Clinical journal of the American Society of Nephrology : CJASN

The term C3 glomerulopathy describes renal disorders characterized by the presence of glomerular deposits composed of C3 in the absence of significant amounts of Ig. On the basis of electron microscopy appearance, subsets of C3 glomerulopathy include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The full spectrum of histologic change observed in C3 glomerulopathy has yet to be defined and pathologic predictors of renal outcome within this patient population remain largely unknown. This study thus characterized a large C3 glomerulopathy cohort and identified clinicopathologic predictors of renal outcome.

All patients with kidney biopsies fulfilling criteria for C3 glomerulopathy from two quaternary renal centers within the United Kingdom and Ireland between 1992 and 2012 were retrospectively reviewed. We recorded histologic, demographic, and clinical data and determined predictors of ESRD using the Cox proportional hazards model.

Eighty patients with C3 glomerulopathy were identified: 21 with DDD and 59 with C3GN. Patients with DDD were younger, more likely to have low serum C3 levels, and more likely to have crescentic GN than patients with C3GN. Patients with C3GN were older and had more severe arteriolar sclerosis, glomerular sclerosis, and interstitial scarring than patients with DDD. Of 70 patients with available follow-up data, 20 (29%) progressed to ESRD after a median of 28 months. Age >16 years, DDD subtype, and crescentic GN were independent predictors of ESRD within the entire cohort. Renal impairment at presentation predicted ESRD only among patients with DDD.

Although detailed serologic and genetic data are lacking, this study nevertheless identifies important clinicopathologic distinctions between patients with DDD and C3GN. These include independent predictors of renal outcome. If replicated in other cohorts, these predictors could be used to stratify patients, enabling application of emerging mechanism-based therapies to patients at high risk for poor renal outcome.

dense deposit disease (DDD) is the prototypical membranoproliferative glomerulonephritis (MPGN), in which fluid-phase dysregulation of the alternative pathway (AP) of complement results in the accumulation of complement debris in the glomeruli, often producing an MPGN pattern of injury in the absence of immune complexes. A recently described entity referred to as GN with C3 deposition (GN-C3) bears many similarities to DDD. The purpose of this study was to evaluate AP function in cases of GN-C3.

Five recent cases of MPGN with extensive C3 deposition were studied. Renal biopsy in one case exhibited the classic findings of DDD. Three cases showed GN-C3 in the absence of significant Ig deposition; however, the classic hallmark of DDD—dense deposits along the glomerular basement membranes and mesangium—was absent. The remaining case exhibited features of both DDD and GN-C3.

Evidence of AP activation was demonstrable in all cases and included increased levels of soluble membrane attack complex (all cases), positive AP functional assays (four cases), and a positive hemolytic assay (one case). Autoantibodies were found to C3 convertase (two cases) and to factor H (one case). Factor H mutation screening identified the H402 allele (all cases) and a c.C2867T p.T956M missence mutation (one case). Laser microdissection and mass spectrometry of glomeruli of GN-C3 (two cases) showed a proteomic profile very similar to DDD.

These studies implicate AP dysregulation in a spectrum of rare renal diseases that includes GN-C3 and DDD.

There is a disproportionate burden of human papillomavirus (HPV) –related genital tract disease in patients with CKD and kidney transplantation; therefore, the potential effect of the quadrivalent HPV vaccine (Gardasil; Merck GmbH, Darmstadt, Germany) is profound. Immune abnormalities associated with CKD and immunosuppression may prevent optimal vaccine response. Our objective was to determine antibody response to the HPV vaccine in adolescent girls with CKD.

This cohort study conducted from 2008 to 2012 included 57 girls aged 9–21 years old with CKD (n=25), on dialysis (n=9), or with status postkidney transplantation (n=23) who received the standard three–dose vaccine series of the HPV vaccine recruited from two pediatric nephrology clinics. Antibody levels to HPV genotypes 6, 11, 16, and 18 were measured before vaccine dose 1 (baseline), <12 months after vaccine dose 3 (blood draw 2), and ≥12 months after vaccine dose 3 (blood draw 3). Seropositivity was defined as antibody level above an established threshold for each HPV genotype. Not all participants completed three blood draws.

Antibody response to all four HPV genotypes was 100% in the CKD and dialysis groups with samples drawn at <12 and ≥12 months after dose 3 of the HPV vaccine. Among patients with transplants, the percentages of patients achieving seropositivity were significantly lower at blood draw 2 for HPV genotypes 6 (63.6%; P=0.003), 11 (63.6%; P=0.003), and 18 (72.7%; P=0.02) and blood draw 3 for HPV genotypes 6 (62.5%; P=0.02), 11 (50%; P=0.001), 16 (75%; P=0.04), and 18 (50%; P=0.001).

Antibody response to the quadrivalent recombinant HPV vaccine was robust and sustained in girls and young women with CKD and on dialysis. A less robust response to the vaccine was observed among those with a kidney transplant. Additional study is needed to determine if vaccination before kidney transplantation or an alternative vaccination regimen would benefit transplant recipients.

Bone demineralization is frequent in renal-stone formers with hypercalciuria. Although this pathologic link has been recognized for decades, the underlying mechanisms and risk factors associated with osteopenia/osteoporosis in this population remain partially understood.

This study retrospectively analyzed determinants of low bone mineral density (BMD) in 65 idiopathic hypercalciuric male renal-stone formers. Clinical and biologic evaluation included BMD measurement, bone-remodeling markers, analysis of calcium metabolism with oral calcium load test, and dietary inquiry.

Patients with osteopenia (n = 23, 35% of the population) presented significantly higher fasting calciuria as compared with normal bone density patients (n = 42) (calcium/creatinine ratio was 0.32 versus 0.24 mmol/mmol; P = 0.006). Analysis of the whole population revealed a negative association between fasting hypercalciuria and BMD (P = 0.003), independent of confounding variables including body-mass index and tobacco consumption. The fasting calcium/creatinine ratio above 0.25 mmol/mmol was associated with a 3.8-fold increase in the risk of low BMD.

In our study, fasting hypercalciuria after a 2-day calcium-restricted diet appears as the only biologic factor associated with low BMD, suggesting a bone-calcium efflux. Our results support the view of a parathyroid-independent pathologic process that remains to be identified. Hypercalciuric patients with low BMD do not excrete more calcium in 24-hour urine samples than patients without low BMD.

Nephrology fellows often face difficult conversations about dialysis initiation or withdrawal but are frequently unprepared for these discussions. Despite evidence that communication skills are teachable, few fellowship programs include such training. A communication skills workshop for nephrology fellows (NephroTalk) focused on delivering bad news and helping patients define care goals, including end-of-life preferences. This 4-hour workshop, held in October and November 2011, included didactics and practice sessions with standardized patients. Participants were nephrology fellows at Duke University and the University of Pittsburgh (n=22). Pre- and post-workshop surveys evaluated efficacy of the curriculum and measured changes in perceived preparedness on the basis on workshop training. Overall, 14% of fellows were white and 50% were male. Less than one-third (6 of 22) reported prior palliative care training. Survey response rate varied between 86% and 100%. Only 36% (8 of 22) and 38% (8 of 21) of respondents had received structured training in discussions for dialysis initiation or withdrawal. Respondents (19 of 19) felt that communication skills were important to being a “great nephrologist.” Mean level of preparedness as measured with a five-point Likert scale significantly increased for all skills (range, 0.5–1.14; P<0.01), including delivering bad news, expressing empathy, and discussing dialysis initiation and withdrawal. All respondents (21 of 21) reported they would recommend this training to other fellows. NephroTalk is successful for improving preparedness among nephrology fellows for having difficult conversations about dialysis decision-making and end-of-life care.