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This Month's Highlights

	Basic Science Articles

Top Basic Science Articles

MDCK Cells, CsA, and TGF-.

Nephron Number, Adult Hypertension, and Postnatal Nutrition.

The roles of prenatal and postnatal nutrition on development of nephron number and hypertension are important topics. Wlodek et al. examined these issues in a rat model of uteroplacental insufficiency induced by ligation of the maternal uterine blood vessels. Three groups of rats were studied: control, restricted maternal uteroplacental blood flows, and rats from litters that were reduced to be equal to the restricted group. Offspring (control, reduced and restricted) were cross-fostered onto a control (normal lactation) or restricted mother with impaired lactation. Restricted-on-restricted male offspring developed a nephron deficit (–26%) and glomerular hypertrophy, along with hypertension (+16 mmHg) by 20 wk. Restricted offspring with access to normal lactation had improved postnatal growth, improved nephron number, and normal blood pressure. This study identifies prenatal and postnatal nutritional impact on the programming of adult hypertension and for the first time shows that correcting growth restriction during lactation can restore a prenatal nephron deficit. See Wlodek et al., pages 1688–1696.

Next Steps Toward an Anti-CKD Therapeutic Cocktail?

Inhibition of angiotensin-II and/or its receptor has been shown in numerous animal and human studies to confer significant renoprotection, yet the overall impact on the natural history of human chronic kidney disease (CKD) has been relatively modest. Vitamin D analogs, in use for many years to treat renal osteodystrophy, are making a comeback as agents that may also diminish renal scarring. Using a rat 5/6 nephrectomy model, Mizobuchi et al. report in this issue of JASN that combined therapy with enalapril and paricalcitol for four months more effectively preserved renal structure and function than either drug used alone. An important observation, the paricalcitol effect was observed using a dose that altered serum calcium levels. Although much remains to be learned about the mechanism of action of paricalcitol as an antifibrotic drug, it appears to act synergistically with an angiotensin-converting enzyme inhibitor to block monocyte chemoattractant protein-1–associated renal inflammation and Smad2-associated TGF- signaling. See Mizobuchi et al., pages 1796–1806.

Differential Binding of Chemokines by Kidney Cells.

Renal inflammation is often restricted to either tubulointerstitium or glomerular structures, but how this is mediated remains poorly understood. Because cell recruitment toward sites of inflammation is in part mediated by chemokines with chemoattractant properties and because kidney cells are capable of presenting chemokines on their surfaces, Segerer and colleagues hypothesized that differential binding of chemokines to various renal structures may influence the character of the inflammatory response. This group developed an in vitro assay for assessing binding of a prototypic chemokine CCL5 to archived kidney tissue sections. They found that CCL5 binds to endothelial, tubular, and interstitial tissue in well-preserved kidneys, but binds well only to glomerular tissues with acute glomerulonephritis. Through mutagenesis experiments the authors provide evidence that the binding requires two clusters of basic amino acids found in the N-terminus of the CCL5 molecule. The results provide a potential mechanism for differential recruitment of inflammatory cells into glomerular versus tubulointerstitial compartments of the kidney. See Segerer et al., pages 1835–1844.

ACEI in Young People with IgA Nephropathy—The Data Are Finally In.

The importance of evidence from carefully conducted randomized controlled trials to guide therapy has never been more apparent for nephrologists interested in the rational evidence-based practice of medicine. In this issue of JASN, Coppo and her colleagues provide an important contribution for our understanding of the therapy of IgA nephropathy, the most common glomerular disease in the world. They have conducted a multicenter, randomized, placebo-controlled, double-blind trial of an angiotensin-converting enzyme inhibitor therapy of progressive nephropathy in children and young people with IgA nephropathy. They report that the primary outcome measured as a 30% decrease of CrCl was reached in 3.1% of the treatment group and 14.7% of the placebo group, a quite acceptable NNT (number needed to treat) of 10 patients. Similar benefit was noted for secondary outcomes that included measures of proteinuria. The authors remind us that their carefully designed, conducted, and reported trial suffers, as do all clinical trials, from inevitable limitations that clinicians should consider as they seek to apply this evidence in their practice. Perhaps the most important limitation, unfortunately, is that, despite the importance of the disease to nephrology practice and the centrality of renin-angiotensin-aldosterone system blockade to contemporary care of progressive kidney disease, we have had to wait so long for this trial and are left to wonder when similar, hopefully supporting, evidence will be available. See Coppo et al., pages 1880–1888.

Mutation Screening in Primary Hyperoxaluria.

Primary hyperoxaluria (PH) is an autosomal recessive disorder that produces hyperoxaluria, calcium oxalate kidney stones, and progressive renal failure. Type 1 PH (PH1) is caused by mutations in the hepatic enzyme alanine:glyoxylate aminotransferase (AGT). Monico and her colleagues at the Mayo Clinic sequenced the entire gene encoding AGT, AGXT, in 55 individuals with biopsy-proven PH1. This series of patients is the largest reported to date. The mutation detection rate was very high at 98%. Of the 21 new mutations identified, many were missense mutations (amino acid substitutions), which can be difficult to distinguish from polymorphisms. Using a combination of chemical differences, evolutionary conservation, and absence in a normal control population, Monico et al. were able to distinguish potentially pathogenic mutations from polymorphisms. These findings suggest that direct DNA sequencing may be a useful approach to diagnosis of PH1 and may eliminate the need for liver biopsy. See Monico et al., pages 1905–1914.

ACEI and Nondiabetic Chronic Kidney Disease.

The role of renin-angiotensin-aldosterone system (RAAS) blockade in the management of nonproteiuric chronic kidney disease (CKD) remains an area of uncertainty. The patient-level meta-analysis reported by Kent and his associates in this issue of JASN offers additional evidence that these agents are renal-protective even during the earliest stages of nondiabetic kidney disease. The authors combined data from 11 randomized clinical trials where angiotensin-converting enzyme inhibitor (ACEI) therapy was compared with other antihypertensive therapy. They report a consistent benefit of ACEI across all levels of predicted risk of progressive CKD and again noted a significant interaction between degree of proteinuria and ACEI benefit. Of note, there was no benefit of ACEI therapy if proteinuria was <500 mg/d. One concern is how to square these results, which are consistent with earlier meta-analyses of ACEI benefit for both diabetic and nondiabetic kidney disease, with those reported recently for the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study. As the authors point out, ALLHAT enrollment criteria selected for the very population of nondiabetic low-proteinuric population that was least likely to benefit from ACEI therapy. Although these observations won't resolve the uncertainty raised by ALLHAT about the benefit of RAAS blockade in nondiabetic kidney disease, they provide clear guidance for the next generation of clinical trials of kidney protection for these agents and support their continued inclusion in the care of patients with CKD. See Kent et al., pages 1959–1965.

Mycophenolate versus Azathiaprine and Long-Term Kidney Transplant Outcomes.
Mycophenolate mofetil (MMF) use has largely replaced azathiaprine (AZA) in kidney transplantation because of results from several well-performed studies in the 1990s that indicated a decreased incidence of acute rejection on MMF. The results from the Mycophenolate Steroid Sparing (MYSS) trial published in 2004 revealed that, when used in conjunction with cyclosporine microemulsion, rejection rates were similar at 21 months in the MMF- and the AZA-treated groups. In this issue of JASN, Remuzzi et al. provide long-term follow-up on 248 of the patients in the original MYSS trial. All measured outcomes, including mean GFR, GFR slopes, mortality, graft loss, and late rejection were not different between the two groups. In light of the equivalency of the long-term outcomes and the significantly higher cost of MMF over AZA, the authors suggest that AZA may be a better choice for standard immunosuppression regimens in kidney transplant recipients. See Remuzzi et al., pages 1973–1985.

Related Articles

IgACE: A Placebo-Controlled, Randomized Trial of Angiotensin-Converting Enzyme Inhibitors in Children and Young People with IgA Nephropathy and Moderate Proteinuria

Rosanna Coppo, Licia Peruzzi, Alessandro Amore, Antonio Piccoli, Pierre Cochat, Rosario Stone, Martin Kirschstein, Tommy Linné on behalf of the EC Biomed Concerted Action Project BMH4-97-2487(DG 12-SSMI) and IgACE European Collaborative Group
J. Am. Soc. Nephrol. 2007 18: 1880-1888. [Abstract] [Full Text] [PDF]

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