Kidney Disease in a Patient With a Chronic Rash: A Quiz

A 66-year-old man was referred to our hospital for chronic kidney disease of unknown etiology of at least 1-year duration and non–nephrotic-range proteinuria. His medical history included hypocomplementemic urticarial vasculitis syndrome (HUVS) diagnosed 16 years earlier, with cutaneous and rheumatologic manifestations (arthritis of both hands). He was currently taking prednisolone 5 mg per day, but had previously been treated with azathioprine (stopped for hepatotoxicity) and hydroxychloroquine (stopped for retinopathy). The patient reported persistent rash and arthritic symptoms for several years despite use of prednisolone. Physical examination findings included diffuse rash (Fig 1) and osteoarthritis of the hands. Relevant initial laboratory results are presented in Table 1. Serum immunofixation was positive for 2 monoclonal components (IgMκ and IgGκ), and free light chain ratio was normal (adjusted to his estimated glomerular filtration rate [eGFR]). A kidney biopsy was performed (Fig 2A-C).•What is the differential diagnosis of this patient’s kidney disease?•What additional diagnostic investigation should be performed?•What does the kidney biopsy show?•How should this patient be managed?Table 1Laboratory Test ResultsTestResultReference RangeHemoglobin, g/dL11.313-17White blood cell count, /μL9,2204,500-11,000Platelet count, /μL191,000150,000-450,000Serum creatinine, mg/dL2.320.72-1.25eGFR, mL/min/1.73 m230>90Urea, mg/dL8018-55Calcium (total), mg/dL8.68.4-10.2C-reactive protein, mg/L9.7<5.0Glucose, mg/dL8360-100Albumin, g/L35.432-46Ferritin, ng/mL54.330-340Intact parathyroid hormone, pg/mL82.514.76-83.10Complement component 3, g/L0.270.9-1.8Complement component 4, g/L<0.020.1-0.4Complement component C1q, mg/dL2.626-38Urinary protein-creatinine ratio, mg/g253<200Urinary albumin-creatinine ratio, mg/g114<30Serum protein electrophoresisSharp peak in the γ globulin regionAbbreviation: eGFR, estimated glomerular filtration rate (calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine equation). Open table in a new tab Figure 2Kidney biopsy findings. (A) Periodic acid–Schiff staining; original magnification, ×400. Light microscopy with Congo red staining, under (B) standard conditions and (C) polarized light; original magnification, ×16.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Abbreviation: eGFR, estimated glomerular filtration rate (calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine equation). HUVS is a rare form of systemic vasculitis that is characterized by the presence of chronic urticarial rash and hypocomplementemia, as well as multiorgan involvement, which distinguishes it from the primary HUV. HUVS may share some overlapping features with systemic lupus erythematosus, owing to its involvement as an immune complex–mediated disease; the absence of the antinuclear antibodies allows their differentiation.1Kesarwani V. Phachu D. Trivedi R. Hypocomplementemic urticarial vasculitis syndrome or systemic lupus erythematosus in evolution?.Cureus. 2022; 14e23429https://doi.org/10.7759/cureus.23429Crossref Google Scholar Kidney disease occurs in up to 50% of patients with HUVS.2Jara L.J. Navarro C. Medina G. Vera-Lastra O. Saavedra M.A. Hypocomplementemic urticarial vasculitis syndrome.Curr Rheumatol Rep. 2009; 11 (PMID: 19922730): 410-415https://doi.org/10.1007/s11926-009-0060-yCrossref PubMed Scopus (67) Google Scholar Membranoproliferative glomerulonephritis (GN) is the most frequent finding, but several types of glomerular pathology, including membranous GN, focal segmental glomerulosclerosis, and crescentic GN have also been associated with HUVS.3Ion O. Obrișcă B. Ismail G. et al.Kidney involvement in hypocomplementemic urticarial vasculitis syndrome - a case-based review.J Clin Med. 2020; 9: 2131https://doi.org/10.3390/jcm9072131Crossref Scopus (11) Google Scholar,4Vallianou K. Skalioti C. Liapis G. et al.A case report of hypocomplementemic urticarial vasculitis presenting with membranoproliferative glomerulonephritis.BMC Nephrol. 2020; 21: 351https://doi.org/10.1186/s12882-020-02001-6Crossref Scopus (3) Google Scholar In this case, the absence of hematuria, slow eGFR decline, and only mild proteinuria argues against an inflammatory GN. Other causes of kidney disease with cutaneous and rheumatological manifestations should also be excluded (like systemic lupus erythematosus), as should infectious diseases in an immunosuppressed patient (eg, BK virus or HIV). The finding of a monoclonal immunoglobulin should raise suspicion of an associated kidney disease, with or without deposits, which can present as progressive eGFR decline and mild proteinuria. Although this patient did not have heavy proteinuria, secondary or AA amyloidosis should also be considered in the differential diagnosis of chronic kidney disease etiology because of the long-standing inflammatory state from HUVS. Serologies for systemic lupus erythematosus were negative, as was testing for HIV and hepatitis B and C virus infections. Serum A amyloid was 34.3 mg/L (reference range: <6.4 mg/L). A bone marrow aspirate and biopsy were performed for exclusion of plasma cell dyscrasias. Only 2% of plasma cells were found in the bone marrow aspirate, but bone biopsy showed increased number of CD20-positive lymphoid cells, raising suspicions of a possible low-grade lymphoproliferative disorder. The kidney biopsy shows large areas of amorphous deposits, mainly affecting the interstitium and the blood vessel walls (Fig 2A). The glomeruli were spared. Congo red staining confirmed the amyloid nature of those deposits. In particular, there was an accumulation of congophilic material staining red in the interstitium between the tubules (Fig 2B; a glomerulus without congophilic deposits is also visible), as well as the characteristic apple-green birefringence in polarized light (Fig 2C). Immunofluorescence staining was also performed, which was positive for serum amyloid A protein deposits in the interstitium (Fig 3), as well as C1q. There was no difference in staining for λ and κ light chain. The current approach to AA amyloidosis consists of treating the underlying inflammatory disease.5Dember L.M. Amyloidosis-associated kidney disease.J Am Soc Nephrol. 2006; 17: 3458-3471https://doi.org/10.1681/ASN.2006050460Crossref PubMed Scopus (292) Google Scholar Because it is such a rare disease, there is no consensus regarding the treatment of HUVS, and it should be guided by the disease severity. Systemic glucocorticoids remain the first-line treatment of HUVS but, when the disease is severe, other agents such as azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine, and methotrexate may be added.2Jara L.J. Navarro C. Medina G. Vera-Lastra O. Saavedra M.A. Hypocomplementemic urticarial vasculitis syndrome.Curr Rheumatol Rep. 2009; 11 (PMID: 19922730): 410-415https://doi.org/10.1007/s11926-009-0060-yCrossref PubMed Scopus (67) Google Scholar,6Kolkhir P. Grakhova M. Bonnekoh H. Krause K. Maurer M. Treatment of urticarial vasculitis: a systematic review.J Allergy Clin Immunol. 2019; 143: 458-466https://doi.org/10.1016/j.jaci.2018.09.007Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar The patient was treated with mycophenolate mofetil 2 grams twice daily and his prednisolone dose was escalated to 60 mg daily. Despite adequate control of cutaneous manifestations, eGFR decline continued to progress, and the patient started dialysis 1 year later. AA amyloidosis secondary to hypocomplementemic urticarial vasculitis. Rui Barata, MD, Juliana Damas, MD, Tiago Assis Pereira, MD, Mário Góis, MD, Helena Sousa, MD, Francisco Ribeiro, MD, João Sousa, MD, Fernando Nolasco, PhD. None. The authors declare that they have no relevant financial interests. The authors declare that they have obtained consent from the patient reported in this article for publication of the information about him that appears within this Quiz. Received April 5, 2022. Direct editorial input from the Pathology Editor and the Engagement Editor. Accepted in revised form August 9, 2022.