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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2012  |  Volume : 23  |  Issue : 2  |  Page : 397-402
Interstitial nephritis with moderate-to-heavy proteinuria: An unusual combination

1 Department of Nephrology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

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Date of Web Publication28-Feb-2012


Interstitial nephritis with proteinuria >1 g/day is uncommon and almost always the result of drug-induced ATIN with an associated minimal change glomerulonephritis (GN). Here, we present a series of five unusual cases of interstitial nephritis without GN but with proteinuria >1 g/day, and they were identified from renal biopsies done from February 2008 to March 2009. Out of 236 patients who underwent renal biopsy, only five met the inclusion criteria. Three patients presented with edema and two with oliguria, while none had frank hematuria, fever, arthralgia, skin rash or history of exposure to nonsteroidal antiinflamatory drugs, analgesics, anti­biotics, allopurinol, or Chinese herb before presentation. Urinalysis revealed hematuria in two patients, pyuria in three and nephrotic range proteinuria in two. All had normal complement levels and were negative for antinuclear antibodies, Anti-dsDNA antibody, and antineutrophil cyto-plasmic antibodies. Clinical diagnosis was nephrotic syndrome in two patients, the third had diagnosis of rapidly progressive GN, the fourth had HIV associated nephropathy, and the fifth had unexplained advanced renal failure. Though three patients had renal dysfunction only one required dialysis. Light microscopy of renal biopsies revealed granulomatous interstitial nephritis in three patients and small vessel vasculitis in two of them. One patient had nongranulomatous interstitial nephritis along with vasculitis. Acute interstitial nephritis was the only finding in one patient. In conclusion, patients with interstitial nephritis can present with moderate-to-heavy proteinuria probably due to cytokine-like permeability increasing factor secreted by inflammatory cells in the interstitium.

How to cite this article:
Ghosh B, Singh RG, Usha, Behura SK, Soni A, Sharatchandra LK, Singh S. Interstitial nephritis with moderate-to-heavy proteinuria: An unusual combination. Saudi J Kidney Dis Transpl 2012;23:397-402

How to cite this URL:
Ghosh B, Singh RG, Usha, Behura SK, Soni A, Sharatchandra LK, Singh S. Interstitial nephritis with moderate-to-heavy proteinuria: An unusual combination. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2021 Mar 1];23:397-402. Available from: https://www.sjkdt.org/text.asp?2012/23/2/397/93190

   Introduction Top

Acute tubulointerstitial nephritis (ATIN) has a clinical and a pathological definition as acute renal failure with predominantly interstitial inflammation. The infiltrate is composed of lymphocytes and sometimes of granulocytes, and can include granulomas. It is usually associated with interstitial edema and some degree of tubular damage. Proteinuria in the nephrotic range is uncommon and almost always found in the rare cases of drug-induced ATIN with an associated minimal change glomerulo-nephritis (GN). [1] Here we present a series of five unusual cases of interstitial nephritis with proteinuria >1 g/day. The aim was to deter­mine the correlation regarding etiology, clinical presentation and course, treatment, prognosis, and outcome of this unique clinical entity.

   Subjects and Methods Top

In this retrospective study we went through the renal biopsy registry of our institute from February 2008 to March 2009. Formalin-fixed paraffin embedded tissue were cut 2 μm thick and stained with Hematoxycilin & Eosin, PAS and Acid Fuchsine Orange. Patients with pri­mary interstitial nephritis were identified. Those with primary glomerular diseases including minimal change disease along with interstitial nephritis were excluded. Furthermore, patients with interstitial nephritis and proteinuria <1 g/day were excluded and only those with pro-teinuria >1 g/day were included in this study. Their medical records were reviewed to collect clinical and laboratory data.

   Results Top

A total of 236 patients underwent renal biopsy during the 14 months period from February 2008 to March 2009. Out of them, only 11 (4.66%) had primary interstitial nephritis with no evidence of glomerular disease, and five of them had moderate to heavy proteinuria (i.e., proteinuria > 1 g/day) [Table 1]. The mean age of the patients was 40.4 years (range 12-55 years) with male-to-female ratio of 4:1. Three patients presented with swelling of body (60%), two patients presented with decreased urine output (40%), one had nausea and vo­miting while none had frank hematuria, fever, arthralgia, or skin rash. One patient was known to have HIV for one year and was on treatment (HAART and ATT) for two months for pulmonary tuberculosis. Another patient was hypertensive for three years and was on medications (ramipril and nifedipine retard). No patient had history of exposure to NSAIDs, analgesics, penicillins, cephalosporins, macro-lides, diuretics, rifampicin, allopurinol, triazolam or Chinese herb before presentation. None had diabetes or any rheumatologic disease.
Table 1: Clinical and laboratory characteristics of patients.

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On physical examination, three patients had peripheral pitting edema and two had ascites as well. One patient had significant pallor. No other abnormalities were detected. Urinalysis revealed hematuria in two (40%) patients and pyuria in three (60%). On dipstick exami­nation three (60%) patients had 3+ proteinuria and two (40%) had 2+ proteinuria. Upon quan­tification of proteinuria, two (40%) patients had nephrotic range proteinuria while two patients had proteinuria in the range of 1-2 g/day and one had proteinuria in the range of 2-3.5 g/day. One patient had Hb <8 g/dL and another Hb 8-12 g/dL. Leucocytosis (TLC >10,000/mm [3] ) was present in two (40%) pa­tients, though three (60%) patients had serum creatinine (SCr) >1.5 mg/dL and one (20%) required temporary dialysis. Severe hypoalbu-minemia (S. albumin <2 g/dL) was present in one patient, while two patients had moderate hypoalbuminemia (S. albumin 2-3 g/dL). When corrected for low albumin, only one patient had normal serum calcium level and other four pa­tients revealed mild hypocalcemia. All the pa­tients had normal complement level and were antinuclear antibodies, anti-dsDNA antibody, and antineutropjil cytoplasmic antibodies negative.

The clinical diagnosis was nephrotic syndrome in two (40%) patients while the third had diag­nosis of rapidly progressive glomeruloneph-ritis (RPGN), the fourth had HIV associated nephropathy and the fifth had unexplained ad­vanced renal failure. However, light micros­copic examination of renal biopsies revealed evidence of granulomatous interstitial nephritis in three patients (60%); two (40%) of them also revealed small vessel vasculitis. Another patient had nongranulomatous interstitial neph­ritis along with vasculitis, while the last one presented with acute interstitial nephritis with­out granuloma and vasculitis. Both the patients presenting as nephrotic syndrome had granulo-matous interstitial nephritis but only one had vasculitis (patient 3; [Table 1] and [Figure 1]). The patient with presentation mimicking rapidly progressive GN had granulomatous interstitial nephritis with vasculitis (patient 1; [Table 1]and [Figure 2]). The patient with HIV had vasculitis and interstitial nephritis without granuloma. The patient presenting with advanced renal failure had acute interstitial nephritis (patent 5; [Table 1] and [Figure 3].)
Figure 1: Photomicrograph of patient 3 showing interstitial nephritis with tiny healing epithelioid granuloma surrounded by mononuclear cell and plasma cells (H & E staining, magnification × 400).

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Figure 2: Photomicrograph of patient 1 showing interstitial nephritis with severe patchy mononuclear cell infiltration and dilated tubules filled with hyaline cast (PAS staining, magnification × 400).

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Figure 3: Photomicrograph of patient 5 showing interstitial nephritis with focal collection of lymphocytes with germinal center like area in the center along with other mononuclear cells (H & E staining, magnification ×400).

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   Discussion Top

The most frequent cause of AIN can be found in one of the three general categories: drug-induced, infection-associated, and cases asso­ciated with autoimmune idiopathic lesions. Proteinuria in the nephrotic range is uncom­mon and almost always found in the rare cases of drug-induced ATIN with an associated minimal-change GN. [1]

NSAIDs-induced AIN has unique association with moderate or heavy albuminuria besides other drugs, namely rifampicin, recombinant interferon alpha, ampicillin, and heroin. [1]

In our study the incidence of primary inters­titial nephritis was 4.66% of total renal biopsy. Interstitial nephritis is an uncommon cause of acute renal failure. Reported incidence in the literature varies widely from 2% to 7.6% and may depend on several factors, i.e., geogra­phical location, diagnostic criteria, dietary, envi­ronmental factors and therapeutic practices. [2],[3] Recovery is usual in most cases of acute in­terstitial nephritis even in the presence of oli-guria or dialysis dependence at presentation. [4]

In the present study incidence of primary interstitial nephritis with proteinuria >1 g/day was 2.12%. No other study was available to compare with our data. Most of the studies describing such proteinuria were drug-induced interstitial nephritis and all had glomerular in­volvement as well. Granulomatous interstitial nephritis (GIN) is defined as interstitial nephritis in which the inflammatory infiltrate includes one or more distinct aggregates of epithelioid cells with or without multinucleate giant cells. [5] The patho-genesis of GIN is thought to involve a de-layed-type hypersensitivity reaction, similar to other forms of AIN. [6] It is a rare histological diagnosis that is present in 0.5-0.9% of native renal biopsies [7],[8] and 0.6% of renal transplant biopsies. [9] Incidence of granuloma in patients with interstitial nephritis ranges from 5.9%. [10] However, in the present study, the incidence of GIN was 1.27% of total renal biopsy, while it was present in 60% (n=3) of the patients with primary interstitial nephritis and moderate to heavy proteinuria. GIN has been associated with medications, infections, sarcoidosis, crys­tal deposits, paraproteinemia, and Wegener's granulomatosis and also is seen in an idio-pathic form. [10],[11],[12] Medicines implicated include aspirin, gentamycin, anticonvulsants, antibio­tics, nonsteroidal anti-inflammatory drugs, allo-purinol, and diuretics or combination of drugs. Mycobacteria, Echerichia coli or various orga­nisms and fungi are the main infective causes and seem to be the main causative factor in cases in renal transplants. [9],[13] Few studies have analyzed the natural history and treatment of GIN; the largest included only seven patients. [14] However, the presence of granulomas does not appear to be a poor prognostic factor in adults. [15],[16]

Concurrent nephrotic syndrome due to mini­mal change disease can be seen with NSAIDs and in selected cases induced by ampicillin, rifampin, interferon, ranitidine or triazolam. [17],[18],[19],[20],[21],[22]

The causes of interstitial nephritis including GIN in our patients were unknown. However, tuberculosis, which is rampant in our country and could cause such renal involvement, was not adequately investigated for. All granu-lomas were of a noncaseating type, and interestingly one patient with pulmonary tubercu­losis did not reveal granulomas in his renal biopsy. Similarly specialized tests for sarcoi-dosis like serum ACE level and gallium scan were not carried out, but sarcoidosis was un­likely with the given history, physical exa­mination as well as the absence of hyper-calcemia in our patients. On the contrary, 80% (n=4) of them had hypocalcemia (S. Ca++ <9 mg/dL after correction for hypoalbuminemia). Furthermore, 60% of the patients had evidence of vasculitis. Two of the three patients with vasculitis (66.67%) had GIN. No patient with either GIN or vasculitis or both needed dia­lysis. The sole patient without vasculitis or granuloma required dialysis. He had acute interstitial nephritis and later lost to follow-up while still requiring dialysis at the last visit. In conclusion, the present study showed an incidence of 4.66% for primary interstitial nephritis, 45.45% of which had proteinuria > 1 g/day. The presence of either GIN and/or vasculitis does not give a bad prognosis. Pre­sumably, the inflammatory cells in interstitial nephritis secret cytokine like permeability factor, which produces loss of polyanions and increases permeability of glomerular basement membrane to various proteins leading to heavy proteinuria.

   Acknowledgment Top

The authors would like to thank all the patients who participated in the study. The authors would also like to thank Dr. Anuradha Mazumder for her kind support in editing this article.

   References Top

1.Remuzzi G, Perico N, De Broe ME. Tubulo-interstitial diseases. In, The Kidney, 8 th edn, Brenner BM (Ed), Philadelphia, Elsevier, 2008;1174-202.  Back to cited text no. 1
2.Ball S, Cook T, Hulme B, Palmer A, Taube D. The diagnosis and racial origin of 394 patients undergoing renal biopsy: an association between Indian race and interstitial nephritis. Nephrol Dial Transplant 1997;12(1):71-7.  Back to cited text no. 2
3.Schwarz A, Krause PH, Kunzendorf U, Keller F, Distler A. The outcome of acute interstitial nephritis: risk factors for the transition from acute to chronic interstitial nephritis. Clin Nephrol 2000;54(3):179-90.  Back to cited text no. 3
4.Tagore R, Chua AP, Gopalakrishnan R, Chan N, Lee EJ. Acute Interstitial Nephritis in Singapore: A Report of Five Cases. Singapore Med J 2003;44(9):473-81.  Back to cited text no. 4
5.Joss N, Morris S, Young B, Geddes C. Gra-nulomatous Interstitial Nephritis . Clin J Am Soc Nephrol 2007;2:222-30.  Back to cited text no. 5
6.Ten RM, Torres VE, Milliner DS, Schwab TR, Holley KE, Gleich GJ. Acute interstitial neph­ritis: immunologic and clinical aspects. Mayo Clin Proc 1988;63:921-30.  Back to cited text no. 6
7.O'Riordan E, Willert RP, Reeve R, et al. Iso­lated sarcoid granulomatous interstitial nephritis: Review of five cases at one center. Clin Nephrol 2001;55:297-302.  Back to cited text no. 7
8.Mignon F, Mery JP, Mougenot B, Ronco P, Roland J, Morel- Maroger L. Granulomatous interstitial nephritis. Adv Nephrol Necker Hosp 1984;13:219-45.  Back to cited text no. 8
9.Meehan SM, Josephson MA, Haas M. Granulomatous tubulointerstitial nephritis in the renal allograft. Am J Kidney Dis 2000; 36:E27.  Back to cited text no. 9
10.Viero RM, Cavallo T. Granulomatous inters­titial nephritis. Hum Pathol 1995;26:1347-53.  Back to cited text no. 10
11.Bijol V, Mendez GP, Nose V, Rennke HG. Granulomatous interstitial nephritis: a clinico-pathologic study of 46 cases from a single institution. Int J Surg Pathol 2006;14:57-63.  Back to cited text no. 11
12.Vanhille PH, Kleinknecht D, Morel-Meroger L, et al. Drug-induced granulomatous inters­titial nephritis. Proc Eur Dial Transplant Assoc 1983;20:646-9.   Back to cited text no. 12
13.Goncalves AR, Caetano MA, Paula FJ, Ianhez LE, Saldanha LB, Sabbaga E. Tuberculous interstitial granulomatous nephritis in renal transplants: Report of three cases. Transplant Proc 1992;24:1911.  Back to cited text no. 13
14.Robson MG, Banerjee D, Hopster D, Cairns HS. Seven cases of granulomatous interstitial nephritis in the absence of extrarenal sarcoid. Nephrol Dial Transplant 2003;18:280-4.  Back to cited text no. 14
15.Rossert J. Drug-induced acute interstitial neph­ritis. Kidney Int 2001;60:804-17.  Back to cited text no. 15
16.Vaideeswar P, Mittal BV. Idiopathic necro-tising granulomatous interstitial nephritis. J Post Graduate Med 2001;47(2):111-2.  Back to cited text no. 16
17.Neilson EG. Pathogenesis and therapy of interstitial nephritis. Kidney Int 1989;35:1257.  Back to cited text no. 17
18.Neugarten J, Gallo GR, Baldwin DS. Rifampin-induced nephrotic syndrome and acute inters­titial nephritis. Am J Nephrol 1983;3(1):38-42.  Back to cited text no. 18
19.Averbuch SD, Austin HA 3rd, Sherwin SA, Antonovych T, Bunn PA Jr, Longo DL. Acute interstitial nephritis with the nephrotic syn­drome following recombinant leukocyte a interferon therapy for mycosis fungoides. N Engl J Med 1984;5:310(1):32-5.  Back to cited text no. 19
20.Makino H, Haramoto T, Sasaki T, et al. Massive eosinophilic infiltration in a patient with the nephrotic syndrome and drug-induced interstitial nephritis. Am J Kidney Dis 1995; 26(1):62-7.  Back to cited text no. 20
21.Schwarz A, Krause PH, Keller F, Offermann G, Mihatsch MJ. Granulomatous interstitial neph­ritis after nonsteroidal anti-inflammatory drugs. Am J Nephrol 1988;8(5):410-6.  Back to cited text no. 21
22.Zaigraykin N, Kovalev J, Elias N, Naschitz JE. Levofloxacin-Induced Interstitial Nephritis and Vasculitis in an Elderly Woman. IMAJ 2006; 8:726-7.  Back to cited text no. 22

Correspondence Address:
Biplab Ghosh
Department of Nephrology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, Uttar Pradesh
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PMID: 22382248

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