commentary
the hospitalization should implement appropriate hospitalization timing and include orders for home care if needed (Figure 1). Most of all, however, they should be responsible for timely transmitting of the information necessary for providing the post-hospital care to the managing nephrologist. The hospital has the resources to provide this information in a timely manner, particularly to small, remote dialysis units that presumably do not have a transitions coordinator. Detailed instructions should be provided for the managing physician as well as for the home care nursing team including discharge diagnosis, medications, and special precautions. Improving communication with these postdischarge health care providers may improve health care delivery and patient outcomes, and thereby potentially reduce hospital readmission rates. Postdischarge care should be entirely the responsibility of the nephrologist, and not of the dialysis center. Only the consultant nephrologist could implement the assessment of the dry weight, order medication reconciliations, and, if necessary, reassess the status of the acute illness that has prompted the hospitalization. Early visits to the managing physician after a hospitalization have been shown to decrease the rehospitalization rate.6,7 A carve-out payment to incentivize early postdischarge care is more likely to be successful than a penalty. There has been an outcry against the penalization of dialysis units for hospitalization when the dialysis unit has no direct role in preventing it.8,9 The only help that an outpatient dialysis center could provide is a transitions coordinator, but this position is not always available and/or affordable. He or she could obtain hospitalization and discharge information and help coordinate an early postdischarge nephrologist visit. Ideally, this role would be created with support of the conditions for coverage for dialysis facilities and adjustment to reimbursement. In this issue of the journal, Plantinga et al.4 present another argument against penalizing the dialysis unit for readmissions. I agree with the authors that additional studies of the factors 790
necessary to prevent readmissions in dialysis patient are necessary. There may also be concerns that this penalty and policy may spur dialysis providers to “cherry pick” healthier patients who may be less likely to be rehospitalized. In the meantime, the current legislation should be sent back to the drafting board.
3.
4.
DISCLOSURE
The author declared no competing interests.
5.
ACKNOWLEDGMENTS
ES is supported by a career development award from the Office of Research and Development of the Department of Veterans Affairs (IK2CX001266-01). The opinion expressed in this commentary is the sole responsibility of the author and in no way should be seen as official policy or interpretation by the US Department of Veterans Affairs or the US government.
6.
7.
8.
REFERENCES 1. Centers for Medicare & Medicaid Services. Hospital Readmissions Reduction Program. 42. 2013;CFR part 412 (x412.150 through x412.154). 2. Centers for Medicare & Medicaid Services. Endstage renal disease prospective payment
9.
system, quality incentive program, and durable medical equipment, prosthetics, orthotics, and supplies: final rule. Fed Register. 2014;79(315). Desai NR, Ross JS, Kwon JY, et al. Association Between Hospital Penalty Status Under the Hospital Readmission Reduction Program and Readmission Rates for Target and Nontarget Conditions. JAMA. 2016;316: 2647–2656. Plantinga LC, King L, Patzer RE, et al. Early hospital readmission among hemodialysis patients in the United States is associated with subsequent mortality. Kidney Int. 2017;92:934–941. Graham KL, Wilker EH, Howell MD, Davis RB, Marcantonio ER. Differences between early and late readmissions among patients: a cohort study. Ann Intern Med. 2015;162:741–749. Erickson KF, Winkelmayer WC, Chertow GM, Bhattacharya J. Hemodialysis Hospitalizations and Readmissions: The Effects of Payment Reform. Am J Kidney Dis. 2017;69:237–246. Tung YC, Chang GM, Chang HY, Yu TH. Relationship between Early Physician FollowUp and 30-Day Readmission after Acute Myocardial Infarction and Heart Failure. PLoS One. 2017;12:e0170061. Fishbane S, Wish JB. Quality Measurement in Wonderland: The Curious Case of a Dialysis Readmissions Measure. Clin J Am Soc Nephrol. 2016;11:190–194. Wish JB. The role of 30-day readmission as a measure of quality. Clin J Am Soc Nephrol. 2014;9:440–442.
Complement factor H–related proteins in IgA nephropathy—sometimes a gentle nudge does the trick Joshua M. Thurman1 and Jennifer Laskowski1 Complement activation probably contributes to glomerular inflammation and damage in IgA nephropathy. In this issue, 2 groups report that levels of factor H–related protein 1 are elevated in patients with IgA nephropathy and correlate with disease progression. These studies provide new evidence that the complement cascade is important to the pathogenesis of this disease. These results also suggest that factor H–related protein 1 levels may be useful for identifying those patients at high risk of disease progression. Kidney International (2017) 92, 790–793; http://dx.doi.org/10.1016/j.kint.2017.05.025 Copyright ª 2017, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical investigations on pages 942 and 953 1 Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA
Correspondence: Joshua M. Thurman, Division of Nephrology and Hypertension, B-115, 1775 Aurora Court, M20-3103, Aurora, Colorado 80045, USA. E-mail:
[email protected]
I
gA nephropathy (IgAN) is the most common primary glomerular disease worldwide, and there are not currently any specific therapies for the disorder. Research has revealed that most patients with IgAN have abnormal Kidney International (2017) 92, 782–795
commentary
Kidney International (2017) 92, 782–795
is associated with protection from IgAN.6,7 This SNP (rs6677604) tags the deletion of FHR1 and FHR3. It has a frequency of 0.23 in Europeans and is strongly protective for the development of IgAN. Presumably, the deletion of FHR1 leads to greater control of the alternative pathway by factor H and less complement activation in the glomeruli of patients with IgA1-containing immune complexes (Figure 1). In the current issue of Kidney International, 2 groups further explore the link between the complement FHRs and IgAN. Based on the observation that the deletion of FHR1 is protective for IgAN, the authors of both studies hypothesized that increased expression
injury. Conversely, mutations that increase the affinity of the FHRs for tissue surfaces cause them to inhibit factor H and promote alternative pathway dysregulation. Following this logic, increased expression of FHR proteins should have a similar dysregulating effect on the alternative pathway. Because the alternative pathway is activated in the glomeruli of patients with IgAN, one can infer that factor H and the FHRs modulate the severity of this disease. Several unbiased genetic studies support such a connection between factor H, the complement FHRs, and IgAN. Genome-wide association studies, for example, have found that a single nucleotide polymorphism (SNP)
CRP Mesangial cell C Matrix
En do th e
glycosylation within the hinge region of IgA1 molecules, and the altered sugar side chains lack a terminal galactose. The absence of galactose apparently makes the molecules antigenic, and affected patients form IgG or IgA autoantibodies that react with this region of the IgA1 molecule.1 IgA1-containing immune complexes then deposit in the mesangium and are believed to cause glomerular inflammation and injury. As in other forms of immunecomplex glomerulonephritis, IgA1containing glomerular deposits in IgAN activate the complement cascade. C3 is codeposited with IgA in the biopsies of 90% of patients with IgAN. Although plasma C3 levels are usually within the normal range, complement activation fragments, which are sensitive markers of activation, are frequently elevated.2 Mesangial C3 deposits3 and elevated complement activation products2 also predict IgAN progression, indicating that the complement system is an important mediator of kidney injury in the disease. IgA immune complexes can activate the alternative pathway of complement. This pathway has also been implicated in the pathogenesis of other kidney diseases, including atypical hemolytic uremic syndrome and C3 glomerulopathy. A plasma protein called factor H is a potent regulator of the alternative pathway and is critical for controlling complement activation within the kidney. Defects in factor H function, such as mutations or inhibitory autoantibodies, are strong risk factors for both atypical hemolytic uremic syndrome and C3 glomerulopathy. Another group of proteins called the complement factor H–related proteins (FHRs) also affect the risk of developing these kidney diseases.4 Although the function of the FHRs is incompletely understood, there is experimental evidence that FHR1, FHR2, and FHR5 competitively inhibit factor H.5 Genetic deletion of FHR proteins leaves factor H unopposed and potentiates its ability to control alternative pathway regulation and reduce the severity of inflammatory
ell lc lia
IgA1containing immune complexes
Gd IgA1
Anti-IgA1 antibody
Factor H Podocyte FHR1
GBM
Figure 1 | Complement activation in the glomeruli of patients with IgA nephropathy. Galactose-deficient IgA1 (Gd IgA1) or IgA1-containing immune complexes bind to mesangial cells and deposit in the mesangial matrix of patients with IgA nephropathy, activating the complement system. Factor H is a plasma protein that controls alternative pathway activation in the mesangium and attenuates injury. Factor H–related protein 1 (FHR1) is another plasma protein that is a competitive antagonist of factor H and can increase complement activation. In the current issue of Kidney International, 2 studies show that FHR1 levels are higher in patients with IgA nephropathy than in healthy controls, and elevated FHR1 levels correlate with worse clinical outcomes. C, complement activation; CRP, complement regulatory protein; GBM, glomerular basement membrane.
791
commentary
of the protein would adversely affect the course of disease. Medjeral-Thomas et al. (2017) studied 294 patients with IgAN.8 They found that levels of FHR1 protein in patients with IgAN and 2 copies of the CFHR1 gene are higher than levels in healthy controls and the same copy number. In IgAN patients a high FHR1/factor H ratio is associated with more rapid disease progression. The authors also measured FHR5 concentrations and found that levels of this protein correlated with histologic severity, although it did not predict disease progression. Tortajada and colleagues (2017) measured FHR1 levels in 112 patients with IgAN and 46 patients with polycystic kidney disease.9 They too found that FHR1 levels were higher in IgAN patients compared with healthy controls. By multivariate analysis, FHR1 levels, serum creatinine, and tubulointerstitial fibrosis all predicted progressive disease. Both of these studies found that FHR1 levels correlated with the estimated glomerular filtration rate, suggesting that reduced glomerular filtration rate causes accumulation of the protein. The progression of kidney disease in polycystic kidney disease did not correlate with FHR1 levels, however. Thus, accumulation of FHR1 may be common to many different kidney diseases, but is probably only physiologically important in complement-mediated diseases such as IgAN. Based on our current understanding of the FHRs, their most likely role in IgAN is to modulate alternative pathway activation in the mesangium by antagonizing factor H. Decreased expression or deletion of FHR1 thereby results in greater control of complement activity by factor H and protection against the disease, whereas increased expression of FHR1 increases complement dysregulation. Several additional proteins also likely affect the overall degree of complement activation in the glomeruli. The abundance of immune complexes and their IgG content are important. Factor H levels and polymorphisms as well as the expression of other complement
792
regulatory proteins on mesangial cells may also affect disease severity. In other words, there are complement activators (immune complexes), there are complement inhibitors (factor H), and there are also inhibitors of the inhibitors (FHRs). Although the current studies do not provide specific evidence of increased complement activation in IgAN patients with elevated FHR1 levels, it has previously been reported that deletion of the CFHR1 and CFHR3 genes is associated with decreased glomerular C3 deposition and lower C3a levels in the plasma. These new studies improve our understanding of IgAN in several important ways. First, they provide additional evidence that the complement system is important to the progression of the disease. Case reports suggest that therapeutic complement inhibition may be effective for treating some patients with rapidly progressive IgAN. Measurement of FHR1 levels may now help investigators identify those patients most likely to progress or most likely to benefit from complement inhibition, and could potentially stratify patients for enrollment in a clinical trial of a complement inhibitory drug. The inverse correlation of FHR1 levels with decreased glomerular filtration rate also reveals a mechanism by which renal failure of any cause may secondarily exacerbate complement-mediated diseases. Retention of FHR1 may progressively reduce the efficacy of factor H at controlling the alternative pathway. This could be a mechanism by which renal failure exacerbates inflammatory kidney diseases as well as complement-mediated diseases outside of the kidney. Finally, it is worth noting that native FHR1 has a fairly low affinity for factor H–binding ligands. Although it might be a minor player in the overall degree of complement regulation/dysregulation acutely, the results of these studies indicate that the role of FHR1 in disease progression over time is significant. And if small changes in the concentration of a weak antagonist to factor H can lead to clinically significant changes
in IgAN, then it also stands to reason that a modest increase in alternative pathway regulation could reverse this process and lead to improvements in the course of the disease. This reversal could be accomplished by therapies that block or reduce FHR1, or that increase the concentration of factor H within the mesangium. Such approaches might enable clinicians to subtly shift the balance of complement regulation/dysregulation in the patient’s favor. The primary risk of therapeutic complement inhibitors is infection. For a fulminant disease such as atypical hemolytic uremic syndrome, the risk of infection is clearly outweighed by the benefits of complement inhibition. On the other hand, even a low risk of infection hinders the use of complement inhibitors for chronic diseases that entail long-term treatment. For these diseases it may make more sense to “nudge” the complement system in the right direction rather than to completely block activation. Although the functional activity of the FHRs alone is fairly weak, this weakness may turn out to be an advantage insofar as they provide an opportunity for finetuning of the complement system over the long term. A light touch might be all that is needed. DISCLOSURE
JMT receives royalties from Alexion Pharmaceuticals, Inc. The other author declared no competing interests.
ACKNOWLEDGMENTS
This work was supported by National Institutes of Health Grants R01 DK076690 (JMT). REFERENCES 1. Suzuki H, Fan R, Zhang Z, et al. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest. 2009;119:1668–1677. 2. Zwirner J, Burg M, Schulze M, et al. Activated complement C3: a potentially novel predictor of progressive IgA nephropathy. Kidney Int. 1997;51:1257–1264. 3. Kim SJ, Koo HM, Lim BJ, et al. Decreased circulating C3 levels and mesangial C3 deposition predict renal outcome in patients with IgA nephropathy. PloS One. 2012;7:e40495.
Kidney International (2017) 92, 782–795
commentary
4. Gale DP, de Jorge EG, Cook HT, et al. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet. 2010;376:794–801. 5. Goicoechea de Jorge E, Caesar JJ, Malik TH, et al. Dimerization of complement factor Hrelated proteins modulates complement activation in vivo. Proc Natl Acad Sci U S A. 2013;110:4685–4690. 6. Gharavi AG, Kiryluk K, Choi M, et al. Genomewide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011;43: 321–327.
7. Kiryluk K, Li Y, Sanna-Cherchi S, et al. Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis. PLoS Gen. 2012;8:e1002765. 8. Medjeral-Thomas NR, Lomax-Browne HJ, Beckwith H, et al. Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy. Kidney Int. 2017;92:942–952. 9. Tortajada A, Gutiérrez E, Goicoechea de Jorge E, et al. Elevated factor H-related 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy. Kidney Int. 2017;92:953–963.
APOL1 and blood pressure changes in young adults Girish N. Nadkarni1 and Steven G. Coca2 APOL1 risk variants have been shown to be associated with kidney disease and hypertension. In this study, Chen and colleagues assess the association of these risk variants with longitudinal blood pressure in young adults. We review the current literature on association of these alleles with blood pressure and propose future directions to resolve the existing controversies. Kidney International (2017) 92, 793–795; http://dx.doi.org/10.1016/j.kint.2017.05.030 Copyright ª 2017, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical investigation on page 964
A
frican Americans (AAs) are affected by various kidney diseases, including focal segmental glomerulosclerosis, hypertensionattributable kidney disease, and HIV-associated nephropathy, in greater proportion than other ethnicities.1 The discovery of apolipoprotein L1 (APOL1) variants in African Americans has significantly enhanced our understanding of ethnic disparities in kidney disease. These G1 (2 missense variants in nearly complete linkage disequilibrium) and G2 (6-base pair deletion) alleles in the last exon of the APOL1 gene confer resistance to lethal Trypanosoma 1 Icahn School of Medicine at Mount Sinai, New York, New York, USA; and 2Mount Sinai Hospital, New York, New York, USA
Correspondence: Girish N. Nadkarni, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1243, New York, New York 10128, USA. E-mail:
[email protected]
Kidney International (2017) 92, 782–795
brucei infections in Sub-Saharan Africa, resulting in their considerably higher frequency in individuals of African ancestry. The APOL1 risk genotype (2 copies of G1 or G2 or 1 copy each of G1 and G2) has been associated with progression of nondiabetic chronic kidney disease in AAs.2 Recent data have shown that transgenic APOL1 murine models express a kidney phenotype of glomerulosclerosis and foot process effacement, demonstrating that the expression of the APOL1 risk genotype may be causal for podocyte derangement.3 Thus, there is emerging evidence that a substantial proportion of the ethnic disparities in kidney disease and end-stage renal disease between AAs and other ethnicities may be explained by differences in the APOL1 risk genotype (up to 14% in populations of African ancestry but <0.5% in populations of European ancestry).
However, in addition to kidney disease, there are other significant disparities by which AAs are affected. One of the most prominent among these is blood pressure and hypertension. There are significant ethnic differences both in the incidence and prevalence of hypertension, with diagnosis occurring earlier in life and at higher frequency in AAs compared with other ethnicities.4 AAs have a higher mortality from, and earlier onset of, hypertension complications, including stroke and cardiac disease.5 Finally, the divergence between blood pressure traits appears early in life. According to National Health and Nutrition Examination Survey (NHANES) data, the average systolic and diastolic blood pressures in young AAs (18–39 years of age) are 4 mm Hg and 2 mm Hg higher, respectively, compared with European Americans in the same age group.6 Although socioeconomic differences are very important, estimates indicate that a large proportion of blood pressure traits are heritable and thus have genetic underpinnings. The genetics of hypertension have so far been elusive. Except for a few rare monogenic disorders with a large effect size, most of the common genetic loci identified for blood pressure and hypertension have been of very small effect size and only explain 2% of heritability and variation in hypertension. Considering the Guytonian view of hypertension that long-term changes in blood pressure are inextricably linked to sodium handling by the kidney, it is a logical next step to explore whether APOL1 risk alleles, which are strongly linked to kidney disease, are associated with blood pressure and its changes over time. Chen and colleagues7 (2017) explore the association of APOL1 renal risk alleles and longitudinal blood pressure in young adults without overt kidney dysfunction using elegant methodology in a well- phenotyped longitudinal cohort, the CARDIA (Coronary Artery Risk Development in Young Adults) study. Leveraging 25 years of follow-up data and using linear mixed-effects and latent class modeling, they
793