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This Month’s Highlights

Salt, Water, and Cell Protective Mechanisms—Some New Information.

Water channels participate in transepithelial water flow and in the cellular response to stresses caused by changes in the external milieu. In this issue, Umenishi et al. explore the adaptive responses to challenges with increasing bathing sodium chloride (NaCl) concentrations. An optimal increase in water channels was seen with 100 mM NaCl, but higher concentrations were toxic with actual losses of water channels due to degradation. The medullary interstitial components include hypertonic NaCl as well as other organic solutes, including urea and betaine. To some extent, these other solutes seemed to protect the cells from the deleterious effects of high NaCl concentrations. Heat shock also protected the cells, a response that is well described and is mediated by heat-shock proteins that serve a general protective role. While the latter approach may not have immediate clinical utility, the understanding of the protective role of the various interstitial constituents does have practical implications. See Umenishi et al., pages 600–607.

Nephronophthisis Genes in the Roundworm.

In last month’s issue of JASN, Maureen Barr described the use of the roundworm Caenorhabditis elegans as a model for human renal disease. Another example from Friedhelm Hildebrandt’s group shows how experiments in C. elegans can be used to study nephronophthisis, an autosomal recessive disorder that causes renal failure in children. C. elegans expresses homologues of two nephronophthisis genes, NPHP1 and NPHP4. Hildebrandt’s group found that the homologous genes were expressed in ciliated sensory neurons in the head and tail of the worm. This finding is interesting because homologues of genes that cause polycystic kidney disease (PKD) and Bardet-Biedl syndrome are also expressed in ciliated sensory neurons. Moreover, knockdown of the NPHP1 and NPHP4 homologues resulted in abnormal mating behavior, similar to the knockout of the PKD homologues. These results raise the possibility that the nephronophthisis and PKD genes may function in a common evolutionarily conserved pathway. See Wolf et al., pages 676–687.

Toxic Acute Renal Failure-—DNAse I Does It.

The article by Basnakian et al. is related to and compliments the paper by Iwasaki et al. (see pages 658–666) regarding toxic acute renal failure induced by cisplatin. The authors explore the underlying mechanism of cisplatin nephrotoxcity at a molecular level. In this study, Basnakian and colleagues in Little Rock follow up on their earlier studies demonstrating a role for the predominant renal endonuclease, DNAse I, in hypoxic tubular injury by showing that mice that have had the gene for this enzyme knocked out are dramatically protected from cisplatin-induced nephrotoxicity, both functionally and morphologically. These knockout animals also exhibit an accompanying reduction in DNA fragmentation in tubular cells, the presumed mechanism by which this enzyme causes cell injury and death. These data are an important contribution not only to understanding the mechanisms involved in this form of acute renal failure but in suggesting a way to approach preventing it to benefit the many patients who receive cisplatin in chemotherapeutic protocols. See Basnakian et al., pages 697–702.

The Prediabetic State—A Window of Opportunity for Intervention?

Recent intervention studies in diabetic patients suggest that the earlier renin-angiotensin system (RAS) blockade is begun, the greater the renoprotective benefit. This conclusion is obvious if one compares the percent of risk reduction in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA2) study with the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy Trial (IDNT) studies. The Benedict trial further documented that in nonmicroalbuminuric diabetic patients RAS blockade prevents the onset of microalbuminuria in a substantial proportion of patients. Even this is topped by the article from Nagai et al. in this issue that shows that—at least in the rat—RAS blockade in the prediabetic stage by an angiotensin-converting enzyme inhibitor, an angiotensin receptor blocker, or their combination (but not nonspecific BP lowering) ameliorates indices of renal damage when diabetes finally supervenes, as if the kidney preserved a memory of past RAS blockade. This observation calls for a study in prediabetic humans: If humans resemble rats (a disgusting thought), a similar outcome would certainly have repercussions on the selection of antihypertensive agents for the not uncommon hypertensive patient with metabolic syndrome. See Nagai et al., pages 703–711.

What Are T Cells Doing in Septic Acute Renal Failure?

Previous studies, as well as this study by Singbartl et al., document a role for neutrophils in mediating sepsis-associated acute renal failure. There have also been a few studies implicating T cells in ischemic acute renal failure, although the mechanisms involved are unclear. In this article, Singbartl and colleagues compare neutrophil-dependent, endotoxin-induced acute renal failure in normal mice and animals that lack CD28, a major T cell–associated, co-stimulatory molecule implicated primarily in antigen-driven immune responses. The data show that CD28-deficient animals are rather dramatically protected from renal neutrophil infiltration and endotoxin-induced acute renal failure despite the apparent absence of T cells from the kidney. The effect is associated with a reduction in circulating KC, a neutrophil-specific chemokine, suggesting a plausible mechanism for the role of T cells in this process. We do not conventionally think of T cells as therapeutic targets in acute renal failure, but these findings suggest that they should be added to the list of mediators to explore. See Singbartl et al., pages 720–728.

Clinical Science

Suicide—A Preventable Cause of Mortality in ESRD Patients?
The article by Kurella et al. addresses the problem of suicide in the ESRD program. Sparked by an unfortunate case briefly described, the authors examined USRDS and other national data files to determine the relative rates of suicide among ESRD patients compared with the general population. Overall, suicide-related death rates were 84% higher in ESRD than in the general population, with substantial demographic and regional variation. Older individuals, men, nonblacks, persons with a history of alcohol or drug dependence, and persons with prior hospitalization for mental illness were at particularly increased risk. In contrast, withdrawal from dialysis was associated with less striking regional variation and differences by gender; comorbidity played a much larger role. Using these data, patients at high risk (>2% per year) for death due to suicide can be identified. This report should be shared with dialysis unit social workers and Medical Directors; lives may be saved by suicide prevention efforts. See Kurella et al., pages 774–781.

Effective, but Does It Matter in the Long Run?

Cinacalcet, an oral calcimimetic, is a new therapeutic agent for secondary hyperparathyroidism that increases the sensitivity of calcium-sensing receptors to calcium and reduces parathyroid hormone (PTH) secretion. The use of this, or any therapy, ideally should be based on evidence like that provided by Lindberg and her colleagues in this issue of JASN. Lindberg et al. conducted a multicenter, randomized, placebo-controlled, double-blind study that evaluated the efficacy and safety of cinacalcet therapy for hyperparathyroidism in 395 hemodialysis and peritoneal dialysis patients. During short-term treatment, cinacalcet effectively reduced PTH levels and had an acceptable safety profile. While these results clearly support the short-term use of cinacalcet, important questions about the efficiacy of this agent in reducing the morbidity and mortality associated with secondary hyperparathyroidism in CKD patients, including reduction of cardiovascular calcification, remain unanswered and await appropriately designed clinical trials. See Lindberg et al., pages 800–807.

Are Pretransplant Cardiac Evaluations Enough?

One of the major challenges in renal transplantation is the increased risks of cardiovascular disease and premature death. Indeed, premature death is the most common cause of renal allograft loss, and cardiovascular disease is the most common cause of death posttransplant. Thus, understanding the risks and developing evaluation and preventive strategies are key to improving renal transplant outcomes. In this observational study, Gill et al. made two important and interesting, and even unexpected, observations. First, the increased risk is perioperative; and second, noninvasive surveillance while on the waiting list may not be predictive. The implication is that periodic surveillance of cardiovascular risk while awaiting a transplant may be unnecessary. Of course, such a conclusion can and should be reached only after a prospective study, but the current study is an eye-opener on an important disease in renal transplant recipients. See Gill et al., pages 808–816.

Related Articles

Expression and Phenotype Analysis of the Nephrocystin-1 and Nephrocystin-4 Homologs in Caenorhabditis elegans

Matthias T.F. Wolf, Jeeyong Lee, Franziska Panther, Edgar A. Otto, Kun-Liang Guan, and Friedhelm Hildebrandt
J. Am. Soc. Nephrol. 2005 16: 676-687. [Abstract] [Full Text] [PDF]

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