ADRENAL, HYPERTENSION, RENAL PHYSIOLOGY AND RENAL FAILURE

A More Accurate Method to Estimate Glomerular Filtration Rate From Serum Creatinine: A NewPrediction Equation

A. S. LEVEY, J. P. BOSCH, J. BREYER LEWIS, T. GREENE, N. ROGERS AND D. ROTH, New England Medical Center,Boston, Massachusetts

Ann. Intern. Med., 130: 461–470, 1999

Background: Serum creatinine concentration is widely used as an index of renal function, but thisconcentration is affected by factors other than glomerular filtration rate (GFR).

Objective: To develop an equation to predict GFR from serum creatinine concentration and other factors.Design: Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demo-

graphic and clinical characteristics in patients with chronic renal disease.Patients: 1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease

(MDRD) Study, of whom 1070 were randomly selected as the training sample; the remaining 558 patientsconstituted the validation sample.

Methods: The prediction equation was developed by stepwise regression applied to the training sample.The equation was then tested and compared with other prediction equations in the validation sample.

Results: To simplify prediction of GFR, the equation included only demographic and serum variables.Independent factors associated with a lower GFR included a higher serum creatinine concentration, olderage, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P ,0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFRin the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinineclearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for thisoverestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinineclearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively.

Conclusion: The equation developed from the MDRD Study provided a more accurate estimate of GFR inour study group than measured creatinine clearance or other commonly used equations.

Editorial Comment: The authors developed an equation to predict glomerular filtration ratefrom data on more than 1,500 patients who were enrolled in the Modification of Diet and RenalDisease Study. They compare their equation to the Cockcroft-Gault formula, which is commonlyused to predict glomerular filtration rates for drug dosage alteration. The advantages to thenewly developed equation are that it does not require a time collection or measurement of heightand weight, and it includes a factor for ethnicity. They emphasize that using this equation facili-tates a more accurate assessment of the glomerular filtration rate. Information required includescreatinine, urea and albumin levels, and patient age, sex and ethnicity. The equation is not simpleand requires a calculator. However, the figures to which the glomerular filtration rate measured byiothalamate are compared to serum creatinine provide a nomogram from which the glomerularfiltration rate can be directly read. Once again, these nomograms indicate that a great deal of renalfunction can be lost before creatinine actually becomes abnormal. This finding was more pro-nounced in the elderly and those with little muscle mass. Because of its complexity, I suspect thatthis new formula will not replace the Cockcroft-Gault equation. However, this formula provides amore accurate assessment for those interested.

W. Scott McDougal, M.D.

Gene Transfer in the Kidney

V. RUBIN KELLEY AND V. P. SUKHATME, Renal Divisions, Molecular Autoimmunity, Brigham and Women’sHospital, and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Amer. J. Physiol., 276: F1–F9, 1999

Gene transfer approaches offer the promise of revolutionizing medicine. In this review, we focus on thecurrent and future prospects of somatic gene transfer into the kidney. The advantages and disadvantagesof current vector systems are described, and the ex vivo and in vitro approaches applicable to the kidney arereviewed. We discuss uses of gene transfer approaches to dissect the pathogenesis of kidney disease and thefuture directions and applications of gene transfer to combat kidney destruction.

Editorial Comment: The authors review the various vectors of the state-of-the-art in genetransfer in the kidney, including retroviral, adenoviral and nonviral. The methods of deliveryinclude direct injection into the renal artery or subcapsule, retrograde from the ureter andparenchymal injection. A difficulty in the use of this methodology in the presence of disease isthat delivery may be different for the diseased compared to the normal kidney. In any event ithas enormous potential in the field of transplantation to make the donor kidney compatible forthe recipient, and in cases of autoimmune or polycystic kidney disease when the gene locus hasbeen identified, renal cancer, acute glomerular disease, chronic interstitial diseases and so

ADRENAL, HYPERTENSION, RENAL PHYSIOLOGY AND RENAL FAILURE2228

forth. Although in its infancy, this form of therapy has enormous potential in the future for alltypes of renal disease.

W. Scott McDougal, M.D.

Potentiation of Anti-Cancer Drug Activity at Low Intratumoral pH Induced by the Mitochon-drial Inhibitor m-Iodobenzylguanidine (MIBG) and its Analogue Benzylguanidine (BG)

A. KUIN, M. AALDERS, M. LAMFERS, D. J. VAN ZUIDAM, M. ESSERS, J. H. BEIJNEN AND L. A. SMETS, Departmentof Experimental Therapy, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital andDepartment of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute,Amsterdam, The Netherlands

Brit. J. Cancer, 79: 793–801, 1999

Tumour-selective acidification is of potential interest for enhanced therapeutic gain of pH sensitive drugs.In this study, we investigated the feasibility of a tumour-selective reduction of the extracellular andintracellular pH and their effect on the tumour response of selected anti-cancer drugs. In an in vitro L1210leukaemic cell model, we confirmed enhanced cytotoxicity of chlorambucil at low extracellular pH condi-tions. In contrast, the alkylating drugs melphalan and cisplatin, and bioreductive agents mitomycin C andits derivative EO9, required low intracellular pH conditions for enhanced activation. Furthermore, a strongand pH-independent synergism was observed between the pH-equilibrating drug nigericin and melphalan,of which the mechanism is unclear. In radiation-induced fibrosarcoma (RIF-1) tumour-bearing mice, theextracellular pH was reduced by the mitochondrial inhibitor m-iodobenzylguanidine (MIBG) or its analoguebenzylguanidine (BG) plus glucose. To simultaneously reduce the intracellular pH, MIBG plus glucose werecombined with the ionophore nigericin or the Na1/H1 exchanger inhibitor amiloride and the Na1-dependentHCO3

2/Cl2 exchanger inhibitor 4,49-diisothiocyanostilbene-2,29-disulphonic acid (DIDS). Biochemical stud-ies confirmed an effective reduction of the extracellular pH to approximately 6.2, and anti-tumour responsesto the interventions indicated a simultaneous reduction of the intracellular pH below 6.6 for at least 3 h.Combined reduction of extra- and intracellular tumour pH with melphalan increased the tumour regrowthtime to 200% of the pretreatment volume from 5.7 6 0.6 days for melphalan alone to 8.1 6 0.7 days with pHmanipulation (P , 0.05). Mitomycin C related tumour growth delay was enhanced by the combinedinterventions from 3.8 6 0.5 to 5.2 6 0.5 days (P , 0.05), but only in tumours of relatively large sizes.The interventions were non-toxic alone or in combination with the anti-cancer drugs and did not affectmelphalan biodistribution. In conclusion, we have developed non-toxic interventions for sustained andselective reduction of extra- and intracellular tumour pH which potentiated the tumour responses toselected anti-cancer drugs.

Editorial Comment: I believe that this interesting concept has great merit. The authors use aphysiological approach to alter intracellular pH and, thus, enhance localization of cytotoxicdrugs. From a theoretical point of view it seems important to make the target cell in some wayphysiologically different from its host so that those selective differences may be used to localizedrugs. This approach clearly has been tried with regard to antibody localization and I believethat as cell metabolism is better understood the combination of these manipulations will beimportant to reduce peripheral toxicity and localize chemotherapeutic agents.

W. Scott McDougal, M.D.

Measurement of Glomerular Filtration Rate by the 99mTc-DTPA Renogram is Less Precise ThanMeasured and Predicted Creatinine Clearance

N. G. DE SANTO, P. ANASTASIO, M. CIRILLO, D. SANTORO, L. SPITALI, L. MANSI, L. CELENTANO, D. CAPODICASA, E.CIRILLO, E. DEL VECCHIO, C. PASCALE AND G. CAPASSO, Departments of Nephrology and Nuclear Medicine,Second University of Naples and Department of Nuclear Medicine, Federico II University of Naples,Naples, Italy

Nephron, 81: 136–140, 1999

Permission to Publish Abstract Not Granted

Editorial Comment: Patients with normal renal function and those with renal disease andglomerular filtration rates ranging between 9 and 133 ml. per minute were included in thisstudy. Inulin clearance was used against which measured creatinine clearance, predicted cre-atinine clearance by the Cockroft-Gault formula and a nomogram prediction using diethyl-enetetramine pentaacetic acid (DTPA) were compared. DTPA had the worst correlation, par-ticularly when the glomerular filtration rate was low. It was reasonably accurate whenthe glomerular filtration rate was greater than 100 ml. per minute. Thus, the DTPA determinedglomerular filtration rate is not particularly useful when trying to assess renal function in theimpaired kidney accurately. Creatinine clearance was the most precise of the other tests toassess inulin determined glomerular filtration rate. This information is important for the

ADRENAL, HYPERTENSION, RENAL PHYSIOLOGY AND RENAL FAILURE 2229

clinician to remember when basing decisions, such as nephron sparing surgery, on data fromDTPA scans.

W. Scott McDougal, M.D.

Crystal-Induced Acute Renal Failure

M. A. PERAZELLA, Section of Nephrology, Department of Medicine, Yale University School of Medicine, NewHaven, Connecticut

Amer. J. Med., 106: 459–465, 1999

Several medications—notably acyclovir, sulfonamides, methotrexate, indinavir, and triamterene—areassociated with the production of crystals that are insoluble in human urine. Intratubular precipitation ofthese crystals can lead to acute renal insufficiency. Many patients who require treatment with thesemedications have additional risk factors, such as true or effective intravascular volume depletion andunderlying renal insufficiency, that increase the likelihood of drug-induced intrarenal crystal deposition.Acute renal failure in this setting may be preventable if it is anticipated by appropriate drug dosing, volumeexpansion with high urinary flow, and alkalinization of the urine when appropriate. Renal failure may bereversible if the drug is discontinued, and by volume repletion and alkalinization of the urine whenappropriate. Management of established renal insufficiency includes volume repletion, dialytic support ifnecessary, adjustment of drug doses, and avoidance of further exposure to nephrotoxins.

Editorial Comment: The authors emphasize that drugs such as acyclovir, sulfonamide, meth-otrexate, indinavir and triamterene are associated with the production of crystals which pre-cipitate in urine and may cause intratubular obstruction. Occasionally these crystals may resultin calculi in the collecting system or acute renal failure may develop when they precipitate inthe tubule. Acute renal failure is often accompanied by hypovolemia and patients have otherrisk factors or have received a large bolus of these drugs. Treatment is directed at establishingdiuresis, restoring volume and, in cases of sulfonamides, methotrexate and triamterene use,urine should be alkalized to a level of 7.5 or higher. Each drug and specific therapies are detailedin depth.

W. Scott McDougal, M.D.

Expression of Cell Cycle Inhibitor p27 and Ki-67 in Human Adrenocortical Neoplasms

H. NAKAZUMI, H. SASANO, K. IINO, Y. OHASHI AND S. ORIKASA, Departments of Urology and Pathology, TohokuUniversity School of Medicine, Sendai, Japan

Mod. Path., 11: 1165–1170, 1998

Recent immunohistochemical analysis of cell cycle-related proteins such as p27, a cell cycle inhibitoryprotein, and Ki-67, a proliferation marker, indicated their possible values in predicting the biologic behaviorof various human neoplasms. In this study, we performed an immunohistochemical analysis of p27 andKi-67 in 42 adrenocortical neoplasms (12 adrenocortical carcinomas, 24 adrenocortical adenomas) and 6normal adrenal glands to evaluate their possible values in diagnosing adrenocortical malignancy and inpredicting the biologic behavior of carcinomas. We detected Ki-67 and p27 immunoreactivity in the nucleiof all of our cases, and we observed a significant negative correlation (r 5 20.572, P , .001) between the p27and Ki-67 labeling indexes (LIs). The LIs of p27 and Ki-67 were 61.7 6 2.6 and 0.28 6 0.08 in the normaladrenal cortex and 59.4 6 6.5 and 0.33 6 0.11 in the adenomas, respectively, with no significant differencesbetween the LIs of the adenomas and normal adrenals. The LIs of p27 and Ki-67 in the carcinomas were48.9 6 7.5 and 630 6 6.21, respectively. The LI of p27 in the carcinomas was significantly lower than thatin the adenomas. The LI of Ki-67 in the carcinomas was significantly higher than that in the adenomas(P , .01). Among carcinoma cases, the Ki-67 LI in living cases tended to be lower than that in deceasedcases, and the p27 LI in living cases tended to be higher than that in deceased cases, but these differencesdid not reach statistical significance. These results indicated that decreased p27 protein expression mightcause increased cell proliferation in adrenocortical carcinoma cells in combination with other positive and/ornegative regulators of the cell cycle. These results also suggested that immunohistochemical analysis of p27and Ki-67 might be useful in distinguishing between adrenocortical adenoma and carcinoma.

Editorial Comment: Immunohistochemical analysis was used to identify p27 and Ki-67 mark-ers of the cell cycle to differentiate adenomas and normal adrenal tissue from malignancy.Histological analysis alone may not be able to distinguish between benign and malignantadrenal tissue. The authors observed a significant reduction in p27 and a significant increase inKi-67 in patients with proved adrenal cancers. This information is not new and a number ofstudies have indicated similar findings. However, it is clear to me that as the molecular biologyof such tumors is better understood use of such labeling will allow preemptive adjuvant che-motherapy in highly select patients. Unfortunately, we are not at that point yet.

W. Scott McDougal, M.D.

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