Patients were referred to the UCL Centre for Nephrology tubular clinic and all underwent investigation with serum biochemistry, immunology, and renal biopsy. Urinary acidification testing was performed in 9 patients. GFR was estimated in all patients using the Modification of Renal Diet (MDRD eGFR) equation. 6 patients underwent 3-dose 51Chromium EDTA-GFR (51Cr-GFR) measurements before and after treatment. All patients with pSS who underwent renal biopsy from January 2007-December 2014 were included in this analysis.
The diagnosis of pSS was based on the 2002 American European consensus criteria [7], all patients satisfied the same criteria; ocular and oral symptoms, positive Schirmer test and positive Ro/La antibody status.
All patients who were suspected of having distal renal tubular acidosis (dRTA) underwent urinary acidification testing with a furosemide and fludrocortisone test [8] or an ammonium chloride test [9]. Briefly, the patient is administered either 40 mg of furosemide and 1 mg of fludrocortisone, or 0.1 mg/kg of ammonium chloride orally and the urine pH is monitored hourly. A fall in the urine pH to less than 5.3 represents normal urinary acidification; a failure to do so is diagnostic of dRTA.
Renal biopsy tissue was uniformly fixed in paraffin and sections were stained with hematoxylin and eosin. Immunophenotyping was performed by additional immunostaining with polyclonal antibodies to CD3, CD4, CD8, CD20, CD1a and CD138.
Where slides were available to review, we scored each biopsy to assess the nature of the inflammatory cell infiltrate and the degree of interstitial scarring. The infiltrate was scored as being either patchy or diffuse, the approximate amount of interstitium involved (<25 %, 25–50 %, 50–75 %, >75 %); the intensity of the infiltrate was scored as 1+ (light), 2+ (moderate) or 3+ (heavy); the predominant cell type in the infiltrate was recorded as was the amount of scarring, again recorded as 1–3 +.
Patients were treated with an antiproliferative agent, mycophenolate mofetil (MMF) or, in one case, azathioprine and where possible, a short reducing course of corticosteroid. The dose of MMF was titrated according to symptoms and recovery of renal function, and, in hypergammaglobulinemic patients, with the aim of bringing the IgG level within the normal range.
Statistical analysis was performed using GraphPad Prism 5.03, statistical significance was determined using the student’s t-test for Gaussian and Wilcoxon matched pair signed rank test for non-Gaussian distributed data.
Ethical considerations
All patients provided written informed consent for participation in the study and ethical approval was attained from the local ethics board (Great Ormond Street Hospital Ethics Committee). The authors have respected participants’ rights to privacy by de-identifying all patients data reported. By doing so, the authors feel they have maintained anonymity and confidentiality in accordance with local data protection laws.
Case vignettes
Case 1: A 54-year-old woman with pSS was referred with impaired renal function (eGFR 28 ml/min/1.73 m2). She complained of sicca symptoms, fatigue, urinary frequency and nocturia. She had raised inflammatory markers, a positive ANA, anti-Ro antibody and rheumatoid factor. A renal biopsy demonstrated TIN and she was commenced on MMF 2 g/day and a reducing course of prednisolone 30 mg. Her renal function remained stable for 5 years but the patient unilaterally stopped her immunosuppression; and her serum creatinine rose from 168 to 230 μmol/L. A second biopsy demonstrated TIN with significant scarring and mild glomerular changes (mesangial matrix expansion). Immunosuppression was restarted with renal function settling to baseline.
Case 2: A 52-year-old woman became unwell after a holiday in Pakistan. She presented with severe weakness, hypokalaemia and metabolic acidosis (serum bicarbonate 12 mmol/L). She was referred for investigation of dRTA, which was confirmed on urinary acidification testing. On direct questioning she also reported sicca symptoms, fatigue and arthralgia. She was ANA, anti-Ro and anti-La antibody positive. She was treated with potassium citrate and hydroxychloroquine 400 mg/day. She had deteriorating renal function (serum creatinine rose from 88 to 124 μmol/L) and her renal biopsy demonstrated TIN. MMF (500 mg/day) was started resulting in improvement in her renal function but not in her symptoms.
Case 3: A 36-year-old woman with known pSS was referred with persistent hypokalemic acidosis after elective cholecystectomy. She had dRTA confirmed on urinary acidification testing. There was also proximal tubular dysfunction (phosphate wasting and low molecular weight (LMW) proteinuria) and suggestion of a concentrating defect (low early morning urinary osmolality). Renal biopsy demonstrated TIN and she was treated with bicarbonate and potassium supplements in addition to low dose prednisolone (5 mg/day), hydroxychloroquine (400 mg/day) and MMF (1 g/day). Higher doses of MMF were prohibited by gastrointestinal side effects. She had progressive renal dysfunction (serum creatinine rose from 79 to 115 μmol/L) and a repeat biopsy 4 years after the first demonstrated ongoing TIN with worse scarring. Treatment with rituximab was attempted but abandoned after she developed an anaphylactoid reaction. Therefore MMF was titrated to 2 g/day and the prednisolone dose doubled. Despite this, she has slowly progressive deterioration in her GFR and severe extra-renal features (sicca symptoms, parotitis and arthritis).
Case 4: A 45-year-old woman with known pSS was referred with impaired renal function (eGFR 40 ml/min). She had defective urinary acidification on testing. She was treated with bicarbonate supplements. A renal biopsy confirmed TIN. Her serum creatinine deteriorated from 124 to 159 μmol/L and azathioprine 50 mg/day was started. Her renal function stabilized but her sicca symptoms remain.
Case 5: A 71-year-old woman had longstanding sicca symptoms and chronic hypokalaemia. She presented to hospital with diarrhea with severe hypokalaemia (2.1 mmol/L) and paralysis. The diarrhea was due to a colonic villous adenoma, for which she underwent a hemicolectomy. She was referred to our service for her hypokalaemia which persisted after her surgery. She reported sicca symptoms, arthralgia and systemic upset with associated positive pSS serology. dRTA was confirmed by urinary acidification testing. She underwent renal biopsy which demonstrated TIN with heavy staining for C9 along tubular basement membranes (negative staining for immunoglobulin). Potassium and bicarbonate supplements were commenced along with prednisolone 20 mg/day and hydroxychloroquine 200 mg/day. She was intolerant of both of these (dyspepsia and rash respectively) and developed worsening renal function off immunosuppression (serum creatinine rose from 97 to 159 μmol/L). MMF (1 g/day) was introduced with resolution of her renal impairment and improvement in her extra-renal symptoms.
Case 6: A 54-year-old woman was referred having passed a pure calcium phosphate stone, suggestive of dRTA. She had renal impairment (eGFR 32 ml/min/1.73 m2), imaging which demonstrated multiple stones bilaterally, and a long history of sicca symptoms with systemic upset. Her pSS serology was positive, she had dRTA confirmed on urinary acidification testing and had evidence of proximal tubular dysfunction (LMW proteinuria). A renal biopsy demonstrated TIN. She was treated with potassium citrate, a reducing course of prednisolone, MMF 1 g/day, and hydroxychloroquine 200 mg/day. Consequently, her renal function and symptoms improved.
Case 7: A 48-year-old woman presented to her GP with tiredness. She was found to have renal impairment (eGFR 39 ml/min/1.73 m2) and nephrocalcinosis. On direct questioning, she reported sicca symptoms and a rash. Her pSS serology was positive and she underwent renal biopsy, which demonstrated TIN with areas of calcification. She also had an incidental finding of thin glomerular basement membranes on electron microscopy. She had a systemic acidosis with an inappropriately high urinary pH, confirming dRTA. She was treated with potassium and bicarbonate supplementation, low dose steroid and MMF 500 mg/day; her renal function and symptoms improved.
Case 8: A 43-year-old woman was referred to our center with renal impairment (eGFR 36 ml/min/1.73 m2) and nephrocalcinosis. She reported longstanding sicca symptoms with systemic upset. She was acidotic (serum bicarbonate 18 mmol/L) and hypokalemic (2.8 mmol/L), and had dRTA confirmed by urinary acidification testing. She also had proximal tubular dysfunction (phosphate wasting and LMW proteinuria) and serology for pSS was positive. Renal biopsy demonstrated TIN with positive staining for C9 along tubular basement membranes. She was treated with potassium citrate supplements, a reducing course of prednisolone, and MMF 1.5 g/day. Her renal function stabilized, her electrolytes normalized, and her extra renal symptoms substantially improved.
Case 9: A 51-year-old woman was referred with unexplained renal impairment (eGFR 30 ml/min/1.73 m2). She had a long history of dry eyes for which she had been using artificial tears. pSS serology was positive and she underwent renal biopsy which demonstrated TIN. Subsequent urinary acidification testing demonstrated dRTA. She was treated with a reducing course of prednisolone and MMF 1.5 g/day. Her renal function improved but her sicca and non-specific symptoms persisted.
Case 10: A 61-year-old woman was referred with renal impairment (eGFR 43 ml/min/1.73 m2). She was non-specifically unwell with positive pSS serology and sicca symptoms. She underwent renal biopsy, which demonstrated TIN, and she was treated with a weaning course of prednisolone. Renal function was stable for 4 years off treatment but underwent further renal biopsy to reassess interstitial inflammation. This showed ongoing areas of TIN with increased chronic damage when compared to the initial biopsy. Immunosuppression with both MMF 500 mg/day and subsequently azathioprine 75 mg/day has been complicated by anemia and leucopenia. A bone marrow aspiration and biopsy revealed myelodysplastic changes only. She remains off immunosuppression currently with stable renal function (eGFR 45 ml/min/1.73 m2) and limited symptoms.
Case 11: A 72-year-old woman with longstanding systemic upset and arthralgia was initially misdiagnosed with rheumatoid arthritis. She subsequently developed impaired renal function (eGFR 46 ml/min/1.73 m2). She had mild sicca symptoms and her pSS serology was positive; a renal biopsy demonstrated TIN with C9 staining along tubular basement membranes. She was treated with MMF 1 g/day. Renal function improved as did her symptoms.
Case 12: A 53-year-old man was admitted with a painful peripheral neuropathy. He complained of sicca symptoms, was found to have renal impairment (eGFR 50 ml/min/1.73 m2), and developed a vasculitic rash. Cryoglobulins were present, there was hypocomplementaemia, pSS serology was positive, and a renal biopsy demonstrated TIN with mild mesangial proliferation. He was treated with a reducing course of prednisolone (initially 40 mg/day) and MMF 1 g BD. His renal function improved and his symptoms have settled.