Rapidly progressive glomerulonephritis as an unusual type of renal involvement in sarcoidosis: a case report

Abstract

Introduction

Sarcoidosis is a multisystem inflammatory disease of unknown etiology characterized by the formation of noncaseating epithelioid granulomas. Clinically significant renal involvement is rare in sarcoidosis. It most commonly manifests as chronic tubulointerstitial nephritis and nephrocalcinosis with nephrolithiasis. Further, glomerular involvement is observed sporadically, mainly membranous glomerulopathy or focal segmental glomerulosclerosis.

Case presentation

We describe the clinical case of a 49-year-old patient of Caucasian ethnicity with a history of sarcoidosis of the lungs and intrathoracic lymph nodes who was hospitalized for acute kidney injury, hypercalcemia, hypoxemic respiratory insufficiency, general weakness, weight loss, and fever. Conservative treatment was not successful, and therefore early initiation of renal function replacement in the form of intermittent hemodialysis was necessary. During differential diagnosis process, we found nephrotic range proteinuria with microscopic hematuria; autoantibody panel was completely negative. Histologically, a unique constellation of renal lesions in the form of severe chronic tubulointerstitial nephritis combined with diffuse sclerosing crescentic glomerulonephritis was confirmed. Computed tomography scan of the lungs revealed recurrence of sarcoidosis, and a secondary finding was subpleurally localized primary calcified tuberculous infection. Treatment with corticosteroids was initiated in collaboration with a pulmonologist, with rapid improvement in the patient’s extrarenal clinical condition.

Conclusion

Sarcoidosis needs to be considered in the differential diagnosis of rapidly progressive glomerulonephritis even though it is a very rare type of renal involvement.

Introduction

Sarcoidosis is a multisystem inflammatory disease of unknown etiology characterized by the formation of noncaseating epithelioid granulomas. Any organ can be affected, but the lungs, lymph nodes, eyes and skin are most commonly affected.

Clinically significant renal involvement is rare in sarcoidosis. It most commonly manifests as chronic tubulointerstitial nephritis (TIN) with or without granuloma formation and nephrocalcinosis with nephrolithiasis resulting from abnormal calcium homeostasis. Further, glomerular involvement is observed sporadically, and mainly membranous glomerulopathy or focal segmental glomerulosclerosis is reported in the literature [1].

Case presentation

We describe the clinical case of a 49-year-old male patient of Caucasian ethnicity who visited an emergency department for weeks-long and progressively worsening symptoms. The patient complained of general weakness, malaise, and lack of appetite with progressive weight loss. For the last week, the patient had a daily fever with a peak in the evening reaching above 38 °C.

In the patient’s medical history, we found sarcoidosis of the lungs and intrathoracic lymph nodes, which was verified by cryobiopsy 1 year earlier. At that time, the patient was treated with oral corticosteroids for active disease. Prednisone therapy lasted for a total of 12 months, during which remission of the disease was achieved and therefore prednisone was gradually tapered. The treatment was stopped approximately 4 months before the onset of the current health problems. During the initial differential diagnosis process, renal function was examined regularly. At the time of admission, when the patient had an acute manifestation of the sarcoidosis (fever, respiratory insufficiency, dehydration), the serum creatinine level was 135 umol/l. However, after parenteral rehydration, it normalized in a few days and therefore the finding was assessed as prerenal type of impairment. Urinalysis was also examined at the beginning and proteinuria was positive, but quantification was not performed. The patient was also treated for arterial hypertension for a few years with a triple combination of hypotensive drugs (angiotensin-converting-enzyme inhibitor, beta-blocker, and calcium-channel blocker).

On clinical examination, the patient was eupnoic, cardiopulmonary compensated, euvolemic, and without any swelling of the extremities. His body temperature and blood pressure were normal and he did not complain of urinary problems, but his peripheral blood oxygen saturation was 89–90%. In the initial laboratory tests, acute kidney injury, hypercalcemia, hypoxemic respiratory insufficiency, mildly increased inflammatory activity, and anemia were found (Table 1). The patient was admitted to the local hospital for further differential diagnosis and treatment. Urinalysis revealed a large nonselective glomerular proteinuria (9.7 g per day) with mixed type of erythrocyturia (40% of dysmorphic erythrocytes). Serum albumin and total protein levels were slightly reduced (albumin 30.5 g/l, total proteins 61.3 g/l). Basic imaging investigations were completed. Chest X-ray showed discrete reticulonodular perihilar pattern bilaterally, and echocardiography revealed left ventricular wall hypertrophy, without detection of vegetation on the heart valves. Sonographic examination of the abdomen identified splenomegaly; the kidneys were normal in size and shape, the renal parenchyma was of physiological width with slightly higher echogenicity. In extended laboratory tests, we found normal immunological parameters (level of immunoglobulins, C3 and C4 complement, complete panel of autoantibodies), physiological ratio of kappa/lambda free light chains in serum, and no paraprotein detected in serum and urine by electrophoresis. At the same time, the serological examination for infectious diseases and the cultures of biological materials were negative. During the hospitalization in the internal department, an oncological disease of the gastrointestinal (normal endoscopy findings) and urinary system (normal prostate-specific antigen and clinical examination) was also ruled out. The patient undergoes regular eye examinations for a known cataract. Examination was also performed during the differential diagnostic process and no uveitis was detected. Conservative treatment was primarily initiated, which included parenteral administration of crystalloids, nutritional supplementation, empiric antibiotics, antipyretics, low-flow oxygen therapy, and erythrocyte transfusion for progression of anemia. Despite complex treatment, there was no improvement in renal parameters, and therefore hemodialysis was initiated using dialysis catheter via the right internal jugular vein. The patient’s clinical condition did not improve, and general weakness, weight loss, and fever persisted. Broad-spectrum antibiotic treatment was given for the progressive elevation of inflammatory parameters (C-reactive protein ranged from 122 to 236 mg/l and procalcitonin between 1.5 and 7.9 ug/l), but without any significant response.

Table 1 Baseline laboratory findings

To perform a kidney biopsy and a comprehensive pneumological examination, the patient was transferred to the Nephrology Department at the University Hospital in Martin. The next day, we performed an ultrasound-guided left kidney biopsy under local anesthesia. The immediate postoperative period was uncomplicated. However, 4 days after the procedure, we noted a decrease in blood count and the presence of a subcapsular hematoma on kidney ultrasound. Using computer tomography (CT) angiography, an active contrast medium leak from the peripheral branch of the left renal artery was verified. As a solution, a successful selective embolization of the bleeding branch was performed.

While waiting for the result of the kidney biopsy, the patient underwent a comprehensive examination of the respiratory system. Going back to the first manifestation, histological examination of the lung cryobiopsy showed epithelioid cell granulomas with the presence of giant multinucleated cells. Flow cytometry of bronchoalveolar lavage fluid showed a significantly increased CD4/CD8 T lymphocyte ratio. There was no detectable histological finding that correlated with immunoglobulin G4 (IgG4)-related disease and plasma IgG4 level was normal. Spirometry detected a moderately severe restrictive ventilation disorder and the diffusion capacity of the lungs for carbon monoxide (DLCO) was severely reduced (flow expiratory volume = FEV1 was 55% of predicted, flow vital capicity = FVC was 53% of predicted, total volume capacity = TLC was 60% of predicted, and DLCO 36% of predicted). Chest CT scan showed uniform micronodular dissemination in both lung lobes with perilymphatic and random distribution, as well as interlobular septal thickening. In addition, we also found a positive result of the QuantiFERON TB-Gold test. On the basis of this result, the CT finding was revised, resulting in detection of a calcified primary tuberculosis infection on the caudal edge of right S2. The pulmonologist diagnosed the findings as a relapse of sarcoidosis and latent tuberculosis, and recommended initiating treatment with prednisone 40 mg per day and a 3-month course of isoniazid with rifampicin. We found no association of tuberculosis with diffuse lung involvement and renal failure in the patient. However, antituberculosis treatment was delayed due to a significant elevation of cholestatic liver enzymes after antibiotic treatment (amoxycillin/clavulanate). We did not confirm any other cause by laboratory and imaging investigations. We observed a trend toward a decrease in enzymes after antibiotic treatment.

We received the results of the kidney histopathology. There were 19 glomeruli in the sample examined by light microscopy, 10 of which were globally sclerotic (Fig. 1). Other glomeruli showed significant mesangial sclerotic expansion, mildly increased mesangial cellularity, thickened basement membrane, and the presence of fibrotic crescents (Fig. 2). There were also severe chronic changes in the tubulointerstitium, 90% tubule atrophy, and 80% interstitial fibrosis with predominantly chronic lymphoplasmacytic inflammatory infiltrate (Fig. 3). Neither granulomas nor giant cells with multiple nuclei were detected in the interstitial fibrosis. Using von Kossa staining, nephrocalcinosis was not detected. The vessels showed a mild-to-moderate degree of arterio- and arteriolosclerosis without any inflammation. Vascular granulomatous involvement was not detected using Verhoeff staining. A total of six glomeruli were examined by immunofluorescence and were negative for IgA, IgM, C3, C1q, fibrinogen, kappa and lambda. The pathologist reported only light diffuse linear staining for IgG in the glomerular capillaries. Congo red staining for amyloid deposition from paraffin embedded tissue was negative. Two glomeruli were examined in electron microscopy, one of which was globally sclerotic. The other showed the presence of a fibrocellular crescent, mesangial sclerosis, and a thickened basement membrane. Immune complex deposits were not detected.

Fig. 1

Finding showing globally sclerotic glomeruli, hematoxylin and eosin, magnification × 400

Fig. 2

Fibrocellular crescents in preserved glomeruli, silver stain, magnification × 400

Fig. 3

Finding showing severe interstitial fibrosis (green), Masson–Goldner trichrome, magnification × 100

We diagnosed the patient’s condition as a rapidly progressive glomerulonephritis (RPGN) in the stage of diffuse sclerotization as a result of a relapse of sarcoidosis in coincidence with severe chronic TIN. The diagnosis was established by excluding other, more frequent possible causes of this histological finding in combination with a history of highly active sarcoidosis. Due to the extent of chronic irreversible changes in the kidneys and the patient’s risk profile (latent tuberculosis), we decided to keep the patient on prednisone treatment and not to add other immunosuppressants or cytotoxic agents. On steroid treatment, the patient’s clinical condition promptly improved, and fevers, weakness, and loss of appetite subsided, and the patient began to gain weight. In laboratory tests we monitored the normalization of inflammatory markers and calcium levels. The patient remained hemodialysis dependent and a permcath was implanted. After 3 months, control spirometry showed a significant proportional increase in lung volumes, capacities, and DLCO (FEV1 67% of predicted, FVC 69% of predicted, TLC 76% of predicted, DLCO 53% of predicted), while the slow detraction of prednisone dose continues.

Discussion

Rapidly progressive glomerulonephritis represents one of the most serious conditions in clinical nephrology. Its occurrence is usually associated with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, IgA nephropathy, antiglomerular basement membrane disease, cryoglobulinemia, complement-mediated cases of lupus nephritis, or post-infectious glomerulonephritis. It is characterized by the finding of crescents in the histological examination of a kidney biopsy and rapid deterioration of renal function with active urinary sediment. Without prompt initiation of treatment, it can lead to end-stage renal damage [2].

Renal involvement is a less frequent extrarenal manifestation of sarcoidosis and is described in 4–22% of cases, mostly as TIN or nephrocalcinosis [3]. Combination of RPGN with chronic TIN as in our case is very unusual. There are, thus far, two case reports with this finding in the available literature. The first case is a combination of granulomatous interstitial nephritis, RPGN, and necrotizing vasculitis without the evidence of any other autoimmune disease. In the second one, the authors describe the finding of Amyloid A (AA) amyloidosis with glomerular crescents. However, unlike in our case, both patients had a primary manifestation of sarcoidosis at the time of renal involvement [4, 5].

The patient in our case report, based on the histological findings (90% tubule atrophy and 80% interstitial nephritis), was highly likely to have suffered from renal impairment for a prolonged period of time. Chronic TIN did not lead to alteration of renal function in the long term, and the patient’s urinary findings have not been checked since the confirmation of sarcoidosis. Only a severe relapse of sarcoidosis caused glomerular involvement in the form of crescentic glomerulonephritis in the setting of severe chronic TIN, resulting in rapid and permanent loss of renal function. At this time, we detected large proteinuria, which is not typical for the initial phase of RPGN, nor is it typical of the renal course of sarcoidosis in the form of chronic TIN. Further, it is not uncommon in the advanced form of RPGN, which is accompanied by extensive glomerulosclerosis. In this case, highly active systemic inflammatory disease also contributed to the proteinuria, as it was examined just at the initial phase of sarcoidosis relapse. We proceeded to the diagnosis by excluding other more common causes of RPGN, such as autoimmune or infectious diseases.

Sarcoidosis in not routinely considered to be a part of the differential diagnosis of glomerular involvement, especially RPGN; instead, it is diagnosed on the basis of the exclusion of other possible conditions. Several different types of glomerular involvement have been described, including membranous nephropathy, mesangioproliferative glomerulonephritis, focal segmental glomerulosclerosis, or IgA nephropathy. The fundamental problem is that there are no clinical or histopathological characteristics that distinguish glomerulopathy in sarcoidosis from the primary forms [6,7,8].

Considerable literature is available to guide the management of RPGN not related to sarcoidosis (initial use of cytotoxic or antilymphocyte agents followed by use of maintenance combined immunosuppressants), but it is unclear whether this treatment can be applied to RPGN from sarcoidosis [1]. According to the recommendations for the treatment of active pulmonary sarcoidosis, corticosteroid therapy is primarily indicated. In case of corticosteroid intolerance, relapse occurrence, or continued disease activity with inability to withdraw prednisone below 10–15 mg of daily dose, a cytotoxic agent should be added to the combination. The best experience is documented with azathioprine or methotrexate; mycophenolate mofetil probably appears to be less effective. In third-line therapy, antiinflammatory agents, such as antitumor necrosis factor (TNF)-α inhibitors, are now mainly used. The Foundation for Sarcoidosis Research includes a chapter in its recommendations for the treatment of renal involvement, but glomerular involvement is not included. In the setting of hypercalciuria, the primary recommendation is to initiate treatment with hydroxychloroquine and to administer corticosteroids if the effect is insufficient or renal function is altered. For more severe extrapulmonary involvement, such as cardiac involvement, European recommendations recommend primarily initiating treatment with a dual combination of immunosuppressive agents [9]. Therefore, we are of the opinion that in the glomerular type of renal damage, combined immunosuppression should also be used initially. In the case of RPGN with severely impaired renal function (creatinine above 500 umol/l), the use of aggressive treatment should be considered, similar to that used for RPGN due to other causes.

In both of the above-mentioned case reports, a combination of steroids and azathioprine was used, with which both patients achieved partial remission of renal impairment [4, 5]. In our case, the histological finding in the renal biopsy was decisive for the choice of treatment, when the risks of a more aggressive combined treatment would exceed its benefit. Due to the fact that the patient suffered from latent tuberculosis, and further, restitution of renal function could not be assumed when the characteristics of end-stage renal damage were found, treatment resulted from the involvement of the respiratory system.

Conclusion

Glomerular involvement of sarcoidosis is a rare cause of RPGN, and it can even precede the diagnosis of systemic sarcoidosis. It is important to think about this cause as well, as delayed diagnosis and treatment significantly reduces the probability of renal function restoration. The management of sarcoidosis-related RPGN remains a clinical challenge and requires a multidisciplinary approach. Histological examination of the kidney can help us choose the right strategy and aggressiveness of treatment.