This Month’s Highlights

Cell and Transport Physiology

Low Tonicity Mediates a Downregulation of Cyclooxygenase-1 Expression by Furosemide in the Rat
Renal Papilla
Diuretic Resistance Clarified—A Role for Prostaglandins. Oral furosemide, even when taken
dutifully by the patient at home, often becomes progressively less effective, requiring higher doses
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or intravenous administration. Studies by Craig Brater and others have shown that resistance results
from alterations both in gastrointestinal absorption and in upregulation of NaCl transporters in the
distal convoluted tubule and cortical collecting duct. In this issue, Castrop and co-workers propose
yet another mechanism. Furosemide reduced the medullary interstitial tonicity of rats which, in turn,
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decreased medullary cyclooxygenase-1 and -2 expression. Since PGE2 in the inner medulla de-
creases NaCl resorption by the medullary thick ascending limb and the medullary collecting duct, antagonizes the hydroosmotic
action of vasopressin, and increases vasa recta blood flow, furosemide-induced reduction in PGE2 synthesis would reduce
natriuresis and diuresis. This is furosemide resistance. It remains to be seen whether free water restriction, by raising medullary
tonicity, would permit furosemide once again to benefit the edematous patient.

Immunology and Pathology

Transcription Factor IRF-1 in Kidney Transplants Mediates Resistance to Graft Necrosis during Rejection
A Transcription Factor Protects from Allograft Rejection. Interferon-gamma is an important
cytokine that plays key functions in innate and antigen-specific immunity. However, recent evidence
clearly suggests that interferon-gamma may have a dual function. It has been demonstrated that
IFN-gamma is important in limiting T cell proliferation and promoting T cell apoptosis. In
experimental kidney transplantation, IFN-gamma has been shown to be important in resistance to
host effector mechanisms that result in ultimate graft destruction. The manuscript by Afrouzian et
al. is an extension of those studies and highlights the important role of the transcription factor IRF-1
in donor tissue resistance to injury. Similar to IFN-gamma, IFR-1 confers protection during acute
renal allograft rejection mainly by protecting the microcirculation and preventing epithelial cell
necrosis. The exact mechanisms of how these effects are mediated remain unclear and require further investigations. The studies
have important clinical implications for understanding the mechanisms of graft rejection and for potentially developing novel
therapeutic strategies to prevent graft rejection.

Molecular Medicine, Genetics and Development

A Novel Approach to the Pathogenesis of Active Minimal Change Nephrotic Syndrome Using Subtracted cDNA
Library Screening
T Cells and Minimal Change Nephrotic Syndrome—Another Piece of the Puzzle. Despite
its frequency as a cause of idiopathic nephrotic syndrome, the pathogenesis of minimal change
nephrotic syndrome continues to defy elucidation. Over a quarter of a century ago Shalhoub
proposed that it represented a disorder of T-cell function. Several investigators have since described
circulating permeability factors of uncertain origin and identity in patients with a related disorder,
idiopathic focal glomerulosclerosis, and even in some cases of minimal change. However, the results have
been inconsistent. In this paper by Sahali advantage is taken of the techniques of subtractive cloning and
differential screening to compare gene expression in T-cell-enriched peripheral blood mononuclear cells
in a single patient during both relapse and remission. Of 42 known transcripts which differed, 18 were
related to T-cell signaling. While subject to the obvious reservations of any study in one patient, the
results provide yet another piece of evidence linking T-cells and the TH2 phenotype to minimal change
nephrotic syndrome (See also editorial by Cunard and Kelley on pp 1409 –1411).

Pathophysiology of Renal Disease

Selective Cyclooxygenase-2 Inhibition Impairs Glomerular Capillary Healing in Experimental Glomerulonephritis
Another Role for Cox-2 in Kidney Diseases—A Link to Angiogenesis. The topic of angio-
genesis is getting considerable press in the biomedical world with central roles proposed in diseases
from cancer to resolving acute glomerulonephritis. The rapidly expanding understanding of the
effects of COX-2 inhibitors is here linked to angiogenesis in the kidney by Kitahara, et al., who
demonstrate that administration of two different selective cyclooxygenase-2 (COX-2) inhibitors each
impairs the capillary healing response in the rat anti-Thy 1 model of glomerular injury. This
 observation adds to recent evidence that COX-2 inhibition may have an anti-angiogenic effect. COX-2 inhibition has also been
shown to reduce inflammation. These complex and apparently non-complementary activities of COX-2 inhibitors (i.e.,
suppression of inflammation and impairment of angiogenesis, a key component of the healing response to wounds), if
substantiated in humans, are likely to have significant, but not yet predictable, consequences in inflammatory renal injuries
occurring in patients taking these widely prescribed pharmaceutical agents.

Dialysis
Riboflavin Is a Determinant of Total Homocysteine Plasma Concentrations in End-Stage Renal Disease Patients
Riboflavin, Homocysteine and Atherogenesis—A New Therapeutic Insight? Elevated ho-
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mocysteine levels are observed in more than 90% of ESRD patients and are associated with
increased risk of arteriosclerotic cardiovascular disease. Determinants of plasma homocysteine
levels include plasma levels of folate, cobalamin, vitamin B-12, pyridoxal phosphate and vitamin
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B(6), as well as methylenetetrahydrofolate reductase (MTHFR) polymorphisms. While folate,

vitamin B(6) and vitamin B(12) supplementation normalize plasma homocysteine levels among
patients with normal renal function, supraphysiological doses of these vitamins usually fail to do so
among ESRD patients. The reasons for this folate-resistance are poorly understood. The cross-sectional study of the association
between riboflavin, a cofactor for MTHFR, and homocysteine levels in 54 peritoneal dialysis patients provides additional insight
into this problem. They report for the first time that riboflavin, measured as red blood cell availability, is independently associated
with plasma homocysteine levels in an ESRD population. If these observations were supported in other ESRD populations, it
would be reasonable to conduct clinical trials to examine the role of riboflavin supplementation as a means of lowering
homocysteine levels in folate-replete ESRD patients.

Epidemiology and Outcomes

Prevalence of Low Glomerular Filtration Rate in Nondiabetic Americans: Third National Health and Nutrition
Examination Survey
Measuring GFR—Don’t Throw away Those 24-Hour Jugs Yet! Efforts to delay the pro-
gression of kidney disease depend on the ability of clinicians to identify mild degrees of impaired
renal function and to apply effective interventions during the early phases of renal injury. It has been
recognized for some time that measurement of serum creatinine, particularly in older individuals, is
often not elevated in the presence of mild-to-moderate decreases in GFR. Further, direct measure-
ment of GFR is expensive and technically beyond the capacity of clinical practice, while measure-
ment of creatinine clearance is often inaccurate and difficult to complete in day-to-day practice.
These limitations have led to the development of estimating equations that use serum creatinine and
other patient characteristics to estimate the GFR, and there are recommendations that one or more
of these equations be used to identify individuals with early renal disease. The article by Clase et al.
has important ramifications for the appropriateness of these recommendations. They used NHANES
III data to apply four different GFR estimating equations to determine the prevalence of chronic kidney disease in the US
population. Their main result is that strikingly different estimates of impaired renal function are obtained depending on the
equation employed and that the MDRD and Crockcoft-Gault equations result in estimates of 58% and 39% of the adult US
population with abnormal renal function. These results raise an important issue as to the appropriateness of derived estimates of
GFR as a guide to public policy or clinical algorithms for screening for kidney disease in the general population. The results also
suggest that it may be premature to abandon quantitative urine collection as a means of estimating renal function in clinical
practice. Clearly additional investigation is needed before we can unconditionally rely on one or more estimating equation to
identify individuals who would benefit from aggressive interventions to preserve renal function. This caveat is not a call for
therapeutic nihilism. Individuals at risk for kidney disease, including those with hypertension and family members of patients
with ESRD, should be periodically screened for impaired renal function using serum creatinine, appropriate estimating equations
and 24-hr creatinine clearance, and evidence of impaired renal function should lead to appropriate interventions. In contrast, the
response to a low GFR observed in a low-risk individual remains to be determined, and watchful waiting may be appropriate.

Refining Predictive Models in Critically Ill Patients with Acute Renal Failure
A New Way to Predict Outcome of Acute Renal Failure in the ICU. Developing and using
decision support tools is a key component of evidence-based renal medicine. The study by Ravi
Mehta and his colleagues from the Project to Improve Care in Acute Renal Disease (PICARD)
reports the development of a new tool to predict risk of death among ICU patients with acute renal
failure. Risk stratification equations help clinicians develop a prognosis by combining clinical and
laboratory information into information about the likelihood of a subsequent outcome such as
survival. The scale described by the PICARD study group provides a summary score based on
patient characteristics at the time of onset of treatment, including age, sex, BUN and creatinine levels, urine output, heart rate
and measures of hematologic, liver and pulmonary functions. The resulting score was highly predictive of mortality and predicted
 risk of death better than did either generic severity-of-disease indices like APACHE III or previously reported acute renal failure
severity-of-illness scales. Before the PICARD score can be reliably used clinically, additional validation studies in other
populations are needed. To this end the authors have provided us their full model to facilitate the replication of their results.

Transplantation
Withdrawal of Cyclosporine or Prednisone 6 Months after Kidney Transplantation in Patients on Triple
Drug Therapy
Can We Safely Take Patients off Some Transplant Drugs? Minimizing the toxicity of
calcineurin inhibitors and/or steroids is the current trend in immunosuppression in kidney trans-
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plantation. The approval of new potent immunosuppressive agents, such as mycophenolate mofetil
and rapamycin, allows transplant professionals to test whether this trend is safe and effective. In this
issue of the journal Gregoor et al. report the results of a multicenter randomized trial to compare
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cyclosporine versus steroid withdrawal under the cover of mycophenolate mofetil. The results
highlight the risks and benefits of calcineurin inhibitors withdrawal: higher incidence of rejection but
better renal function. Steroid withdrawal was associated with better control of blood pressure and
lipid abnormalities but without an increased risk of rejection. Interestingly, at two years all groups had similar graft survival. It
is also important to compare and contrast this study with the recently published report by Johnson et al. (Transplantation 2001;
72:777) where rapamycin was used instead of mycophenolate mofetil followed by randomization to cyclosporine withdrawal. In
that study there was a slightly increased risk of rejection, but there was significant improvement in blood pressure control and
renal function in the cyclosporine-withdrawal group.