Referral and comanagement of the patient with CKD.

CKD is a common condition with well-documented associated morbidity and mortality. Given the substantial disease burden of CKD and the cost of ESRD, interventions to delay progression and decrease comorbidity remain an important part of CKD care. Early referral to nephrologists has been shown to delay progression of CKD. Conversely, late referral has been associated with increased hospitalizations, higher mortality, and worsened secondary outcomes. Late referral to nephrology has been consequent to numerous factors, including the health care system, provider issues, and patient related factors. In addition to timely referral to nephrologists, the optimal modality to provide care for CKD patients has also been evaluated. Multidisciplinary clinics have shown significant improvements in other disease states. Data for the use of these clinics have shown benefit in mortality, progression, and laboratory markers of disease severity. However, studies supporting the use of multidisciplinary clinics in CKD have been mixed. Evidence-based guidelines from groups, including Renal Physicians Association and NKF, provide tools for management of CKD patients by both generalists and nephrologists. Through the use of guidelines, timely referral, and a multidisciplinary approach to care, the ability to provide effective and efficient care for CKD patients can be improved. We present a model to guide a multidisciplinary comanagement approach to providing care to patients with CKD.

Potential new therapeutic agents for diabetic kidney disease.

Diabetic nephropathy is the leading cause of end-stage renal disease, and both the incidence and prevalence of diabetic nephropathy continue to increase. Currently, various treatment regimens and combinations of therapies provide only partial renoprotection. It is obvious that new approaches are desperately needed to retard the progression of diabetic nephropathy. Recently, a number of new agents have been described that have the potential to delay the progression of diabetic kidney disease and minimize the growing burden of end-stage renal disease. These include inhibitors and breakers of advanced glycation end products, receptor antagonists for advanced glycation end products, protein kinase C inhibitors, NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase inhibitors, glycosaminoglycans, endothelin receptor antagonists, antifibrotic agents, and growth factor inhibitors. This review addresses these promising new therapeutic agents for delaying the progression of diabetic kidney disease.

Epitope spreading and autoimmune glomerulonephritis in rats induced by a T cell epitope of Goodpasture's antigen.

An amino-terminal region of alpha3 chain of type IV collagen noncollagenous domain [alpha3(IV)NC1] that induces experimental autoimmune glomerulonephritis (EAG) in rats has been identified. Only recombinant antigens that contain a nine-amino acid (AA) span of alpha3(IV)NC1, consistent with a T cell epitope, could induce EAG. It was hypothesized that synthetic peptides of this region should induce EAG. Human and rat peptides of this region were synthesized and rats were immunized to define the nephritogenic epitope. A 13-AA rat peptide induced EAG with proteinuria, decreased renal function, and glomerular basement membrane (GBM)-bound deposits in half of the rats. This peptide induces lymph node cell proliferation and development of antibodies to epitopes of alpha3(IV)NC1 external to the peptide immunogen. Carboxy-terminal extension to 21 amino acids results in all rats' demonstrating anti-GBM antibody and severe EAG. Asparagine at position 19 is critical for EAG induction. None of the 50 rats that were immunized with peptide that contained human sequence with isoleucine at position 19 developed EAG, whereas rat sequence with asparagine 19 induced EAG. Truncation of amino terminal AA of the peptide aborts EAG induction. These studies demonstrate that a T cell epitope of alpha3(IV)NC1 induces lymph node cell proliferation, EAG, and intramolecular epitope spreading; that the length of this peptide influences the formation of anti-GBM antibody; and that the presence of asparagine at position 19 of the peptide is critical to disease induction.

Immunodominant epitopes of alpha3(IV)NC1 induce autoimmune glomerulonephritis in rats.

BACKGROUND: The major Goodpasture antibody binding epitopes have been localized to the amino-terminal third of the noncollagenous domain (NC1) of the alpha3 chain of type IV collagen [alpha3(IV)NC1]. The present study determined whether the same epitopes induce glomerulonephritis in rats. METHODS: We immunized Wistar Kyoto (WKY) rats with human alpha3(IV)/alpha1(IV)NC1 chimeric proteins or full-length recombinant alpha3(IV)NC1 (alpha3732). Chimeric protein constructs were thirds of alpha3(IV)NC1 (CP333) replaced by corresponding sequences of homologous nonreactive alpha1(IV)NC1 (CP111). All chimeric proteins contained 30 amino acids of type X collagen at the amino terminus except alpha3732. Two other constructs, T195 EA (EA) and T194 EB (EB), were entirely alpha1(IV)NC1, except for antibody-immunodominant amino acids from the first and second thirds of alpha3(IV)NC1. RESULTS: Construct immunized animals developed specific antibody responses to recombinant proteins and native human, bovine and rat NC1. CP311 immunized rats, as well as alpha3732 rats, had glomerular IgG, fibrin, and glomerulonephritis with proteinuria by 3 weeks. CP331 produced more severe disease, comparable to positive controls. CP111 produced no disease. EA, but not EB, induced severe glomerulonephritis. Half-dose each of EA plus EB induced disease identical to full-dose EA alone. CONCLUSION: The amino third of alpha3(IV)NC1 which contains the major epitope for Goodpasture antibody binding, also induces glomerulonephritis in rats. The middle third of alpha3(IV)NC1 does not induce glomerulonephritis but appears to enhance disease with the amino terminal third. Finally, the presence of the collagen X leader sequence appears to convey greater nephritogenicity. These studies suggest that not only the nephritogenic epitope itself, but flanking sequences and the conformational context of the nephritogenic epitope may influence its ability to cause glomerulonephritis.

Point mutations of single amino acids abolish ability of alpha3 NC1 domain to elicit experimental autoimmune glomerulonephritis in rats.

We previously showed concordance between Goodpasture syndrome antibody binding and production of experimental glomerulonephritis using human chimeric proteins. We now examine a more limited amino-terminal region of alpha3(IV) non-collagenous domain (NC1) and the impact of single amino acid (AA) mutations of this region on glomerulonephritis induction. Rats were immunized with collagenase-solubilized glomerular basement membrane (csGBM), D3, an alpha1(IV)NC1 chimeric protein with 69 AA of alpha3(IV)NC1 (binds Goodpasture sera), D4, the D3 construct shortened by 4 AA (non-binding), P9, P10, single AA mutants (non-binding), and S2, alpha1(IV)NC1 with 9 AA of alpha3(IV)NC1 (binding). All rats immunized with csGBM and S2 and 50% of D3 rats developed glomerulonephritis. csGBM rats had intense GBM-bound IgG deposits, but S2 and D3 rats had minimal deposits. None of the D4, P9, or P10 rats developed glomerulonephritis. Lymphocytes from nephritic rats proliferated with csGBM, S2, and D3, but not with D4, P9, or P10. Discrete segments of alpha3(IV)NC1 within the alpha1(IV)NC1 backbone can induce glomerulonephritis. Single AA mutations within that epitope render the antigen unresponsive to Goodpasture sera and incapable of inducing glomerulonephritis. These studies support the concordance of glomerulonephritis inductivity and Goodpasture serum binding. Further, they define a critical limited AA sequence within alpha3(IV)NC1 of nine or fewer AA, which confers nephritogenicity to the nonnephritogenic alpha1(IV)NC1 without in vivo antibody binding. This region may be a T-cell epitope responsible for induction of glomerulonephritis in this model in rats and Goodpasture syndrome in man.

Connecting the dots: caring for the patient with progressive CKD.

The approach we take to CKD in the KDIPPP Clinic represents a complicated regimen. It's not something we can do by ourselves, and it requires an integrated team approach. The team approach includes many different individuals all working together (see Fig. 2, p. 25). If we are to be successful, the initiative must include collaboration from the primary care physicians (PCPs), providers, and patients. Patients need to be screened yearly for serum creatinine, blood glucose, and blood pressure if they are at risk for CKD. Creatinine should be expressed as a GFR. Examine the urine to see if it is abnormal and check for microalbuminuria. The PCP, the patient, and the nephrologist must team up to establish the balance of care (see Fig. 3, p. 26). As the CKD patient progresses from the presence of risk factors to CKD Stages 1, 2, 3, and finally 4 and 5, the input from the PCP and the nephrologist gradually changes, from nearly full-time PCP care in the early stages to nearly full-time nephrology team care in the later stages. When patients migrate through progression, prevention, education, access placement, and RRT, the degree of involvement and interaction must be individualized. I recommend follow-up every year or two for patients in CKD Stages 1 and 2; follow-up every six months for Stage 3, and increased nephrology input as CKD progresses. We need to work together to treat these patients. If we do, then we're going to end up with better patient outcomes and better lives. The KDIPPP Clinic has been successful at meeting these goals.