Glomerulopatia da fibronectina: case report di glomerulonefrite membranoproliferativa

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Anna Sannino

DOI: 10.69097/43-02-2026-09

Anna Sannino1, Pierluigi d’Angiò2, Simona Laurino2, Antonella Marino3, Maria Luigia Sellitti4, Valentina Urciuoli4, Armando Genovese1, Giuseppe Gigliotti2

1 UOC Nefrologia, Dialisi e Trapianto, AOU San Giovanni di Dio e Ruggi d’Aragona, Via San Leonardo, 84131 Salerno, Italia
2 UOC Nefrologia e Dialisi, P.O. Maria SS Addolorata, piazza Scuola Medica Salernitana, 84025 Eboli, Italia
3 UOSD Nefrologia e Dialisi, P.O. S. Giuseppe Moscati, via Gramsci, 81031 Aversa, Italia
4 UOSD Nefrologia e Dialisi, AOU Policlinico Federico II, Via S. Pansini, 80131 Napoli, Italia

Corrispondenza a:
Anna Sannino
UOC Nefrologia, Dialisi e Trapianto
AOU San Giovanni di Dio e Ruggi d’Aragona, Via San Leonardo, 84131 Salerno, Italia
Tel. 3495154034
E-mail: anna.sannino94@gmail.com

 

Abstract

Background. La glomerulopatia da fibronectina (FNG) è una rara glomerulopatia autosomica dominante caratterizzata da proteinuria, ematuria, ipertensione e perdita progressiva della funzione renale fino all’insufficienza renale terminale (ESRD) in un periodo di 15-20 anni. La malattia è causata da mutazioni nel gene FN1. Attualmente non esiste un trattamento specifico.
Caso clinico. Una donna di 22 anni mostrava proteinuria sub-nefrosica ed ematuria microscopica. La biopsia renale evidenziava espansione mesangiale e depositi densi, compatibili con FNG. Il test genetico ha confermato una mutazione nel gene FN1 (c.5773T>A, W1925R). Non sono stati riscontrati segni di malattia renale nei genitori della paziente; successivamente il fratello è risultato positivo alla stessa mutazione genetica. È stata trattata con ACE-inibitori e dieta iposodica. Dopo 3 anni, la funzione renale si è mantenuta stabile, con creatinina sierica di 0,5 mg/dL e proteinuria ridotta a 0.7 g/24h.
Discussione. La FNG è causata da mutazioni nel gene FN1, con depositi renali anomali di fibronectina. Non esiste un trattamento mirato, ma la terapia conservativa con ACE-inibitori può aiutare a rallentare la progressione della malattia. L’utilizzo di terapia steroidea è controverso, con successi limitati nel prevenire l’ESRD.
Conclusione. La diagnosi precoce ed il trattamento conservativo sono cruciali per la gestione della FNG. Sono necessari ulteriori studi per chiarire le terapie efficaci e comprendere meglio la progressione della malattia.

Parole chiave: glomerulopatia da Fibronectina, mutazione FN1, proteinuria, biopsia renale, terapia conservativa, ESRD

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Background

Fibronectin glomerulopathy (FNG) is a rare autosomal dominant glomerulopathy that manifests at various ages in both sexes [1]. Common clinical features are mild proteinuria and varying degrees of hematuria, hypertension and slow progression to end-stage renal disease over 15–20 years [1]. Decline of kidney function over time is variable. Serum fibronectin levels are usually normal, and systemic manifestations have not been reported. Recurrence in the transplant may occur [2].

Currently, there is no specific treatment for fibronectin glomerulopathy.

 

Case report

A 22-year-old Italian female presented to our department for evaluation of sub-nephrotic proteinuria without edema. She didn’t take any medications and her medical history was indifferent. Her blood pressure was 120/80 mmHg, heart rate 85bpm. Blood chemistry tests showed BUN 17 mg/dL, serum creatinine 0,6 mg/dL. Her estimated glomerular filtration rate (eGFR) was 120 mL/min/1.73m2, as calculated using the CKD-EPI equation; urinalysis revealed proteinuria and microscopic hematuria in dipstick; the 24-hour urine collection showed urine total protein of 1700 mg/day (Table 1).

Blood test
White Blood Cell 9400 /μL
Hemoglobin 12.3 g/dL
Platelet 303×103/μL
Total protein 6.3 g/dL
Albumin 3.6 g/dL
Urea nitrogen 17 mg/dL
Creatinine 0.6 mg/dL
eGFR 120 mL/min/1.73m2
Cholesterol 194 mg/dL
HDL/LDL 58/120 mg/dL
Triglycerides 154 mg/dL
C-reactive protein 0.05 mg/dL

 

Immunoserology
IgG 996 mg/dL
IgA 346 mg/dL
IgM 230 mg/dL
Complement 3 136 mg/dL
Complement 4 23 mg/dL
ANA neg
Anti-GBM antibody neg
MPO-ANCA neg
PR3-ANCA neg
PLA2R neg
HBs-Ag –
HCV-Ab –

 

Urinalysis
specific gravity 1.020
pH 6.2
Red Blood Cell 5-10/high power
Protein 1700mg/24h
Table 1. Laboratory data from initial admission.

Renal ultrasound showed kidneys with normal size and increased parenchymal echogenicity.

A renal biopsy was performed: immunofluorescent staining revealed mild glomerular deposition of IgA, C3 and Lambda while the results for IgG, IgM, C4, Kappa and Fibrinogen were negative. Light microscopy examination detected thirteen glomeruli one of which was sclerotic. The other glomeruli had normal size, exhibited significant mesangial expansion and lobular accentuation, normal glomerular basement membranes, thickening of Bowman’s capsule without extracapillar proliferation. The renal tubular epithelial cells were vacuolated, and there were no pathological changes in the renal interstitium, it appeared edematous with diffuse inflammatory infiltrates. (Figure 1, 2, 3 e 4)

Congo-red staining was negative for amyloid; electron microscopy showed mesangial and subendothelial electron-dense deposits (EDD) with high density, mostly granular with focal fibrillary substructure (Figura 5).

Immunohistochemistry for CD3 showed strong positive staining in the interstitial inflammatory infiltrate while immunohistochemistry for CD20 and CD138 were negative. Also immunohistochemistry for DNAJB9 was negative.

Genetic testing of whole-blood samples (using the Sanger method) revealed an FN1 gene mutation with a thymine changed to adenine at nucleotide 5773 of the complementary DNA (c.5773T>A) causing a substitution in which the tryptophan at amino acid 1925 is replaced by arginine (W1925R).

The conclusive diagnosis was Fibronectin glomerulopathy (FNG).

Family history was investigated. The patient’s brother had never undergone nephrological evaluation before. Following sister’s diagnosis of the disease, he underwent urinalysis, which revealed proteinuria and microscopic hematuria too – in normal renal function; consequently, genetic testing was performed, confirming the same pathogenic mutation identified in his sister (W1925R).

None of the patient’s parents showed renal disease or proteinuria; her father died young without apparent cause.

The patient started conservative therapy with ACE-I and low salt diet. Three years after kidney biopsy, serum creatinine was 0.5 mg/dL (eGFR 125 mL/min/1.73m2) and proteinuria reduced to 0.7g/24h, chemistry panel was unchanged.

Hematoxylin and eosin staining: increased mesangial matrix, renal interstitium appeares edematous with inflammatory infiltrate.
Figure 1. Hematoxylin and eosin staining: increased mesangial matrix, renal interstitium appeares edematous with inflammatory infiltrate.
Periodic acid–Schiff staining shows PAS–positive material expanding the mesangium
Figure 2. Periodic acid–Schiff staining shows PAS–positive material expanding the mesangium with lobular formation and limited increase in mesangial cellularity, also present along the glomerular basement membranes; vacuolated renal tubular epithelial cells with no pathological interstitium.
On Masson’s trichrome staining, fibronectin glomerulopathy shows reddish-violet
Figure 3. On Masson’s trichrome staining, fibronectin glomerulopathy shows reddish-violet amorphous mesangial and subendothelial deposits that do not stain blue like collagen, highlighting the non-collagenous nature of the accumulated material.
Periodic acid silver methenamine staining reveals thickening of the basement membrane
Figure 4. Periodic acid silver methenamine staining reveals thickening of the basement membrane with silver methenamine stain-negative and PAS-positive areas in the mesangium space (×200).
Electron microscopy: mesangial and subendothelial deposits (mostly granular) with focal fibrillary substructure.
Figure 5. Electron microscopy: mesangial and subendothelial deposits (mostly granular) with focal fibrillary substructure.

 

Discussion

In this report, we present a case of FNG with a pathological diagnosis of Membranoproliferative Glomerulonephritis (MPGN). The diagnosis was confirmed by Electron Microscopy (EM) and genetic analysis – patient’s parents did not have a history of kidney disease – with later genetic diagnosis confirmed also in the patient’s brother as well.

FNG is caused by mutations in the fibronectin 1 gene (FN1) on chromosome 2 [3] and is featured by massive deposition of mutant fibronectin in the mesangium and along capillary walls [2, 4, 5].

Molecular Background

Fibronectin (FN) is a high-molecular-weight glycoprotein component of the extracellular matrix. It is normally produced by the liver and renal mesangial cells [2]. FN is present in plasma as a soluble form (pFN) or deposited in extracellular matrix as insoluble organized fibrils (cellular FN) [6]. The Hep-II and -III domains play a main role in regulating FN assembly into organized fibrils in extracellular matrix, through complex FN–FN and FN–cell surface proteoglycan interactions [7–10].

The pathogenic mechanism of fibronectin accumulation is not completely understood but may involve the production of a fibronectin variant that cannot be cleared, or the formation of a variant fibronectin formed by attachment of a circulating factor. The deposits consist predominantly of the soluble plasma-derived form of fibronectin, rather than the insoluble cellular form. Another proposed mechanism is a defect in the catabolism of fibronectin [2].

Fibronectin 1 (FN1) gene mutation is usually detected in about 40% of patients in Castelletti study group [3] and is believed to be responsible for the occurrence of the disease. However, no specific treatment is currently available. [3, 11, 12]. The W1925R variant identified in the present case was reported in literature to cause glomerulopathy with fibronectin deposits [3]: in this study W1925R variant was identified in all affected by FG and was not found in any of 100 healthy subjects [3].

They sequenced the FN1 in 15 unrelated pedigrees and found three heterozygous missense mutations, the W1925R, L1974R, and Y973C, that cosegregated with this glomerulopathy [3].

Mutations in the FN1 gene have been implicated in a variety of collagen-related diseases due to fibronectin’s essential role in the extracellular matrix and its interactions with collagen. Studies have shown that alterations in FN1 have been linked to early-onset osteoarthritis, where impaired interactions between fibronectin and collagen type II affect cartilage integrity [13]. Furthermore, skeletal dysplasias have been associated with FN1 mutations, as fibronectin is critical for the correct formation of collagen fibers in bones [14]. In the context of Ehlers-Danlos syndrome, a connective tissue disorder primarily caused by defects in collagen, FN1 mutations may exacerbate collagen dysfunction, further destabilizing the extracellular matrix and contributing to the clinical manifestations of the disease [15].

Our W1925R mutation introduces a basic amino acid in the Hep-II hydrophobic core; this mutation could theoretically increase the Hep-II affinity for heparin, by providing additional cationic charge to the domain; however, it could also alter the folding of the domain and impair its function. So they suggest that GFND-associated mutations in FN1 impair the control of the assembly of FN into fibrils and the balance between soluble and insoluble FN, which could explain the abnormal incorporation of nonfibrillary pFN in the glomerular matrix that has been documented in renal biopsy [3].

Pathophysiology

Usually, the biopsy shows by light microscopy lobular accentuation with mesangial expansion with minimal hypercellularity and variable expansion of glomerular basement membranes by strongly periodic acid-Schiff-positive and silver-negative material. Congo red stain is negative. There are nonspecific tubulointerstitial and vascular changes with increased fibrosis with progression of disease. Immunofluorescence/immunohistochemistry microscopy is usually negative, but may show nonspecific staining for immunoglobulins and C3 [2]. Electron microscopically, fibronectin deposition is shown as finely granular or fibrillary substructures with randomly arranged 12–16-nm fibrils [2, 4, 5] and we could testify it with the help of electron microscope.

Clinical Management

Ti Zhang et al. Reported a case series of 19 patients with FNG diagnosis that were treated with renin-angiotensin system blockade, including 11 patients who were treated with Tripterygium Wilfordii Hook (TWHF), and 4 patients with corticosteroid therapy in combination with immunosuppressive therapies, including 2 with mycophenolate mofetil (MMF) and 2 with tacrolimus. The mean follow-up duration was 78 months (range 14–147 months, median 87). At last follow-up, 7 patients progressed to ESRD despite supportive therapy and required initiation of dialysis, 2 of whom received renal transplantation [16]. In most of cases reported in literature, corticosteroid therapy doesn’t help to reduce or prevent kidney disease progression [17, 18]. Steroid therapy has been tested, but its effectiveness is controversial. Prednisolone treatment decreased proteinuria in some patients with nephrotic-level proteinuria [19] but did not yield a clear treatment response in other patients [17, 18] and is commonly attempted in cases with a histological diagnosis of MPGN [20].

Currently angiotensin-converting enzyme inhibitors and ARBs are generally used for renal protection. The initiation of steroid therapy for FNG should be carefully considered on an individual basis [17].

 

Conclusion

We encountered a case of FNG in a 22-year-old female patient presenting with sub-nephrotic range proteinuria, supported by both histological features of membranoproliferative glomerulonephritis on kidney biopsy and subsequently confirmed by genetic testing. Following the patient’s diagnosis, genetic screening was also extended to first-degree relatives (brother), with a positive result for the disease.

We therefore decided to use a conservative therapy, because of the steroids side effects and the absence of nephrotic syndrome in our patient, with a normal kidney function.

After three years kidney function remained stable and proteinuria reduced to 0.7 g/die.

 

Bibliography

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  2. Lusco MA, Chen YP, Cheng H, et al. AJKD atlas of renal pathology: fibronectin glomerulopathy. Am J Kidney Dis. (2017) 70:e21–2. https://doi.org/10.1053/j.ajkd.2017.09.001
  3. Castelletti F, Donadelli R, Banterla F, et al. Mutations in FN1 cause glomerulopathy with fibronectin deposits. Proc Natl Acad Sci USA. (2008) 105:2538–43. https://doi.org/10.1073/pnas.0707730105
  4. Strøm EH, Banfi G, Krapf R, Abt AB, et al. Glomerulopathy associated with predominant fibronectin deposits: a newly recognized hereditary disease. Kidney Int. (1995) 48:163–70. https://doi.org/10.1038/ki.1995.280
  5. Ohashi T, Erickson HP. Fibronectin aggregation and assembly: the unfolding of the second fibronectin type III domain. J Biol Chem. (2011) 286:39188–99. https://doi.org/10.1074/jbc.M111.262337
  6. Yamada KM, Kennedy DW (1979) Fibroblast cellular and plasma fibronectins are similar but not identical. J Cell Biol 80:492–498. https://doi.org/10.1083/jcb.80.2.492
  7. Santas AJ, Peterson JA, Halbleib JL, et al. Alternative splicing of the IIICS domain in fibronectin governs the role of the heparin II domain in fibrillogenesis and cell spreading. J Biol Chem (2002) 277:13650–13658. https://doi.org/10.1074/jbc.m111361200
  8. Bultmann H, Santas AJ, Peters DM. Fibronectin fibrillogenesis involves the heparin II binding domain of fibronectin. J Biol Chem. 1998. 273:2601–2609. https://doi.org/10.1074/jbc.273.5.2601
  9. Maqueda A, Moyano JV, Hernandez Del Cerro M, et al. The heparin III-binding domain of fibronectin (III4-5 repeats) binds to fibronectin and inhibits fibronectin matrix assembly (2007) Matrix Biol 126:642–651. https://doi.org/10.1016/j.matbio.2007.06.001
  10. Mao Y, Schwarzbauer B. Fibronectin fibrillogenesis, a cell-mediated matrix assembly process. (2005) Matrix Biol 25:389–399. https://doi.org/10.1016/j.matbio.2005.06.008
  11. Ohtsubo H, Okada T, Nozu K, et al. Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits. Pediatr Nephrol. (2016) 31:1459–67. https://doi.org/10.1007/s00467-016-3368-7
  12. Aslam N, Singh A, Cortese C, Riegert-Johnson DL. A novel variant in FN1 in a family with fibronectin glomerulopathy. Hum Genome Var. (2019) 6:11. https://doi.org/10.1038/s41439-019-0042-1
  13. van Hoolwerff M, Rodríguez Ruiz A. et al. High-impact FN1 mutation decreases chondrogenic potential and affects cartilage deposition via decreased binding to collagen type II. Nature Genetics, 2021 Nov 5;7(45):eabg8583. https://doi.org/10.1126/sciadv.abg8583
  14. Neha E.H. Dinesh, Philippe M. Campeau, Dieter P. Reinhardt. The integral role of fibronectin in skeletal morphogenesis and pathogenesis. Matrix Biology 134 (2024) 23–29. https://doi.org/10.1016/j.matbio.2024.08.010
  15. Nicoletta Zoppi, Marco Ritelli, Marina Colombi. Type III and V collagens modulate the expression and assembly of EDA(+) fibronectin in the extracellular matrix of defective Ehlers-Danlos syndrome fibroblasts. Biochim Biophys Acta (2012) 1820(10):1576-87. https://doi.org/10.1016/j.bbagen.2012.06.004
  16. Ti Zhang, Wei Zhang, Ke Zuo and Zhen Cheng. Clinicopathologic Features and Outcomes in Fibronectin Glomerulopathy: A Case Series of 19 Patients, Brief research report article Front. Med., 14 August 2020, Volume 7 – 20. https://doi.org/10.3389/fmed.2020.00439
  17. Hata M, Mori T, Hirose Y, et al. A case of unexpected diagnosis of fibronectin glomerulopathy with histological features of membranoproliferative glomerulonephritis. BMC Nephrol. 2024;25(1):25. https://doi.org/10.1186/s12882-024-03456-7
  18. Yoshino M, Miura N, Ohnishi T, et al. Clinicopathological analysis of glomerulopathy with fibronectin deposits (GFND): a case of sporadic, elderly-onset GFND with codeposition of IgA, C1q, and fibrinogen. Intern Med. 2013;52(15):1715–20. https://doi.org/10.2169/internalmedicine.52.0046
  19. Goldman BI, Panner BJ, Welle SL, Gross MD, Gray DA. Prednisone-induced sustained remission in a patient with familial fibronectin glomerulopathy (GFND). CEN Case Rep. 2021;10(4):510–4. https://doi.org/10.1007/s13730-021-00595-w
  20. Noris M, Remuzzi G. Translational mini-review series on complement factor H: therapies of renal diseases associated with complement factor H abnormalities: atypical haemolytic uraemic syndrome and membranoproliferative glomerulonephritis. Clin Exp Immunol. 2008;151(2):199–209. https://doi.org/10.1111/j.1365-2249.2007.03558.x

Sindrome nefrosica e insufficienza renale rapidamente progressiva in paziente con componente monoclonale: un caso clinico

Pubblicato il Scarica PDF

DOI: 10.69097/43-01-2026-13

Claudia Lopez1, Marica Giliberti1, Di Leo Vincenzo1, Adriano Montinaro1, Adele Mitrotti1-2, Michele Rossini1, Loreto Gesualdo1

1 Dipartimento di Medicina di Precisione e Rigenerativa e Unità di Nefrologia, Dialisi e Trapianti dell'Area Ionica (DiMePre-J), Università degli Studi di Bari Aldo Moro, Italia
2 Divisione di Nefrologia e Dialisi, Mater Dei Hospital, Bari, Italia

Corrispondenza a:
Adele Mitrotti
E-mail: a.mitrotti83@gmail.com

 

Abstract

Presentiamo il caso di una donna di 53 anni con sindrome nefrosica, progressivo peggioramento della funzione renale, anemia e riscontro di componente monoclonale IgG lambda. Il quadro clinico era caratterizzato da proteinuria in range nefrosico, sedimento urinario attivo, ipocomplementemia selettiva (C3 ridotto), splenomegalia e linfoadenopatie multiple. Gli esami immunologici e infettivologici risultavano negativi. L’elettroforesi sierica e urinaria documentava una componente monoclonale IgG λ con marcato incremento delle catene leggere libere λ. È stata eseguita biopsia renale per definire il quadro istopatologico e orientare la gestione terapeutica. Il caso evidenzia l’importanza di un tempestivo inquadramento multidisciplinare nelle nefropatie associate a gammopatia monoclonale di significato renale (MGRS).

Parole chiave: Sindrome Nefrosica, Proteinuria, Complemento, Gammopatie Monoclonali, Biopsia Renale

Presentazione del caso

Una donna caucasica di 53 anni veniva inviata all’osservazione nefrologica presso il Policlinico di Bari per sindrome nefrosica in quadro di progressivo deterioramento della funzione renale e anemia.

 

Anamnesi

L’anamnesi familiare era negativa per nefropatie. In anamnesi patologica remota si segnalava un episodio di tubercolosi in età giovanile. La paziente riferiva buono stato di salute fino al novembre 2022, quando veniva ricoverata presso l’Unità Operativa di Cardiologia del P.O. “Di Venere” per miocardite. In tale occasione si documentava:

  • Creatinina sierica (sCr): 1,41 mg/dL
  • Proteinuria: 200 mg/mmol
  • Leucocituria: 500 cellule/µL
  • Elettroforesi proteica: “probabile componente monoclonale”

La TC del torace evidenziava linfoadenopatie multiple (diametro massimo 2,4 cm) in sede epi-aortica, finestra aorto-polmonare, subcarenale e ascellare bilateralmente.

A partire da giugno 2024 la paziente riferiva un calo ponderale di 12 kg, comparsa di edemi declivi ed episodi di macroematuria.

Nel novembre 2024 accedeva al Pronto Soccorso per anemia (Hb 8,3 g/dL) e peggioramento della funzione renale (sCr 3,39 mg/dL). Un mese dopo si ripresentava per ulteriore riduzione dell’emoglobina (7,8 g/dL) e incremento della sCr (3,6 mg/dL), venendo ricoverata in Nefrologia.

 

Esami strumentali e laboratoristici

L’ecografia renale mostrava reni in sede, di dimensioni ai limiti superiori della norma (rene destro 125 mm, sinistro 137 mm), con spessore cortico-midollare conservato; si evidenziava splenomegalia. All’ingresso presso la Nefrologia del Policlinico di Bari (dicembre 2024) si documentava:

  • sCr 3,84 mg/dL (eGFR 13 ml/min/1,73 m²)
  • Proteinuria 8,3 g/24h (precedentemente 11 g/24h)
  • Albuminuria 5 g/24h
  • Albumina sierica 2,7 g/dL
  • Hb 9,5 g/dL
  • Piastrine 84×10³/µL
  • C3 ridotto (0,66 g/L), C4 nei limiti
  • Quantiferon positivo

Esame urine: sedimento attivo con >40 emazie/HPF e 10–20 leucociti/HPF; urinocoltura negativa.

Le indagini autoimmuni (ANA, ANCA, anti-GBM, anti-PLA2R) risultavano negative. Sierologie per HIV, HBV e HCV negative. L’elettroforesi sierica evidenziava una componente monoclonale IgG λ (0,19 g/dL). Le catene leggere libere sieriche mostravano λ 589 mg/L, κ 17,42 mg/L con rapporto κ/λ alterato. Nelle urine si documentava proteinuria di Bence Jones λ (51,8 mg/24h) e IgG λ completa (50,54 mg/24h).

 

Iter diagnostico

In data 30 dicembre 2024 veniva eseguita biopsia renale percutanea eco-guidata al fine di definire il pattern istopatologico e orientare la gestione terapeutica, tenendo in considerazione alcuni aspetti principali tra cui:

  • Sindrome nefrosica con sedimento attivo
  • Progressivo declino della funzione renale
  • Ipocomplementemia selettiva (C3 ridotto)
  • Presenza di componente monoclonale IgG λ
  • Evidenza di catene leggere monoclonali sieriche e urinarie
  • Segni sistemici (calo ponderale, splenomegalia, linfoadenopatie, citopenie)

Veniva eseguita analisi del frustolo bioptico in microscopia ottica, microscopia elettronica e immunofluorescenza.

Microsocpia Ottica – Colorazione Ematossilina Eosina (H&E).
Microsocpia Ottica – Colorazione Ematossilina Eosina (H&E).

Microsocpia Ottica – Colorazione Ematossilina Eosina (H&E).
Microsocpia Ottica – Colorazione Ematossilina Eosina (H&E).
Microsocpia Ottica – Colorazione Ematossilina Eosina (H&E).
Microsocpia Ottica – Colorazione Ematossilina Eosina (H&E).
Microsocpia Ottica – Colorazione PAS (Periodic Acid–Schiff).
Microsocpia Ottica – Colorazione PAS (Periodic Acid–Schiff).

Microsocpia Ottica – Colorazione Ematossilina Eosina (H&E).
Microsocpia Ottica – Colorazione Ematossilina Eosina (H&E).
Microsocpia Ottica – Colorazione PAS (Periodic Acid–Schiff).
Microsocpia Ottica – Colorazione PAS (Periodic Acid–Schiff).
Microsocpia Ottica – Colorazione Tricromica di Masson.
Microsocpia Ottica – Colorazione Tricromica di Masson.
Microsocpia Ottica – Colorazione PAS (Periodic Acid–Schiff).
Microsocpia Ottica – Colorazione PAS (Periodic Acid–Schiff).

Microsocopia Elettronica
Microsocopia Elettronica.
Immunofluorescenza
Immunofluorescenza.

 

E adesso mettiamoci alla prova!

Alla luce del quadro clinico e laboratoristico descritto, quale diagnosi ipotizzereste? E quale trattamento riterreste più appropriato?

La soluzione nel nostro prossimo numero!

Esplorare la complessità della Sindrome Nefrosica nella Malattia del Rene Policistico Autosomico Dominante: Case report e revisione della letteratura

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Alessandro Barruscotti

DOI: 10.69097/42-03-2025-04

Alessandro Barruscotti1, Gabriella Moroni2, Liliana Italia De Rosa1, Kristiana Kola1, Martina Catania1, Francesca Tunesi 1, Matteo Brambilla Pisoni3, Sara Farinone4, Paolo Manunta1,3, Giuseppe Vezzoli1,3, Maria Teresa Sciarrone Alibrandi1,3

1 Vita Salute San Raffaele University, 20132 Milan, Italy
2 Department of Biomedical Sciences Humanitas University, Nephrology and Dialysis Division, IRCCS Humanitas Research Hospital, Milan, Italy
3 O.U. Nephrology and Dialysis, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
4 Clinical and Health Psychology unit, IRCCS San Raffaele Hospital, Milan, Italy

Corrispondenza a:
Liliana Italia De Rosa
Vita Salute San Raffaele University, (Postgraduate School of Nephrology), Milan, Italy
Via Olgettina 60
20132, Milan, Italy
Phone +39 02 2643 2123
E-mail: derosa.liliana@hsr.it

 

Abstract

La malattia policistica autosomica dominante (ADPKD) è una condizione genetica caratterizzata dallo sviluppo di numerose cisti renali e dall’aumento del volume renale totale, che spesso porta a un progressivo declino della funzione renale. Sebbene la glomerulonefrite sia potenzialmente riconosciuta come una complicanza, la sua presenza nei pazienti con ADPKD è considerata rara, e l’incidenza della sindrome nefrosica in questa popolazione è eccezionalmente bassa.
Presentiamo il caso di una giovane donna con ADPKD che ha sviluppato una sindrome nefrosica, verosimilmente attribuibile a malattia a lesioni minime. Le sfide diagnostiche, le strategie terapeutiche e la letteratura esistente su questa rara associazione vengono qui esaminate in modo approfondito.

Parole chiave: malattia policistica autosomica dominante, sindrome nefrosica, biopsia renale, MCD, caso clinico

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

ADPKD is a genetic disorder characterized by the formation of renal cysts, culminating in renal enlargement and dysfunction. ADPKD is the fourth leading cause of ESKD [1]. Among the clinical manifestations of ADPKD, urinary alteration is unusual. Typically, proteinuria when present is < 1 g/die and urinary sediment is generally inactive. Although glomerulonephritis can complicate ADPKD, the concurrent presentation of nephrotic syndrome, especially MCD, is quite exceptional [2, 3]. Thus, the occurrence of nephrotic proteinuria in the course of ADPKD is very rare. In these situations, the clinicians have to decide to run the risk of a kidney biopsy or attempt to make the diagnosis through clinical and immunological tests.

The decision to conduct a biopsy in ADPKD patients depends on factors like safety considerations and whether obtaining tissue diagnosis would impact treatment decisions.

Among complication rates after kidney biopsy, bleeding is the most common clinically significant event (70% of patients) [4]. In the systemic review of Corapi [5], also, macroscopic hematuria was observed in 3.5% (95% confidence intervals: 2.2–5.1%), blood transfusion in 0.9% (0.4–1.5%), angiographic intervention in 0.6% (0.4–0.8%), nephrectomy in 0.01% and death in 0.02%.

In patients suffering from ADPKD all these risks are increased depending on the progression of the disease and the number of cysts due to the risk of rupture.

In situations where a biopsy is deemed necessary open renal biopsy is typically carried out for individuals with ADPKD. However, novel approaches have been described for use in “high-risk” settings where conventional contraindications to kidney biopsy exist. Alternative approaches such as open surgery, transvenous methods (like trans-jugular or trans-femoral), laparoscopy, or transurethral methods are also possible options [6].

The literature indicates that, in the general adult population, membranous nephropathy (MN) is the most prevalent form of idiopathic nephrotic syndrome, followed in frequency by minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). Approximately 30% of nephrotic syndrome cases in adults may be associated with underlying systemic conditions such as diabetes mellitus, amyloidosis, or systemic lupus erythematosus. Similarly, MN and FSGS are the most common primary pathological lesions observed in adult patients with nephrotic syndrome and coexisting ADPKD. However, the literature also reports other pathological types, including mesangial proliferative glomerulonephritis, IgA nephropathy, amyloidosis, crescentic glomerulonephritis, diabetic nephropathy, lupus nephritis, and post-infectious mesangial proliferative glomerulonephritis [7].

In a literature review of 1995 [8], 22 patients with ADPKD and nephrotic syndrome were identified and 14 received kidney biopsy exhibiting various histological diagnoses including focal glomerular sclerosis, minimal change disease, membranous nephropathy, and IgA nephropathy. A more recent review in 2010 [9] found only a few new cases of nephrotic syndrome associated with ADPKD in adults in addition to those reported in the previous literature revision. We have collected all cases of ADPKD and nephrotic syndrome published since 2000.

FSGS appears to be more frequent in ADPKD, likely due to maladaptive mechanisms driven by early-onset glomerular hyperfiltration, often starting in childhood. Although the precise pathways through which glomerular hyperfiltration leads to segmental scarring and renal function decline are not fully understood, studies suggest that a reduction in renal mass triggers intrarenal vasodilation, increased glomerular capillary pressure, and enhanced plasma flow per nephron [6, 8]. This compensatory hyperfiltration initially maintains GFR but also causes glomerular enlargement, with expansion of matrix components and increased endothelial and mesangial cells [10].

The process of diagnosing glomerulonephritis in ADPKD patients typically involves assessment along with evaluation of the urinalysis in quantitative terms of proteinuria with the respective electrophoresis of urinary proteins (selective or non-selective glomerular proteinuria) and blood tests.

Diagnostic tests for glomerulonephritis in ADPKD patients certainly include, as in the workup of any glomerular disease, urine sediment examination. The presence of dysmorphic erythrocytes and/or erythrocyte casts suggests a glomerular disease, and particularly a proliferative form of glomerulonephritis. However, the sensitivity and specificity of this test alone may not be sufficient for a definitive diagnosis and are often used in conjunction with other immunological and clinical measures.

Furthermore, while not a direct test for glomerulonephritis, genetic testing for ADPKD may be performed to confirm the diagnosis of ADPKD, which can help in understanding the patient’s overall kidney health and potential complications [1]. Actually, in ADPKD prognosis differs by genetic mutation, with PKD1 mutations typically indicating earlier onset and more aggressive disease progression compared to PKD2 mutations [11].

The first report of a case of ADPKD and minimal change disease was done in 1991 by Nakahama et al. [12]. Minimal change disease (MCD) is commonly a major cause of nephrotic syndrome, particularly in children in whom it accounts for approximately 90% of cases. The exact cause of MCD is not well understood, but it is believed to involve T-cell-related mechanisms [13].  However, several potential pathways that result in podocyte activation and proteinuria have been identified, such as some drugs, malignancies including Hodgkin disease, mycosis fungoides, chronic lymphocytic leukemia, or secondary allergic forms (pollens, house dust, insect stings). In 2022 a study by Watts et al. [14] discovered nephrin autoantibodies in a subset of adults and children with minimal change disease. A recent study of August 2024 by Hengel et al. [15] confirms that the circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity and provides further support for an autoimmune etiology.

The estimated incidence ranges from 2 to 7 new cases per 100,000 children. While the exact prevalence remains uncertain it is approximately estimated to be between 10 and 50 cases per 100,000 children [9]. MCD is uncommon in adults, and the precise occurrence is undetermined. In preadolescents, MCD makes up 85-95% of all cases of nephrotic syndrome, while in adolescents and young adults the prevalence is 50%, and in adults MCD accounts for 10-15% of primary nephrotic syndrome cases. Corticosteroid treatment is usually effective in inducing remission, but relapse is common and repeated therapy is often required. Among children with MCD, 25% never relapse, 25% relapse infrequently, and 50% have numerous relapses [16].

While there are anecdotal case reports of ADPKD associated with nephrotic syndrome, including MCD, the prevalence of such associations is extremely low [2, 17].

First author Age Sex Kidney Biopsy Diagnosis Therapy Outcome
Ekaterini et al. [9] 9 M No – CS (oral) Remission
Savaj et al. [18] 29 M Yes FSGS CS + cyclosporine Remission
Peces et al. [19] 38 M Yes MN 1. CS

2. CS + Chlorambucil

 

3. CS + MFM

 1. Resistence

2. Partial remission for ten months

3. Remission
Hiura et al. [20] 70 M Yes IgAN CS Remission
Sar et al. [21] 39 M No Amyloidosis secondary TBC Colchicine + TBC terapy N/A
Akinbodewa et al. [22] 24 F Yes SLE stage II Prednisolone + MFM Remission
D’Cruz et al. [23] 35 M Yes D-PGN Conservative Partial remission
Visciano B et al. [2] 26 M Yes MPGN CS (oral) Remission
Yenigun et al. [24] 52 M Yes Amyloidosis Colchicine Started hemodialysis
Oda Y et al. [25] 23 M Yes FSGS Conservative

 

 Started hemodialysis
Table 1. Cases of nephrotic syndrome related to ADPKD since 2000. MCD: minimal change disease; FSGS: focal segmental glomerulosclerosis; MN: membranous nephropathy; IgAN: IgA nephropathy; D-PGN: diffuse proliferative glomerulonephritis; SLE: Systemic lupus erythematosus; MPGN: mesangial proliferative glomerulonephritis. N/A: Data not available. mycophenolate mofetil (MFM).

In this paper, we present a case of a young woman with ADPKD who developed nephrotic syndrome, likely due to MCD, highlighting the importance of vigilance for glomerular involvement in ADPKD patients presenting with nephrotic-range proteinuria. Timely diagnosis and personalized treatment are essential for optimizing outcomes in such rare occurrences.

 

Case report

A 52-year-old woman with a medical history notable for allergies to NSAIDs, dust mites, cypress pollen, and cat dander. The patient’s mother is alive and has hemophilia A, while the father is affected by autosomal dominant polycystic kidney disease. Remarkably, the patient herself is a carrier of hemophilia A, inherited maternally.

At the age of 20, diagnosis of ADPKD was made based on familial history, with Ravin and Pei ultrasound criteria being met. Genetic testing revealed an intronic mutation in PKD2. The patient has never experienced gross hematuria, abdominal pain, or renal infections.

At the age of 40, hypertension was first diagnosed, and treatment with an angiotensin receptor blocker was initiated with beneficial effects.

At 42 years old, in September 2014, the patient developed nephrotic syndrome characterized by weight gain, proteinuria of 6 grams in 24 hours, and severe hypoalbuminemia, despite normal renal function. Immunologic screening was negative, including PLA2R and sUPAR. Urinary sediment examination was inactive. Secondary oncologic, pharmacologic and infectious causes of glomerulopathy were excluded. Due to the presence of renal polycystic disease with a large cyst (approximately 7 cm) in the left lower renal pole and the high risk of bleeding in a patient with hemophilia A, a renal biopsy was contraindicated. Ex adiuvantibus corticosteroid therapy was initiated with intravenous methylprednisolone of 1 gram day for three consecutive days followed by oral prednisone at 0.5 mg/kg/day. After three months of steroid therapy, proteinuria resolved almost completely (224 mg/24h) with a creatinine level of 0.66 mg/dl. Corticosteroid therapy was then tapered off also due to poor tolerance and different side effects. Three months later, there was a significant recurrence of nephrotic syndrome (urinary protein 14 grams/24h) despite persistence of normal renal function (creatinine 0.6 mg/dl). The response to corticosteroids therapy and the recurrence of NS after its withdrawal suggested a MCD. Due to the inability to use calcineurin inhibitors in ADPKD for their nephrotoxic effects [26], exacerbating renal deterioration, treatment with rituximab was initiated. Following the first administration of rituximab (1 gram), complete remission of the disease was achieved. Two subsequent recurrences of proteinuria occurred following allergic episodes, both of which responded promptly to rituximab boluses. The last recurrence occurred in 2018, which spontaneously regressed. To date, there have been no further recurrences, with proteinuria within normal limits and normal renal function. The patient is currently followed up at our clinic for genetically determined renal cystic diseases (Figure 1).

Figure 1. Summary of the patient‘s clinical history.
Figure 1. Summary of the patient‘s clinical history.

 

Discussion

In our case, the diagnosis of MCD is inherently presumptive yet highly plausible, given the severity of nephrotic syndrome, selective glomerular proteinuria, rapid response to corticosteroids therapy, recurrences post-allergic episodes, and maintained renal function despite significant proteinuria and frequent relapses. The conjunction of nephrotic syndrome, notably MCD, with ADPKD epitomizes a rare clinical phenomenon. Our case underlines the importance of an accurate evaluation of the patient with urinary and blood tests to achieve the best diagnostic hypothesis in the absence of a histological diagnosis. In this regard, new urinary markers such as urinary CD80 have shown great promise in aiding the diagnosis of MCD [27]. Given the complexity of patients suffering from ADPKD, renal biopsy must be evaluated in terms of the risk/benefit ratio, particulary in cases in which there is a lack of response to therapy or in cases of steroid resistance. As previously stated, ADPKD patients face heightened risks with renal biopsy. Indeed, unlike our situation, histological diagnosis is frequently essential, making open renal biopsy pivotal in crafting appropriate treatment strategies due to the diverse glomerular subtypes associated with nephrotic syndrome. Interventions to make renal biopsy more accessible and safer are vital to overcome barriers to precise diagnosis and timely treatment. An appraisal of existing literature highlights the scarcity of reported cases and underscores the exigency for further prompt and decisive actions.

 

Conclusion

Nephrotic syndrome, attributed to conditions such as MCD, can rarely manifest in ADPKD. It’s essential to maintain vigilance for glomerular involvement in ADPKD patients with nephrotic-range proteinuria. A precise diagnosis is imperative to initiate customized treatment for resolution. This approach is critical not only for addressing associated systemic effects like hypercholesterolemia and hypercoagulability but also for slowing the progression of renal failure.

In ADPKD patients, already predisposed to chronic renal damage early intervention is particularly crucial. Prompt diagnosis and personalized management are pivotal for optimizing outcomes in these rare instances. Further research efforts are warranted to refine management strategies for this uncommon association.

 

Bibliography

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Stato dell’arte e prospettive future nella terapia di induzione delle vasculiti ANCA-associate con coinvolgimento renale: dall’istopatologia alla terapia

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Martina Uzzo

Martina Uzzo1, Federico Alberici2,3

1 Dipartimento di Medicina e Chirurgia, Università di Milano-Bicocca e ASST Monza, Monza, Italia
2 Dipartimento di Medicina e Chirurgia, Scienze Radiologiche e Salute Pubblica, Università di Brescia, Brescia, Italia
3 Unità di Nefrologia, Spedali Civili, ASST Spedali Civili di Brescia, Brescia, Italia

Corrispondenza a:
Martina Uzzo
UO Nefrologia e Dialisi, Ospedale San Gerardo
Via Pergolesi, 33
20900, Monza (MB), Italia
Tel.: 039 2331
E-mail: m.uzzo@campus.unimib.it

 

Abstract

Le AAV, vasculiti ANCA-associate (anticorpi anti-citoplasma dei neutrofili), sono rare malattie autoimmuni sistemiche caratterizzate dall’infiammazione di piccoli e medi vasi. Il coinvolgimento renale vasculitico è una delle manifestazioni più severe di malattia, che comporta un’elevata mortalità in caso di ritardo diagnostico ed impatta significativamente sulla prognosi a lungo termine dei pazienti. Sono state recentemente individuate classificazioni e score istopatologici che meglio definiscono il coinvolgimento renale nelle AAV e correlano con la prognosi renale a lungo termine. Il regime terapeutico di induzione delle AAV è costituito da alte dosi di glucocorticoidi associati a farmaci immunosoppressori: ciclofosfamide (CYC), rituximab (RTX) o una combinazione dei precedenti. L’uso del RTX è in espansione: trial randomizzati e controllati ne hanno dimostrato la non-inferiorità rispetto alla terapia standard con CYC nelle AAV in generale, oltre ad un miglior profilo di sicurezza; inoltre, l’introduzione di biosimilari ha ridotto il costo del farmaco. Tuttavia, nei pazienti con coinvolgimento renale grave, l’equivalenza di RTX e CYC è ancora dibattuta.

La ricerca del regime di induzione ideale nelle AAV è volta ad una sempre maggiore personalizzazione: da una parte viene indagato l’uso più appropriato delle terapie già esistenti; dall’altra, le nuove scoperte in ambito patogenetico hanno permesso l’introduzione di nuovi target terapeutici, come il fattore C5a del complemento.

Grazie a questa nuova gestione delle AAV, la prognosi renale e la sopravvivenza in generale sono visibilmente migliorate. Saranno necessari ulteriori studi per ottenere una sempre maggiore personalizzazione dell’approccio terapeutico di induzione delle glomerulonefriti ANCA-associate e delle AAV in generale.

 

Parole chiave: ANCA, vasculiti, glomerulonefrite, rituximab, ciclofosfamide, biopsia renale

Introduzione

Le AAV, vasculiti ANCA-associate (anticorpi anti-citoplasma dei neutrofili), sono rare vasculiti necrotizzanti autoimmuni che coinvolgono i vasi di medio e piccolo calibro. Le AAV includono tre patologie differenti: la granulomatosi con poliangioite (GPA, in passato nota come malattia di Wegener), la poliangioite microscopica (MPA) e la granulomatosi eosinofila con poliangioite (EGPA, in passato nota come sindrome di Churg Strauss) [1]. L’incidenza in Europa è rispettivamente di 2.1-14.4, 2.4-10.1 e 0.5-3.7 per milione e la prevalenza di 46-184 per milione. La sopravvivenza a 5 anni è intorno al 74-91% per la GPA, 45-76% per l’MPA e 60-76% per l’EGPA [2]. Il picco di incidenza si colloca fra i 65-75 anni, con una lieve prevalenza maschile.

Nel corso della malattia, circa il 90% dei pazienti sviluppa anticorpi ANCA, rivolti contro proteine contenute nel citoplasma dei neutrofili: sebbene esistano degli overlap, gli ANCA anti PR3 (anti-proteinasi 3) sono più frequenti nella GPA, mentre gli ANCA anti MPO (anti-mieloperossidasi) nella MPA; il 40% dei pazienti con EGPA sviluppa positività agli ANCA, in prevalenza MPO, spesso associata a forme con coinvolgimento vasculitico. Esistono alcune eccezioni: il 10% dei pazienti è ANCA negativo ed è possibile sviluppare entrambi gli anticorpi, prevalentemente nelle forme secondarie [3,4].

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Aspetti clinici e diagnostici delle masse renali solide rilevate incidentalmente

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Anna Mudoni

Anna Mudoni1, Marina Cornacchiari2, Amelia Liccardo3, Pierpaolo Di Nicolo'4, Luca Di Lullo5, Carlo Guastoni2, Marco Mereghetti6

1 Unità Operativa di Nefrologia e Dialisi Ospedale Cardinale G Panico Tricase (LE)
2 Unità Operativa di Nefrologia, ASST MILANO OVEST
3 Unità Operativa di Nefrologia e Dialisi Multimedica Presidio di Castellanza (VA)
4 Unità Operativa di Nefrologia e Dialisi S. Maria della Scaletta, Imola-Bologna
5 Unità Operativa Complessa di Nefrologia e Dialisi, Ospedale “L. Parodi – Delfino”, Colleferro (RM)
6 Unità Operativa di Medicina, ASST MILANO OVEST

Autore corrispondente:
Anna Mudoni
Unità Operativa di Nefrologia e Dialisi
Ospedale Cardinale G Panico Tricase (LE)
Telefono 333 6868124; 0833 773111
E-mail mudonia@libero.it

 

Abstract

Il riscontro di masse renali è aumentato negli ultimi decenni grazie dell’uso diffuso dell’imaging (ecografia, tomografia computerizzata e risonanza magnetica).

La maggior parte delle masse renali viene rilevata incidentalmente in seguito ad un esame ecografico eseguito di routine o per altre motivazioni.

In questa review gli autori esaminano le caratteristiche cliniche ed ecografiche di alcune masse solide riscontrate durante l’esecuzione di esami ecografici nella pratica quotidiana nefrologica, il ruolo della biopsia percutanea e della sorveglianza attiva, con uno sguardo al futuro attraverso le tecniche di fusione.

La tecnologia di navigazione e la fusione di immagini multimodali rappresentano un importante sviluppo nella radiologia interventistica, in particolare per l’effettuazione di biopsie percutanee difficili e le ablazioni di piccole masse renali.

Parole chiave: masse renali, imaging, CEUS, biopsia ecoguidata, sorveglianza attiva

Introduzione

Il riscontro di masse renali durante gli ultimi trent’anni è andato via via aumentando (1) grazie alla diffusione delle tecniche di imaging, in primo luogo l’ecografia (US), ma anche la tomografia assiale computerizzata (TC) e la risonanza magnetica nucleare (MRI).

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Un caso di Amiloidosi AL a presentazione insolita

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Anna Zito, Antonio De Pascalis, Paolo Ria, Annarita Armeni, Alessandro D'Amelio, Marcello Napoli

Unità Operativa Nefrologia e Dialisi, Ospedale “Vito Fazzi”, Lecce

Autore Corrispondente:
Dott.ssa Anna Zito
UO Nefrologia e Dialisi, Ospedale Vito Fazzi,
73100 Lecce, Italia
Tel 3475842910
E-mail: annavelvet@gmail.com

 

Abstract

Presentiamo il caso di un uomo di età avanzata con sindrome nefrosica e lieve insufficienza renale in cui le approfondite indagini laboratoristiche e strumentali effettuate non fornivano indizi utili per la diagnosi. Non era possibile identificare alcun segno o sintomo specifico della patologia poi identificata con analisi istologica e immunoistochimica su tessuto renale e midollare, l’amiloidosi primaria o AL. A questa era associata una discrasia linfoplasmacellulare che non aveva dato alcun segno di sé ai comuni esami laboratoristici quali l’elettroforesi delle sieroproteine e l’immunofissazione sierica e urinaria.

Il caso clinico descritto offre lo spunto per una disamina aggiornata della condizione nosologica diagnosticata e per considerare come, in contesti clinici e laboratoristici scarsamente orientativi, indagini tradizionalmente considerate di secondo livello, quali la biopsia renale, risultino unico strumento diagnostico.

Parole chiave: amiloidosi AL, bortezomib, biopsia renale

CASO CLINICO

Descriviamo il caso clinico di un uomo di 74 anni, giunto all’osservazione del Nefrologo per sindrome nefrosica in presenza di lieve insufficienza renale (sCr 1,5 mg/dL; eGFR sec. CKD-EPI 45 mL/min/1,73 mq, MDRD 48 mL/min/1,73 mq) e proteinuria in range nefrosico (4,22 g/24 ore). In anamnesi si segnalavano: trait talassemico, note di gastrite erosiva ed una pregressa frattura costale post-traumatica. Clinicamente si riscontravano habitus pletorico, incremento ponderale di nove chili nelle ultime dieci settimane, ipotensione arteriosa. Gli esami laboratoristici routinari evidenziavano stato anemico (Hb 10,7 g/dL), beta2-microglobulina al di sopra dell’intervallo di normalità (4,54 mg/L), elevazione di Nt-proBNP (1.419 pg/mL). Indici infiammatori ed autoimmunità: negativi. Elettroforesi e immunofissazione sierica e urinaria non segnalavano anomalie. All’Rx torace si notava una velatura del seno costo-frenico bilateralmente e un ingrandimento dell’ombra cardiaca. All’elettrocardiogramma erano presenti bassi voltaggi diffusi. L’ecocardiogramma rilevava segni di ipertrofia con disfunzione diastolica e aspetto di pattern restrittivo al Doppler transmitralico.

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