Article ID: 2023-0020-CR
We describe a case of sarcoidosis in a previously healthy 39-year-old man with the development of an acute kidney injury, requiring renal replacement therapy, as the first manifestation of the disease. The course of the disease was complicated by a сatheter-associated bloodstream infection. According to the histological examination of kidney biopsy samples, granulomatous interstitial nephritis was diagnosed. Extensive examination of the patient revealed persistent hypercalcemia, elevated transaminase levels, intrathoracic lymphadenopathy, and infiltrates in the lungs. Other diseases, such as anti-neutrophil cytoplasmic antibody-associated vasculitis, tuberculosis, autoimmune liver diseases, and systemic lupus erythematosus, were ruled out. The patient was treated with pulse therapy of methylprednisolone, which then switched to oral glucocorticoids (prednisolone 60 mg/day followed by a gradual decrease in the dose). The 9-month follow-up revealed a regression of lung lesions and improvement of the impaired renal function. The prednisolone dose was reduced to 7.5 mg/day, and renal replacement therapy was discontinued.
Sarcoidosis is a systemic disease characterized by granulomatous non-caseous inflammation with predominant lung damage and various extrapulmonary manifestations. The incidence of renal sarcoidosis (RS) varies from 0.3% in Northern Europe to 3.5% in Japan.1
There are several variants of kidney damage in sarcoidosis.2 The most common is the disruption of calcium metabolism, which results in hypercalcemia and hypercalciuria, followed by the development of nephrolithiasis and nephrocalcinosis. More uncommon variants are glomerulopathies and granulomatous interstitial nephritis (GIN), the frequency of which ranges from one study to another. One of the rare clinical manifestations of GIN in patients with sarcoidosis is an acute kidney injury (AKI), which occurs in less than 1% of cases.3,4 Here, we report our clinical observation of a patient whose first manifestation of sarcoidosis was AKI.
A previously healthy 39-year-old Russian man was admitted with complaints of growing weakness and fatigue. He considered himself ill since 1 July 2022, when, after working on removing graffiti with a chemical aerosol, he began to notice weakness, dizziness, cramps in his legs, and a dry mouth. The patient denied any chronic diseases and described his previous check-up from about a year earlier when no changes were detected in his blood tests, urine analysis, or chest fluorography. Following examination by a general practitioner, laboratory tests revealed elevated levels of creatinine (1134 μmol/L), urea (37.5 mmol/L), and potassium (6.6 mmol/L). The patient was urgently admitted to his local hospital, and renal replacement therapy (RRT) was initiated on 15 July 2022. Subsequent laboratory tests showed decreased levels of creatinine (570 μmol/L), urea (12.5 mmol/L), and potassium (5.1 mmol/L).
The patient’s condition worsened on 24 July 2022 with a sudden rise in body temperature to 39.5 °C and elevated levels of serum inflammatory markers: C-reactive protein (CRP, 238 mg/L) and procalcitonin (PCT, 47.1 ng/mL). Catheter-associated bloodstream infection was diagnosed, and the central venous catheter (CVC) was removed (culture revealed the growth of methicillin susceptible Staphylococcus aureus, 105 CFU/L). Antibiotics (ampicillin + sulbactam) were given for 10 days with a positive clinical response. The patient became afebrile, and CRP and PCT levels returned to normal. During his hospital stay, a persistent mild elevation of serum calcium (up to 2.6 mmol/L) was observed, and elevated levels of aspartate transaminase (AST, 47.9 U/L) and alanine transaminase (ALT, 96.7 U/L) were noted. The patient’s radiological findings (electrocardiogram, chest X-ray, and abdominal ultrasound) were unremarkable during his hospital stay.
The patient was hospitalized and admitted to the nephrology department for further examination on 5 September 2022. On admission, the patient’s condition was satisfactory. He showed clear consciousness, and his nutrition was rated as normal. His skin was pale, no swelling was observed, the peripheral lymph nodes were not enlarged, and the musculoskeletal system was without pathological changes. The following observations were made: respiratory rate, 18 /min; on-air oxygen saturation, 98%; blood pressure, 120/80 mmHg; heart rate, 71 beats/min. Percussion, palpation, and auscultation of the lungs, heart, and abdomen were unremarkable. The liver and spleen were not enlarged. The stool was normal, urination was free and painless, and the amount of urine was up to 900 mL/day. The kidney area was unchanged, and Pasternacki’s symptom was negative on both sides. The following hematology data were recorded (normal laboratory values): hemoglobin 115 (120–140) g/L, red blood cells 3.8 (3.7–4.7)×1012 /L, mean corpuscular hemoglobin 29 (27–31) pg, mean corpuscular volume 87 (80–95) fL, white blood cells 5.5 (4–9)×109 /L, platelets 291 (180–400)×109 /L, erythrocyte sedimentation rate 29 (2–10) mm/h. The following biochemical data were recorded: total protein 78 (63–87) g/L, albumin 41 (35–53) g/L, total bilirubin 13.9 (3–17) μmol/L, glucose 5.6 (3.8–6.3) mmol/L, potassium 4.9 (3.5–5.1) mmol/L, calcium 3.7 (2.15–2.5) mmol/L, phosphate 1.72 (0.96–1.76) mmol/L, AST 59 (≤40) U/L, ALT 140 (≤40) U/L, creatinine 570 (74–110) μmol/L, urea 24 (2.1–7.1) mmol/L, CRP 16 (0–5) mg/L. Urinanalysis gave the following data: transparency cloudy, relative density 1014 (1005–1025), protein 0.3 (≤0.1) g/L, leukocytes 12–15 (5–15) in the field of vision, and erythrocytes 3–4 (0–11) in the field of vision.
According to ultrasound and computed tomography (CT) scans, the kidneys were of normal size and no significant structural changes were detected. A kidney biopsy was ordered to clarify the cause of AKI. Histological examination revealed enlarged glomeruli without mesangial and endocapillary hypercellularity. The walls of the capillary loops were not thickened, single-circuit. There were many large granulomas in the interstitium, consisting of epithelioid and giant multinucleated cells, with a lymphoid cell reaction at the periphery (Fig. 1). There was edema and emerging interstitial fibrosis with concomitant tubular atrophy, diffuse focal infiltration of the interstitium by mononuclear cells with an admixture of plasma cells and slight invasion into the tubules. Immunofluorescence was negative for deposits of immunoglobulin G, immunoglobulin A, immunoglobulin M, C1q, C3, kappa and lambda light chain proteins.
Histological images of the kidney biopsy sample of 39-year-old patient.
(A) Interstitial granuloma (periodic acid-Schiff stain, ×100). (B) Interstitial granuloma consisting of epithelioid and giant multinucleated cells. The glomerulus looks unchanged (periodic acid-Schiff stain, ×200). (C) Small-caliber artery with fibrin deposits in the projection of the smooth muscle layer and perivascular infiltration with the formation of granuloma (Masson’s trichrome, ×200).
On chest X-ray, an expansion of the root of the right lung was observed. Chest CT revealed infiltrates in S5,9 of the right lung, in S8 of the left lung, and enlargement of the intrathoracic lymph nodes (Fig. 2). The patient was examined by an ophthalmologist and a cardiologist, and no pathological changes were found.
Chest CT scan of 39-year-old patient.
The intrathoracic lymph nodes were enlarged up to 14 mm (A, B, C, D, E). Infiltrates were observed in S5,9 of the right lung (F, G) and S8 of the left lung (H).
Taking into account intrathoracic lymphadenopathy and lung infiltrates, histological picture compatible to GIN, along with negative results of immunofluorescence in the kidney biopsy, persistent hypercalcemia generalized sarcoidosis with the involvement of lungs and kidney was proposed as the most likely diagnosis. Negative laboratory tests (C3 and C4 complement levels, antinuclear factor, anti-dsDNA antibodies, autoantibodies against myeloperoxidase, proteinase 3, and glomerular basement membrane), absence of autoimmune liver disease and viral hepatitis B and C markers, and negative Diaskintest helped to rule out tuberculosis, systemic lupus erythematosus, and common forms of systemic vasculitis.
The patient was prescribed methylprednisolone pulse therapy (1000 mg/day iv, total dose of 3000 mg) and then switched to oral prednisolone (60 mg/day). During hospitalization, the patient’s condition improved, his calcium levels in blood returned to normal, and repeat chest CT revealed partial resolution of the infiltrative changes in the lungs. Given that the patient’s creatinine level remained elevated (510 μmol/L), tunneled CVC was implemented to provide permanent vascular access for RRT. The patient was discharged under the supervision of a nephrologist at the outpatient dialysis center. He was advised to continue prednisolone, slowly reducing the dosage. During the observation, the patient’s creatinine level gradually decreased, and the lung lesions did not relapse. At the last contact in May 2023, the patient was continuing to take prednisolone (7.5 mg/day), his creatinine level was 256 µmol/L, and RRT was discontinued.
This case report presents an uncommon manifestation of generalized sarcoidosis with AKI. The patient underwent a typical diagnostic continuum: a statement of AKI of unknown etiology requiring RRT, a kidney biopsy to determine the cause of AKI, morphological verification of GIN, exclusion of other possible causes of GIN, a diagnostic concept of sarcoidosis, and a targeted examination to identify extrarenal lesions typical of sarcoidosis.
There are several scenarios for detecting RS. Most often, it is diagnosed in patients with previously verified bronchopulmonary sarcoidosis. In one of our earlier observations, RS was detected 3 years after lung involvement.5 In other situations, kidney damage is the first manifestation of the disease when extrarenal lesions remain latent and are detected only during examination of the patient, which was the case in the current study. Cases of isolated primary kidney damage in the form of GIN have been described by Robson et al.6
Stehlé et al.7 evaluated biopsy-proven glomerular lesions in patients with sarcoidosis. In 42% of cases, glomerulopathy was diagnosed on average 9.7 years after the diagnosis of pulmonary sarcoidosis; in 23% of cases, it preceded the diagnosis of sarcoidosis for an average of 8 years; and in 35% of patients, pulmonary and extrapulmonary lesions manifested simultaneously.
In our case, RS was suspected on the basis of a kidney biopsy, which is the only method of investigation for patients with AKI of unknown cause and absence of extrarenal manifestations. The most frequent variant, GIN, was revealed, which usually has a latent course with mild abnormalities in the urinalysis. However, in some cases, AKI develops such that RRT is required, as was the case with our patient.
Mahfoudhi et al.8 described 12 cases of AKI in patients with various manifestations of sarcoidosis with a median creatinine level of 520 (138–1490) μmol/L. Based on kidney biopsy, GIN was observed in all patients; RRT was required in 5 cases. Glucocorticoids were prescribed to all patients. No recurrence of RS was observed during the 5-year follow-up. In another study, 47 patients with RS received oral prednisone at a dose of 1 mg/kg per day with an average duration of 18 months.9 A good response to glucocorticoids correlated with baseline serum calcium levels. Relapses were renal in 3 cases, extrarenal in 10, and involved multiple organs in 4 cases.
In a recent Italian study, 31 patients with GIN and AKI were described, predominantly male.10 The most frequent symptoms were performance status decline, respiratory symptoms, fever, and weight loss. Of note, isolated RS was observed in 4 cases, and lung involvement was observed in 14 cases with most of these documented in conjunction with RS. In our case, the patient did not have respiratory complaints at admission, and lung and intrathoracic lymph node involvement was detected by chest CT. All patients with RS and AKI were treated with oral prednisone (0.5–1 mg/kg per day).10 The primary endpoint was a newly developed chronic kidney disease (CKD) after 1 year of follow-up, the secondary endpoint was the response to the first-line steroid therapy, and the combined one was the response to initial steroid therapy and the outcome at the end of the 1-year observation. Altogether, 13 of 20 patients with normal renal function developed CKD after a year of follow-up, 6 of 21 had complete recovery and normal renal function, and 10 of 21 showed partial recovery and final CKD. Unfavorable prognostic factors were identified as the presence of giant cells in the kidney biopsy, pronounced interstitial infiltration, and fibrosis.
For the patient under discussion in the present study, pulse therapy with methylprednisolone was initiated during the hospital stay, and further treatment with oral prednisolone was carried out. At the time of discharge, we noted that resolution of infiltrative changes in the lungs was near complete. At the 9-month follow-up, we observed an improvement in renal function.
In conclusion, we emphasize that cases of severe renal dysfunction that immediately require RRT remain very rare. In the present case, no complete recovery of renal function was observed despite treatment. This outcome was probably caused by late identification of the cause of AKI and significant kidney damage. The details of this case may serve as a lesson for clinicians facing similar cases in the future.
The authors have declared that no conflict of interest exists.
