Pathological changes of renal biopsy in Sjögren Syndrome

We are presenting the case of a 53-year-old woman with a history of Sjögren syndrome and a secondary antiphospholipid syndrome admitted at the Nephrology department for the evaluation of renal failure. The patient was initially diagnosed with tubulointerstitial nephritis and subsequently a membranoproliferative type I glomerulonephritis, secondary to cryoglobulins during the course of the disease. Repeated renal biopsies were required to confirm the diagnosis.


Introduction
Sjögren syndrome (SS) is a systemic autoimmune disease with multi-organ involvement, including the kidney. The prevalence of renal involvement varies among different series, but overt renal disease is considered to be a rare manifestation. Renal involvement might be present at diagnosis or develop soon after. The most frequent SS-associated nephropathies are tubulointerstitial nephritis (TIN) and less frequently membranoproliferative glomerulonephritis (MPGN) related to cryoglobulinemia [1]. Renal biopsy is the cornerstone in the diagnosis of renal involvement in these patients.
We present a 53-year-old woman with primary SS and renal failure initially in the context of TIN. With time the diagnosis was changed to a membranoproliferative type I glomerulonephritis secondary to cryoglobulins.

Patient and observation
A 53-year-old woman with a medical history of primary Sjögren syndrome and secondary antiphospholipid syndrome was admitted to the nephrology department for renal biopsy due to worsening renal function (creatinine ranging from 1.5 to 1.9mg/dL), progressive proteinuria with a peak level of 2g/24h and microhematuria ( Table 1). The renal picture was associated to arthralgias, erythematous skin lesions, and neuropathic pain in lower extremities. Her family history was noncontributory. Her current medications included prednisone 10mg daily, azathioprine 100mg twice a day, valsartan 20mg daily, carvedilol 25mg twice a day, doxazosin 8mg daily, furosemide 20mg daily, gabapentin 30mg twice a day, and amitriptyline 50mg at night. Her medical history and interstitial tubular fibrosis were observed ( Figure 6A, Figure 6B).
All of these findings were consistent with a Cryoglobulinemic glomerulonephritis with a pattern of membranoproliferative type I.

Discussion
Sjögren syndrome is a chronic, slowly-progressive autoimmune disorder characterized by lymphoplasmacytic infiltration of the exocrine glands, mainly the salivary and the lacrimal glands. The syndrome could present as an isolated condition or in association with other autoimmune conditions as in the case presented [1]. The clinical spectrum is wide; patients generally present with symptoms related to xerostomia and keratoconjunctivitis but they may also present with pulmonary, neurological, cardiovascular, and kidney manifestations. The prevalence of renal involvement in Sjögren syndrome ranges from 2 to 67 percent [1][2][3]. This wide variation probably results from the different classification criteria used in the studies, as well as the selection of the patients. In this respect, TIN is the most common kidney manifestation in Sjögren syndrome and results from interstitial lymphoplasmacytic inflammation [4,5].
TIN is most often manifested by tubular acidosis but also by hypokalemia and/or hypophosphatemia and might evolve to renal insufficiency [6]. Tubular acidosis is the consequence of the inability of the distal renal tubule to secrete hydrogen ions. Hyposthenuria has also been described and it is due to an abnormality in the urine concentration mechanism [6,7]. Chronic renal impairment is associated with tubular atrophy and interstitial fibrosis. The presence of tubular granulomata has also been reported mostly in patients presenting with other conditions such as sarcoidosis.
Glomerular involvement is less often seen [7]. This may include membranoproliferative/cryoglobulinemic glomerulonephritis (GN), membranous nephropathy, mesangioproliferative GN, and focal segmental glomerulosclerosis [8,9]. In terms of renal prognosis, those patients presenting with TIN have a more favorable prognosis compared with those with GN. Poor prognosis in patients with GN is probably related to mixed cryoglobulinemia and the risk of lymphoma in cryoglobulinemic GN [8,9]. Our patient presented in 2013 with a clinical picture consistent with leucocytoclastic vasculitis in the course of a Sjogren syndrome with cryoglobulinemia, but cryoglobulins were negative, and the renal biopsy was compatible with tubulointerstitial nephritis.
These results would have been carefully evaluated as laboratory testing of cryoglobulins is fraught with false-negative results due to suboptimal specimen collection and handling. Therefore, repeating testing must be done when this condition is suspected. This may explain why cryoglobulin testing came back negative even though