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This Month’s Highlights

	Basic Science Articles

Top Basic Science Articles Clinical Science Articles

Regulation of 11 -HSD2 via Purinergic Pathways.

Role of Protein Kinase X in Kidney Development.

Protein kinase X (PRKX) is a cAMP-dependent protein kinase that is distinct from protein kinase A (PKA). PRKX is highly expressed in the branching ureteric bud of the fetal kidney but is absent in the adult kidney, which suggests that it might play an important role in kidney development. To test this hypothesis, Li et al. expressed constitutively active PRKX in mouse embryonic kidney culture. Overexpression of PRKX stimulated the branching of the ureteric bud and induced an increased number of glomeruli. PRKX also stimulated the migration of human fetal collecting duct cells in a modified Boyden chamber assay. These results suggest that PRKX plays an important role in epithelial cell migration and branching morphogenesis during kidney development. Moreover, the expression of PRKX is abnormally increased in autosomal dominant polycystic kidney disease (ADPKD). It is tempting to speculate that V2 vasopressin receptor antagonists that inhibit cAMP-dependent signaling and that are being considered as potential treatments for ADPKD may exert their salutary effects through inhibition of PRKX. See Li et al., pages 3543–3552.

Complement Inhibition in Lupus Nephritis—Can C5a Be a Target?

Traditional views of the immunopathogenesis of glomerular diseases such as lupus nephritis recognize complement as the principal mediator of antibody-induced tissue injury and ascribe two roles to complement activation: the generation of leukocyte chemotactic factors such as C5a leading to neutrophil recruitment, and the formation of C5b-9, which activates resident glomerular cells. In this study, Wenderfer and colleagues extend this view by developing and studying the spontaneous development of lupus nephritis in MRL^lpr mice bred to be deficient in C5a receptor function. The C5aR-deficient mice are dramatically protected from nephritis despite no reduction in glomerular complement deposits, apparently due to a newly appreciated role for C5a signaling in the T helper cell response and a deficient Th-2, or cell-mediated, immune response. These findings not only extend our understanding of the multiple roles complement activation is playing in glomerulonephritis, but also raise the tantalizing prospect of targeting C5a receptors as an approach to therapy in lupus nephritis. See Wenderfer et al., pages 3572–3582.

Kidney Scarring—It Can Go Away!

Once scarred, you remain so for life, right? The study reported by Cochrane et al. in this issue of JASN suggests otherwise. In both human and experimental kidney diseases there are already several examples of reversible extracellular matrix expansion. But scarring implies that collagen deposition is also associated with structural damage and functional impairment. In the kidney, tubular damage is especially critical. Tubules are able to self-renew after short-duration ischemia/necrosis, but undergo irreversible atrophy with sustained injury that ensues with fibrosis. This study suggests that tubules (perhaps along with extrarenal progenitor cells) retain their regenerative potential for much longer than previously recognized. When a mouse ureter was occluded for one week and then released (a challenging technical procedure due to the tenuous ureteral blood supply), serial observations over the next six weeks showed a progressive decline in interstitial collagen levels that was associated with remarkable restoration of outer medullary tubules and glomerular filtration. Exactly how the interstitial matrix was remodeled and intact nephrons were restored are fertile areas for further investigation. See Cochrane et al., pages 3623–3630.

	Clinical Science Articles

Top Basic Science Articles Clinical Science Articles

 
Interstitial Nephritis in Hereditary Systemic Amyloidosis.

Hereditary systemic amyloidosis refers to a heterogenous group of rare autosomal dominant disorders that are caused by mutations in certain plasma proteins, such as transthyretin, apolipoprotein A-I (apoA-I), apoA-II, and fibrinogen. The mutations cause misfolding and aggregation of the proteins, which results in their deposition as amyloid fibrils in visceral organs, including the kidney, liver, and heart. Gregorini et al. studied five unrelated Italian families with systemic amyloidosis due to a Leu75Pro missense mutation in exon 4 of the apoA-I gene. Kidney biopsies showed the accumulation of amyloid exclusively in the medullary interstitium rather than in glomeruli and blood vessels, which distinguishes this disorder from typical systemic amyloidosis. Clinically, the affected individuals presented with signs of tubulointerstitial nephritis. Although the mechanism is unclear, this entity is unlikely to be specific for this mutation because a deletion/insertion mutation of exon 4 of apoA-I has also been reported to produce medullary amyloidosis in a Spanish family. Hereditary systemic amyloidosis should be considered in patients presenting with interstitial nephritis, hepatomegaly, and a positive family history. See Gregorini et al., pages 3680–3686.

Genes or Environment or Both?

The report by Tillin et al. and the accompanying editorial by Ramirez in this issue of JASN remind us that the ethnic differences in risk of CKD and ESRD are observed throughout the world’s populations and regions. This report examined the association between albumin excretion rates and ethnicity among a diverse population of Europeans, South Asians, and African-Caribbeans living in the United Kingdom. Tillin and colleagues observed substantial ethnic variations in both the prevalence of proteinuria and its association with subsequent risk of cardiovascular disease. These observations serve to remind us of the utility of study designs that compare disease associations across geographic regions comprising different ethnic populations, among ethnic groups within a single region, and between migrant and nonmigrant ethnic groups. When these contrasts demonstrate differences in disease prevalence, they engender hypotheses directed at environmental and biologic factors associated with ethnicity and place of residence. For example, Tillin et al. speculate that the differences that they observed may reflect variable susceptibility to the metabolic syndrome and hyperinsulinemia among different ethnic groups. This question, like other possible explanations for these observations, needs to be answered by carefully designed studies that will sort out the factors that contribute to these ethnic variations in risk. This information is essential if we are to intelligently address the worldwide epidemic of kidney disease. See Tillin et al., pages 3702–3710.

A Cure for Uremic Pruritis.

Uremic pruritis is a commonly encountered, frustrating problem that has defied successful therapy. In this issue of JASN, Wikstrom and colleagues report that Nalfurafine, a -opioid receptor agonist, can dramatically improve uremic itching in randomized, double-blind, placebo-controlled studies. Improvements in excoriations and sleep disturbances were also noted. Observed side effects were minimal. Is Nalfurafine a long-sought-after solution for this problem? See Wikström et al., pages 3742–3747.—

A Benefit for Statins in CKD.

The high expectations for a cardioprotective role of lipid-lowering therapy with statins for patients with kidney disease were recently dealt a setback with the publication of the 4D Study results (N Engl J Med 353: 238–248, 2005), which reported that prevalent hemodialysis patients randomly assigned to receive 20 mg of atorvastatin daily had comparable cardiovascular outcomes to untreated patients. Tonelli and his colleagues report in this issue of JASN that, in secondary analyses of three large clinical trials of pravastatin, a cardioprotective benefit of statin therapy was observed among diabetic individuals and those with chronic kidney disease. Of interest is that both Tonelli et al. [1.12 (0.63, 1.97)] and the 4D investigators [1.21 (0.81, 1.55)] reported a nonsignificant increased risk for stroke-related events with statin therapy among diabetic patients with kidney disease. These results serve to remind us that extrapolation of clinical trial results to individuals with chronic kidney disease is not necessarily straightforward. See Tonelli et al., pages 3748–3754.

Related Articles

Renal Structural and Functional Repair in a Mouse Model of Reversal of Ureteral Obstruction

Anita L. Cochrane, Michelle M. Kett, Chrishan S. Samuel, Naomi V. Campanale, Warwick P. Anderson, David A. Hume, Melissa H. Little, John F. Bertram, and Sharon D. Ricardo
J. Am. Soc. Nephrol. 2005 16: 3623-3630. [Abstract] [Full Text] [PDF]

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