- Email: [email protected]
Overlap of ultrastructural findings in C3 glomerulonephritis and dense deposit disease
letter to the editor
6.
Brouard S, Pallier A, Renaudin K et al. The natural history of clinical operational tolerance after kidney transplantation through twentyseven cases. Am J Transplant 2012; 12: 3296–3307. Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 2006; 313: 670–673.
Sophie Brouard
140 MDRD eGFR (ml/min per 1.73m2)
5.
1,2,3
1 INSERM, UMR 1064, Nantes, France; 2CHU de Nantes, ITUN, Nantes, France and 3CIC Biothérapie, Nantes, France Correspondence: Sophie Brouard, INSERM, UMR 1064, 30 Bd Jean Monnet, Nantes 44093, France. E-mail: [email protected]
Kidney International (2015) 88, 1448–1449; doi:10.1038/ki.2015.297
120 100 80 60 40 20
Can ultrasound kidney length qualify as an early predictor of progression to renal insufficiency in autosomal dominant polycystic kidney disease? To the Editor: We read with great interest the article of Bhutani et al.,1 which highlights the prognostic value of ultrasound (US) kidney length (KL) in the CRISP cohort2 of autosomal dominant polycystic kidney disease (ADPKD) patients, which included a selected population of young patients (age 15–46 years) with estimated glomerular filtration rate (eGFR) values over 70 ml/min per 1.73 m2. The authors demonstrated that US KL over 16.5 cm predicts the onset of chronic kidney disease stage 3 within 8 years, and suggest that it could represent an alternative to height-adjusted total kidney volume (HtTKV)3 to assess ADPKD prognosis and enable therapeutic decision making. Although we understand that the US KL threshold proposed by the authors allows anticipating a few years—or months—the eGFR decline in young patients who have a preserved kidney function, the applicability of this prognostic biomarker in the general ADPKD population remains uncertain. Using personal data from the Genkyst cohort,4 we observed that before exceeding this US KL threshold, a significant number of the patients had already eGFR values below 70 ml/min per 1.73 m2 (Figure 1). Furthermore, patients with an eGFR over 70 ml/min per 1.73 m2 and a US KL over 16.5 cm represent a minority of the patients of our cohort. Therefore, we are unsure whether US KL can qualify as an early prognostic biomarker. In addition, Bhutani et al.,1 while referring to HtTKV, argue that it is ‘stronger than and replaces PKD1 genotype’. We previously reported the determinant influence of not only the gene involved (PKD1 vs. PKD2) but also of the type of PKD1 mutation (truncating vs. non-truncating variants).4 To our knowledge, there are currently no data in the literature allowing the authors to draw conclusions on the superiority of HtTKV on this latter prognostic factor. We believe that taking into account patient’s genotype together with imaging data may provide an earlier stratification of the risk of progression to renal insufficiency in ADPKD. Kidney International (2015) 88, 1445–1450
0 10.5 12.5 14.5 16.5 18.5 20.5 22.5 24.5 26.5 28.5 Left kidney length (cm)
Figure 1 | Estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease (MDRD) equation according to ultrasound kidney length (US KL) in 243 non-ESRD patients from the Genkyst cohort who had US KL measurement concomitant to eGFR values. 1.
Bhutani H, Smith V, Rahbari-Oskoui F et al. A comparison of ultrasound and magnetic resonance imaging shows that kidney length predicts chronic kidney disease in autosomal dominant polycystic kidney disease. Kidney Int 2015; 88: 146–151. 2. Grantham JJ, Torres VE, Chapman AB et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354: 2122–2130. 3. Chapman AB, Bost JE, Torres VE et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2012; 7: 479–486. 4. Cornec-Le Gall E, Audrézet M-P, Chen J-M et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol 2013; 24: 1006–1013.
Emilie Cornec-Le Gall1,2 and Yannick Le Meur1,2 1 Service de Néphrologie, Centre Hospitalier Régional Universitaire de Brest, Brest, France and 2Université Européenne de Bretagne, Université de Bretagne Occidentale, Brest, France Correspondence: Emilie Cornec-Le Gall, Department of Nephrology, Brest University Hospital, Brest 29609, France. E-mail: [email protected]
Kidney International (2015) 88, 1449; doi:10.1038/ki.2015.285
Overlap of ultrastructural findings in C3 glomerulonephritis and dense deposit disease To the Editor: C3 glomerulopathy results from dysregulation of the alternative pathway of complement with glomerular deposition of activated and breakdown components of complement system and ensuing glomerular inflammation. On the basis of ultrastructural studies, C3 glomerulopathy is further subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (GN).1 DDD is characterized by dense osmiophilic band-like deposits within the glomerular basement membranes and as rounded deposits in the mesangium. C3GN, in comparison, is typically characterized by subendothelial and mesangial deposits, although intramembranous and subepithelial deposits may also be present. In some cases, the deposits 1449
letter to the editor
a
b
5 µm
c
2 µm
d
5 µm
e
5 µm
f
2 µm
10 µm
g
h
Certain biopsies of C3 glomerulopathy are difficult to label as either DDD or C3GN as there is an overlap in ultrastructural findings, although one pattern may dominate over the other. Thus, while most capillary loops may show the intramembranous dense deposits of DDD, a few loops may show discrete deposits of C3GN. The reverse can also be present, in that the predominant finding are the subendothelial deposits of C3GN, while some loops may show the dense deposits of DDD. The crossover of ultrastructural findings of C3GN and DDD is understandable as both diseases result from deposition of activated and breakdown fragments of complement factors. The findings are consistent with proteomic profile of C3GN and DDD glomeruli, which shows significant overlap in the composition of deposits.2,3 To highlight the overlap of ultrastructural findings of C3GN and DDD, we show four cases with crossover features. Figure 1a–d shows two cases with predominant features of C3GN with mesangial and numerous capillary wall deposits. However, few loops show typical intramembranous dense deposits of DDD. Figure 1e and f shows two cases with predominant features of DDD with many capillary loops showing intramembranous dense deposits. However, few capillary loops show typical subendothelial electron deposits of C3GN. It appears reasonable to render the diagnosis of C3GN or DDD depending on the predominant ultrastructural finding. DISCLOSURE
All the authors declared no competing interests. 1.
2 microns
2 microns
Figure 1 | Electron microscopy findings of crossover of C3 glomerulonephritis (GN) and dense deposit disease (DDD). Each panel represents one case. Black arrows point to mesangial and capillary wall deposits of C3GN, white arrows point to intramembranous dense deposits of DDD. Top panel. (a) Numerous mesangial and capillary wall deposits and (b) subendothelial and intramembranous deposits seen in C3GN. Few intramembranous electron dense deposits seen in DDD are also present; (a, original magnification × 2500; b, original magnification × 7400). 2nd panel. (c) Numerous mesangial and capillary wall deposits of C3GN and (d) few intramembranous electron dense deposits seen in DDD; (c, original magnification × 6000; d, original magnification × 5000). 3rd panel. (e) Few mesangial and capillary wall deposits of C3GN and (f) numerous typical intramembranous electron dense deposits seen in DDD; (e, original magnification × 2900; f, original magnification × 6800). Bottom panel. (g) Few capillary wall deposits of C3GN and (h) numerous typical intramembranous electron dense deposits seen in DDD; (g, original magnification × 5800; h, original magnification × 500).
form a complex pattern with layers of subendothelial, intramembranous, and subepithelial deposits that is associated with fraying of the glomerular basement membranes.1
1450
Pickering MC, D'Agati VD, Nester CM et al. C3 glomerulopathy: consensus report. Kidney Int 2013; 84: 1079–1089. 2. Sethi S, Gamez JD, Vrana JA et al. Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway. Kidney Int 2009; 75: 952–960. 3. Sethi S, Fervenza FC, Zhang Y et al. C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int 2012; 82: 465–473.
Sanjeev Sethi1, Fernando C. Fervenza2, Richard J.H. Smith3 and Mark Haas4 1 Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; 2Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Department of Internal Medicine, Rochester, Minnesota, USA; 3Molecular Otolaryngology and Renal Research Laboratories, Division of Nephrology, Departments of Internal Medicine and Pediatrics, Carver College of Medicine, Iowa City, Iowa, USA and 4Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA Correspondence: Sanjeev Sethi, Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota 55905, USA. E-mail: [email protected]
Kidney International (2015) 88, 1449–1450; doi:10.1038/ki.2015.313
Kidney International (2015) 88, 1445–1450
6.
Brouard S, Pallier A, Renaudin K et al. The natural history of clinical operational tolerance after kidney transplantation through twentyseven cases. Am J Transplant 2012; 12: 3296–3307. Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 2006; 313: 670–673.
Sophie Brouard
140 MDRD eGFR (ml/min per 1.73m2)
5.
1,2,3
1 INSERM, UMR 1064, Nantes, France; 2CHU de Nantes, ITUN, Nantes, France and 3CIC Biothérapie, Nantes, France Correspondence: Sophie Brouard, INSERM, UMR 1064, 30 Bd Jean Monnet, Nantes 44093, France. E-mail: [email protected]
Kidney International (2015) 88, 1448–1449; doi:10.1038/ki.2015.297
120 100 80 60 40 20
Can ultrasound kidney length qualify as an early predictor of progression to renal insufficiency in autosomal dominant polycystic kidney disease? To the Editor: We read with great interest the article of Bhutani et al.,1 which highlights the prognostic value of ultrasound (US) kidney length (KL) in the CRISP cohort2 of autosomal dominant polycystic kidney disease (ADPKD) patients, which included a selected population of young patients (age 15–46 years) with estimated glomerular filtration rate (eGFR) values over 70 ml/min per 1.73 m2. The authors demonstrated that US KL over 16.5 cm predicts the onset of chronic kidney disease stage 3 within 8 years, and suggest that it could represent an alternative to height-adjusted total kidney volume (HtTKV)3 to assess ADPKD prognosis and enable therapeutic decision making. Although we understand that the US KL threshold proposed by the authors allows anticipating a few years—or months—the eGFR decline in young patients who have a preserved kidney function, the applicability of this prognostic biomarker in the general ADPKD population remains uncertain. Using personal data from the Genkyst cohort,4 we observed that before exceeding this US KL threshold, a significant number of the patients had already eGFR values below 70 ml/min per 1.73 m2 (Figure 1). Furthermore, patients with an eGFR over 70 ml/min per 1.73 m2 and a US KL over 16.5 cm represent a minority of the patients of our cohort. Therefore, we are unsure whether US KL can qualify as an early prognostic biomarker. In addition, Bhutani et al.,1 while referring to HtTKV, argue that it is ‘stronger than and replaces PKD1 genotype’. We previously reported the determinant influence of not only the gene involved (PKD1 vs. PKD2) but also of the type of PKD1 mutation (truncating vs. non-truncating variants).4 To our knowledge, there are currently no data in the literature allowing the authors to draw conclusions on the superiority of HtTKV on this latter prognostic factor. We believe that taking into account patient’s genotype together with imaging data may provide an earlier stratification of the risk of progression to renal insufficiency in ADPKD. Kidney International (2015) 88, 1445–1450
0 10.5 12.5 14.5 16.5 18.5 20.5 22.5 24.5 26.5 28.5 Left kidney length (cm)
Figure 1 | Estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease (MDRD) equation according to ultrasound kidney length (US KL) in 243 non-ESRD patients from the Genkyst cohort who had US KL measurement concomitant to eGFR values. 1.
Bhutani H, Smith V, Rahbari-Oskoui F et al. A comparison of ultrasound and magnetic resonance imaging shows that kidney length predicts chronic kidney disease in autosomal dominant polycystic kidney disease. Kidney Int 2015; 88: 146–151. 2. Grantham JJ, Torres VE, Chapman AB et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354: 2122–2130. 3. Chapman AB, Bost JE, Torres VE et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2012; 7: 479–486. 4. Cornec-Le Gall E, Audrézet M-P, Chen J-M et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol 2013; 24: 1006–1013.
Emilie Cornec-Le Gall1,2 and Yannick Le Meur1,2 1 Service de Néphrologie, Centre Hospitalier Régional Universitaire de Brest, Brest, France and 2Université Européenne de Bretagne, Université de Bretagne Occidentale, Brest, France Correspondence: Emilie Cornec-Le Gall, Department of Nephrology, Brest University Hospital, Brest 29609, France. E-mail: [email protected]
Kidney International (2015) 88, 1449; doi:10.1038/ki.2015.285
Overlap of ultrastructural findings in C3 glomerulonephritis and dense deposit disease To the Editor: C3 glomerulopathy results from dysregulation of the alternative pathway of complement with glomerular deposition of activated and breakdown components of complement system and ensuing glomerular inflammation. On the basis of ultrastructural studies, C3 glomerulopathy is further subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (GN).1 DDD is characterized by dense osmiophilic band-like deposits within the glomerular basement membranes and as rounded deposits in the mesangium. C3GN, in comparison, is typically characterized by subendothelial and mesangial deposits, although intramembranous and subepithelial deposits may also be present. In some cases, the deposits 1449
letter to the editor
a
b
5 µm
c
2 µm
d
5 µm
e
5 µm
f
2 µm
10 µm
g
h
Certain biopsies of C3 glomerulopathy are difficult to label as either DDD or C3GN as there is an overlap in ultrastructural findings, although one pattern may dominate over the other. Thus, while most capillary loops may show the intramembranous dense deposits of DDD, a few loops may show discrete deposits of C3GN. The reverse can also be present, in that the predominant finding are the subendothelial deposits of C3GN, while some loops may show the dense deposits of DDD. The crossover of ultrastructural findings of C3GN and DDD is understandable as both diseases result from deposition of activated and breakdown fragments of complement factors. The findings are consistent with proteomic profile of C3GN and DDD glomeruli, which shows significant overlap in the composition of deposits.2,3 To highlight the overlap of ultrastructural findings of C3GN and DDD, we show four cases with crossover features. Figure 1a–d shows two cases with predominant features of C3GN with mesangial and numerous capillary wall deposits. However, few loops show typical intramembranous dense deposits of DDD. Figure 1e and f shows two cases with predominant features of DDD with many capillary loops showing intramembranous dense deposits. However, few capillary loops show typical subendothelial electron deposits of C3GN. It appears reasonable to render the diagnosis of C3GN or DDD depending on the predominant ultrastructural finding. DISCLOSURE
All the authors declared no competing interests. 1.
2 microns
2 microns
Figure 1 | Electron microscopy findings of crossover of C3 glomerulonephritis (GN) and dense deposit disease (DDD). Each panel represents one case. Black arrows point to mesangial and capillary wall deposits of C3GN, white arrows point to intramembranous dense deposits of DDD. Top panel. (a) Numerous mesangial and capillary wall deposits and (b) subendothelial and intramembranous deposits seen in C3GN. Few intramembranous electron dense deposits seen in DDD are also present; (a, original magnification × 2500; b, original magnification × 7400). 2nd panel. (c) Numerous mesangial and capillary wall deposits of C3GN and (d) few intramembranous electron dense deposits seen in DDD; (c, original magnification × 6000; d, original magnification × 5000). 3rd panel. (e) Few mesangial and capillary wall deposits of C3GN and (f) numerous typical intramembranous electron dense deposits seen in DDD; (e, original magnification × 2900; f, original magnification × 6800). Bottom panel. (g) Few capillary wall deposits of C3GN and (h) numerous typical intramembranous electron dense deposits seen in DDD; (g, original magnification × 5800; h, original magnification × 500).
form a complex pattern with layers of subendothelial, intramembranous, and subepithelial deposits that is associated with fraying of the glomerular basement membranes.1
1450
Pickering MC, D'Agati VD, Nester CM et al. C3 glomerulopathy: consensus report. Kidney Int 2013; 84: 1079–1089. 2. Sethi S, Gamez JD, Vrana JA et al. Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway. Kidney Int 2009; 75: 952–960. 3. Sethi S, Fervenza FC, Zhang Y et al. C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int 2012; 82: 465–473.
Sanjeev Sethi1, Fernando C. Fervenza2, Richard J.H. Smith3 and Mark Haas4 1 Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; 2Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Department of Internal Medicine, Rochester, Minnesota, USA; 3Molecular Otolaryngology and Renal Research Laboratories, Division of Nephrology, Departments of Internal Medicine and Pediatrics, Carver College of Medicine, Iowa City, Iowa, USA and 4Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA Correspondence: Sanjeev Sethi, Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota 55905, USA. E-mail: [email protected]
Kidney International (2015) 88, 1449–1450; doi:10.1038/ki.2015.313
Kidney International (2015) 88, 1445–1450