Hematuria and Proteinuria in a Patient with Recurrent Pulmonary Illnesses: A Quiz

A 19-year-old man presented to an adult nephrology practice to establish care. He had a history of recurrent hematuria and proteinuria in the setting of upper respiratory tract illnesses. This was first noted at age 14 when he had gross hematuria associated with episodes of fever and pharyngitis 2 months apart. Pharyngeal swab was negative for Streptococcus both times. He felt generally well otherwise. His pediatrician suspected IgA nephropathy (IgAN) and referred him to a pediatric nephrologist, who reported the same impression and recommended a conservative management strategy. On physical examination at his initial adult nephrology visit, blood pressure was 138/87 mm Hg and 130/78 mm Hg and he had no edema. Laboratory studies showed serum creatinine concentration (Scr) of 1.1 mg/dL (Scr was 0.7 mg/dL seven years earlier and 1.0 mg/dL in the year before). Urine dipstick showed blood (3+) and protein (2+). Urinalysis revealed hematuria (374 red blood cells per high-power field) and 30 mg/dL protein. Spot urinary albumin-creatinine ratio was 111 mg/g. Spot urinary protein-creatinine ratio was 580 mg/g. Medical history was significant for beta-thalassemia intermedia. Family history was positive for nephrolithiasis in his maternal grandfather.•What is the differential diagnosis of intermittent microscopic hematuria and proteinuria in the setting of respiratory illnesses?•What studies should be included in the diagnostic evaluation of this patient?•What is the clinical presentation and pathophysiologic mechanism of this patient’s disease?•What are the treatment options and long-term prognosis of this disease? The differential diagnosis is summarized in Box 1. The most likely differential diagnoses in this young male patient with initially normal kidney function and no extrarenal disease include IgAN, postinfectious glomerulonephritis, and C3 glomerulopathy. Less likely possibilities include idiopathic membranoproliferative glomerulonephritis and atypical hemolytic uremic syndrome.Box 1Differential Diagnosis of Intermittent Hematuria and Proteinuria in the Setting of Respiratory Illnesses•IgA nephropathy (IgAN) and IgA vasculitis•Postinfectious glomerulonephritis (PIGN)•C3 glomerulopathy♢C3 glomerulonephritis (C3GN)▪Complement factor H–related protein 5 (CFHR5) nephropathy♢Dense deposit disease (DDD)•Idiopathic membranoproliferative glomerulonephritis (MPGN)•Atypical hemolytic uremic syndrome (HUS) •IgA nephropathy (IgAN) and IgA vasculitis•Postinfectious glomerulonephritis (PIGN)•C3 glomerulopathy♢C3 glomerulonephritis (C3GN)▪Complement factor H–related protein 5 (CFHR5) nephropathy♢Dense deposit disease (DDD)•Idiopathic membranoproliferative glomerulonephritis (MPGN)•Atypical hemolytic uremic syndrome (HUS) Laboratory work-up included serum protein electrophoresis and testing for anti–streptolysin O antibodies, anti–deoxyribonuclease B antibodies, κ and ƛ serum free light chains, lactate dehydrogenase, haptoglobin, complement C3, C4, factor H, and C3 nephritic factor; all were unremarkable. Kidney biopsy (Fig 1) showed mild mesangial hypercellularity with predominant glomerular C3 deposits. There was no glomerular staining for IgG, IgM, IgA, C1q, light chains, or fibrin. Electron microscopy revealed segmental mesangial, subepithelial, and subendothelial immune-type electron-dense deposits with segmental duplication of glomerular basement membranes. No “hump-like” subepithelial deposits were identified. These findings were consistent with C3 glomerulonephritis, a subtype of C3 glomerulopathy. Family history was notable for Cypriot ancestry on his paternal side and Greek ancestry on his maternal side, raising concern for complement factor H–related protein 5 (CFHR5) nephropathy. CFHR5 nephropathy is an autosomal dominant disease with >90% penetrance and is endemic in Cyprus, where the carrier rate for the fusion gene (CFHR5-CFHR5) is ∼1 in 6,500 and over 100 persons are affected.1Gale D.P. de Jorge E.G. Cook H.T. et al.Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.Lancet. 2010; 376: 794-801Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar Genetic testing confirmed the presence of the CFHR5-CFHR5 fusion gene. The clinical and histological features of CFHR5 nephropathy strongly resemble those of IgAN, although in CFHR5 nephropathy no IgA deposition is seen. Kidney biopsy and genetic testing are central to its diagnosis and to distinguish it from IgAN. The CFHR5-CFHR5 fusion gene found in CFHR5 nephropathy encodes an elongated version of the CFHR5 protein, which acts as a competitive inhibitor of factor H, resulting in complement dysregulation. CFHR5 nephropathy typically presents with microscopic hematuria, almost always with respiratory infections; 25%-50% of patients have macroscopic hematuria. Proteinuria is typically mild (<1 g/d) and only present after kidney function has become impaired.2Gale D.P. Pickering M.C. Regulating complement in the kidney: insights from CFHR5 nephropathy.Dis Model Mech. 2011; 4: 721-726Crossref Scopus (25) Google Scholar, 3Kadkhodayi-Kholghi N. Bhatt J.S. Gor J. McDermott L.C. Gale D.P. Perkins S.J. The solution structure of the complement deregulator FHR5 reveals a compact dimer and provides new insights into CFHR5 nephropathy.J Biol Chem. 2020; 295: 16342-16358Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 4Murphy B. Georgiou T. Machet D. Hill P. McRae J. Factor H-related protein-5: a novel component of human glomerular immune deposits.Am J Kidney Dis. 2002; 39: 24-27Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar There is no proven treatment for CFHR5 nephropathy. Disease progression correlates with infectious episodes, and tonsillectomy has shown occasional good long-term results based on anecdotal and uncontrolled reports.5Athanasiou Y. Voskarides K. Gale D.P. et al.Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.Clin J Am Soc Nephrol. 2011; 6: 1436-1446Crossref PubMed Scopus (109) Google Scholar Conventional immunosuppressive agents are not beneficial.1Gale D.P. de Jorge E.G. Cook H.T. et al.Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.Lancet. 2010; 376: 794-801Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar Plasma exchange during episodes of macroscopic hematuria and acute kidney dysfunction has shown short-term benefit. It is unknown whether eculizumab is beneficial.1Gale D.P. de Jorge E.G. Cook H.T. et al.Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.Lancet. 2010; 376: 794-801Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar Progressive deterioration of kidney function occurs in more than 80% of male patients (but only a small proportion of female patients) and leads to kidney failure usually between 30 and 70 years of age.1Gale D.P. de Jorge E.G. Cook H.T. et al.Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.Lancet. 2010; 376: 794-801Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar Kidney transplantation provides good outcomes, but the disease does recur, consistent with its genetic etiology.1Gale D.P. de Jorge E.G. Cook H.T. et al.Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.Lancet. 2010; 376: 794-801Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar This patient was started on lisinopril 10 mg daily. Home blood pressures have remained stable. Over the ensuing several months, Scr ranged from 1.5 to 1.9 mg/dL and urinary protein-creatinine ratio has ranged from 610 to 810 mg/g (Table 1). Continued supportive care is planned.Table 1Kidney Function and Proteinuria Over TimeScr (mg/dL)UPCR (mg/g)UACR (μg/mg)–7 years0.7–1 year1.0Time of presentationaTime of presentation to adult nephrology clinic.1.1111+1 month1.2+5 months1.41,000+7 months1.6580+12 months1.6510+15 months1.9610+16 months1.5+17 months1.7810+19 months1.83Abbreviations: UPCR, urinary protein-creatinine ratio; UACR, urinary albumin-creatinine ratio; Scr, serum creatinine.a Time of presentation to adult nephrology clinic. Open table in a new tab Abbreviations: UPCR, urinary protein-creatinine ratio; UACR, urinary albumin-creatinine ratio; Scr, serum creatinine. CFHR5 nephropathy causing C3 glomerulonephritis owing to a heterozygous CFHR5 mutation. Kelly V. Liang, MD, Brigid K. Ellis, DO, Michael B. Stokes, MD, Richard J. Smith, MD, Xin Gu, MD, and Daniel P. Gale, MD. Dr Smith’s research is supported in part by National Institutes of Health grant R01 DK110023. The funding agency had no role in defining the content of the article or decision to publish this case. Dr Gale reports receiving grants from Travere and consulting fees from Alexion, Novartis, and Otsuka, and serving as a Trustee of Alport UK. Dr Smith reports serving on the Scientific Advisory Board of Novartis. Dr Ellis reports receiving 2 scholarly articles on C3GN from a representative of Alexion in 2021. The other 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 August 6, 2021. Direct editorial input from the Pathology Editor and a Deputy Editor. Accepted in revised form October 30, 2021.