Sarcoidosis: The Nephrologist’s Perspective

doi:10.1053/j.ajkd.2006.07.022

American Journal of Kidney Diseases

Volume 48, Issue 5, November 2006, Pages 856-870

https://doi.org/10.1053/j.ajkd.2006.07.022 Get rights and content

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Case Report

A 42-year-old white man was seen in the nephrology clinic with 3 months of polyuria, polydipsia, and nocturia and a serum creatinine level of 2.8 mg/dL (248 μmol/L); it had been 1.3 mg/dL (115 μmol/L) 2 years prior. Sarcoidosis was diagnosed 3 years earlier by means of cervical lymph node biopsy showing noncaseating granulomatous inflammation with negative acid-fast bacteria and fungal stains (Fig 1). He had never required corticosteroid therapy and did not use prescription or nonsteroidal

Pathogenesis

Aberrant calcium and vitamin D metabolism in patients with sarcoidosis has been observed since the 1930s.²¹ Normal hydroxylation of 25-hydroxyvitamin D to 1,25-dihydroxy vitamin D (calcitriol) occurs in renal proximal tubular cells by means of 1-α hydroxylase, a cytochrome P-450 enzyme.²² In patients with sarcoidosis and other chronic granulomatous diseases, granulomas and activated pulmonary macrophages often express 1-α hydroxylase in a fashion resistant to such normal negative feedback

Pathogenesis and Epidemiology

Noncaseating sarcoid granulomas in the kidney were described first by Garland and Thomson⁴³ in 1933, and the first patient with renal failure, with a serum creatinine level of 1.9 mg/dL (168 μmol/L), caused by sarcoid GIN was reported by Berger and Relman⁴⁴ in 1955. Autopsies of patients with sarcoidosis described interstitial renal granulomas in 7% to 23% of cases,45, 46, 47 although many remained clinically silent. Renal failure from GIN is infrequent, with a low, but uncertain, incidence;

Renal Tubular Dysfunction

Renal tubular dysfunction in patients with sarcoidosis frequently accompanies hypercalcemia and/or GIN. Polyuria or frank nephrogenic diabetes insipidus may be caused by nonspecific tubular injury or hypercalcemia. Neurosarcoidosis may cause central diabetes insipidus. Hypercalcemia impairs urinary concentration in part due to blunting of anti-diuretic hormone effect, both by inhibiting the binding of anti-diuretic hormone to vasopressin V2 receptors, and by inhibiting cyclic adenosine

Kidney Transplantation

Patients with sarcoidosis have received transplanted hearts, lungs, livers, and kidneys without an apparent increase in morbidity compared with other transplant recipients.¹⁴³ Shen et al¹⁴⁴ reported the first recurrence of sarcoid GIN in a renal allograft 6 years after deceased donor renal transplantation in the same patient described 9 years earlier by Turner et al⁶⁹ (Table 2) when she had GIN in her native kidneys. The patient’s renal function improved with an increased dose of prednisone.

Conclusion

Sarcoidosis concerns nephrologists; it causes renal disease on several fronts because of either the more common findings of hypercalcemia and hypercalciuria, the familiar lesion of GIN, or specific renal tubular, glomerular, or structural disease. We have reviewed these to facilitate understanding, recognition, and treatment of these entities. Corticosteroids are the predominant form of treatment in many cases. Further insight into the pathogenesis of sarcoidosis may allow for a more customized

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Cited by (121)

Organ involvement in newly diagnosed sarcoidosis patients in the Netherlands: The first large European multicentre prospective study
2024, Respiratory Medicine
Clinical presentation and prevalence of organ involvement is highly variable in sarcoidosis and depends on ethnic, genetic and geographical factors. These data are not extensively studied in a Dutch population.
To determine the prevalence of organ involvement and the indication for systemic immunosuppressive therapy in newly diagnosed sarcoidosis patients in the Netherlands.
Two large Dutch teaching hospitals participated in this prospective cohort study. All adult patients with newly diagnosed sarcoidosis were prospectively included and a standardized work-up was performed. Organ involvement was defined using the WASOG instrument.
Between 2015 and 2020, a total of 330 patients were included, 55% were male, mean age was 46 (SD 14) years. Most of them were white (76%). Pulmonary involvement including thoracic lymph node enlargement was present in 316 patients (96%). Pulmonary parenchymal disease was present in 156 patients (47%). Ten patients (3%) had radiological signs of pulmonary fibrosis. Cutaneous sarcoidosis was present in 74 patients (23%). Routine ophthalmological screening revealed uveitis in 29 patients (12%, n = 256)). Cardiac and neurosarcoidosis were diagnosed in respectively five (2%) and six patients (2%). Renal involvement was observed in 11 (3%) patients. Hypercalcaemia and hypercalciuria were observed in 29 (10%) and 48 (26%, n = 182) patients, respectively. Hepatic involvement was found in 6 patients (2%). In 30% of the patients, systemic immunosuppressive treatment was started at diagnosis.
High–risk organ involvement in sarcoidosis is uncommon at diagnosis. Indication for systemic immunosuppressive therapy was present in a minority of patients.
Kidney manifestations of sarcoidosis
2024, Journal of Autoimmunity
Renal involvement is a clinically relevant organ manifestation of sarcoidosis, leading to increased morbidity and complications. Although the exact incidence remains unknown, renal disease is likely to occur in up to one third of all sarcoidosis patients. Every patient with newly diagnosed sarcoidosis should receive a renal work-up and screening for disrupted calcium metabolism.
Amid various forms of glomerulonephritis, granulomatous interstitial nephritis is the most common one, but it rarely leads to renal impairment. Histologically, granulomas can be absent. Nephrocalcinosis and nephrolithiasis are frequent forms when hypercalcaemia or hypercalciuria occur. Drugs used for treatment of systemic sarcoidosis can also cause renal damage.
Due to its high heterogeneity, renal sarcoidosis can be difficult to treat. Glucocorticoids and various immunosuppressive treatments have been proven to be effective based on case series, but clinical trials are lacking. A treatment guideline for renal sarcoidosis is urgently needed.
In this review article, we present an overview of the different forms of renal sarcoidosis and the diagnostic steps to confirm renal involvement; in addition, we provide insights on the management and available treatments. A better understanding regarding the pathogenesis of sarcoidosis is the key for the development of more specific, targeted therapies.
The Utility of Laboratory Investigations for the Assessment and Management of Rheumatic Immune-Related Adverse Events
2024, Rheumatic Disease Clinics of North America
Tubulointerstitial kidney diseases. Chronic interstitial nephritis
2023, Medicine (Spain)
La enfermedad renal intersticial comprende un grupo de trastornos que provocan inflamación intersticial asociada a daño tubular. Tradicionalmente, la nefritis intersticial se ha clasificado morfológica y clínicamente en formas agudas y crónicas. La nefritis intersticial aguda (NIA) suele inducir un rápido deterioro de la función renal, con una marcada respuesta inflamatoria intersticial caracterizada por infiltración de células mononucleares con o sin eosinófilos, edema intersticial y afectación tubular. En cambio, la nefritis intersticial crónica (NIC) sigue un curso más indolente y se caracteriza por fibrosis intersticial, atrofia tubular y, casi siempre, infiltrado intersticial de células mononucleares. La lesión tubulointersticial es clínicamente importante porque predice la función renal presente y futura.
Interstitial kidney disease covers a group of disorders which cause interstitial inflammation associated with tubular damage. Traditionally, interstitial nephritis has been classified morphologically and clinically as either acute or chronic. Acute interstitial nephritis (AIN) usually induces rapid deterioration of kidney function, with a marked inflammatory interstitial response that is characterized by the infiltration of mononuclear cells with or without eosinophils, interstitial oedema and tubular involvement. On the other hand, chronic interstitial nephritis (CIN) follows a more indolent course, and it is characterized by interstitial fibrosis, tubular atrophy and, almost always, interstitial infiltrate of mononuclear cells. The tubulointerstitial lesion is clinically important because it is a predictor of present and future kidney function.
Heterogeneity of Target Antigens in Sarcoidosis-Associated Membranous Nephropathy
2023, Kidney International Reports
Membranous nephropathy (MN) is the most common glomerular disease associated with sarcoidosis. The target antigen M-type phospholipase A2 receptor 1 (PLA2R) has been identified in a subset of sarcoidosis-associated MN. The target antigen is not known in the remaining sarcoidosis-associated MN.
Data of patients with history of sarcoidosis and biopsy-proven MN were retrieved and analyzed. Mass spectrometry (MS/MS) was performed on all kidney biopsies of sarcoidosis-associated MN to detect the target antigens. Immunohistochemistry (IHC) studies were performed to confirm and localize the target antigens along the glomerular basement membrane (GBM).
Eighteen patients with history of sarcoidosis and biopsy-proven MN were identified, of whom 3 were known to be PLA2R-negative, and in the remaining patients the target antigen was unknown. Thirteen (72%) patients were males; the median age at MN diagnosis was 54.5 years. The median proteinuria at presentation was proteinuria 9.8 g/24 h. Eight patients (44.4%) had concurrent sarcoidosis. Using MS/MS, we detected PLA2R and neural epidermal growth factor-like-1 protein (NELL1) in 7 (46.6%) and 4 (22.2%) patients, respectively. In addition, 1 case each (5.5%) was positive for thrombospondin type 1 domain-containing 7A (THSD7A), protocadherin-7 (PCDH7), and putative antigen Serpin B12. No known target antigen was detected in the remaining 4 patients (22.2%).
Patients with sarcoidosis and MN exhibit heterogeneous target antigens. We identified, along with PLA2R, the presence of previously unreported antigens, including NELL1, PCDH7, and THSD7A. The incidence of the target antigens in sarcoidosis appears to mirror the overall incidence of target antigens in MN. MN in sarcoidosis may be the result of a heightened immune response and is not associated with a single target antigen.
Renal involvement in sarcoidosis: Prognostic and predictive factors
2022, Nephrologie et Therapeutique
La sarcoïdose est une maladie systémique granulomateuse qui atteint avec prédilection l’appareil respiratoire et les vaisseaux lymphatiques. L’atteinte rénale est rare, peu étudiée, et n’est retrouvée que dans moins de 10 % des cas. L’objectif de notre étude était d’identifier les facteurs de mauvais pronostic rénal et les facteurs prédictifs d’atteinte rénale au cours de la sarcoïdose.
Il s’agit d’une étude rétrospective, incluant les patients hospitalisés dans notre service pour une sarcoïdose avec atteinte rénale, sur une période de 40 ans. Pour étudier la survie rénale, nous avons identifié deux groupes de patients présentant des manifestations rénales de la sarcoïdose en suivant leur évolution : un groupe A (n = 26) qui représente les patients avec une rémission rénale ou une aggravation rénale, mais sans évolution vers l’insuffisance rénale chronique terminale, et un groupe B (n = 8) représentant ceux ayant une évolution vers l’insuffisance rénale chronique terminale. Dans le but d’identifier les facteurs prédictifs d’atteinte rénale chez les patients ayant une sarcoïdose, nous avons comparé les caractéristiques cliniques et paracliniques de nos patients (groupe 1) à celles de 44 malades porteurs d’une sarcoïdose sans atteinte rénale suivis dans notre service pendant la même période (groupe 2).
L’atteinte rénale était observée chez 34 patients (43,6 %) hospitalisés pour sarcoïdose. Il s’agissait de 28 femmes et 6 hommes, soit un sex-ratio à 0,21. L’âge moyen lors du diagnostic de la sarcoïdose était de 47,1 ans. Le délai médian entre le diagnostic de la sarcoïdose et l’atteinte rénale était de 2 mois (extrêmes 1–72). La néphropathie tubulo-interstitielle était l’atteinte rénale la plus fréquente, retrouvée chez 24 malades (70,6 %). Une hypercalcémie et une hypercalciurie ont été retrouvées dans respectivement 52,9 et 46,4 % des cas. L’insuffisance rénale était notée chez 25 patients (73,5 %). Une corticothérapie était instaurée chez 33 malades (97 %) associée à un traitement immunosuppresseur dans 3 cas. Les facteurs prédictifs d’insuffisance rénale chronique terminale en analyse univariée étaient l’âge avancé au moment du diagnostic de la néphropathie (p = 0,007), la présence de comorbidités (p = 0,002), l’atteinte multiviscérale (p = 0,041), l’insuffisance rénale inaugurale au moment du diagnostic de la sarcoïdose (p = 0,013), la fibrose interstitielle (p = 0,006) et la présence de granulomes (p = 0,007). Les facteurs prédictifs d’atteinte rénale chez les patients atteints d’une sarcoïdose étaient l’atteinte multiviscérale, le syndrome inflammatoire biologique et l’hypercalcémie.
Malgré sa rareté, l’atteinte rénale au cours de la sarcoïdose peut conditionner le pronostic, d’où l’intérêt de la dépister précocement afin de prévenir l’évolution vers l’insuffisance rénale terminale.
Sarcoidosis is a systemic granulomatous disease that primarily affects the respiratory system and lymphatic vessels. Renal involvement is rare, poorly studied and found in less than 10% of cases. The objective of our study was to identify factors of poor renal prognosis and predictive factors of renal involvement during sarcoidosis.
It's a retrospective study including patients hospitalized in our department for sarcoidosis with renal involvement over a period of 40 years. To study renal survival, we identified two groups of patients with renal manifestations of sarcoidosis by following their evolution: group A (n = 26) represents those with renal remission or deterioration of renal function but without progression to end-stage renal disease and group B (n = 8) those with progression to end-stage renal disease. To detect the predictive factors of end-stage renal disease in patients with sarcoidosis, we compared the clinical and paraclinical characteristics of our patients (group 1) to those of 44 patients with sarcoidosis without renal impairment followed in our department during the same period (group 2).
Renal involvement was observed in 34 patients hospitalized for sarcoidosis (43.6%). There were 28 women and 6 men with a sex ratio of 0,21. The mean age at diagnosis of sarcoidosis was 47.1 years. The median time from sarcoidosis diagnosis to renal disease was 2 months (range 1–72). Tubulointerstitial nephropathy was the most frequent renal manifestation observed in 24 patients (70.6%). Hypercalcemia and hypercalciuria were found in 52.9% and 46.4% respectively. Renal failure was noted in 25 patients (73.5%). Corticosteroid therapy was initiated in 33 patients (97%) associated with immunosuppressive therapy in 3 cases. Predictive factors of end-stage renal disease were advanced age at diagnosis of nephropathy (P = 0.007), comorbidities (P = 0.002), multi-organ involvement (P = 0.041), initial renal failure (P = 0.013), interstitial fibrosis (P = 0.006) and renal granulomas (P = 0.007). Predictive factors of renal impairment during sarcoidosis were multi-organ involvement, inflammatory syndrome and hypercalcemia.
Renal envolvement, although rare during sarcoidosis, can influence the prognosis hence the great interest of its early detection to prevent progression to end-stage renal failure.

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Originally published online as doi:10.1053/j.ajkd.2006.07.022 on October 3, 2006.

Support: None. Potential conflicts of interest: None.

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Nephrology Grand RoundSarcoidosis: The Nephrologist’s Perspective

Section snippets

Case Report

Pathogenesis

Pathogenesis and Epidemiology

Renal Tubular Dysfunction

Kidney Transplantation

Conclusion

First page preview

Lancet

Am J Med Sci

Am J Med

Am J Med

Am J Med

Am J Med

Urol Clin North Am

Am J Med

Am J Kidney Dis

Am J Kidney Dis

Am J Med

Am J Med

Am J Kidney Dis

Sarcoidosis

JAMA

Sarcoidosis

Postgrad Med J

Histoplasmosis with hypercalcemia, renal failure, and papillary necrosisConfusion with sarcoidosis

JAMA

Clinical characteristics of patients in a case control study of sarcoidosis

Am J Respir Crit Care Med

Fatal renal failure as the first manifestation of sarcoidosis diagnosed on necropsy in a young man: A case report

J Clin Pathol

A patient with sarcoidosis presenting with acute renal failure: Implications for granulomatous interstitial nephritis and hypercalcemia

Intern Med

Renal failure and hypercalcemia as initial manifestations of extrapulmonary sarcoidosis

South Med J

Effective reduction in the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia with short-course chloroquine therapy

Ann Intern Med

Granulomatous interstitial nephritis, hypercalcemia and rapidly progressive kidney failure secondary to sarcoidosis with exclusive renal involvement

Am J Nephrol

Granulomatous interstitial nephritis due to isolated renal sarcoidosis

Clin Exp Nephrol

Seven cases of granulomatous interstitial nephritis in the absence of extrarenal sarcoid

Nephrol Dial Transplant

Puzzling hypercalcemia: Sarcoidosis without lung involvement

J R Soc Med

Benign lymphogranuloma and its cutaneous manifestations

Br J Dermatol

Defining organ involvement in sarcoidosis: The ACCESS proposed instrumentA Case Control Etiologic Study of Sarcoidosis

Sarcoidosis Vasc Diffuse Lung Dis

Renal manifestations of sarcoidosis

Arch Intern Med

The kidney in sarcoidosis

J Am Soc Nephrol

Hypercalcemia in granulomatous disorders: A clinical review

Curr Opin Pulm Med

Regulation of 1,25-dihydroxyvitamin D3 production by cultured alveolar macrophages from normal human donors and from patients with pulmonary sarcoidosis

J Clin Endocrinol Metab

A 41 year old man with fatigue, weight loss, hypercalcemia, and hepatosplenomegaly

Am J Med Sci

Hypercalcemia in an anephric patient with sarcoidosis: Evidence for extrarenal generation of 1,25-dihydroxyvitamin D

N Engl J Med

Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis

J Clin Invest

Vitamin D conversion by sarcoid lymph node homogenate

Ann Intern Med

Clinical impact of bone and calcium metabolism changes in sarcoidosis

Thorax

Renal involvement in sarcoidosis

Postgrad Med J

Abnormal calcium homeostasis in sarcoidosis

N Engl J Med

A case of renal sarcoidosis: A special reference to calcium metabolism as a diagnostic and the therapeutic implications

Clin Exp Nephrol

Parathyroid-hormone-related protein in sarcoidosis

Am J Pathol

Hypercalcemic nephropathy

Arch Intern Med

Renal cortical nephrocalcinosis

Nephrol Dial Transplant

Nephrology Grand Round
Sarcoidosis: The Nephrologist’s Perspective

Regulation of 1,25-dihydroxyvitamin D₃ production by cultured alveolar macrophages from normal human donors and from patients with pulmonary sarcoidosis

Metabolism of 25-hydroxyvitamin D₃ by cultured pulmonary alveolar macrophages in sarcoidosis