Comments for:

Longitudinal study of living kidney donor glomerular dynamics after nephrectomy
Colin R. Lenihan, … , Bryan D. Myers, Jane C. Tan
Colin R. Lenihan, … , Bryan D. Myers, Jane C. Tan
Published February 17, 2015
Citation Information: J Clin Invest. 2015;125(3):1311-1318. https://doi.org/10.1172/JCI78885.
View: Text | PDF
Clinical Research and Public Health

Longitudinal study of living kidney donor glomerular dynamics after nephrectomy

Abstract

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.

Authors

Colin R. Lenihan, Stephan Busque, Geraldine Derby, Kristina Blouch, Bryan D. Myers, Jane C. Tan

×

The term “benign hyperfiltration” is a misnomer

Submitter: Tarak Srivastava | tsrivastava@cmh.edu

Authors: Ashraf El-Meanawy, Virginia J. Savin, Ram Sharma, Mukut Sharma, and Tarak Srivastava

The Children’s Mercy Hospital, Kansas City, MO

Published September 29, 2015

The article by Lenihan et al. (1), and the accompanying commentary suggest that kidney donors develop “benign hyperfiltration” (2). The investigators measured, although not in all subjects, GFR, RPF, CT/MRI at 3 points during a median period of 6.1 years, plasma oncotic pressure (π) at 2 points, and estimated Kf from initial biopsy only (1). Other results are estimates based on a model with assumptions that need further consideration:

(a) The model predicts increase in Kf but the measured mean Kf is either lower (3,4), unchanged (5) or minimally increased (6) in uninephrectomized rats. In equations,

SNGFR=Kf∫[(Pg(x)-PB)-σ(πg(x)-πB)]dx;     SNGFR=Kf.PUF    or   SNGFR=k.Lp.Area(∆P-∆π)

Kf is dependent on Lp and the filtering area, and PUF is dependent on ∆P and ∆π[7]. If the measured π remains unchanged then PUF is proportional to ∆P (1). If ∆P is constant, then the change in SNGFR would be due to Kf, which becomes a circular argument. The measured PUF or ∆P in uninephrectomized rats is significantly elevated (3-6).

(b) Authors assume a parallel 1:1 increase in the filtering area with renal cortex. However, the increase in glomerular size does not parallel the increase in kidney size after the initial change (8). Instead, the increase in proximal tubule size plays a prominent part in cortical hypertrophy following uninephrectomy (9,10).

(c) Authors assume filtration disequilibrium. In filtration pressure disequilibrium, if ∆P remains constant the change in GFR would be modest even with doubling of plasma flow as ∆π is decreased, and there is no additional recruitment of filtering area (7). If filtration disequilibrium is assumed then a huge increase in area will be needed to explain the increase in observed SNGFR. If filtration equilibrium is assumed then a unique Kf cannot be assigned (2).

Kidney donors have increased risk for end stage renal disease (ESRD) with a median period of ~15 years (11-13). Similarly, 20%-40% of children born with solitary kidney develop ESRD as young adults, with manifestation of renal injury starting at ~15 years of age (14-16). A much longer follow-up would be needed to designate hyperfiltration as “benign” since younger donors (<35 years) are known to be at the highest risk for ESRD (17-20). Additionally, glomerular hypertrophy following uninephrectomy increases biomechanical stress leading to podocyte injury (21). We have found that uninephrectomy in mice is associated with increased fluid flow shear stress and upregulation of the COX2-PGE2-EP2 axis in podocytes (22,23).

With accumulating evidence in mind, we feel it would be inaccurate to term hyperfiltration as “benign” in either kidney donors or children with solitary kidney.

References:

1. Lenihan CR et al. Longitudinal study of living kidney donor glomerular dynamics after nephrectomy. J Clin Invest. 2015;125(3):1311-1318.

2. Blantz RC, Steiner RW. Benign hyperfiltration after living kidney donation. J Clin Invest. 2015;125(3):972-974.

3. Celsi G, Savin VJ, Henter JI, Sohtell M. The contribution of ultrafiltration pressure for glomerular hyperfiltration in young nephrectomized rats. Acta Physiol Scan. 1991;141(4):483-487.

4. Celsi G, Larsson L, Seri I, Savin V, Aperia A. Glomerular adaptation in uninephrectomized young rats. Pediatr Nephrol. 1989;3(3):280-285.

5. Deen WM, Maddox DA, Robertson CR, Brenner BM. Dynamics of glomerular ultrafiltration in the rat. VII. Response to reduced renal mass. Am J Physiol.1974;227(3):556-562.

6. Oliver JD 3rd et al. Proteinuria and impaired glomerular permselectivity in uninephrectomized fawn-hooded rats. Am J Physiol. 1994;267(6 Pt 2):F917-925.

7. Arendshorst WJ, Navar LJ. Renal circulation and glomerular hemodynamics. In: Schrier RW, Gottschalk CW, eds. Diseases of the kidney (6th edition). New York, USA: Little, Brown and Company; 1997:59-106.

8. Nagata M, Schärer K, Kriz W. Glomerular damage after uninephrectomy in young rats. I. Hypertrophy and distortion of capillary architecture. Kidney Int. 1992;42(1):136-147.

9. Hayslett JP, Kashgarian M, Epstein FH. Functional correlates of compensatory renal hypertrophy. J Clin Invest. 1968;47(4):774-799.

10. Anderson S, Meyer TW. Pathophysiology and nephron adaptation in chronic renal failure. In: Schrier RW, Gottschalk CW, eds. Diseases of the kidney (6th edition). New York, USA: Little, Brown and Company; 1997:2555-2580.

11. Muzaale AD, Massiei AB, Wang MC, Montgomery RA, McBride MA, Wainright JL, Segev DL. Risk of end-stage renal disease following live kidney donation. JAMA. 2014;311(6):579-586.

12. Mjøen G at al. Long-term risks for kidney donors. Kidney Int. 2014;86(1):162-167.

13. Gibney EM, King AL, Maluf DG, Garg AX, Parikh CR. Living kidney donors requiring transplantation: focus on African Americans. Transplantation. 2007;84(5):647-649.

14. Sanna-Cherchi S et al. Renal outcome in patients with congenital anomalies of the kidney and urinary tract. Kidney Int. 2009;76(5):528-533.

15. Westland R, Schreude MF, Bökenkamp A, Spreeuwenberg MD, van Wijk JA. Renal injury in children with a solitary functioning kidney—the KIMONO study. Nephrol Dial Transplant. 2011;26(5):1533-1541.

16. Westland R, Schreuder MF, Ket JC, van Wijk JA. Unilateral renal agenesis: a systematic review on associated anomalies and renal injury. Nephrol Dial Transplant. 2013;28(7):1844-1855.

17. Steiner RW, Ix JH, Rifkin DE, Gert B. Estimating risks of de novo kidney diseases after living kidney donation. Am J Transplant. 2014;14(3):538-44.

18. Steiner RW. 'Normal for now' or 'at future risk': a double standard for selecting young and older living kidney donors. Am J Transplant. 2010;10(4):737-741.

19. Gibney EM, Parikh CR, Garg AX. Age, gender, race, and associations with kidney failure following living kidney donation. Transplant Proc. 2008;40(5):1337-1340.

20. Cherikh WS et al. Ethnic and gender related differences in the risk of end-stage renal disease after living kidney donation. Am J Transplant. 2011;11(8):1650-1655.

21. Nagata M, Kriz W. Glomerular damage after uninephrectomy in young rats. II. Mechanical stress on podocytes as a pathway to sclerosis. Kidney Int. 1992;42(1):148-160.

22. Srivastava T et al. Fluid flow shear stress over podocytes is increased in the solitary kidney. Nephrol Dial Transplant. 2014;29(1):65-72

23. Srivastava T et al. Cyclooxygenase-2, Prostaglandin E2 and Prostanoid receptor EP2 in fluid flow shear stress mediated injury in solitary kidney. Am J Physiol Renal Physiol. 2014;307(12):F1323-1333.

 

 

Response to Srivastava et al.

Submitter: Jane Tan | janetan@stanford.edu

Authors: Colin Lenihan, Stephan Busque, Geraldine Derby, Kristina Blouch, Bryan Myers, and Jane Tan

Division of Nephrology, Stanford University School of Medicine

Published September 29, 2015

We examined the hypothesis that post-donation hyperfiltration by the remaining kidney after donation is sustained by hyperperfusion accompanied by increases in either Kf or ΔP, or some combination of changes in both of these determinants of GFR (1). Srivastava et al. maintain that we estimated Kf from baseline biopsy only. While we used morphometry of the baseline biopsy to determine single nephron Kf, serial physiological studies were performed in all patients.  Thus, whole kidney Kf was calculated serially from our physiological determinations at each time interval. The quotient whole kidney/single nephron Kf was then used to calculated the initial glomerular number at baseline. We did not measure oncotic pressure directly at the final study interval; however, serum albumin levels remained constant throughout the study, supporting the extrapolation of late post-donation plasma oncotic pressure from the earlier two determinations. We acknowledge that our modeling assumes filtration disequilibrium in humans, as justified in the discussion of the article (1).

It is highly likely that the renocortical hypertrophy observed following living kidney donor nephrectomy is associated with i) glomerular hypertrophy, ii) an increase in glomerular filtering surface area, and iii) an elevated whole-kidney Kf . There is considerable variation in the rat literature regarding the relative contributions of PGC and single nephron Kf to the increase in single nephron GFR observed following uninephrectomy. Such variations likely reflect the effects of anesthesia, rat strain, age and volume status. However, our supposition that increased Kf is an important contributor to post-nephrectomy hyperfiltration is consistent with many rat studies in which uninephrectomy resulted in an increase in single nephron GFR, mean glomerular volume and single nephron Kf but an unchanged PGC (2-4).

The study cited by the correspondents reports that uninephrecomized rats (compared to controls) exhibit a proportionally greater increase in glomerular tuft volume than kidney weight (5). Two other rat studies, observed that mean glomerular volume increased either i) proportionally slightly less than kidney weight or ii) proportionally slightly more than kidney weight in uninephrectomized rats relative to controls (2,3). In these studies, the increase in single nephron Kf was proportionally similar to the observed increase in glomerular volume. In humans, both mean glomerular volume and glomerular number are positively correlated with kidney weight, lending further support to the association between kidney size and filtering surface area (6). While we cannot be sure of the relation between glomerular volume, whole kidney Kf and renocortical hypertrophy in living donors, we submit that the assumption of a proportional increase is reasonable.

 The interpretation of the study cited by the authors comparing living donors and patients born with a solitary kidney is misleading; such patients frequently suffer from anomalies of the remaining kidney and of the urinary tract that likely contribute to their long term risk of renal failure (7). We agree that glomerular hypertrophy is not necessarily benign (3-8); however, the outcomes reported in most long term studies of uninephrectomy have been very reassuring (9,10). Importantly, sixty years after the first donor surgery, there is little evidence for the widespread development of post-kidney donation ‘hyperfiltration injury’.

References:

1. Lenihan CR et al. Longitudinal study of living kidney donor glomerular dynamics after nephrectomy. J Clin Invest. 2015;125(3):1311-1318.

2. Meyer TW, Rennke HG. Progressive glomerular injury after limited renal infarction in the rat. Am J Physiol.1988;254:F856-62.

3. Miller PL, Rennke HG, Meyer TW. Glomerular hypertrophy accelerates hypertensive glomerular injury in rats. Am J Physiol. 1991;261:F459-65.

4. Finn WF. Compensatory renal hypertrophy in Sprague-Dawley rats: glomerular ultrafiltration dynamics. Ren Physiol. 1982;5:222-234.

5. Nagata M, Schärer K, Kriz W. Glomerular damage after uninephrectomy in young rats. I. Hypertrophy and distortion of capillary architecture. Kidney Int. 1992;42:136-147.

6. Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec. 1992;232:194-201.

7. Westland R, Schreuder MF, Ket JC, van Wijk JA. Unilateral renal agenesis: a systematic review on associated anomalies and renal injury. Nephrol Dial Transplant. 2013;28:1844-1855.

8. Fries JW, Sandstrom DJ, Meyer TW, Rennke HG. Glomerular hypertrophy and epithelial cell injury modulate progressive glomerulosclerosis in the rat. Lab Invest. 1989;60:205-218.

9. Narkun-Burgess DM et al. Forty-five year follow-up after uninephrectomy. Kidney Int. 1993;43:1110-1115.

10. Ibrahim HN et al. Long-term consequences of kidney donation. N Engl J Med. 2009;360:459-469.

Advertisement