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• W2016530300 abstract "Sarcoidosis is a chronic relapsing multi-systemic disorder characterized by the development of non-caseating granulomas. Granulomatous tubulo-interstitial nephritis is an uncommon manifestation of this condition. We identified 39 patients with sarcoidosis and renal disease from a single center of whom 17 patients had biopsy-proven tubulo-interstitial nephritis. They were analyzed with respect to demographic and clinical features, including response to corticosteroids and length of follow-up. They all presented with significant renal impairment. At presentation the mean±s.d. estimated glomerular filtration rate (eGFR) was 26.8±14 ml/min by modification of diet in renal disease (MDRD) equation 7. With treatment there was a significant improvement in renal function with eGFR 49.6±5.2 ml/min (P<0.01) at 1 year, and 47.9±6.8 ml/min (P<0.05) at the last review. The median follow-up was 84 months (range 6–284 months). Patients with chronic kidney disease (CKD) 3, the mean eGFR was 38.30±2.4 ml/min at presentation and 60.2±7.4 ml/min at 1 year (P=0.02) and in CKD 4 it improved from 19±2 to 38±6.6 ml/min at 1 year (P<0.05). After the 1st year, the change in eGFR was +0.8 ml/min/year for CKD 3 and -2 ml/min/year for CKD 4 (P<0.05). Three patients ceased their therapy either due to complications or poor compliance and experienced a worsening of renal function which was then reversed on re-commencing corticosteroids. Corticosteroids are effective in advanced tubulo-interstitial nephritis due to sarcoidosis. Long-term treatment is necessary to preserve renal function and to delay the onset of end-stage renal disease. Sarcoidosis is a chronic relapsing multi-systemic disorder characterized by the development of non-caseating granulomas. Granulomatous tubulo-interstitial nephritis is an uncommon manifestation of this condition. We identified 39 patients with sarcoidosis and renal disease from a single center of whom 17 patients had biopsy-proven tubulo-interstitial nephritis. They were analyzed with respect to demographic and clinical features, including response to corticosteroids and length of follow-up. They all presented with significant renal impairment. At presentation the mean±s.d. estimated glomerular filtration rate (eGFR) was 26.8±14 ml/min by modification of diet in renal disease (MDRD) equation 7. With treatment there was a significant improvement in renal function with eGFR 49.6±5.2 ml/min (P<0.01) at 1 year, and 47.9±6.8 ml/min (P<0.05) at the last review. The median follow-up was 84 months (range 6–284 months). Patients with chronic kidney disease (CKD) 3, the mean eGFR was 38.30±2.4 ml/min at presentation and 60.2±7.4 ml/min at 1 year (P=0.02) and in CKD 4 it improved from 19±2 to 38±6.6 ml/min at 1 year (P<0.05). After the 1st year, the change in eGFR was +0.8 ml/min/year for CKD 3 and -2 ml/min/year for CKD 4 (P<0.05). Three patients ceased their therapy either due to complications or poor compliance and experienced a worsening of renal function which was then reversed on re-commencing corticosteroids. Corticosteroids are effective in advanced tubulo-interstitial nephritis due to sarcoidosis. Long-term treatment is necessary to preserve renal function and to delay the onset of end-stage renal disease. Sarcoidosis is a multi-systemic disorder characterized by the development of non-caseating granulomas. Typically, it presents in adulthood and is more common amongst black patients, who have a 2.4% lifetime risk of developing the disease.1.Rybicki B.A. Major M. Popovich Jr., J. et al.Racial differences in sarcoidosis incidence: a 5 year study in a health maintenance organization.Am J Epidemiol. 1997; 145: 234-241Crossref PubMed Scopus (685) Google Scholar The etiology is unclear though infectious agents, occupational exposure to organic and inorganic agents, autoimmunity, and genetic factors have been implicated.2.Newman L.S. Rose C.S. Maier L.A. Sarcoidosis.N Engl J Med. 1997; 336: 1224-1234Crossref PubMed Scopus (1330) Google Scholar The illness may be self-limiting or chronic, with episodic recrudescence and remissions. The majority of patients present with systemic symptoms, with respiratory involvement occurring at some time in the course of disease in virtually all patients. Renal manifestations of sarcoidosis are most commonly due to disorders in calcium homeostasis. Hypercalciuria is common and is present in up to half of patients with sarcoidosis, but overt hypercalcemia is only a feature in approximately 10% of patients, leading to renal impairment in some.3.Sharma O.P. Vitamin D, calcium and sarcoidosis.Chest. 1996; 109: 535-539Crossref PubMed Scopus (204) Google Scholar Granulomatous tubulo-interstitial nephritis (TIN), a diagnosis only made at biopsy, is a less common cause of renal impairment and is often accompanied by systemic manifestations,4.Gobel U. Kettritz R. Schneider W. Luft F.C. The protean face of renal sarcoidosis.J Am Soc Nephrol. 2001; 12: 616-623PubMed Google Scholar although it has been described in the absence of extrarenal sarcoid in a small case series.5.Robson M. Banerjee D. Hopster D. Cairns H.S. Seven cases of granulomatous interstitial nephritis in the absence of extra renal sarcoid.Nephrol Dial Transplant. 2003; 18: 280-284Crossref PubMed Scopus (68) Google Scholar There is some evidence that subclinical TIN is present in between 7 and 27% of all patients from post-mortem series, but has not been thought to contribute greatly to clinical sequelae.6.Longcope W.T. Freiman D.G. A study of sarcoidosis; based on a combined investigation of 160 cases including 30 autopsies from The Johns Hopkins Hospital and Massachusetts General Hospital.Medicine (Baltimore). 1952; 31: 1-132Crossref PubMed Scopus (354) Google Scholar Alternative causes such as drugs and tuberculosis (TB) must be excluded from the differential diagnosis.7.Schwarz A. Krause P.H. Kunzendorf U. et al.Granulomatous interstitial nephritis after non-steroidal anti-inflammatory drugs.Am J Nephrol. 1988; 8: 410-416Crossref PubMed Scopus (44) Google Scholar The mainstay of treatment in an acute setting has been corticosteroids with a good success rate,5.Robson M. Banerjee D. Hopster D. Cairns H.S. Seven cases of granulomatous interstitial nephritis in the absence of extra renal sarcoid.Nephrol Dial Transplant. 2003; 18: 280-284Crossref PubMed Scopus (68) Google Scholar, 8.Hannedouche T. Grateau G. Noel L.H. et al.Renal granulomatous sarcoidosis: report of six cases.Nephrol Dial Transplant. 1990; 5: 18-24Crossref PubMed Scopus (72) Google Scholar, 9.Brause M. Magnusson K. Degenhardt S. et al.Renal involvement in sarcoidosis – a report of 6 cases.Clin Nephrol. 2002; 57: 142-148Crossref PubMed Scopus (26) Google Scholar There is however a paucity of data on the impact of maintenance therapy to long-term outcome, the risk of relapse and progression of chronic kidney disease (CKD). We present the largest single center series of biopsy-proven TIN due to sarcoidosis that were treated and maintained on corticosteroids. Thirty nine patients were assessed by the renal unit between January 1982 and December 2004 with sarcoidosis and significant renal disease. Twenty patients (51.2%) underwent a renal biopsy. Of the remaining 19 patients, four patients had presented with hypercalcemia with either nephrocalcinosis or overt calculi on screening. The remaining non-biopsied patients not in end-stage renal failure either had an alternative diagnosis or had mild stable chronic renal impairment (CKD 1/2) with no indication for renal biopsy (Figure 1). Of the twenty patients who underwent a renal biopsy, 17 were diagnosed with TIN. All patients with TIN had evidence of systemic sarcoidosis of which nine cases had a previous history of extrarenal sarcoid with median disease duration of 4 years (range 3 months–14 years). The remaining eight patients were either referred by their family practitioner or presented to the accident and emergency department with unexplained renal impairment and were subsequently diagnosed with TIN and systemic sarcoid. Only two of the eight patients were on corticosteroids at the time of diagnostic biopsy both of whom had stage 4 lung disease. Three patients presenting with nephrotic range proteinuria had a primary glomerular lesion with no interstitial involvement (Figure 1). Of those with interstitial nephritis, eight patients were male and nine female, with a mean age of 44±15 years. Nine patients (53%) were of afro-Caribbean origin and six were Caucasian (35%). Demographics and clinical presentation, with estimated glomerular filtration rate (eGFR) are summarized in Table 1. Renal function in all patients at the time of diagnosis was severely impaired, with mean eGFR 26.8±14 ml/min. Eight patients (47%) had preceding pulmonary involvement, with confirmation on chest X-ray or high-resolution computed tomography of the chest. Serum angiotensin-converting enzyme (ACE) level was only elevated in three patients at the time of diagnosis. Two patients presented with an acute systemic illness with severe renal impairment. There were no cases with renal limited granulomatous TIN in this series. Early morning urine cultures and Ziel–Nielsen staining were negative in all cases.Table 1Demographics of patients with confirmed sarcoid interstitial nephritis on renal biopsy%Age44±15.8Sex Male847 Female953Race Black953 White635 Indo-Asian212Clinical features Chest847 Lymph nodes424 Uveitis635 Hypercalcemia424Elevated SACE318Creatinine (mean±s.d.)366±299 μmol/leGFR (mean±s.d.)26.8±14 ml/minFollow-up (mean±s.d.)88±73SACE, serum angiotensin-converting enzyme; eGFR, estimated glomerular filtration rate; s.d., standard deviation. Open table in a new tab SACE, serum angiotensin-converting enzyme; eGFR, estimated glomerular filtration rate; s.d., standard deviation. The typical histological appearances of granulomatous interstitial nephritis on renal biopsy are shown in Figure 2. Glomeruli were normal except in two patients of whom one had membranous glomerulonephritis with granulomatous TIN. In the other there were changes consistent with steroid-induced diabetes mellitus as the biopsy was carried out late in the course of sarcoidosis. There was no correlation between presenting creatinine and the degree of tubular atrophy (Spearman's r=0.045, P=NS). All patients had evidence of tubular fibrosis on renal biopsy. Granulomas were present in all but four cases. Three of the patients with no granulomas had advanced scarring, normal serum calcium, extrarenal sarcoid and a steroid-responsive course. Five patients had evidence of intracellular calcification, but this was not associated with elevated serum calcium in four patients. The presence of intracellular calcium was not associated with differences in either presenting renal function or response to corticosteroids. All patients were initially treated with prednisolone at a starting dose of 0.5 mg/kg body weight which approximated to a daily dose of 30–60 mg daily. Mean eGFR in patients with TIN was 26.8±14 ml/min. All patients showed a beneficial response to prednisolone within the 1st year (Figure 3a) with median follow-up of 84 months (range 6–264 months). All patients irrespective of the stage of CKD showed a satisfactory response to treatment with an improvement of mean eGFR from 26.8±14 to 49.6±5.2 ml/min (P<0.01) at 1 year, and 47.9±6.8 ml/min (P<0.05) at last follow-up (Figure 3b). In patients presenting with stage 3 CKD, the mean eGFR was 38.3±2.4 ml/min at presentation and 60.2±7.4 ml/min at 1 year (P=0.02), and in stage 4 CKD mean eGFR improved from 19±2 to 38±6.6 ml/min at 1 year (P<0.05). There was no difference in the response to treatment between black and non-black patients. There was a satisfactory response to corticosteroids irrespective of the degree of tubulo-interstitial scarring with significant improvement in eGFR at 1 year in patients with grade 2 and 3 changes on biopsy (Figure 4). We then investigated the change in eGFR during the course of follow-up in different stages of CKD. After the 1st year, the change in eGFR was +0.8 ml/min/year for CKD 3 and -2 ml/min/year for CKD 4 (P<0.05). However, the mean duration of follow-up in CKD 4 was 137±25 months compared to 66.4±19.7 months in CKD 3 (P=0.08). It was our unit policy to taper the daily prednisolone dose by 5 mg each week once the renal function has improved and/or stabilized. The patients are then maintained on 5–7.5 mg daily indefinitely. Three patients ceased their therapy either due to side effects or poor compliance and experienced a significant deterioration in renal function, which was then reversed on re-commencing corticosteroids. One patient was lost to follow-up after 11 years with discontinuation of treatment, and subsequently presented in end-stage renal failure. The patient with both membranous nephropathy and TIN was commenced on mycophenolate mofetil in addition to prednisolone and is maintained on both. Another two patients with multiple relapses as evidenced by a rise in creatinine were successfully treated with mycophenolate mofetil and Azathioprin, respectively, as steroid-sparing agents. Thirteen patients were treated for hypertension and were all on either an ACE inhibitor or angiotensin receptor blocker during the follow-up period. Of this group seven patients were on one or more additional agents to control blood pressure. There was a nonsignificant improvement in ΔGFR/year in those patients on ACE/angiotensin receptor blocker (ΔGFR/year on ACE/angiotensin receptor blocker +1.6± 3.5 ml/min, not on ACE/angiotensin receptor blocker -0.9± 1.7 ml/min, P=NS). In all but one patient with nephrotic syndrome, 24 h urinary protein excretion was <0.5 g with preservation of serum albumin. Three patients developed side effects that could be attributed to steroids. One patient developed acute psychosis with high-dose steroids that responded to a dose reduction. Two patients developed type 2 diabetes (one, insulin treated and one, diet controlled). Renal involvement in sarcoidosis is uncommon and patients often present with significant renal disease to the nephrologists late in the course of their disease as reflected by the presenting eGFR and the presence of tubular atrophy. High-dose corticosteroid therapy is the established treatment option for acute granulomatous interstitial nephritis. Its efficacy in patients with biopsy-proven advanced renal disease is unclear. In previously published literature, corticosteroids do appear to have a positive impact on preventing the progression of advanced renal disease.5.Robson M. Banerjee D. Hopster D. Cairns H.S. Seven cases of granulomatous interstitial nephritis in the absence of extra renal sarcoid.Nephrol Dial Transplant. 2003; 18: 280-284Crossref PubMed Scopus (68) Google Scholar There is no evidence to dictate the duration of maintenance therapy. The majority of patients in this series were either CKD 3 or CKD 4 and in both groups there was a significant improvement of renal function at 1 year. Clinical disease in systemic sarcoidosis is highly variable with a tendency to wax and wane either spontaneously or with steroids. In the pulmonary sarcoidosis the relapse rate is 20–50% when corticosteroids were stopped.10.Hunninghake G.W. Gilbert S. Pueringer R. et al.Outcome of the treatment for sarcoidosis.Am J Respir Crit Care Med. 1994; 149: 889-893Crossref Scopus (221) Google Scholar, 11.Gottlieb J.E. Israel H.L. Steiner R.M. et al.Outcome in sarcoidosis: the relationship of relapse to corticosteroid therapy.Chest. 1997; 111: 623-631Crossref PubMed Scopus (254) Google Scholar In advanced renal disease the discontinuation is likely to lead to deterioration of renal function which may irreversibly progress to end-stage renal disease. In this series, low-dose steroids were maintained with good preservation of renal function. In those patients presenting to nephrologists in CKD 4, there was a slow decline of GFR over a prolonged follow-up of 14 years after the initial improvement, but this was not dissimilar to the rate observed in age-related decline of renal function.12.Cirillo M. Anastasio P. De Santo N.G. Relationship of gender, age, and body mass index to errors in predicted kidney function.Nephrol Dial Transplant. 2005; 20: 1791-1798Crossref PubMed Scopus (190) Google Scholar Patients who either discontinued treatment or were non-compliant developed worsening of renal function which subsequently improved on recommencing steroids. Only one patient who was not on maintenance steroids developed end-stage renal disease. The benefit of long-term steroid use needs to be balanced against the potential adverse effects. Two patients in our series developed type 2 diabetes. There is a risk of moderate reduction in bone mineral density with low-dose maintenance steroid therapy.13.de Deus R.B. Ferreira A.C. Kirsztajn G.M. Heilberg I.P. Osteopenia in patients with glomerular diseases requiring long-term corticosteroid therapy.Nephron Clin Pract. 2003; 94: 69-74Crossref PubMed Scopus (10) Google Scholar Therefore, prophylactic treatment with bisphosphanates and vitamin D preparations are indicated. In our unit all patients on maintenance steroids were commenced on a calcium–vitamin D supplement. Another option would be the institution of steroid-sparing agents (mycophenolate mofetil, azathioprin) as practiced in our unit for patients who relapsed on maintenance steroids. The differential diagnosis of TIN is extensive with infections (e.g., TB) and drugs (e.g., antibiotics, non-steroidal anti-inflammatory agents) should be considered and excluded. In our series, all patients had systemic evidence of sarcoidosis of which four did not have the typical feature of granulomas in the renal biopsy. This is likely to be due to their advanced disease at presentation or sampling effect. The response to treatment in the latter mirrored the patients with granulomatous interstitial nephritis. Two patients had treatment for TB prior to be diagnosed with sarcoid TIN. In one patient the TB was never proven but was treated empirically for chest symptoms as her daughter at the time was diagnosed with the disease. The second patient completed a course of treatment for pulmonary TB 9 years after the diagnosis of respiratory sarcoid. After 4 years sarcoid TIN was diagnosed with no active evidence of TB. Isoniazid prophylaxis was given with corticosteroids in both patients with induction of remission of sarcoid and no reactivation of TB. Serum ACE levels were raised in only a minority of patients. It lacks specificity for both the diagnosis and as a predictor of disease progression.14.Beneteau-Burnat B. Baudin B. Angiotensin-converting enzyme: clinical applications and laboratory investigations on serum and other biological fluids.Crit Rev Clin Lab Sci. 1991; 28: 337-356Crossref PubMed Scopus (83) Google Scholar, 15.Studdy P.R. Lapworth R. Bird R. Angiotensin-converting enzyme and its clinical significance – a review.J Clin Pathol. 1983; 36: 938-947Crossref PubMed Scopus (121) Google Scholar This series demonstrate that sarcoid interstitial nephritis typically presents with already advanced renal disease. Despite this, it is an important diagnosis to confirm, as there is excellent response to corticosteroid therapy even with advanced chronic changes on biopsy. Long-term maintenance treatment with low-dose corticosteroids helps to preserve renal function and prevent the onset of end-stage renal disease. There is however side effects from maintenance corticosteroids which need to be balanced against the risk of progression to end-stage renal disease. The efficacy of steroid-sparing agents such as mycophenolate mofetil or azathioprin requires further investigation. We identified 39 patients referred to the Barts and the Royal London Hospital Renal unit during the period January 1982 to December 2004 with sarcoidosis and renal disease. The indications for renal biopsy were unexplained progressive renal impairment, proteinuric renal disease with or without a previous history of sarcoidosis. Contraindications were overt nephrocalcinosis and small kidneys on renal imaging. In 20 patients a native renal biopsy was indicated and technically possible of which 17 patients were diagnosed with TIN. The breakdown of the whole cohort is in Figure 1. The patients with TIN were analyzed with respect to epidemiological and clinical features, including response to therapy with corticosteroids and length of follow-up. eGFR was calculated by the 4-variable modification of diet in renal disease equation 7.16.Levey A.S. Bosch J.P. Lewis J.B. et al.A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in Renal Disease Study Group.Ann Intern Med. 1999; 130: 461-470Crossref PubMed Scopus (12275) Google Scholar Renal biopsy samples were processed in the routine manner and embedded in paraffin wax. The sections were stained with hemotoxylin and eosin. All of the specimens were reviewed by three observers and the changes within glomeruli, tubules, interstitium, and vessels documented. These included tubulitis, interstitial inflammation, scarring, and the presence or absence of calcium deposits and/or granulomas. Tubulo-interstitial scarring was scored based on the degree of fibrosis in the cortical sample where scarring in up to 5% of the tissue was graded as 0; 6–25% fibrosis in the sample was graded 1 (mild); 26–50% graded 2 (moderate), and >50% graded 3 (severe). Once the diagnosis of TIN was made, patients were commenced on prednisolone 0.5 mg/kg body weight. The starting dose was usually between 30 and 60 mg daily. Once renal function improved or stabilized, the daily prednisolone dose was tapered by 5 mg per week until maintenance dose of 5–7.5 mg was achieved. GraphPad Prism version 3.00 for Windows XP, GraphPad Software, San Diego, CA, USA was used for the analysis. Mann–Whitney U and paired t-tests were used to compare year 0 and year 1 eGFR in different groups. Spearman's rank coefficient was used to correlate renal function with interstitial scarring. A P-value of <0.05 was considered significant." @default.
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• W2016530300 title "Sarcoid tubulo-interstitial nephritis: Long-term outcome and response to corticosteroid therapy" @default.
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