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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2020  |  Volume : 31  |  Issue : 3  |  Page : 589-596
Granulomatous interstitial nephritis in the military hospital of Morocco: Causes and outcomes


1 Department of Nephrology-Dialysis, Military Hospital Mohammed V, Rabat, Morocco
2 Department of Nephrology-Dialysis, Military Hospital Mohammed V, Agadir, Morocco

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Date of Submission24-Jan-2019
Date of Decision12-Mar-2019
Date of Acceptance17-Mar-2019
Date of Web Publication10-Jul-2020
 

   Abstract 


Granulomatous interstitial nephritis (GIN) is a rare cause of renal failure. Most frequent etiologies are sarcoidosis, drugs, granulomatosis with polyangiitis, and infections agents (particularly renal tuberculosis). The aim of this retrospective study was to evaluate the clinical features, causes, and outcomes of patients with GIN in adult patients in a region of Morocco. All native renal biopsy (January 2008 to December 2017) were reviewed, but only cases of GIN were analyzed. Eleven cases of GIN were identified in this study, constituting 2.7 % of all native renal biopsies performed on this period (n = 407). There were 7 (63.6%) women, and the average age was 44.2 ± 13.9 years. The mean serum creatinine level at the renal biopsy was 39.1 ± 20.7 mg/L. The most common etiology was sarcoidosis (45.4%, n = 5) followed by drug-induced GIN (27.2%, n = 3). A good renal outcome was reported in patients with drug-induced GIN and sarcoidosis. However, no renal recovery was described in patients with other etiologies. One information from our report and the previously studies is that better data collection systems such as biopsy registries are needed to provide data on the epidemiology and treatment of rare kidney diseases.

How to cite this article:
Zajjari Y, Azizi M, Bahadi A, Montasser D, Aatif T, Alayoud A, El Kabbaj D. Granulomatous interstitial nephritis in the military hospital of Morocco: Causes and outcomes. Saudi J Kidney Dis Transpl 2020;31:589-96

How to cite this URL:
Zajjari Y, Azizi M, Bahadi A, Montasser D, Aatif T, Alayoud A, El Kabbaj D. Granulomatous interstitial nephritis in the military hospital of Morocco: Causes and outcomes. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Sep 22];31:589-96. Available from: http://www.sjkdt.org/text.asp?2020/31/3/589/289445



   Introduction Top


Granulomatous interstitial nephritis (GIN) is a rare histological entity detected in 0.4–5.9% of all native renal biopsies. Most frequent etiologies are sarcoidosis, drugs, granulomatosis with polyangiitis (GPA) and infections agents (particularly renal tuberculosis).

Differentiating between these causes using histological features is difficult. Therefore, the diagnosis often depends on clinical features, especially the presence of extrarenal disease.

Although renal outcomes and treatment modalities have not been clearly defined in the literature, early identification of etiology and early initiation of treatment may improve outcomes.[1]

According to the best of our knowledge, few studies of GIN have been published, and none of them have been reported in the Arab and African countries.[1],[2],[3],[4],[5],[6],[7],[8],[9]

Thus, the aim of this study was to evaluate the causes of GIN in adult patients in a region of Morocco. We also described the clinical features and histological characteristics, as well as the treatment and outcome of patients with GIN.


   Materials and Methods Top


This was a retrospective study of adult patients who underwent renal biopsy for investigation of GIN in the Military Hospital Mohammed V in Rabat, Morocco, between January 2008 and December 2017.

Renal biopsies were processed for light and immunofluorescence microscopy in all specimens. In all cases, sections were stained with Hematoxylin and Eosin, Masson’s trichrome, periodic acid-Schiff, and Silver Jone’s stain.

Aggregates of epithelioid histiocytes with or without giant cells within the interstitium were labeled as a granuloma. All cases with histological evidence of GIN on renal biopsy were included in this study. Furthermore, the structural characteristics of granuloma were described, such as the presence or absence of necrosis and the association giant cells and Schumann or asteroid bodies.

We recorded the following data for each patient: age, gender, presence of fever, arthralgia, skin rash, uveitis, eosinophilia, proteinuria, hematuria, leucocyturia, calcium concentrations, serum creatinine, estimated glomerular filtration rate (eGFR), and histopathological findings. The eGFR was calculated using the modified diet in renal disease study equation.

Ethical approval for this study was received from the Institutional Ethical Committee of our hospital.

Numerical data were expressed as the mean and standard deviation, and the categorical data were expressed as a percentage and numerical values.


   Results Top


Over the 10 year period, 11 cases of GIN were identified in this study, constituting 2.7% of all native renal biopsies performed on this period (n = 407). There were seven (63.6%) women, and the average age was 44.2 ± 13.9 years, with a range of 22 to 64 years. Twenty-four-hour urinary protein excretion was 0.8 ± 0.2 (range 0.5–1.5) g/day. Leukocyturia was observed in all patients associated with microscopic hematuria in five (45.4%) patients. All patients had significant renal dysfunction. The mean serum creatinine level at the time of renal biopsy was 3.91 ± 2.07 (range: 1.8–9.1) mg/dL, and the mean of eGFR was 18.7 ± 8.4 mL/min/1.73 m2. There was a need of renal replacement therapy at presentation in only one patient. Hypercalcemia and elevated serum enzyme concentration were reported in three patients.

The most common diagnosis was sarcoidosis (45.4%, n = 5) followed by drug-induced GIN (27.2%, n = 3), GPA (18.1%, n = 2) and tuberculosis (9.1 %, n = 1).

The clinical features, causes, and outcomes were listed in [Table 1].
Table 1: Clinical features and outcomes of patients with granulomatous interstitial nephritis.

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Renal sarcoidosis diagnosis was established in all patients after finding GIN on renal biopsy. However, all had an extra-renal disease. Three patients had hilar, and mediastinal lymphadenopathy and three patients had elevated serum angiotensin-converting enzyme (ACE) and hypercalcemia. Other manifestations of extrarenal sarcoidosis in our patients included: uveitis (4 cases), arthralgia (4 cases), extra-renal granuloma (2 cases), liver disease (1 case), cardiac arrhythmias (1 case) and erythema nodosum. On histological examination, mononuclear cell infiltrates with non-necrotizing granulomatous inflammation and mild to moderate interstitial fibrosis were associated in all patients. The calcified structures within the Langhans-type giant cells, known as Schaumann bodies, have been reported in only one case ([Table 1], case 7).

All patients were treated with corticosteroids (two patients with intravenous pulse methyl-prednisolone, 500 mg daily for three days, followed by oral prednisone 1 mg/kg daily and three patients with oral prednisone 0.5 to 1 mg/kg daily. Regarding the outcome, complete recovery (normalized renal function) was documented in only one patient (case 5, [Table 1]) and moderate chronic kidney disease was found in four patients (Cases 3, 4, 6, 7; [Table 1]).

In two cases, GPA was the causative agent. In these cases, GIN was associated with necrotizing crescentic glomerulonephritis, pulmonary symptoms and a positive cytoplasmic antineutrophil antibodies directed against proteinase 3. The patients were treated with corticosteroids, cyclophosphamide, azathioprine, and plasmapheresis (case 1; [Table 1]). Despite this, our patients deteriorated their renal function and required dialysis at two and 24 months, respectively (Case 1, 2; [Table 1]).

Three cases were classified as drug-induced. The clinical features included manifestations of hypersensitivity such as fever, skin rash, and eosinophilia (Case 9, 10, 11; [Table 1]). The drugs implicated were allopurinol, amoxicillin, and ciprofloxacin. On histological examination, no necrotizing lesions were observed. A good outcome was recorded in all patients after the withdrawal of the culprit drugs (three patients) and the use of corticosteroids in two patients (two patients) (Case 9, 10, 11; [Table 1]).

In one patient, tuberculosis was demonstrated in a 45-year-old man with a history of lung tuberculosis. The tuberculin skin test was ulcerated, and we found a lymphadenopathy caseating granuloma in the cervical lymph node. Renal biopsy showed GIN associated with a high percentage of interstitial fibrosis (70%). The patient was treated with combinations of isoniazid, rifampin, pyrazinamide and ethambutol for the first two months and for the next 10 months, two drugs were continued (Isoniazid, Rifampin). Despite this, his renal function deteriorated and 16 months later, he started RRT (Case 8; [Table 1]).


   Discussion Top


GIN is a rare cause of renal failure with multiple etiologies. We report our experience with 11 patients during a 10 year period. This constitutes 2.7 % of all native renal biopsies performed in this period (n = 407). This is the first case series from Morocco. Prior to this, a few publications of GIN were reported. [Table 2] compares our findings with several clinical series of GIN in the literature.
Table 2: Comparison of our findings to other series of granulomatous interstitial nephritis.

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In our study, the most common cause of GIN was sarcoidosis (45.4%). This finding was similar to previous European studies reported by Javaud et al and Oliveira et al where the prevalence of sarcoidosis patients with GIN were 50% and 61.9%, respectively [Table 2].[1],[6]

In the study of Mahévas et al that included 47 adult patients with renal sarcoidosis, the GIN was described in 37 patients. However, interstitial nephritis without granulomas occurred in only 10 patients. Hence, GIN is the most typical histologic presentation in patients with renal sarcoidosis.[10] Furthermore, other histologic features are less common in renal sarcoidosis but may be observed alone or in association with GIN such a glomerular nephropathies (Ig A nephropathy, membranopro-liferative glomerulonephritis, membranous nephropathy, and crescentic glomerulonephritis) or nephrocalcinosis.[11],[12]

In our cases with renal sarcoidosis, the GIN occurred without necrotizing lesions or glomerular nephropathies. However, we described Schaumann bodies in only one case (Case 7, [Table 1]).

In sarcoidosis, most patients with GIN also have extrarenal manifestations (such as pulmonary, ocular, and cutaneous), but it can also occur in isolation.[5] In this study, all patients with renal sarcoidosis had extrarenal manifestations.

Corticosteroid is the mainstay therapy of renal sarcoidosis. However, other treatments may be prescribed in cases of contraindications or ineffectiveness for corticosteroids, like immunosuppressive agents (azathioprine and mycophenolate mofetil).[13] In our study, corticosteroids were used alone in all patients with normalization of renal function in 1 patient (Case 5; [Table 1]) and improvement of renal function in four patients (Cases 3, 4, 6, 7; [Table 1]).

GPA is an autoimmune disease of unknown cause. The clinical feature include necrotizing glomerulonephritis, positive cytoplasmic anti- neutrophil antibodies directed against proteinase 3, necrotizing granulomatous inflammation of the respiratory tract and necrotizing systemic vasculitis affecting small vessels. GIN can be a histologic finding in patients with GPA. In our study, two cases were reported. Thus, our review of the literature demonstrates a prevalence of GPA in patients with GIN that varies from 5% to 25%.[2],[3],[4],[6]

The granulomatous inflammation in sarcoidosis and drug-induced GIN is typically non necrotizing, whereas, necrotizing lesions are common in patients with tuberculosis or GPA.[4],[6] In our study, drug-induced GIN was found in three patients (27.1%) and all patients had manifestations of hypersensitivity (fever, arthralgia and/or eosinophilia)without necrotizing lesions on renal biopsy. A good outcome was recorded in all patients after the withdrawal of the culprit drugs and the use of corticosteroids if necessary. In the literature, the prevalence of medication-induced GIN is variable from 4.7% to 44.7%.[1],[2],[3],[4],[5],[6],[7],[8],[9] This difference may be explicated by the difference of indications of renal biopsy for unexplained acute renal failure and relative reluctance to biopsy in cases with suspicions of clinical diagnosis or patients whose renal recovery was achieved after the withdrawal of the culprit drug.

In Morocco, tuberculosis is still endemic. Despite this, only one case of tuberculosis was associated with GIN. In contrast, in other studies reported in India, tuberculosis was the most cause of GIN[8],[9] [Table 2].

This study had several limitations. First, it had a relatively small sample size due to the fact that renal biopsy was not indicated systematically in acute kidney injury. Hence, our results do not clearly describe the spectrum of GIN. Second, this was a retrospective study, and indications for corticosteroids in the management of the GIN were not standardized.


   Conclusion Top


GIN is a rare cause of renal failure with multiple etiologies. The relative contribution of sarcoidosis, drugs, infections, and associated conditions to the pathogenesis of GIN is not known and may vary considerably. Histologic features are not specific enough to determine the etiology. The treatment and outcome in GIN are variable, depending on the stage and etiology. In our study, sarcoidosis was the most common etiology. Furthermore, one information from our report and the previously studies is that better data collection systems such as biopsy registries are needed to provide data on the epidemiology and treatment of rare kidney diseases.

Conflict of interest: None declared.



 
   References Top

1.
Oliveira B, Jayawardene S, Shah S. Single-centre experience of granulomatous interstitial nephritis-time for a new approach? Clin Kidney J 2017;10:249-54.  Back to cited text no. 1
    
2.
Mignon F, Méry 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. 2
    
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Viero RM, Cavallo T. Granulomatous interstitial nephritis. Hum Pathol 1995;26:1347-53.  Back to cited text no. 3
    
4.
Bijol V, Mendez GP, Nosé 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. 4
    
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Joss N, Morris S, Young B, Geddes C. Granulomatous interstitial nephritis. Clin J Am Soc Nephrol 2007;2:222-30.  Back to cited text no. 5
    
6.
Javaud N, Belenfant X, Stirnemann J, et al. Renal granulomatoses: A retrospective study of 40 cases and review of the literature. Medicine (Baltimore) 2007;86:170-80.  Back to cited text no. 6
    
7.
Pasquet F, Chauffera M, Karkowskia L, et al. Granulomatous Interstitial Nephritis: A Retrospective Study of 44 Cases. La Rev de Méd Int 2010;31:670-6.  Back to cited text no. 7
    
8.
Naidu GD, Ram R, Swarnalatha G, Uppin M, Prayaga AK, Dakshinamurty KV. Granulomatous interstitial nephritis: Our experience of 14 patients. Indian J Nephrol 2013;23:415-8.  Back to cited text no. 8
[PUBMED]  [Full text]  
9.
Agrawal V, Kaul A, Prasad N, Sharma K, Agarwal V. Etiological diagnosis of granulomatous tubulointerstitial nephritis in the tropics. Clin Kidney J 2015;8:524-30.  Back to cited text no. 9
    
10.
Mahévas M, Lescure FX, Boffa JJ, et al. Renal sarcoidosis: Clinical, laboratory, and histologic presentation and outcome in 47 patients. Medicine (Baltimore) 2009;88:98-106.  Back to cited text no. 10
    
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Rajakariar R, Sharples EJ, Raftery MJ, Sheaff M, Yaqoob MM. Sarcoid tubulo-interstitial nephritis: Long-term outcome and response to corticosteroid therapy. Kidney Int 2006;70: 165-9.  Back to cited text no. 11
    
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Toda T, Kimoto S, Nishio Y, Ehara T, Sasaki S. Sarcoidosis with membranous nephropathy and granulomatous interstitial nephritis. Intern Med 1999;38:882-6.  Back to cited text no. 12
    
13.
Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet PY, Müller-Quernheim J. Sarcoidosis. Lancet 2014;383:1155-67.  Back to cited text no. 13
    

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Correspondence Address:
Yassir Zajjari
Department of Nephrology-Dialysis, Military Hospital Mohammed V, Hay Ryad BP 10100, Rabat
Morocco
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DOI: 10.4103/1319-2442.289445

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