavir | 1 |
| indinivir | 1 |
| furosemide | 1 |
| cocaine | 1 |
| omeprazole | 1 |
| Biopsies with a second major diagnosis (n [%]) | 24 (70) |
| FSGS (noncollapsing) | 8 (24) |
| ATN | 6 (21) |
| other | 10 (34) |
| Outcome (n [%]) | |
| full renal recovery | 9 (31) |
| ESRD within 18 months | 6 (21) |
| ESRD caused by AIN | 4 (14) |
| insufficient follow-up data | 4 (14) |
ATN, acute tubular necrosis; hpf, high-power field; SMZ/TMP, sulfamethoxazole/trimethoprim.
n = 17 when a single culprit drug was identified.
The treating clinician considered a drug-mediated AIN as a possible cause in 21 (72%) patients. A single culprit drug was identified in 17 (57%) patients, and NSAIDs were the most commonly identified agent (21%) followed by sulfamethoxazole/trimethoprim (10%; Table 3). ARV agents were implicated in only three cases. The majority (72%) of patients had a coexisting pathologic diagnosis on biopsy including seven (24%) with noncollapsing FSGS and four (14%) with acute tubular necrosis in addition to other diagnoses shown in Table 4.
Table 4.
29 Cases of biopsy-proven interstitial nephritis in patients with HIV
| Patient | Gender | Age | CD4 | HIV Viral Load (thou sands) | ARV? | Comorbidities | Presentation | Proteinuria | Other Biopsy Diagnosis | Fever/Rash/ Pyuria/Hematuria | Baseline Scr | Peak Scr | Outcome | Culprit | Other Exposures |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | M | 49 | 287 | <0.4 | Yes | Type 2 diabetes, Hep C | Worsening proteinuria with previous diabetic nephrosclerosis and PIGN | 2577 | Diabetic nephropathy | Hematuria | 1.5 | 12.7 | ESRD on hemodialysis | ?ABC | 3TC/ZDV, EFZ, ramapril |
| 2 | F | 42 | 2 | 3.5 | Yes | Hep C, IVDU | AKI, proteinuria | 3240 | ATN | Pyuria/hematuria | 1.0 | 6.8 | Returned to baseline in 2 months | SMZ/TMP | ABC, RTV, 3TC, valcyclovir, atanazovir |
| 3 | M | 54 | 77 | <0.4 | Yes | HTN | AKI | 1585 | NA | None | 0.8 | 6.1 | CKD, Scr 1.4 at 18 months | SMZ/TMP | FTC/TDF, ATV, RTV, dilantin, |
| 4 | M | 44 | 258 | <0.4 | Yes | Type 2 diabetes, HTN | AKI, uremia | 3961 | ATN | Pyuria/hematuria | ? | 17.6 | 3 months of HD, then CKD with Scr 3.5 | NSAIDs | Lisinopril, glucovance, T20, tipranavir |
| 5 | F | 52 | 453 | 1.6 | Yes | Hep C, IVDU | AKI and proteinuria, low complement | 6520 | PIGN | Pyuria/hematuria | 1.0 | 5.0 | Returned to baseline within 6 weeks | ? | LP/r, TDF/FTC |
| 6 | M | 58 | 458 | <0.4 | Yes | HTN | AKI, peripheral eosinophilia, glucosuria (with normal serum glucose) | 3280 | ATN | Pyuria/hematuria | 1.0 | 5.7 | Partial recovery, Scr 1.3 after 18 months | Omeprazole | Lisinopril, LPV/r, ddI, 908, |
| 7 | M | 41 | 35 | 23.1 | Yes | HTN, Hep C, IVDU | Acute on chronic renal insufficiency, proteinuria | 600 | Focal Thrombotic Microangiopathy | None | 1.3 | 3.0 | CKD, Scr 1.8 at 18 months | SMZ/TMP | T-20, TPV, RTV, azithromycin, furosemide |
| 8 | F | 51 | 321 | 4.6 | No | HTN, Hep C, IVDU | AKI, edema | 1966 | FSGS | Pyuria/hematuria | ? | 3.6 | No significant recovery, CKD | NSAIDs | Nifedipine |
| 9 | F | 42 | 165 | 138.1 | No | HTN, Hep C, IVDU | AKI after multidrug overdose | 4000 | NA | Pyuria/hematuria | 1.0 | 5.2 | ESRD on hemodialysis | ? | Alprazolam, promethazine, clonazepam |
| 10 | F | 55 | 496 | <0.4 | Yes | HTN, Hep C, IVDU | Proteinuria, early stage 3 CKD | 2700 | Podocyte effacement | Pyuria/hematuria | 1.1 | 7.0 | Returned to baseline in 1 month | Cocaine | ABC/LPV, RTV, ATV, losartan |
| 11 | M | 71 | 474 | <0.4 | Yes | HTN | Acute on chronic renal insufficiency | 3240 | PIGN | Pyuria/hematuria | 1.7 | 10.1 | ESRD on hemodialysis | ATV | RTV, ABC/LPV |
| 12 | F | 32 | 899 | 317.0 | No | Hep C, IVDU | AKI during admission for subacute bacterial endocarditis | 1518 | NA | None | 0.8 | 5.6 | Returned to baseline within 3 weeks | NSAIDS | None |
| 13 | F | 41 | 144 | 472.6 | No | HTN, IVDU | Stage 4 CKD | 2530 | FSGS | None | 3.0 | 8.9 | ESRD on hemodialysis | Hydralazine/ dapsone | None |
| 14 | M | 45 | 386 | 34.3 | Yes | HTN, Hep C, IVDU | Acute on chronic renal insufficiency, previous ICGN | 7473 | ICGN | Pyuria/hematuria | 1.2 | 6.1 | CKD, Scr 2.8 at 18 months | ? | ABC/3TC, ATV, metoprolol, nifedipine, atorvastatin |
| 15 | M | 54 | 195 | <0.4 | Yes | HTN, Hep C, IVDU | AKI, proteinuria | 12,900 | Amyloid/FSGS | Pyuria/hematuria | 1.3 | 2.7 | ESRD on HD in 9 months; amyloid only on rebiopsy | ? | LP/r, AZT/3TC, benztropine, SMZ/TMP, fluphenazine, haloperidol, fenofibrate |
| 16 | M | 51 | 225 | 10.5 | Yes | HTN, Hep C, IVDU | Acute on chronic renal insufficiency | 310 | FSGS | None | 1.2 | 2.4 | Partial recovery, Scr 1.7 after 12 months | ? | EFV, ABC/AZT/3TC, nifedipine, valsartan, minocycline |
| 17 | F | 51 | 77 | >100.0 | No | HTN, Hep C, IVDU | Acute on chronic renal insufficiency | 1638 | NA | Pyuria/hematuria | 2.1 | 5.7 | Return to baseline within 6 months | Furosemide | None |
| 18 | M | 64 | 280 | <0.4 | Yes | None | Acute on chronic renal insufficiency | 370 | FSGS | None | 1.3 | 2.4 | Return to baseline within 3 months | NSAIDs/ampicillin | None |
| 19 | M | 39 | 74 | <0.4 | Yes | None | AKI on treatment for MAC | 779 | NA | None | 1.1 | 4.0 | Partial recovery, Scr 1.4 after 12 months | SMZ/TMP, ethambutol | Clarithromycin, rifabutin, NFV, D4T, 3TC |
| 20 | M | 42 | 64 | 52.8 | No | Hep C | Slow recovery from previous ischemic ATN requiring dialysis | 1672 | NA | None | 1.6 | 5.6 | CKD, Scr 4.1 at 18 months | Dapsone | Pentamidine, dapsone, nortryptiline, pantoprozole, lamotrigine, azithromycin |
| 21 | M | 49 | 533 | 38.7 | No | HTN, Hep C, IVDU | AKI and proteinuria | 1062 | 50% global sclerosis | None | 2.5 | 8.3 | ESRD on HD within 6 months | ? | Clonidine |
| 22 | F | 28 | 42 | 30.0 | No | None | AKI, proteinuria, hematuria | 438 | ICGN | Fever/pyuria/hematuria | 1.7 | 3.3 | Return to baseline within 12 months | NSAIDs/amoxicillin | None |
| 23 | M | 39 | 429 | 0.4 | Yes | IVDU | AKI | 100 | Crystal nephropathy | Pyuria | 0.7 | 1.4 | Return to baseline within 3 months | IDV | AZT/3TC, RTV, atorvastatin |
| 24 | M | 57 | 87 | 0.4 | Yes | Hep C, IVDU | AKI, sepsis | 598 | FSGS | Pyuria/hematuria | 0.7 | 5.4 | CKD, Scr 2.2 at 18 months, required acute HD | NSAIDs | EFV, D4T, 3TC, dapsone |
| 25 | F | 29 | 229 | 12.3 | No | None | AKI | 6000 | Chronic HTN changes | Pyuria/hematuria | ? | 6.0 | ESRD on HD within 18 months | NSAIDs | |
| 26 | F | 34 | 320 | 0.4 | Yes | Hep C, IVDU | AKI, proteinuria | 7000 | FSGS | None | 1.4 | 1.7 | CKD, Scr 1.7 at 18 months | ? | ABC/AZT/3TC, LPV/r, levothyroxine, atorvastatin |
| 27 | M | 55 | 634 | 16.7 | No | Hep C, IVDU | Acute on chronic renal failure, proteinuria | 4000 | NA | Pyuria/hematuria | 1.6 | 3.2 | CKD, Scr 2.8 at 18 months | Ciprofloxacin | None |
| 28 | M | 68 | 188 | >100.0 | No | None | Acute on chronic renal failure | 578 | NA | None | 1.3 | 4.1 | Return to baseline within 6 months | NSAIDs | Excedrin™, cough syrup |
| 29 | F | 41 | 410 | 0.4 | Yes | HTN, Hep C, IVDU | Acute on chronic renal insufficiency, sterile pyuria | 1000 | ATN | Pyuria | 1.4 | 1.7 | Return to baseline within 9 months | ? | EFV, ABC/3TC, paroxitine, mirtazipine, quetiapine, nifedipine, lisinopril |
Patients 3, 6, 11, and 21 received steroids. 3TC, lamivudine; ABC, abacavir; AKI, acute kidney injury; ATN, acute tubular necrosis; ATV, atanazivir; AZT, zidovudine; CKD, chronic kidney disease; d4T, stavudine; EFV, efavirenz; FTC, emtricitabine; HD, hemodialysis; HTN, hypertension; ICGN, immune complex glomerulonephritis; IDV, indinavir; IVDU, intravenous drug use; Hep C, hepatitis C; LPV/r, lopinavir/ritonovir; PIGN, postinfectious glomerulonephritis; Scr, serum creatinine; T20, enfuvirtide; TDF, tenofovir; TPV, tiprinavir.
Full renal recovery was noted in only nine (31%) patients with a mean time to recovery of 5.7 months (SD 5.4 months). During the 18 months of the study period, six (21%) patients progressed to ESRD. The treating clinician concluded that AIN was the primary cause of ESRD in four (14%) patients.
Discussion
AIN was prevalent in our population of patients who had HIV infection and underwent renal biopsy. As a group, they did not often have classic features of AIN. Even in those without a secondary diagnosis of glomerular disease, mean proteinuria was >1 g/d. This is perhaps higher than one would expect with a tubulointerstitial process, although well described in those with NSAID-induced AIN, in whom a minimal-change lesion may coexist. Renal outcomes were generally poor in this series, with only nine (31%) returning to baseline renal function within the 18-month study period.
Commensurate with high rates of opportunistic and other infections in patients with HIV infection, it might be expected that infectious conditions would account for a higher proportion of HIV-related AIN than in the individuals without HIV; however, we found that drugs were implicated in a majority of HIV-related AIN cases. In our series, 72% of cases of AIN were attributed to a drug cause, which is similar to reports in the individuals without HIV. For example, in pooled data from three studies of 128 undifferentiated patients with AIN reported by Baker and Pusey (5) the cause of AIN was reported as drug related in 71% of cases.
For the 28% of patients who did not have a drug identified, no alternative cause was identified in the medical record. It is possible that our series contained cases of viral or mycobacterial induced AIN that were not appreciated. Similarly, some cases may have been caused by DILS or IRIS. We could not, with confidence, make those diagnoses upon retrospective chart review. One may also speculate that the interstitial inflammation resulted from the HIV itself; that some cases represent an “early HIVAN” or HIVAN associated with noncollapsing FSGS; however, in addition to absence of collapsed glomeruli, there was no evidence of tubular microcysts, also seen in HIVAN. Of note, the mean viral loads and CD4 counts of those with FSGS were similar to those with other glomerular diagnoses and to those with no glomerular diagnosis at all (Table 4).
We found that >11% of renal biopsies of patients with HIV infection revealed AIN. Nochy et al. (14) reported a frequency of 52% in their 1993 biopsy series of 60 patients with HIV infection; however, since clear criteria for the pathologic diagnosis of HIVAN were established, reported frequencies have been lower. The 2007 series from Schmid et al. (3) of 30 patients who had HIV infection and underwent biopsy reported AIN in six (20%) patients. Frequency of AIN in non-HIV biopsy series varies widely as well and depends on the indications for biopsy. Davison et al. (15) reported an interstitial nephritis frequency of 5.9% in the UK MRC Glomerulonephritis Register in 1998 on a total of 7161 adult patients who underwent renal biopsy for various indications. Farrington et al. (16) found AIN in 27% of 109 patients who underwent biopsy for unexplained renal impairment with normal kidney size.
The high number of patients with additional pathologic diagnoses in our series is comparable to the general population. Again, the 1998 report by Davison et al. (15) found that, whereas interstitial nephritis was seen in 5.9% of biopsies, it was the sole pathologic feature in only 2.2% of biopsies. It is possible that those with preexisting kidney disease are being monitored more closely for renal changes that prompt biopsies, thereby producing a selection bias.
Limitations include the potential lack of generalizability to all HIV populations. Our population had particularly high hepatitis C infection and injection drug use rates. In addition, approximately half of the patients were on ARVs and one quarter had advanced disease reflected by low CD4 counts. Also, the high rate of progression of renal insufficiency in this population may reflect underlying renal disease. Specifically, all patients except one who went on to develop ESRD had chronic kidney disease; however, in all cases, the acute change in kidney function was associated with a biopsy-proven AIN lesion, and the lack of recovery could reflect a lack of renal reserve in those with already advanced kidney disease. Finally, although the lack of confirmation of the diagnosis by a single blinded pathologist is a limitation, the pathologic diagnosis was made at the time of biopsy by renal pathologists who were in reality blinded to the objectives of the study.
Conclusions
In this selected group of patients who had HIV infection and underwent renal biopsy, AIN was prevalent and often had a heterogeneous presentation. Given the complexity of the presentation of AIN in HIV, we believe that renal biopsy is often required for definitive diagnosis. Although our data represent the largest series to date characterizing AIN in patients with HIV, further study into the precise risks for this disease in the HIV population is required.
Disclosures
None.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
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