Clinicopathological manifestations of biopsy-proven renal sarcoidosis: A retrospective cohort study

doi:10.21203/rs.3.rs-4860432/v1

Background

While many studies have reported renal involvement in sarcoidosis, there is limited description of the pathological manifestations of renal sarcoidosis. The relationship between clinical presentation, renal pathology, and prognosis remains unclear. The aim of this study is to examine the clinical, laboratory, and histological characteristics, as well as the prognosis of patients with renal sarcoidosis (RS).

Methods

We conducted a retrospective, single-center study of RS in renal biopsy cases treated in our department between January 2019 and December 2023.

Results

We identified 5 patients (4 men, 1 woman; median age 52 years, IQR 36–61 years). All patients had renal insufficiency with a median creatine level of 456 µmol/L (IQR 430.5-942.5µmol/L) and a median proteinuria of 0.5 g/24 h (IQR 0.2–0.73 g/24 h). Three (60%) of the five patients presented with both hypercalcemia and hypercalciuria. Histologically, two of the three patients who with hypercalcemia presented with renal calcinosis and tubulointerstitial nephritis (TIN) without granuloma. The other patient with hypercalcemia presented with renal calcinosis and acute tubular necrosis (ATN). The other two (40%) patients who with normal serum calcium presented with noncaseating granulomas interstitial nephritis (GTIN). For light microscopy, the interstitial inflammatory infiltrate also contains lymphocytes, monocytes cells, and sometimes eosinophils. By immunohistochemical stain, the infiltrating lymphocytes were CD4 + T cells that formed nodular granulomas, surrounded by CD8 + T cells. Chronic lesions such as interstitial fibrosis was mild in all five patients. A favorable response to steroid therapy was noted in all cases, and only one (case 4) had biopsy-proven recurrence of sarcoidosis granulomatous interstitial nephritis.

Conclusions

RS is extremely rare among kidney biopsy cases. Early and accurately diagnosis depends on renal pathology. The hallmark histological manifestation of RS is noncaseating GTIN, with CD4 + T cells primarily located in the center and CD8 + T cells primarily located in the periphery. Early diagnosis and prompt treatment with corticosteroids can improve the prognosis.

sarcoidosis

renal sarcoidosis

pathology

treatment

outcome

Sarcoidosis is a systemic inflammatory disease that can affect multiple organs. It is characterized by an increased cellular immune response to an unknown antigen, resulting in the accumulation of lymphocytes and other mononuclear cells in non-caseating epithelioid granulomas[1, 2]. While the lungs and lymph nodes are the most commonly affected sites (75–90%), other organs such as the eyes, bone marrow, kidneys, liver and spleen can also be affected[3].

The prevalence of renal sarcoidosis (RS) in the world is not known exactly, but case studies report a range of 0.3–3.5% [4]. RS is often asymptomatic and may be underdiagnosed, especially when it occurs without pulmonary involvement. Even when sarcoidosis affects the kidney, renal dysfunction is an extremely rare manifestation, and may be overlooked in many patients. A wide spectrum of renal abnormalities has been reported in RS, but the two most common findings are granulomatous interstitial nephritis (GIN) and stone disease or nephrocalcinosis secondary to hypercalcemia[5, 6]. Apart from GIN, sarcoidosis can cause various types of glomerulonephritis, such as focal and segmental glomerulosclerosis mesangial proliferative glomerulonephritis, IgA nephropathy, membranoproliferative and crescentic glomerulonephritis[7].

The hallmark histological form of RS is the noncaseating GTIN, which contains epithelioid cells or multinucleated giant cells. However, granulomas may not be present due to sampling error [8, 9]. There is some evidence to suggest that subclinical GTIN is present in between 7% and 27% of all patients in post-mortem series[10, 11]. RS deserves special attention due to its potential to progress to chronic kidney disease (CKD) and end-stage renal disease in some patients[12, 13, 5]. Early and accurate diagnosis of renal sarcoidosis is crucial because of the significant efficacy of corticosteroid therapy, even in patients with severe progressive renal failure.

Although kidney biopsy is considered the gold standard for diagnosis and prediction of outcome in RS, especially in the absence of other extrarenal signs[14], it is not commonly performed due to the frailty of many patients, the severe increase in serum creatinine or the high risk of complications associated with the technique. Few studies have investigated the specific pathological manifestations of renal sarcoidosis (RS). This study aims to address these limitations by examining a cohort of patients with biopsy-confirmed RS in a single center to explore (a) the pathological manifestations of RS, and (b) the clinicopathological characteristics and outcomes of these patients.

Patients

We conducted a retrospective single-center study of patients diagnosed with RS in our Department of Nephrology between Jan 2019 and Dec 2023. Patients meet the following inclusion criteria: 1) confirmed sarcoidosis according to the statement of the Official American Thoracic Society [2]; 2) renal histology compatible with the diagnosis of RS (interstitial nephritis with or without granuloma, and renal calcinosis); and 3) exclusion of any alternative diagnosis. All data were collected by 1 author, and were systematically reviewed by the same person and another author.

Clinical and Laboratory Data at presentation

For all cases, age, sex, history, medical examination, affected organs and laboratory tests were compiled. The laboratory workup included serum creatinine level (µmol/L), estimated glomerular filtration rate (eGFR), serum kalium, serum angiotensin-converting enzyme (ACE), serum calcium, parathyroid hormone, blood eosinophils, anti-neutrophil cytoplasmic antibodies (ANCA), serum IgG4 levels, results of urine sediment examination and 24-h urine protein levels. Hypercalcemia was defined as total plasma calcium > 2.75 mmol/L. The normal ACE level was 68 U/L.

Renal Pathology

Renal biopsy specimens were examined in our Laboratory of Renal Pathology. All kidney biopsy samples were processed for light microscopy (LM), immunofluorescence (IF) and electronic microscopy (EM) examination. For LM, kidney biopsy specimens were stained with hematoxylin and eosin, periodic acid-Schiff (PAS), Masson’s trichrome, periodic acid-silver methenamine, respectively. The changes within glomeruli, tubules, and interstitium were documented. These acute lesions included tubulitis, interstitial inflammation with or without granulomas, and the presence or absence of calcium deposits. The interstitial infiltrate was described as the area infiltrated by inflammatory cells in the interstitium. Immunohistochemical (IHC) staining (CD3, CD4, CD8, CD20, and CD38) were performed to identify cell components. The chronic lesion included tubular atrophy and tubulo-interstitial scarring. Interstitial fibrosis was estimated by the area of fibrosis in the cortical sample. IF was performed using antibodies against IgG, IgM, IgA, C3, C1q. Also, Ultrastructural evaluation was performed using a transmission electron microscope (Thermo Scientific, TECNAI SPIRIT, United States). All of the specimens were reviewed by three observers in our center.

Follow up

Specific treatment of RS (steroid and/or immunosuppressive treatment) was recorded for all patients. Patients were followed up in the outpatient clinic or by telephone. We evaluated the outcomes and the responses to therapy based on the serum creatine. We collected creatine at the time of kidney biopsy, at one month, three months, six months, and at the end of follow-up.

Statistical analysis

Statistical analysis was performed with SPSS version 24.0 statistical software package (SPSS, Chicago, IL). Continuous data were expressed as means with standard deviations (SDs) or as medians with interquartile ranges (IQRs). Categorical data were presented as proportions. Mann-Whitney U and paired t-tests were used to compare month 0 with month 1 serum creatine. P < 0.05 was considered to denote statistical significance.

Clinical and laboratory data of patients

Five patients were retrospectively identified. The demographic, clinical manifestations and laboratory characteristics are summarized in Table 1. The median age of the patients at kidney biopsy was 52 years old (IQR 36–61), and the median duration from initial onset symptoms to renal biopsy was 2 months (IQR 2–11). The primary presenting symptoms included bone pain and constitutional symptoms such as fatigue, anorexia, or fever exceeding 38℃. All patients presented with pulmonary and lymph node involvement, which was confirmed through chest computed tomography. Three (60%) of the five patients presented with hypercalcemia and hypercalciuria. Only two patients underwent serum angiotensin-converting enzyme (ACE), both of which were normal. Four patients had lower than normal PTH levels (PTH < 10 ng/L; normal range, 10–65 ng/L). Blood eosinophils, anti-neutrophil cytoplasmic antibodies (ANCA), and serum IgG4 levels were within normal range for all patients.

At the time of renal biopsy, all patients had severely impaired renal function, with a median serum creatinine of 456 µmol/L (IQR 430.5–942.5) and a mean eGFR of 20.5 (IQR12.2–38.5) ml/min per 1.73m². The mean proteinuria level at the onset of renal involvement was estimated to be 0.5 g/d (IQR 0.2–0.73). No patients had microscopic hematuria, hypouricemia, hypophosphatemia, or glucosuria. Renal dysfunction was the primary reason for the renal biopsy in these cases.

Table 1

Demographics and clinical characteristics.
	case 1	case 2	case 3	case 4	case 5
Age (years)	31	52	41	61	61
Gender	M	M	M	F	M
Time from initial symptom to kidney biopsy (months)	2	2	2	10	12
initial symptom	bone pain	fatigue	bone pain and fever	fatigue	anorexia
Extra-renal manifestations	lung and lymph nodes	lung and lymph nodes	lung and lymph nodes	lung and lymph nodes	lung and lymph nodes
Elevated SACE	NA	NA	NA	N	N
Blood eosinophilia	N	N	N	N	N
ANCA positive	N	N	N	N	N
Secrum IgG4 elevated	N	N	N	N	N
Hypercalcemia	Y	Y	Y	N	N
PTH (pg/mL)	6.6	NA	8.09	6.26	3.27
Creatinine (µmol/L)	449	412	415	902	983
eGFR (mL/min per 1.73m²)	23.0	18.3	20.5	5.4	6.19
Hypercalciuria	Y	Y	Y	N	N
24-h urine protein (g/24h)	0.5	0.8	0.66	0.18	0.23
Cause of renal biopsy	AKI	AKI	AKI	AKI	AKI

SACE = serum angiotensin-converting enzyme; ANCA = anti-neutrophil cytoplasmic antibodies; eGFR = estimated glomerular filtration rate; PTH = parathyroid hormone; AKI = acute kidney injury; NA = not applicable; N = no; Y = yes.

Pathology features

The primary histopathologic findings from the renal biopsy specimen revealed interstitial nephritis. Out of the total patients, two (40%) patients were diagnosed with non-caseating GTIN. Another two (40%) patients were diagnosed with TIN without granuloma, and renal calcinosis simultaneously. The remaining patient (20%) was diagnosed with acute tubular necrosis and renal calcinosis. A detailed summary of the pathological findings in these patients are listed in Table 2.

Table 2

Pathologic findings in patients.
	Case 1	Case 2	Case 3	Case 4	Case 5
Pathological diagnosis	ATN	TIN	TIN	GTIN	GTIN
Acute lesion Renal tubules
calcinosis	Y	Y	Y	N	N
loss of brush border	Y	Y	Y	Y	Y
Renal interstitium
Granulomatous lesions		-	-	-	multiple	multiple
Inflammation cells	Lymphocytes, Monocytes	Lymphocytes, Monocytes, eosinophils	Lymphocytes, Monocytes	Lymphocytes, Monocytes	Lymphocytes, Monocytes, eosinophils
Infiltrate area	10%	25%	15%	60%	65%
Chronic lesion
tubular atrophy	Y	Y	Y	Y	Y
interstitial fibrosis	< 5%	< 5%	< 5%	< 5% (first renal biopsy) 30% (second renal biopsy)	< 5%

ATN = acute tubular necrosis; TIN = tubulointerstitial nephritis; GTIN = granulomatous tubulointerstitial nephritis; Y = yes; N = no.

Four patients (cases 2, 3, 4 and 5) showed evidence of an acute interstitial inflammation on renal biopsy histology. The light microscopy revealed diffuse interstitial inflammation consisting of numerous lymphocytes and epithelioid cells or multinucleated giant cells associated with non-caseating granulomas, and few eosinophils (Fig. 1). Only case2 and case5 display a minor presence of eosinophils. There was no infiltration of neutrophilic granulocytes in the kidney biopsy specimens. Acid-fast staining was negative in all patients. The presence of granulomatous inflammation was extensive, typically involving more than 60% of the kidney sample in case 4 and case 5. IHC staining was performed in these two cases. They were diagnosed with GTN and showed predominant infiltration of CD4 + T cells, which formed nodular granulomas surrounded by CD8 + T cells (Fig. 2). Additionally, small units of infiltrative CD20 + B cells were detected in the interstitium. CD38 + and CD138 + cells were extremely rare.

All patients exhibit signs of tubulitis and tubular degeneration, including loss of brush border, tubular dilatation, cytoplasmic vacuolization, and prominent nucleoli. In addition, tubular lumen calcinosis was observed in three patients (cases 1–3), all of whom had hypercalcemia (Fig. 3).

Nevertheless, chronic lesions of interstitial fibrosis and tubular atrophy were also observed. The area of tubulointerstitial fibrosis was mild (less than 5%) in all patients. However, the degree of tubulointerstitial fibrosis at the second renal biopsy was progressive in case 4, 8 months after the first renal biopsy.

The glomeruli were nearly normal in all cases. Immunofluorescence showed no deposits in four patients, while one patient showed IgM within the mesangial area. At the electron microscope level, no specific findings are detected.

Treatment and Outcome

These five patients were treated with oral prednisone at different doses ranging from 0.8 to 1 mg/Kg/day. Two patients received a dose of 0.8 mg/Kg/day, while three patients received a dose of 1 mg/Kg/day. The mean follow-up time after renal biopsy was 23.0 (IQR 8.5–25.5) months. After one month of treatment, there was a significant improvement in renal function when compared to the time of the initial diagnosis. The improvement was evident through a substantial reduction in median creatinine levels, decreasing from 533.7 µmol/L to 235.5 µmol/L (P = 0.041). Among the patients, four individuals (cases 1–3 and 5) experienced consistent renal function from one month after treatment until the final follow-up. The treatment and outcomes of the patients are summarized in Table 3.

Table 3

Follow up summary for patients.
	Case 1	Case 2	Case 3	Case 4	Case 5	P value
Initially Prednisone dose (mg/Kg/d)	1	0.8	1	1	0.8
Follow up time (Month)	27	23	24	10	7
Months of treatment	20	12	21	10	7
Current prednisone dose (mg/Kg/d)	0	0	0	15mg/d	5mg/d
Serum Creatinine (µmol/L)
At renal biopsy	449	412	456	902	983
one month of treatment	87	212	178	450	485	0.041*
three months of treatment	75	179	110	151	343
six months of treatment	73	160	108	198	341
Current	83	150	104	158	336
Recurrent	No	No	No	Yes	No

* Creatine at renal biopsy vs one month of treatment, P = 0.041.

Recurrence was observed in a single patient, specifically Case 4, who had initially been treated with oral prednisone. The patient's creatinine levels decreased from 902 µmol/L to 450 µmol/L within one month of starting steroid therapy. However, after six months on steroids, there was a subsequent increase in creatinine levels from 151 µmol/L to 198 µmol/L over a period of three months. This increase occurred while the oral prednisone dose was gradually reduced to 5 mg per day. The second kidney biopsy revealed GTIN and more severe interstitial fibrosis compared to the first biopsy (Table 2). These findings were interpreted as being most consistent with recurrent sarcoidosis. Consequently, the oral prednisone dose was increased to 15 mg per day. Additionally, the patient received treatment with azathioprine, with a dosage of 50 mg two times per day. As a result of these interventions, the creatinine levels improved to 158 µmol/L during the final observation period.

This study demonstrates that biopsy-proven RS had a high prevalence of M/F ratio and hypercalcemia. All patients underwent renal puncture for acute kidney injury. The typical pathological presentations were acute TIN (with or without granulomas) and nephrocalcinosis. The infiltrating lymphocytes were CD4 + T cells forming nodular granulomas surrounded by CD8 + T cells. Glucocorticoids significantly improves the clinical manifestations of sarcoidosis, normalizes hypercalcemia and decreases the serum creatine.

A male predominance was observed in RS, despite reports that sarcoidosis is more common in females (30% more than males)[15–17]. This finding is consistent with several studies of renal sarcoidosis [18, 5], which predict that males are more likely to have renal involvement. The specific mechanisms behind the apparent gender differences in RS are currently unclear.

We found that patients with RS had prominent hypercalcemia. Hypercalcemia is present in 10–17% of patients with sarcoidosis[19]. The reported incidence of hypercalcemia in studies of biopsy-proven RS ranges from 23.4–37.5%[20, 18, 5]. However, in our study, the prevalence of hypercalcemia was 60%, which is significantly higher than previously reported in the literature. These differences deserve further discussion. In sarcoidosis, hypercalcemia is also secondary to increased synthesis of calcitriol or active Vitamin D 3 (1,25 Di‑Hydroxy Vitamin D) by macrophages of the granulomatous lesion[21, 22]. Serum calcium rises when the kidney's ability to excrete calcium can't cope. This may reflect a ‘threshold effect’ in calcium metabolism. Higher level of serum calcium can lead to calcium salt deposits in kidney tissue and damage kidney function[13]. The reason for renal biopsy in all patients in this study was AKI, and two patients had significant bone pain and hypercalcemia. Therefore, it is believed that there is a selection bias that leads to an unusually high percentage of patients with hypercalcemia in this study.

Currently, there is more detailed research into the pathological manifestations of pulmonary sarcoidosis. Pulmonary sarcoidosis is characterized by the presence of well-formed, discrete, non-necrotizing granulomas. These granulomas are composed of lymphocytes, which are surrounded by epithelioid histiocytes, multinucleated giant cells, plasma cells, and fibroblasts in the periphery. The central portion of the granuloma consists of predominantly CD4 + lymphocytes, whereas CD8 + lymphocytes are present in the peripheral zone [23, 2, 24, 25]. In some patients without lung pathology, bronchoalveolar lavage and lymphocyte subpopulations studies may be helpful. A CD4/CD8 ratio greater than 3.5 has a sensitivity of 53%, specificity of 94%, positive predictive value of 76%, and negative predictive value of 85%[26, 24]. IHC was used in this study to identify the inflammatory cellular components of diffuse infiltrate in granulomatous lesions. The granuloma in the renal interstitium was found to be composed mainly of T lymphocytes. CD4 + T cells were located in the central region of the granuloma, whereas CD8 + somatic cells surrounded the periphery. This is consistent with the pathological manifestations of pulmonary sarcoidosis. The distribution of different T-cell types was correlated with the pathogenesis of sarcoidosis. Sarcoid granulomas form in response to a persistent antigenic stimulus that is unlikely to be properly degraded, inducing a local Th1-type T cell (CD4+) mediated immune response. As a result of their chronic stimulation, macrophages release inflammatory mediators locally, leading to an accumulation of Th1 cells at sites of ongoing inflammation and contributing to the development of the granuloma structure, which can lead to fibrosis in persistent disease. There is a shift in the cytokine pattern from a Th1 to a Th2 phenotype with secretion of IL-4, IL-5, IL-6, IL-9, and IL-10[24].

Sarcoidosis is considered an exclusionary diagnosis since there are various potential causes of granulomatous nodules, such as tuberculosis infection, lymphoproliferative disorders, IgG4-related kidney disease, ANCA-associated small vessel vasculitis, etc. To distinguish RS from these diseases, patients should undergo laboratory tests, imaging studies, and histopathological examinations [27, 24, 23, 25]. In this study, all patients underwent thorough examinations to rule out the above conditions. Diseases that may demonstrate eosinophilia on renal pathology are mainly allergic interstitial nephritis and IgG4-associated nephropathy, whereas in the present study we found that eosinophilic cells were also seen on renal pathology in patients with RS, as reported in Francesco's study[28]. However, the exact mechanism is still unclear. Sarcoidosis is believed to be caused by prolonged exposure to unidentified antigens, which triggers the accumulation of CD4 + T cells and the secretion of diverse cytokines like IL-5. This cytokine plays a role in promoting the development of eosinophils and controlling eosinophilic inflammation[29]. It is thought that this may be the mechanism by which there is eosinophilic infiltration in the pathology of nodular disease.

The initial treatment for sarcoidosis is glucocorticoids, the most effective, rapid-acting and available drug. It’s the first line of treatment[19, 1, 30]. The optimal prednisone dose and duration of prednisone for RS is not standardized[31, 32]. The severity of tubular necrosis, interstitial inflammation, and fibrosis can impact the clinical progression. Patients with moderate fibrosis tend to have a more favorable outcome, as supported by previous literature and our own study [20, 5, 18]. Therefore, it is recommended to start steroid therapy early in order to manage renal fibrosis effectively. The most reliable factor determining remission of RS is a good treatment response after 4–6 weeks[9]. In our study, all patients exhibited a response to steroid treatment, resulting in a significant decrease in creatine levels and the normalization of serum calcium within one month. Furthermore, none of the patients progressed to end-stage renal disease. Therefore, as there is an excellent response to corticosteroid therapy even in patients with severe progressive renal failure, confirmation of RS is an important diagnostic workup[33, 34, 28, 35].

RS is uncommon and has no specific clinical manifestations. RS should be considered in the setting of hypercalcemia and acute renal failure. Renal biopsy remains the gold standard for diagnosis. Renal biopsy provides information on the interstitial inflammation, tubular and vascular changes, and chronicity indices. The lymphocyte composition of granulomas is predominantly CD4 + T cells in the center and CD8 + T cells in the periphery. Steroid therapy is effective in suppressing active inflammation, improving renal function and preventing residual chronic kidney disease. However, it is important to monitor for recurrence and consider a second kidney biopsy if necessary.

Author contributions

Aichun Liu collected the clinical data and wrote the manuscript. Yina Wang, Yan Yu, Bao Dong and Meishun Cai were responsible for the work in the field of renal pathology. Yina Wang and Li Zuo reviewed and revised the manuscript.

Funding Sources This research was supported by Peking University People’s Hospital Research and Development Fundings (RDJP2022-31).

Data availability statement

All data generated or analyzed during this study are included in this published article.

Ethics approval and consent to participate All the study procedures followed the ethical guidelines of the Helsinki Declaration of 1975, as revised in 2008, and the Ethics Committee of Peking University People’s Hospital approved the study. The approval number from Peking University People’s Hospital was 2023PHB190-001, and all the participants provided their written informed consent.

Conflict of interest: None declared.

Consent for publication Not applicable.

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No competing interests reported.

Clinicopathological manifestations of biopsy-proven renal sarcoidosis: A retrospective cohort study

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Abstract

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Introduction

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