Basic Science Articles
Another Addition to the Spectrum of Bartter Syndrome.
Bartter syndrome is a recessive genetic disorder associated with reduced NaKCl2 co-transporter activity and is associated with severe salt wasting, usually in the perinatal period. In this issue of JASN, Pressler et al. describe two brothers who presented with hyperuricemia, metabolic alkalosis, hypokalemia, and bilateral medullary nephrocalcinosis at the age of 13 and 15 yr. Impaired NaCl reabsorption along the thick ascending limb was inferred from responsiveness to furosemide. Genetic analysis revealed that both boys were compound heterozygotes for mutations in the SLC12A1 gene coding for the NaKCl2 co-transporter. Functional analysis of these mutants in the Xenopus oocytes expression system revealed significant residual transport activity of the NKCC2 p.F177Y mutant and no activity for the NKCC2-D918fs frameshift mutant. However, co-expression of the two mutants was not significantly different from that of NKCC2-F177Y alone. The partial function of NKCC2-F177Y explains this mild, late-onset phenotype in these brothers and thereby expands the spectrum of Bartter syndrome. See Pressler et al., pages 2136–2142.
ILK—Another Player in Disorders of the Podocyte.
Integrin-linked kinase (ILK) is an intracellular serine/threonine kinase that received its name because it was found to interact with the cytoplasmic domains of integrins and to mediate the integrin signaling in diverse types of cells. ILK also interacts with numerous cytoskeletal-associated proteins. Dysregulation of ILK expression has been implicated in proteinuric states, but the role of ILK in podocyte biology has not previously been determined. In a study published in this issue of JASN, Dai et al. utilized a Cre-loxP system to delete ILK selectively from podocytes and found that not only did the animals develop heavy proteinuria and progressive glomerulosclerosis, but that there also was aberrant podocyte distribution of nephrin and α-actinin 4. In further studies, the authors demonstrated that ILK directly complexed with these slit diaphragm–associated proteins. Therefore, ILK may link integrins and slit diaphragm proteins in the podocyte. Abnormalities in ILK may contribute to proteinuric disorders of the podocyte. See Dai et al., pages 2164–2175.
A Role for ADMA in the Hypertension of CKD.
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). ADMA is increased in patients with chronic kidney disease (CKD) and by inhibiting NOS contributes to their hypertension. The precise mechanism underlying ADMA accumulation in these patients is not fully understood. In their report in this month’s JASN, Matsuguma et al. investigated this issue in a rat remnant kidney model. Plasma ADMA levels were elevated in rats in proportion to the reduction in renal mass and correlated with systolic BP levels. Moreover, enhanced expression of an ADMA-metabolizing enzyme by gene transfer reduced the rats’ BP and reduced plasma and urinary ADMA levels. These results suggest that ADMA levels are increased in CKD due to loss of its metabolizing enzyme, associated with reduction of renal mass, thus contributing to hypertension in CKD patients. Enhancement or induction of ADMA metabolizing activity represents a novel therapeutic strategy for the treatment of CKD-related hypertension. See Matsugama et al., pages 2176–2183.
Can Stem Cells Repair the Injured Glomerulus?
In immune glomerular diseases, acute injury is followed by progression or resolution determined by factors that are incompletely understood. For diseases of the mesangium such as IgA nephropathy, lupus nephritis, and MPGN, the ATS model of mesangial injury induced by antibody to mesangial cells allows both mesangial injury and repair to be studied. Injury involves an initial phase of mesangial lysis followed by proliferation of mesangial cells that repair the glomerulus. In this study, Kunter et al. re-examine the injury and recovery phase of the ATS model with intrarenal infusion of mesenchymal stem cells (MSC) superimposed. They find that the MSC localize in the injured mesangium, where they greatly reduce injury and accelerate repair, although they do not themselves seem to transform into glomerular cells. The findings, although unexplained, are provocative and should lead to more studies to define what these cells are doing in the damaged glomerulus and how that can be translated into therapy. See Kunter et al., pages 2202–2212.
Clinical Science Articles
Surprises from Sickle Cell Disease.
Sickle cell anemia is associated with a spectrum of kidney injury that is poorly understood. In this issue of JASN, Guasch and his colleagues examined the prevalence and severity of albuminuria among a large cohort of patients with hemoglobinopathies, including 184 patients with sickle cell anemia. Some degree of albuminuria was present in two thirds of patients with sickle cell anemia and a third of those with other hemoglobinopathies; albuminuria was independent of the degree of anemia. The authors also report that one fifth of patients with sickle cell anemia had some degree of chronic kidney disease. The prevalence of albuminuria and chronic kidney disease observed by Guasch et al. is higher than previously reported. If this observation is confirmed in other populations and shown to be a risk factor for progressive chronic kidney disease, as in other kidney diseases, the management of sickle cell anemia–associated nephropathy will play an increasing role as more of these patients survive into later adulthood. See Guasch et al., pages 2228–2235.
Anemia, CKD, and CVD—Does More Hemoglobin Help?
The association between anemia and increased risk of cardiovascular disease (CVD) in chronic kidney disease (CKD) is poorly understood. Clinical trials that examine the reduction in CVD risk associated with anemia correction in individuals with CKD have been disappointing, generally finding no cardioprotective benefit of hemoglobin levels above those currently considered to be the standard of care. The report by Walker et al. in this issue of JASN is consistent with this threshold effect. During three years of follow-up they noted, after controlling for level of serum creatinine and other characteristics, that hemoglobin lower than 12 to 12.9 g/dl was associated with increased risk of coronary heart disease, stroke, heart failure, and progression to ESRD, but above that level of hemoglobin no benefit, and perhaps increased risk, was noted for coronary heart disease and stroke, while increasing protection was observed for heart failure. These observations suggest that hemodynamic and metabolic perturbations that influence disease processes in different vascular beds may vary with hemoglobin level. See Walker et al., pages 2293–2298.
Trial of Exercise Training and Nandrolone on Muscle Function in Hemodialysis Patients.
Hemodialysis patients frequently experience progressive muscle wasting and weakness, which has a negative effect on physical functioning, quality of life, and overall morbidity and mortality. Current therapeutic options with proven efficacy to reverse muscle wasting are limited. In this issue of JASN, Johansen and colleagues report the results of a randomized clinical trial comparing the actions of the anabolic steroid nandrolone decanoate and resistance exercise training on body composition and muscle function in a cohort of 79 hemodialysis patients. The primary outcomes in this carefully conducted trial were changes in lean body mass, quadriceps muscle area, and knee extensor muscle strength. The use of nandrolone decanoate (but not resistance exercise training) resulted in a significant increase in lean body mass. Both exercise and nandrolone contributed to an increase in quadriceps muscle mass. Exercise was associated additionally with an improvement in self-reported physical functioning. This important study is one of the largest carefully conducted, randomized trials examining interventions designed to improve physical performance in hemodialysis patients. Further studies, perhaps adding nutrition to an exercise and anabolic steroid intervention, may someday make uremic muscle wasting a treatable condition. See Johansen et al., pages 2307–2314.
Association of IL-6 Gene Polymorphism with Posttransplant Diabetes.
New-onset diabetes after transplantation (NODAT) occurs in up to 35% of kidney transplant recipients and is associated with increased mortality and graft loss. Risk factors include obesity, increased age, African-American or Hispanic ethnicity, hepatitis C virus infection, and the use of corticosteroids and calcineurin inhibitors. Certain HLA haplotypes have also been associated with NODAT, but the studies are contradictory. In a retrospective analysis of 217 kidney transplant recipients, Bamoulid and colleagues found an association between a G/C polymorphism in the IL-6 gene promoter and the risk of NODAT. GG homozygotes, particularly those who were overweight, had increased circulating IL-6 levels, increased insulin resistance, and higher incidence of NODAT as compared with CC homozygotes. The association between the GG genotype and increased risk of NODAT was verified in an independent, prospective study of 132 patients. Although these findings must be confirmed in larger populations, they suggest that a proinflammatory state promotes NODAT. Genotyping may be useful in the future for individualizing therapy in patients who are at increased risk for posttransplant diabetes. See Bamoulid et al., pages 2333–2340.
