Case 2

A 29-year-old white male with declining renal function was referred to our nephrology outpatient clinic.

His medical history was remarkable for recurrent renal colic but concurrent non-steroidal anti-inflammatory drug abuse was denied. He reported asthenia, anorexia, generalized myalgia and oedema of both lower limbs lasting one month.

His physical examination was remarkable only for bilateral malleolar oedema. Initial laboratory showed BUN 23.8 mg/dL, SCr 1.84 mg/dL and serum (albumin-corrected) calcium 10.2 mg/dL. Urinary sediment had no cells or casts; 24-hour urine collection showed 0.42 g of protein and urinary calcium of 0.08 g/day.

Renal ultrasound revealed normal sized kidneys with increased echogenicity and decreased differentiation but no evidence of obstruction or nephrolithiasis.

A systemic sarcoidosis diagnosis was established and the patient was treated with three pulses of 500 mg of intravenous methylprednisolone for a total of three days and continued on 1mg/kg/day prednisolone scheme for two months, with improvement of both renal function and respiratory symptoms.

Two years later, while on a 5 mg/day prednisolone daily dose, SCr 1.4 mg/dL is maintained.

Case 3

A 48-year-old white male with 3 years of hyperuricaemia and gouty arthritis was referred to our nephrology outpatient consultation due to a newly diagnosed anaemia and declining renal function. At the appointment, he further reported systemic symptoms including asthenia, anorexia and muscular weakness on the previous 4 months. He was taking alopurinol 300mg and, six months previously, he had a normal serum creatinine on routine evaluation.

Physical examination was unremarkable. Initial laboratory tests revealed BUN 31.8 mg/dL, SCr 2.78 mg/dL, serum (albumin-corrected) calcium 9.9 mg/dL. Urinalysis showed no active sediments. A 24-hour urine collection showed 0.2 g of protein and urinary calcium excretion was normal.

The diagnosis of stage II systemic sarcoidosis with pulmonary and renal involvement was finally established.

Treatment with prednisolone, 1 mg/kg/day, was initiated and one month later renal function showed some improvement, with SCr 2.17mg/dL.

Corticosteroid therapy was gradually tapered without relapse and was discontinued six months later. Serum creatinine reached a minimum of 1.81mg/dL. After one year without treatment, the patient’s SCr is of 2mg/dL.

DISCUSSION

Sarcoidosis is a systemic disease of unknown aetiology, characterized by chronic non-caseating granulomatous inflammation with tissue destruction⁷.

Diagnosis of sarcoidosis relies on the demonstration of non-caseating granulomas in a biopsy specimen and clinical exclusion of other causes of granulomatous inflammation. Renal involvement is only seen in a small number of patients. The incidence of renal sarcoidosis varies widely (0.7%–10%), in part due to varying definitions used in different studies^9,10. Although sarcoidosis is primarily a granulomatous inflammation, granulomatous interstitial nephritis (GIN) accounts for only a small proportion of clinically significant kidney failure in patients with sarcoidosis. The mechanism most frequently implicated in renal dysfunction is due to disturbances in calcium metabolism. Macrophages within sarcoid granulomas have elevated 1α-hydroxy lase activity resulting in overproduction of 1, 25-dihydroxyvitamin D3 which in turn leads to hypercalcaemia, nephrocalcinosis or urolithiasis¹¹.

In sarcoid nephropathy, hypercalcaemia occurs in approximately 10% of patients, whereas hypercalciuria is about three times more frequent¹².

Renal function impairment without calcium nephropathy is uncommon. In all three cases presented here, serum calcium levels were normal. No renal calculi were found. After excluding abnormalities affecting calcium homeostasis, tubulointerstitial diseases are the most commonly encountered renal abnormalities in sarcoidosis – they are histopathologically described as GIN¹³. True prevalence of GIN in sarcoidosis is unknown, mainly because a systematic kidney biopsy is rarely performed, even with mild renal signs, and may be present without pulmonary involvement¹⁴. Also, one should remember that GIN by itself is not pathognomonic of sarcoidosis. Granulomatous interstitial nephritis has been associated with medication, infections, crystal deposits, paraproteinaemia, and Wegener’s granulomatosis also is seen in an idiopathic form^15,16.

Other causes of GIN have to be ruled out, and notably drug induced. Medicines implicated include anticonvulsants, antibiotics, non-steroidal anti-inflammatory drugs, allopurinol and diuretics, although proof that a particular drug is responsible is often circumstantial¹⁵. Supportive evidence may include a temporal relation between starting the drug and the development of renal failure or cessation of the drug and an improvement in renal function. In two of our patients (cases 1 and 2) abnormal renal function was noted at a time when no medication was taken. In the other patient (case 3) there was no clear relation between starting a drug and the development of disease, since he had been medicated with allopurinol three years before the diagnosis of renal failure.

Moreover, in our series of cases, two patients (cases 2 and 3) had the finding of granulomas in another organ, which turns the diagnosis of drug-induced GIN unlikely. Consistent with a pattern of tubulointerstitial disease, proteinuria is either absent or mild.

Urine analysis shows leucocytes and granular casts. Rarely, the patient may present as frank haematuria lasting several weeks. The GIN is usually associated with enlarged kidneys mimicking renal amyloidosis or diabetic nephropathy. In the first patient described here, abdominal ultrasound showed an enlarged liver with scattered, slightly increased areas of echogenicity.

This suggested sarcoidosis of the liver, although liver biopsy was not performed. Serum ACE concentration is a poor marker of active renal lesion and may even be normal in active GIN with severe renal failure^12,17, as we noticed in the third patient.

In most cases, diagnosis of GIN is made in the context of typical extra-renal manifestations of sarcoidosis and/or hypercalcaemia. Rarely, renal involvement may be isolated and preceding other sites of the disease for months to years¹⁸. In all patients presented here, occurrence of renal failure led to the diagnosis of sarcoidosis. Glomerular involvement in sarcoidosis is not very common and the exact mechanisms of glomerular disease in sarcoidosis are not known. The spectrum of commonly reported glomerular diseases include focal segmental sclerosis, membranous glomerulonephritis (GN), mesangioproliferative glomerulonephritis, mesangiocapillary glomerulonephritis, IgA nephropathy and crescentric glomerulonephritis.

Due to the absence of a consistent glomerular pathology and a well described aetiological pathway, most cases are believed to be coincidental associations^12,19.

Many of the agents used in the therapy of sarcoidosis target, among other cytokines, TNF-alpha.

These agents include non-specific inhibitors of TNFalpha release, such as steroids, methotrexate, azathioprine, antimalarials, and phosphodiesterase inhibitors, as pentoxifylline and thalidomide. The mainstay of treatment of sarcoid GIN is glucocorticoids.

The other agents have been tried in systemic extra-renal sarcoidosis although no data on treating renal sarcoidosis exists^12,20,21. Initial treatment of GIN requires a daily dose of prednisone or prednisolone preferably 1 – 1.5 mg/kg. Response to treatment can often be dramatic in terms of improvement of renal insufficiency. An important point to realize here is that steroid treatment has to be prolonged and must exceed at least six months as nephropathy relapses are very frequent with short term therapy.

A commonly followed strategy is to give the initial dose for two months followed by progressive taper and switching to an alternate day therapy. A maintenance therapy period for one year at least is recommended^15,22.

One of our patients (case 2) was started on steroid therapy with 3 pulses of intravenous methylprednisolone. The authors are unaware of the exact reason why methylprednisolone was considered. We presume that this was probably because sarcoidosis is often mixed up with autoimmune diseases. There is no consensus on the appropriate therapy for patients who are intolerant of corticosteroids or who relapse frequently upon dose reduction or discontinuation. The use of alternative agents may be indicated if the side effects of corticosteroids are intolerable or if there is progression of disease despite adequate therapy. Three agents are currently available as specific TNF- α antagonists: etanercept, infliximab and adalimumab²³. Etanercept is an ineffective therapeutic agent in the treatment of sarcoidosis^24,25. In contrast, multiple case reports and a small randomized controlled trial²⁶ suggest that infliximab is an effective therapy in both refractory pulmonary sarcoidosis and extrapulmonary diseases, including uveitis, neurosarcoidosis, cardiac sarcoidosis and GIN. There are two case reports of treatment with infliximab in renal sarcoidosis. Thumfart and colleagues8 described the case of a boy presenting with severe arterial hypertension and acute renal failure caused by an isolated sarcoid granulomatous interstitial nephritis. Renal function improved initially with prednisone treatment but later the patient showed signs of severe steroid toxicity and progressive renal failure. Monthly treatment with infliximab was started, resulting in steady improvement in renal function and resolution of renal granuloma.

In addition, antihypertensive medication could be reduced. Ahmed and associates²⁷ presented a patient with acute renal failure due to isolated granulomatous infiltration of the renal parenchyma. Renal biopsy showed granulomatous interstitial nephritis with non-caseating granulomas. There was no evidence of extrarenal sarcoid involvement. Prednisone 60 mg daily resulted in significant improvement in renal function. Because of recurrent flares on steroid taper and steroid toxicity, treatment with infliximab was instituted and resulted in stabilization of renal function. Gupta et al.²⁸ described the successful treatment of a case of granulomatous interstitial nephritis using adalimumab. The combination of clinical improvement and complete lack of granulomatous features on follow-up biopsy strongly suggests immunomodulation by adalimumab-induced resolution of sarcoid nephropathy. Adalimumab, like infliximab, is not without systemic side effects although most are relatively minor. Among those causing the most concern is the risk of reactivation of tuberculosis. In the cohort described by Preddie et al.²⁹, eight patients had received corticosteroids and had experienced relapses, intolerance and resistance to therapy. All of them were treated with mycophenolate mofetil (MMF) for interstitial nephritis. In each case, serum creatinine stabilized or improved on therapy. Five patients had been able to discontinue treatment with MMF successfully. The remaining three patients were maintained on MMF, unable to discontinue without relapse. This may mean that there was a trading of steroid dependence and adverse effects for MMF dependence and adverse effects. Therefore, optimal therapeutic management of GIN can only be determined after further investigation.

Our three patients presented renal failure as the first evidence of sarcoidosis. All of them had also some degree of pulmonary involvement at the moment of diagnosis despite the absence of respiratory symptoms.

The first two patients had renal failure secondary to GIN. The last patient had only evidence of interstitial nephritis and deposits of medullary calcium in his renal biopsy; nevertheless, we cannot rule out the hypothesis of concurrent GIN; even though we had not found granulomatous lesions, it is possible that these had not been seen because of randomness of biopsy sampling. Other causes of granulomatous lesions in all three patients had been excluded.

According to some reports^7,12, renal sarcoidosis should be considered a potentially serious manifestation of the disease, with rapidly progression of renal failure to end stage renal disease despite treatment with corticosteroids. All our patients had been treated with prednisolone at the time of diagnosis, with satisfactory recovery of their renal function. This is probably explained by an aggressive treatment with steroids since the beginning.

In conclusion, we have presented three patients with interstitial nephritis with renal failure as the presenting manifestation of sarcoidosis. All patients were started on a forward regimen of 1 mg/Kg/day of prednisolone, with renal function improvement.

References