Direct Kidney Involvement by Tropherymawhipplei

Introduction

Whipple disease (WD) is a rare disease typically associated with malabsorption, caused by Tropheryma whipplei.^1,S1 Though commonly regarded as a gastrointestinal pathogen, WD is actually a multisystemic infection with symptoms reported in the joints, heart, lungs, and central nervous system.^1,S1 Nevertheless, renal involvement, particularly direct infection of the kidney by the T. whipplei organism, has not been well-recorded in the literature.

Case Report

The patient is a 45-year-old woman who presented with night sweats, chronic diarrhea, and persistently elevated serum creatinine with a baseline of 0.8 to 1.6 mg/dl, measuring 1.43 mg/dl at the time of biopsy. She has a history of marginal zone B-cell lymphoma since 2020 and has had multiple deep venous thromboses. She currently takes subcutaneous methotrexate and tofacitinib to manage seronegative psoriatic arthritis. A recent bone marrow biopsy with flow cytometry did not find involvement by B-cell lymphoma or other clonal B or T-cell populations. To help determine the etiology of the rising creatinine, a kidney biopsy was performed.

Results

Kidney biopsy showed approximately 45 glomeruli, of which 15 (33%) were globally sclerosed and 2 were segmentally sclerosed. No glomerular basement spikes, pinholes, or double contours were seen, and there were no crescents, necrotizing, or embolic lesions. Three glomeruli had foam cell infiltrates within Bowman’s capsule compressing the glomerular tuft (Figure 1). These foam cells were filled with periodic acid-Schiff-positive (PAS), diastase resistant (PAS-D+), and Jones silver-positive rod-like material, reminiscent of crystals or bacterial organisms. Similar cells were also noted focally within the interstitium, and those cells stained with CD68, suggesting that the cells were histiocytes. Though some tubules had cytoplasmic and luminal investment by the same PAS-D-positive and Jones silver-positive material, intratubular foam cells were not observed. The material was positive for Grocott-Gomori methenamine-silver fungal stain. The tubulointerstitial compartment had approximately 25% interstitial fibrosis and tubular atrophy with mild focal mononuclear inflammation. The vessels showed moderate arteriosclerosis without vasculitis or involvement by the distinctive foamy histiocytes.

Figure 1.

(a) Tropheryma whipplei organisms show chunky rod-shaped and geometric-shaped bacilli that are reminiscent of crystals by light microscopy, found in macrophages within the interstitium and glomerulus (PAS-D). (b) High-power magnification of these bacilli within a glomerulus. The bacilli stain quite strongly and are diastase-resistant. By contrast, mycobacteria, another diagnostic consideration, will stain more faintly and delicately by PAS and will also highlight with acid-fast stains, such as Ziehl-Neelson or Fite stains (not shown) (PAS-D photographed). (c) The organisms also appear argyrophilic on Jones and Grocott-Gomori methenamine-silver stain (GMS photographed). (d) Organism-laden macrophages in Bowman’s space can mimic crescentic lesions. PAS-D, periodic acid Schiff staining with diastase.

Immunofluorescence studies on frozen tissue and pronase-treated paraffin-embedded tissue, including a phospholipase A2 receptor stain, were negative. On electron microscopy (EM), a few tubules showed luminal trilaminar bacilli in longitudinal- and cross-section (Figure 2). Three glomeruli showed occasional subendothelial cell tubuloreticular inclusions, but there were no immune-complex deposits or effaced podocyte foot processes.

Figure 2.

(a) Tropheryma whipplei inside a tubular lumen (8kx, EM). (b) found in cross-and longitudinal-section (30kx, EM). (c, d) These bacilli have distinctive trilaminar cell walls (c, 20kx, EM; d, 80kx, EM), with an outer membrane that is thinner and more symmetric than those seen in gram-negative bacteria by EM. EM, electron microscopy.

There was insufficient material for formalin-fixed paraffin-embedded tissue-based polymerase chain reaction (PCR). Nevertheless, the light microscopy and ultrastructural features were most consistent with direct kidney involvement by T. whipplei. Based on these findings, whole blood PCR and duodenal biopsy were done. Whole blood PCR was positive for T. whipplei, and the duodenal biopsy showed foamy macrophages filled with PAS-D-positive organisms within the lamina propria. This prompted the clinical team to start intravenous ceftriaxone for treatment and prednisone for prevention of immune reconstitution inflammatory syndrome. Methotrexate and tofacitinib were held. No additional follow-up is currently available.

Discussion

Though WD is a rare disease afflicting approximately 1 in 1 million people annually, its causative organism T. whipplei is relatively common.^1,S1 It is found in soil and wastewater and thought to be transmitted fecally-orally in communities with poor sanitation.^1,S1 Infection is thought to occur through macrocytic phagocytosis, where the organisms replicate within the acidic lysosomes of the macrophages. WD is a rare disease typically associated with malabsorption, caused by T. whipplei.^1,S1 WD is a multisystemic infection with findings reported in multiple organs and organ systems, including the small bowel, joints, heart, lungs, and central nervous system.^1,S1 Nevertheless, renal involvement has not been well-documented in the literature.

Classically, T. whipplei is encountered in small bowel biopsies, where intestinal villi are distended by organism-laden macrophages within the lamina propria.^1,S1 The organisms highlight strongly with PAS-D and are negative for acid-fast stains such as Fite or Ziehl-Neelson, which can help exclude the possibility of atypical mycobacteriosis, particularly in the immunocompromised.^1,S1 In addition, T. whipplei tends to show strong, coarse staining pattern with PAS-D, whereas mycobacteria tend to show only faint, delicate staining.^1,S1 Often, the diagnosis is validated by real-time PCR or immunohistochemistry.²

Many indirect renal sequelae of T. whipplei infection have been described in the literature. Overall, kidney involvement appears quite rare; other symptoms usually predominate and possibly obscure renal manifestations.^1,3 Some authors hypothesize that renal involvement occurs late in the course of WD or that the urogenital system is more resistant to direct infection by the organism.^1,3 This is a possibility because chronic renal injuries such as glomerulosclerosis, interstitial fibrosis, and tubular injury have been described in WD cases.^4,5 These findings were also seen in our patient and seem to be disproportionate to her age and her underlying hypertension; it may possibly indicate late-stage WD.^2,3 Nonspecific segmental glomerulonephritis has also been described and “wire-loop” lesions reminiscent of lupus nephritis were observed in 1 autopsy series.^5,S2,S3 Other glomerulonephritides in WD have been described, including cases of IgA nephropathy.^2,S4 Recently, a case of phospholipase A2 receptor-positive membranous glomerulonephritis associated with WD has been reported, possibly demonstrating a causal link between WD and membranous glomerulonephritis.⁶ In that particular case, both the characteristic subepithelial deposits and the organisms highlighted with phospholipase A2 receptor immunohistochemical stain.⁶ In our case, phospholipase A2 receptor was negative in both the organisms and the glomeruli by direct immunofluorescence. An association between systemic serum amyloid A amyloidosis involving the kidney and WD has also been fairly well-established.^4,S5–S8 Nevertheless, these reported cases and associations highlight nonspecific injury responses to systemic inflammatory states rather than specific responses to the organisms themselves.

Direct involvement in the kidney by the organism appears rare or is underreported. Interstitial nephritis, including granulomatous interstitial nephritis, have been described, though it is unclear if the pathogenesis is direct or indirect.^7,S9–S11 The granulomas do not contain the T. whipplei organisms when observed under light microscopy in the described cases.^3,S10,S11 However, 1 lymph node case was positive on EM for rare organisms within granulomas, and 1 such kidney case was positive for 16S rRNA PCR retrospectively.⁷ In that latter case, granulomatous inflammation preceded onset of systemic WD and was thought to be a harbinger of clinically apparent WD.⁷ In 1 WD case with renal necrotizing granulomas, the patient had tuberculosis,³ an overlapping cause of granulomatous inflammation. It is possible that epithelioid granulomas can be distinct from PAS-positive organism-containing macrophages in which the granulomas form because of exposure to partially digested bacterial antigen.¹ In the few cases where PAS-positive organisms are described, they appear in scattered organism-laden macrophages through the glomeruli and the tubulointerstitium, not usually in granulomas.^2,S2,S3 PAS-positive organism laden macrophages have been reported in approximately 5 cases in the primary literature (see Supplementary Table S1).^2,S2,S3 The significance of these macrophages is unclear but the organismal appearance in the kidney may indicate high bodily levels of the organism, leading to its increased filtration by the kidney.²

Further, the histologic differential diagnosis can be vast. Especially in our case, another serious diagnostic consideration is crystal-storing histiocytosis (CSH). Clinically, CSH is a rare manifestation of lymphoproliferative or plasmacytic disorders and has been reported in lymphoplasmacytic lymphoma, mucosal-associated lymphoid tissue lymphoma, extranodal marginal zone lymphoma, and plasma cell dyscrasias, which all can produce crystalline immunoglobulins that then accumulate within histiocytes.^8,S12 CSH involving the kidney has been well-documented, particularly in the interstitial and glomerular compartments.^8,S12 Like WD, CSH presents with PAS-D eosinophilic rods within histiocytes.^8,S12 Immunofluorescence histology can be useful in this differential diagnosis; CSH tends to have κ light chain, possibly with an accompanying heavy chain.^8,S12 EM can also be used to resolve this dilemma; CSH has crystals that appear distinctly rhomboidal or needle-shaped with periodicity or lattice-like substructure on EM.^8,S12

Lysosomal storage diseases can mimic WD, with kidney involvement most commonly by Fabry disease. Less commonly, Gaucher disease can also involve the kidney and can be a striking mimic of WD. Fabry disease is a genetic deficiency in α-galactosidase A enzyme that leads to the engorgement of glycosphingolipids within many tissues, including podocytes.⁹ Engorged podocytes impart a foamy appearance to the glomeruli and can eventually lead to focal segmental glomerulosclerosis. Foamy macrophages, particularly in the interstitium, are sometimes seen. In Fabry disease, the foamy podocytes are PAS-positive, but they show distinct dense granule inclusions when stained with toluidine blue. EM shows characteristic zebra or myelin bodies in podocytes and other affected sites. Gaucher disease, another sphingolipid accumulation disorder, has distinctive “tissue paper” CD68+ macrophages that occlude the glomerular loops, imparting a foamy appearance.^9,S13 On PAS-D, these cells appear filled with rod-like material, like WD. But on EM, by contrast, Gaucher disease has macrophages containing twisted microtubular-like fibrils.^9,S13

Treatment regimens are not well-established; however, many of the case reports in the literature have endorsed a 2-week regimen of intravenous ceftriaxone followed by a year of trimethoprim-sulfamethoxazole.² Steroids may be added to prevent immune reconstitution inflammatory syndrome.² Follow-up with PCR and intestinal biopsies may be helpful to see treatment response (Table 1).²

Table 1.

Key teaching points

1.Whipple disease is a debilitating, potentially lethal, and possibly underreported disease. It is a rare, multisystemic, bacterial disease caused by Tropheryma whipplei that can affect the kidneys in rare cases

2.Whipple disease can present in many ways in the kidney, but characteristic macrophages filled with PAS-D+ bacterial rods are the most helpful diagnostic clue, especially in conjunction with electron microscopy

3.Diagnosis should be validated with polymerase chain reaction and small bowel biopsy

PAS-D+, Periodic acid-Schiff-positive.

Conclusion

In conclusion, this is a 45-year-old with seronegative rheumatoid arthritis, marginal zone lymphoma, and acute kidney injury who presents with WD involving the kidney. EM and whole blood PCR confirmed the presence of T. whipplei.

Disclosure

The authors declare that they have no conflict of interest.

Patient Consent

The authors declare that they have obtained consent from the patient discussed in the report.

Supplementary Material

Supplementary Reference.

Table S1. Findings in cases of reported Whipple disease in the kidney.