Acquired immunodeficiency syndrome-associated renal disease in children

Acquired immunodeficiency syndrome-associated renal disease in children E d w a r d Connor, MD, Suresh G u p t a , MD, V i j a y Joshi, MD, Frederick DiCarlo, MD, J a c o b O f f e n b e r g e r , MD, A n t h o n y Minnefor, MD, C o n s t a n c l a Uy, MD, J a m e s Oleske, MD, a n d N o r m a n Ende, MD From the Departments of Pediatrics and Pathology, The Children's Hospital of New Jersey and the Universityof Medicine and Dentistry of New Jersey Medical School, Newark; the Barnett Memorial Hospital Center, Paterson, New Jersey; the Department of Pediatrics, Newark Beth Isreal Medical Center, Newark, New Jersey; and the Department of Pediatrics, St. Joseph's Hospital and Medical Center, Paterson, New Jersey

Five children with acquired immunodeficiency syndrome (AIDS) and clinically significant renal disease had detailed pathologic examination of renal tissue (biopsy specimens, autopsy specimens, or both). All patients had proteinuria, hypoalbuminemia, and edema; one patient had persistent azotemia. In two cases, renal disease was the first manifestation of human Immunodeficiency virus (HIV) infection. All patients had progressive renal disease, and four of the five died. Pathologic studies revealed focal glomerulosclerosis and mesangial proliferative glomerulonephritis with deposits of immunoglobulins and complement demonstrated by immunofluorescence a n d electron microscopy. Characteristic tubuloreticular structures were also demonstrated in the glomerular endothelial or epithelial cells in two cases. Renal disease is part of the multisystem involvement in children with AIDS. The pathogenesis of renal disease is not known, but circulating immune complexes are known to occur in children with HIV infection and m a y be involved. (J PEDIATR1988;413:39-44)

Symptomatic infection with human immunodeficiency virus I is a chronic multisystem disease with prominent immunologic, lymphoreticular, neurologic, and pulmonary symptomsJ -5 Renal disease has been found in as many as half of adult patients with AIDS but has not been described as a significant part of AIDS in pediatric patients. 6-8 Renal abnormalities in adult patients include proteinuria, abnormalities of urinary sediment, altered creatinine clearance, and electrolyte and acid-base derangements.68 Histopathologic examination of renal tissue has revealed a variety of glomerular and tubular lesions, including focal and segmental glomerulosclerosis, mesangial proliferation, acute tubular necrosis, interstitial nephritis, and nephrocalcinosis.6'7,9-12 Submitted for publication Octl 6, 1987; accepted Feb. 1, 1988. Reprint requests: Edward M. Connor, MD, Children's Hospital of New Jersey, 15 South 9th St., Newark, NJ 07107.

Among adult patients with acquired immunodeficiency syndrome, the frequency of renal complications varies from center to center; most reported cases have occurred on the East Coast, where intravenous drug use is a more common risk factor for AIDS. 7 It has been suggested that

CHAP CDC ELISA HIV

Children's Hospital AIDS Program Centers for Disease Control Enzyme-linked immunosorbent assay Human immunodeficiencyvirus I

the effects of intravenous drugs themselves may play an important role in the development of renal disease. 7, t0,11 The evaluation of children who were perinatally infected with HIV affords the opportunity to study the pattern of renal disease unrelated to drug abuse. Over the past 3 years we have seen serious renal disease

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Connor et al.

The Journal of Pediatrics July 1988

Table. Clinical data A g e at HIV Patient Dx No, (mo)

1

3

A g e at Dx of renal disease (mo)

6

Race

White

AIDSAssociated infection

PCP Candida

Medications before onset of renal disease

Blood pressure (mm/Hg)

TMP-SMZ Pentamidine

86/NA (106/66)t

esophagitis 2

5

15

3

48

108

4

6

6

5

60

60

Electrolytes (mEq/L) Urinalysis

4+ protein 4+ blood Gross hematuria 119/92 4+ protein (105/67-69) 25 WBC/ HPF

Haitian Candida Pentamidine esophagitis Vancomycin TMP-SMZ Amphotericin B B l a c k MAI None 130/90 (115/74)

Na

K+

Cl

HCO3-

132 2.5 106

15

130 3.8 102

15

4+ protein

132 2.7 104

7.6

B l a c k Candida esophagitis

None

88/NA (106/66)

4+proteha 2+ blood 25 WBC/ HPF 10 casts/ HPF

118 3.6 101

11

B l a c k PCP

None

NA

4+ protein

138 4.1 104

20

Dx, Diagnosis;PCP, Pneumocystis carinii pneumonia;TMP-SMZ, trimethoprim-sulfamethoxazole;AMI, Mycobacteriurn aviurn intracellulare; NA, not available;WBC/HPF, whitebloodcell/high-powerfield;GN, glomerulonephritis;TRS, lubuloretieularstruetures~ *Calculated creatinine= C= = Height (cm) X K/P= (SchwartzG, BrionLP, Spitzer A. PediatrClinNorth Am 1987;34:571-89). "~90thpercentilesystolic/diastolicfor age (Task Forceon BloodPressureControl in Children_Pediatrics 1987;79:1-25).

in five ,children with AIDS. In this article we report their clinical course and pathologic findings. METHODS Between March 1984 and March 1987, a total of 175 children with symptomatic HIV infection were identified through the Children's Hospital AIDS Program. Medical records were reviewed, and five children with renal disease who had pathologic examination of renal tissue were identified. The medical records and the pathologic data on these five patients were reviewed in detail and compose the subject of this report, Overall, among symptomatic HIVinfected children enrolled in CHAP, approximately 40% had intermittent abnormalities on urinalysis, electrolyte determination, or both. Evidence for clinically apparent renal disease was found in the medical records of only the five children reported here. Cases were classified as AIDS if they fulfilled the CDC case definition.13,14 All children had seropositive test results for HIV by ELISA and Western blot. Renal biopsy specimens from three patients and renal

tissue from autopsy of two patients (collected within 6 hours of death) were processed for light, immunofluorescence, and electron microscopy.* Specimens for light microscopy from all patients were processed routinely and stained with hematoxylin-and-eosin, periodic acid-Schiff, Jones, and trichrome stains. Tissue for immunofluorescence studies was snap frozen and examined by direct immunofluorescence technique. Material for electron microscopic examination was available from four patients (three biopsies and one autopsy) and was processed by standard methods. RESULTS Clinical data (Table). All patients had AIDS, and all had acquired HIV infection perinatally. The mean age at clinical presentation of symptomatic HIV infection was 24.4 months (3 to 60 months), and the mean age at clinical *Dr. Norman Ende performed the light, immunoflu0rescence, and electron microscopic studies on renal biopsy and autopy specimens.

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Serum Anion cholesterol gap (mg/d!)

A I D S - a s s o c i a t e d renal disease

Calculated creatinine* Serum clearence albumin (ml/min/ (gm/dl) 1.73 m 2)

Renal ultrasonography

BUN/CR (mg/dl)

Specimen source

11

241

3.9

27

.20/0.7

Hydronephrosis Acute Cystitis

Biopsy

13

339

1.3

32

14/0.9

Normal

Biopsy

20.4

243

1.2

21

48/3.1

Normal

Biopsy

6

58

1.6

36

32/0.8

Normal

Autopsy

14

NA

2.6

NA

14/0.5

Normal

Autopsy

presentation of progressive renal disease was 39 months (6 to 108 months)i All five patients were girls. The mean interval between the onset of HIV symptoms and the development of renal disease was 14.6 months ( 0 t o 60 months). In two cases, renal disease represented the first manifestation of HIV infection that brought thepatient to medical attention. All patients had proteinuria, all had edema, and four of five patients progressed to end-stage renal disease and died. In one case the patient's renal status stabilized. The most common clinical presentation included edema and proteinuria associated with intermittent hematuria, hypo: natremia, and metabolic acidosis. In one patient, macroscopic hematuria was found throughout the course and was associated With evidence of acute cystitis. Hypertension occurred in two patients and required antihypertensive therapy. Two patients received known or potentially nephrotoxic drugs before the development of clinical evidence of renal dise~/se; in three cases, no such medications were known to have been given. Patient 4 received multiple drugs after the development of renal signs and symptoms but before the time of pathologic examination of renal tissue; these drugs

Histopathologic diagnosis

Mesangial proliferative GN with immune complex deposits Focal segmental glomerulosclerosis, focal interestitial nephritis, TRS Mesangial proliferative GN with sclerosis, TRS Immune complex GN, mesangial proliferative GN with focal global glomerulosclerosis, calcification, focal and difuse; interstitial nephritis, focal Focal segmental glomerulosclerosis

41

Outcome (age)

Died (7 mo)

Alive (18 too)

Died (114 mo)

Died (17 mo)

Died (60 mo)

included amphotericin B, phenytoin, cloramphenicol, trimethoprim-sulfamethoxasole, isoniazid, rifampin, streptomycin, ticarcillin, nafcillin, and tobramycin. All patients had seronegative test results for hepatitis B virus. Three patients were being treated with intravenous gammaglobulin at the time of pathologic examination. Autopsy and pathologic examination failed to reveal evidence of renal infection. Urine Cultures were sterile in four patientsi in one child, midstream urine grew Escherichia coli. Four of the five patients had no evidence of anatomic abnormalities of the urinary tract, either by radiographic studies or at postmortem examination of fatal cases. Presentation with renal disease in one patient (patient 1) included gross hematuria; renal ultrasound examination revealed mild hydronephrosis, the intravenous pyelogram showed enlarged kidneys bilaterally, and a cystogram revealed no reflux but evidence of acute (probably chemically induced)cystitis. Pathologie~studies (Table). Focal glomerulosclerosis (Fig. 1) was found in two patients and mesangial proliferative glomerulonephritis (Fig. 2) in three patients, as demonstrated by light microscopy and confirmed by electron microscopy. Immunoglobulin and complement depos-

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Connor et al.

The Journal of Pediatrics July 1988

Fig. 1. Renal biopsy specimen from patient 2, demonstrating focal segmental glomerulosclerosis.Lobules are nearly compIetely sclerosed, focally attached to the capsule. (Periodic acid--Schiffstain; •

Fig. 2. Renal biopsy specimen from patient 1, demonstrating mesangial proliferative glomerulonephritiswith mesangial widening and increased amount of mesangial matrix and number of cells. (Toluidine blue stain; •

its (C3) were demonstrated in all cases by immunofluorescent microscopy. Electron-dense material (Fig. 3) was demonstrated by electron microscopy in four cases; electron microscopy was not performed in one case. Tubuloreticular structures were seen in the glomerular endothelium in one of the cases of glomerulosclerosis and in the glomerular epithelium cells in one of the cases of mesangial proliferative glomerulonephritis. At autopsy, mild bilateral hydronephrosis associated

with mild ureteral stenosis in the lower third was noted in one case (patient 1). There was no evidence of renal infections or other specific lesions. DISCUSSION In 1984, Rao et al. 9 in Brooklyn and Pardo et al. ~ in Miami reported the Occurrence of clinically significant renal disease in adult patients with AIDS. Their patients had nephrotic syndrome, and examination of renal tissue

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AIDS-associated renal disease

43

Fig. 3. Electron micrograph of renal biopsy specimen from patient I. Mesangial proliferation and mesangial electron-dense deposits are seen. (Uranyl acetate and lead acetate stain; •

revealed primarily focal and segmental glomerulosclerosis with deposition of immunoglobulin and complement. The clinical course of adult patients with these findings was characteristically associated with rapid progression and high mortality rates. As clinical data were collected from AIDS centers nationally, it became apparent that the renal involvement in AIDS represents a clinical and laboratory spectrum with potentially diverse causes. 7 Electrolyte and acid-base abnormalities may occur as a result of AIDSassociated conditions, such as vomiting, diarrhea, chronic pulmonary or central nervous system disease, and malnutrition, or as a complication of AIDS-associated infections.7 Patients may develop renal insufficiency as a complication of treatment with known nephrotoxic medications or as a complication of substance abuse. It has also been suggested that renal disease may occur as a consequence of HIV infection itself. It has been postulated that this type of renal disease is manifested by the occurrence of glomerular lesions characterized clinically by proteinuria and histologically most often by focal and segmental glomerulosclerosis3-12 This condition has been referred to as AIDS-associated nephropathy. TM However, this type of renal disease may occur with heroin use, and intravenous drug use is a common risk factor for AIDS, especially on the East Coast, where the incidence of AIDS-associated nephropathy may be highest; thus the determination of the true etiopathogenesis of AIDSassociated nephropathy has been complicated. Here we report the clinical and pathologic findings in five children with AIDS and renal disease. Drug use is not

a complicating factor in these young children, so the finding of glomerular lesions suggests that these are truly AIDS-associated abnormalities--either a primary lesion caused by HIV or a secondary lesion resulting from immune dysregulation or other, as-yet-undefined factors. The fact that renal disease was the first manifestation of HIV infection in two patients also supports this contention. The pathologic lesions in our patients were focal glomerulosclerosis and mesangial proliferative glomerulonephritis. The precise pathogenesis of these lesions is not known. The presence of immune complex deposits in the glomeruli may be related to circulating immune complexes, known to occur in children with AIDS. 15 Demonstration of tubuloreticular structures is of particular interest because they occur in diseases associated with altered immunity, such as systemic lupus erythematosus. 16They have been previously demonstrated in the kidney and mononuclear cells in adults with AIDS. t7 In addition, elevated serum levels of a-interferon have been reported in both lupus erythematosus and AIDS. 18.19 Tubuloreticular structures could be related to antiviral or immunostimulatory effects of ainterferon.2~ As we have become more aware of the problem of renal disease in children with HIV infection, we have increased our efforts to identify patients at risk by means of simple methods such as serial urinalysis and serum electrolyte measurements. Preliminary data indicate that over 40% of children with symptomatic HIV infection have transient proteinuria. Our impression ls that renal complications of pediatric HIV infection are more common than was

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Connor et al.

originally thought, and that morbidity rates and even mortality rates associated with renal disease are substantial. Considering the escalation of the number of pediatric HIV cases in the United States, the natural history of renal complications and the factors related to its pathogenesis and treatment should be defined.

REFERENCES 1. Conaor E, Minnefor A, Oleske J. Human immunodeficiency virus infection in infants and children. In: Gottlieb MS, et al., eds. Current topics in AIDS; vol I. London: John Wiley & Sons, 1987;185-209. 2. Oleske J, Minnefor A, Cooper R Jr, et al. Immune deficiency syndrome in children. JAMA 1983;249:2345-9. 3. Scott GB, Buck BE, Leterman JG, et al. Acquired immunodeficiency syndrome in infants. N Engl J Med 1984;310:7681. 4. Rubinstein A. Acquired immunodeficiency syndrome in infants. Am J Dis Child 1983;137:825-7. 5. Pahwa S, Kaplan M, Fikrig S, et al. Spectrum of human T-cell lymphotropic virus type III infection in children. JAMA 1986;255:2299-305. 6. Pardo V, Aldana M, Colton R, et al. Glomerular lesions in the acquired immunodeficiency syndrome. Ann Intern Med 1984;101:429-34. 7. Humphreys M, Schoenfeld P. Renal complications in patients with the acquired immunodeficiency syndrome (AIDS). Am J Nephrol 1987;3:1-7. 8. Vaziri ND, Barbari A, Licorish K, et al. Spectrum of renal abnormalities in acquired immunodeficiency syndrome. J Natl Med Assoc 1985;77:369-75. 9. Rao TK, Filippone E J, Nicastri AD, et al. Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med 1984;310:669-73.

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10. Rao TK, Friedman EA, Nicastri AD. The types of renal disease in the acquired immunodeficiency syndrome. N Engl J Med 1987;316:1062-8. 11. Chander P, Soni A. Suri A, et al. Renal ultrastructural markers in AIDS-associated nephropathy. Am J Pathol 1987; 126:513-26. 12. Patrick AL, Roberts LA, Burton EN, et al. Focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. West Indian Med J 1986;35:200-2. 13. Centers for Disease Control. Classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age. MMWR 1987;36:225-36. 14. Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR 1987;36(suppl):l-15. 15. Calvelli TA, Rubinstein A. Intravenous gammaglobulin in infant acquired immunodeficiency syndrome. Pediatr Infect Dis 1986;5(suppl):S207-10. 16. Grimley PM, Schaff Z. Significance of tubuloreticular inclusions in the pathology of human diseases, pathobiol Ann 1976;6:221-57. 17. Sidhu GS, Stahl RE, E1-Sadr W, et al. Ultrastructural markers of AIDS. Lancet 1983;1:990-1. 18. Grimley PM, Kang YH, Frederick W, et al. Interferon related leukocyte inclusions in acquired immunodeficiency syndrome: localization in T cells. Am J Clin Pathol 1984;81:147-55. 19. Casette S, Klippel JH, Preble OT, et al. Association of human leukocyte interferon and lymphocyte tubuloreticular inclusions in systemic lupus erythematosis (SLE). Arthritis Rheum 1982;25(suppl):S57. 20. Grimley PM, Serrate S, Kang YH, et al. Ultrastructure of large granular lymphocytes [letter]. Lab Invest 1984;51:598600.