Geraldine C. Derby

Chronic injury of human renal microvessels with low-dose cyclosporine therapy

Physiologic and morphologic techniques were used to study kidneys of cardiac transplant recipients treated with either low-dose (low-CsA) or high-dose (high-CsA) cyclosporine. After 12 months both low-CsA (4.6 +/- 0.4) and high-CsA (6.3 +/- 0.3 mg/Kg/24 hr, p less than 0.01) were associated with azotemia and hypertension; GFR with each regimen was depressed below values in a third group treated without CsA (no-CsA) by 40-47%, while corresponding renal vascular resistance was elevated greater than 2-fold (P less than 0.01). Morphologic changes in both CsA groups included an obliterative arteriolopathy with downstream collapse or sclerosis of glomeruli. Determination of renal arcuate vein occlusion pressure revealed an increasing renal artery-to-peritubular capillary pressure gradient between 1 and 12 months of CsA therapy. Fractional clearances of dextrans of graded size were elevated at each time compared with the no-CsA group. Analysis of dextran transport with an isoporous membrane model indicates that transglomerular hydraulic pressure difference (delta P) approximated 39 with no-CsA, but was reduced with low-CsA therapy to about 30 at 1 month, and about 34 mmHg after 12 months. We conclude that chronic CsA therapy induces constriction and eventual occlusion of afferent arterioles, causing downstream glomerular damage that is irreversible. Low versus high dosage of CsA confers only marginal protection against this serious microvascular injury.

Surgery for ventricular tachycardia: efficacy of left ventricular aneurysm resection compared with operation guided by electrical activation mapping.

Sixty-five patients underwent surgery for recurrent ventricular tachyarrhythmias. The 32 patients in group 1 underwent simple left ventricular aneurysm resection. The 33 patients in group 2 underwent myocardial resection or incision guided by intraoperative mapping of the electrical activation sequence. The clinical, hemodynamic and angiographic characteristics of the two groups were similar. Although actuarial survival in the two groups was similar through 24 months, late attrition in group 1 patients has left only 21 i 13% (± SEM) alive by life-table analysis at 94 months. Arrhythmia recurrence has been greater in group I than in group 2. In group 1, 50 ± 9% at I month and 56 ± 9% of patients at risk at 3 months had recurrences by actuarial analysis. In group 2, only 13 ± 6% at 1 month, 17 ± 7% at 3 months and 29 ± 9% at 24 months relapsed. Death was caused by ventricular tachyarrhythmias in 12 of the 17 patients (71%) who died in group 1, but only three of 12 (25%) who died in group 2. We conclude that surgery of the left ventricle, guided and modified by intraoperative mapping of the electrical activation sequence, frequently eliminates ventricular tachyarrhythmias and may be more effective than blind resection of left ventricular aneurysm.

The diuretic properties of dopamine in patients after open-heart operation.

Dopamine and dobutamine were administered to 12 patients who had undergone open cardiac operations. To eliminate the effects of variation in systemic blood flow upon renal function the drug infusion rates were adjusted to achieve equal cardiac outputs. Under conditions of equivalent systemic pressure and flow, dopamine (5.0 ± 1 μg · kg-1 · min-1) and dobutamine (3.5 ± 1.8 μg · kg-1 · min-1) had similar effects upon glomerular filtration rate (90 ± 29 vs. 83 ± 27 ml · min-1 · 1.73 m-2) and effective renal plasma flow (375 ± 119 vs. 357 ± 126 ml · min-1 · 1.73 m-2). However, dopamine administration resulted in a significantly greater diuresis (2.8 ± 2.7 vs. 1.0 ± 0.3 ml/min), natriuresis (0.32 ± 0.39 vs. 0.07 ± 0.10 mEq Na+/min), and kaliuresis (0.15 ± 0.06 vs. 0.10 ± 0.03 mEq K+/min) (P < 0.05). In patients with modest depression of cardiac performance and renal vasoconstriction, dopamines selective renal vasodilator effects were not evident. Furthermore, these data suggest that dopamine inhibits tubular solute reabsorption directly. Thus, the diuresis and natriuresis that frequently accompany dopamine administration may occur independently of any effects of dopamine upon renal blood flow.

Effects of aging on glomerular function and number in living kidney donors

To elucidate the pathophysiologic changes in the kidney due to aging, we used physiological, morphometric, and imaging techniques to quantify GFR and its determinants in a group of 24 older (≥ 55 years) compared to 33 younger (≤ 45 years) living donors. Mathematical modeling was used to estimate the glomerular filtration coefficients for the whole kidney (K(f)) and for single nephrons (SNK(f)), as well as the number of filtering glomeruli (N(FG)). Compared to younger donors, older donors had a modest (15%) but significant depression of pre-donation GFR. Mean whole-kidney K(f), renocortical volume, and derived N(FG) were also significantly decreased in older donors. In contrast, glomerular structure and SNK(f) were not different in older and younger donors. Derived N(FG) in the bottom quartile of older donors was less than 27% of median-derived N(FG) in the two kidneys of younger donors. Nevertheless, the remaining kidney of older donors exhibited adaptive hyperfiltration and renocortical hypertrophy post-donation, comparable to that of younger donors. Thus, our study found the decline of GFR in older donors is due to a reduction in K(f) attributable to glomerulopenia. We recommend careful monitoring for and control of post-donation comorbidities that could exacerbate glomerular loss.

Action of drugs in patients early after cardiac surgery: I. comparison of isoproterenol and dopamine

Dopamine and isoproterenol were each administered in two different doses to 12 patients with coronary artery disease in the period immediately after open heart surgery. The two doses of dopamine resulted in respective increases in cardiac output of 23 and 43 percent and reductions in systemic vascular resistance of 23 and 32 percent; neither dose significantly altered heart rate. The two doses of isoproterenol caused respective increases of 23 and 37 percent in cardiac output and 18 and 28 percent in heart rate and reductions in systemic vascular resistance of 22 and 29 percent. We conclude that lack of chronotropic effect of dopamine as compared with isoproterenol may make the former the agent of choice in patients requiring inotropic agents for their care in the early period after cardiac surgery.

Longitudinal study of living kidney donor glomerular dynamics after nephrectomy

BACKGROUND Over 5,000 living kidney donor nephrectomies are performed annually in the US. While the physiological changes that occur early after nephrectomy are well documented, less is known about the long-term glomerular dynamics in living donors. METHODS We enrolled 21 adult living kidney donors to undergo detailed long-term clinical, physiological, and radiological evaluation pre-, early post- (median, 0.8 years), and late post- (median, 6.3 years) donation. A morphometric analysis of glomeruli obtained during nephrectomy was performed in 19 subjects. RESULTS Donors showed parallel increases in single-kidney renal plasma flow (RPF), renocortical volume, and glomerular filtration rate (GFR) early after the procedure, and these changes were sustained through to the late post-donation period. We used mathematical modeling to estimate the glomerular ultrafiltration coefficient (Kf), which also increased early and then remained constant through the late post-donation study. Assuming that the filtration surface area (and hence, Kf) increased in proportion to renocortical volume after donation, we calculated that the 40% elevation in the single-kidney GFR observed after donation could be attributed exclusively to an increase in the Kf. The prevalence of hypertension in donors increased from 14% in the early post-donation period to 57% in the late post-donation period. No subjects exhibited elevated levels of albuminuria. CONCLUSIONS Adaptive hyperfiltration after donor nephrectomy is attributable to hyperperfusion and hypertrophy of the remaining glomeruli. Our findings point away from the development of glomerular hypertension following kidney donation. TRIAL REGISTRATION Not applicable. FUNDING. NIH (R01DK064697 and K23DK087937); Astellas Pharma US; the John M. Sobrato Foundation; the Satellite Extramural Grant Foundation; and the American Society of Nephrology.

Vulnerability of patients with obstructive hypertrophic cardiomyopathy to ventricular arrhythmia induction in the operating room: Analysis of 17 patients

To evaluate vulnerability to ventricular arrhythmia induction, programmed electrical stimulation was performed in the operating room in 17 consecutive patients undergoing myotomy-myectomy for obstructive hypertrophic cardiomyopathy (HC). A control group of 5 patients undergoing coronary artery bypass grafting with normal left ventricular function and no previous myocardial infarction also was tested. Of the 17 patients with HC, 14 had inducible sustained ventricular tachycardia (VT) or ventricular fibrillation (VF), 1 had inducible unsustained VT and the remaining 2 had less than 6 ventricular beats. In contrast, none of the 5 control patients had an inducible sustained ventricular arrhythmia, 1 had inducible unsustained VT, and the remaining 4 had less than 3 ventricular beats. The difference between the 2 groups with respect to induction of a sustained ventricular arrhythmia, unsustained VT or less than 6 ventricular beats was significant (p less than 0.001). It is concluded that patients with severe obstructive HC are unusually vulnerable to ventricular arrhythmia induction. This suggests that spontaneous ventricular tachyarrhythmias may be an important cause of sudden death in patients with HC.

Course of preeclamptic glomerular injury after delivery

We evaluated the early postpartum recovery of glomerular function over 4 wk in 57 women with preeclampsia. We used physiological techniques to measure glomerular filtration rate (GFR), renal plasma flow, and oncotic pressure (pi(A)) and computed a value for the two-kidney ultrafiltration coefficient (K(f)). Compared with healthy, postpartum controls, GFR was depressed by 40% on postpartum day 1, but by only 19% and 8% in the second and fourth postpartum weeks, respectively. Hypofiltration was attributable solely to depression, at corresponding postpartum times, of K(f) by 55%, 30%, and 18%, respectively. Improvement in glomerular filtration capacity was accompanied by recovery of hypertension to near-normal levels and significant improvement in albuminuria. We conclude that the functional manifestations of the glomerular endothelial injury of preeclampsia largely resolve within the first postpartum month.

Effect of L-arginine therapy on the glomerular injury of preeclampsia: a randomized controlled trial.

OBJECTIVE: To assess the benefit of l-arginine, the precursor to nitric oxide, on blood pressure and recovery of the glomerular lesion in preeclampsia. METHODS: Forty-five women with preeclampsia were randomized to receive either l-arginine or placebo until day 10 postpartum. Primary outcome measures including mean arterial pressure, glomerular filtration rate, and proteinuria were assessed on the third and 10th days postpartum by inulin clearance and albumin-to-creatinine ratio. Nitric oxide, cyclic guanosine 3′5′ monophosphate, endothelin-1, and asymmetric-dimethyl-arginine and arginine levels were assayed before delivery and on the third and 10th days postpartum. Healthy gravid women provided control values. Assuming a standard deviation of 10 mm Hg, the study was powered to detect a 10-mm Hg difference in mean arterial pressure (α .05, β .20) between the study groups. RESULTS: No significant differences existed between the groups with preeclampsia before randomization. Compared with the gravid control group, women with preeclampsia exhibited significantly increased serum levels of endothelin-1, cyclic guanosine 3′5′ monophosphate, and asymmetric-dimethyl-arginine before delivery. Despite a significant increase in postpartum serum arginine levels due to treatment, no differences were found in the corresponding levels of nitric oxide, endothelin-1, cyclic guanosine 3′5′ monophosphate, or asymmetric-dimethyl-arginine between the two groups with preeclampsia. Further, there were no significant differences in any of the primary outcome measures with both groups demonstrating similar levels in glomerular filtration rate and equivalent improvements in both blood pressure and proteinuria. CONCLUSION: Blood pressure and kidney function improve markedly in preeclampsia by the 10th day postpartum. Supplementation with l-arginine does not hasten this recovery. LEVEL OF EVIDENCE: I

Imprecision of Creatinine-Based GFR Estimates in Uninephric Kidney Donors

BACKGROUND AND OBJECTIVES To ensure long-term safety of living kidney donors, it is now recommended that they be followed for at least 2 years after donation and that serum creatinine levels be monitored. Such levels are often subjected by clinical laboratories to estimating equations and are reported as estimated GFR (eGFR). The accuracy of such equations in uninephric living donors has yet to be validated. This is especially important in older living donors, who often have senescence-related depression of GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We compared urinary creatinine clearance, four-variable Modification of Diet in Renal Disease estimating equation (eGFR), and the recently reported CKD-EPI GFR estimating equation with true GFR measured by the urinary iothalamate clearance (iGFR) in 64 subjects after kidney donation. RESULTS Creatinine clearance overestimated iGFR. Both creatinine-based estimating equations were poorly correlated with and underestimated iGFR. More than half of kidney donors had eGFR <60 ml/min per 1.73 m(2) after donation, a level that categorized them as having stage 3 chronic kidney disease by our current laboratory reporting, whereas only 25% had iGFR <60 ml/min per 1.73 m(2). This misclassification disproportionately affected older donors age > or =55 years, of whom 80% had eGFR <60 ml/min per 1.73 m(2). Neither significant albuminuria nor hypertension was observed. CONCLUSIONS The current practice of reporting eGFR after donation commonly leads to a misclassification of chronic kidney disease, particularly in older donors. To ensure long-term well-being of living kidney donors, more precise estimates of GFR are required, particularly among older potential donors.