J. J. Homan van der Heide

Body Mass Index and Glomerular Hyperfiltration in Renal Transplant Recipients: Cross‐Sectional Analysis and Long‐Term Impact

Obesity is a risk factor for renal graft loss. Higher body mass index (BMI) in native kidneys is associated with glomerular hyperfiltration. Whether higher BMI in renal transplants is associated with hyperfiltration is unknown. We investigated the impact of BMI on renal hemodynamics 1 year post‐transplant. We analyzed glomerular filtration rate (GFR, 125I‐iothalamate) and effective renal plasma flow (ERPF, 131I‐hippurate) in 838 kidney transplants. Data were analyzed for all patients and for the subpopulation without diabetes. Long‐term impact of BMI and renal hemodynamics were explored by Cox‐regression. With higher BMI GFR and filtration fraction (FF) increased significantly. Multivariate analysis supported impact of BMI on GFR (adjusted r2 of the model 0.275) and FF (adjusted r2 of the model 0.158). This association was not explained by diabetes mellitus. On Cox‐regression analysis, lower GFR and higher FF were independent determinants of overall graft loss and graft loss by patient mortality. Lower GFR and higher BMI were determinants of death‐censored graft loss, with borderline contribution of higher FF. In renal transplants higher BMI is independently associated with higher GFR and FF one year posttransplant, suggesting glomerular hyperfiltration with altered afferent–efferent balance. Mechanisms underlying the long‐term prognostic impact of hyperfiltration deserve further exploration.

THE EFFECTS OF DIETARY SUPPLEMENTATION WITH FISH OIL ON RENAL-FUNCTION IN CYCLOSPORINE-TREATED RENAL-TRANSPLANT RECIPIENTS

The effect of a daily supplementation of 6 g fish oil (30% C20:5 omega-3 (EPA) and 20% C22:6 omega-3 for three months on renal function variables was investigated in a placebo-controlled (6 g corn oil, 50% C18:2 omega-6) prospective, randomized, double-blind study in stable cyclosporine-treated renal transplant recipients, at least nine months after grafting. Ten patients ingested placebo capsules and eleven patients fish oil. When measuring glomerular filtration rate and effective renal plasma flow (ERPF) before (baseline [BL]) and after 3 months of oil ingestion nothing changed in the placebo-treated group: GFR-BL = 64.5 GFR-3 months = 60 ml/min/1.73m2 (NS; median, Wilcoxon test) ERPF BL = 229.5 and ERPF-3 months = 242.5 ml/min/1.73m2 (NS). In the fish oil-treated group GFR rose by 20.3% from GFR-BL = 56 to GFR-3 months = 68 ml/min/1.73m2 and ERPF by 16.4% from ERPF-BL 218 to ERPF-3 months = 245 ml/min/1.73m2, (P less than 0.01). In the placebo-treated group mean arterial pressure and calculated total renal vascular resistance (TRVR) did not change: MAP-BL = 106 mmHg and MAP-3 months = 109 mmHg, TRVR being 20856 dyne.sec/cm5 and 19862 dyne/sec/cm5, respectively (NS). In the fish oil-treated group MAP and TRVR fell by 8.6% and 21.1%, respectively: MAP-BL = 106 mmHg and MAP-3 months = 98 mmHg (P less than 0.01), TRVR-BL = 21952 dyne/sec/cm5 and TRVR-3 months = 17087 dyne/sec/cm5 (P less than 0.01). According to these results fish oil supplementation has considerable effects on renal function and blood pressure in stable CsA-treated renal transplant recipients.

Nephrectomy Elicits Impact of Age and BMI on Renal Hemodynamics: Lower Postdonation Reserve Capacity in Older or Overweight Kidney Donors

Renal functional reserve could be relevant for the maintenance of renal function after kidney donation. Low‐dose dopamine induces renal vasodilation with a rise in glomerular filtration rate (GFR) in healthy subjects and is thought to be a reflection of reserve capacity (RC). Older age and higher body mass index (BMI) may be associated with reduced RC. We therefore investigated RC in 178 consecutive living kidney donors (39% males, age 48 ± 11 years, BMI 25.5 ± 4.1). RC was determined as the rise in GFR (125I‐iothalamate), 4 months before and 2 months after donor nephrectomy. Before donor nephrectomy, GFR was 114 ± 20 mL/min, with a reduction to 72 ± 12 mL/min after donor nephrectomy. The dopamine‐induced rise in GFR of 11 ± 10% was reduced to 5 ± 7% after donor nephrectomy (p < 0.001). Before donor nephrectomy, older age and higher BMI did not affect reserve capacity. After donor nephrectomy, the response of GFR to dopamine independently and negatively correlated with older age and higher BMI. Moreover, postdonation reserve capacity was absent in obese donors. The presence of overweight had more impact on loss of RC in younger donors. In conclusion, donor nephrectomy unmasked an age‐ and overweight‐induced loss of reserve capacity. Younger donors with obesity should be carefully monitored.

Predictive capacity of pre-donation GFR and renal reserve capacity for donor renal function after living kidney donation

Kidney transplantation from living donors is important to reduce organ shortage. Reliable pre‐operative estimation of post‐donation renal function is essential. We evaluated the predictive potential of pre‐donation glomerular filtration rate (GFR) (iothalamate) and renal reserve capacity for post‐donation GFR in kidney donors.

Obesity and Renal Hemodynamics

Obesity is a risk factor for renal damage in native kidney disease and in renal transplant recipients. Obesity is associated with several renal risk factors such as hypertension and diabetes that may convey renal risk, but obesity is also associated with an unfavorable renal hemodynamic profile independent of these factors, and that may exert effects on renal damage as well. In animal models of obesity-associated renal damage, micro-puncture studies showed glomerular hypertension and hyperfiltration. In humans an elevated glomerular filtration rate has been demonstrated in several studies, sometimes associated with hyperperfusion as well, independent of blood pressure or the presence of diabetes. An elevated filtration fraction was found in several studies, consistent with glomerular hypertension. This renal hemodynamic profile resembles the hyperfiltration pattern in diabetes and is therefore assumed to be a pathogenetic factor in renal damage. Of note, the association between body mass index and renal hemodynamics is not limited to overt obesity or overweight, but is also present across the normal range, without a particular threshold. Multiple factors are assumed to contribute to these renal hemodynamic alterations, such as insulin resistance, the renin-angiotensin system and the tubulo-glomerular responses to increased proximal sodium reabsorption, and possibly also inappropriate activity of the sympathetic nervous system and increased leptin levels. Obesity has a high world-wide prevalence. On a population-basis, therefore, its contribution to long-term renal risk may be considerable, especially as it is usually clustered with risk factors like hypertension and insulin resistance. In short-term studies the renal hemodynamic alterations in obesity and the associated proteinuria were reversible by weight loss, and renin-angiotensin system-blockade, respectively. These interventions are therefore likely to have the potential to limit the renal risks of obesity.

Kidney Injury Molecule-1 is an Early Noninvasive Indicator for Donor Brain Death-Induced Injury Prior to Kidney Transplantation

With more marginal deceased donors affecting graft viability, there is a need for specific parameters to assess kidney graft quality at the time of organ procurement in the deceased donor. Recently, kidney injury molecule‐1 (Kim‐1) was described as an early biomarker of renal proximal tubular damage. We assessed Kim‐1 in a small animal brain death model as an early and noninvasive marker for donor‐derived injury related to brain death and its sequelae, with subsequent confirmation in human donors.

Markers of the Hepatic Component of the Metabolic Syndrome as Predictors of Mortality in Renal Transplant Recipients

Cardiovascular disease (CVD) is a leading cause of mortality in renal transplant recipients (RTRs). Metabolic syndrome (MS) is highly prevalent in RTRs. Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic component of MS. We investigated associations of NAFLD markers with MS and mortality. RTRs were investigated between 2001 and 2003. NAFLD markers, alanine aminotransferase (ALT), gamma‐glutamyl transferase (GGT) and alkaline phosphatase (AP) were measured. Bone and nonbone fractions of AP were also determined. Death was recorded until August 2007. Six hundred and two RTRs were studied (age 52 ± 12 years, 55% men). At baseline 388 RTRs had MS. Prevalence of MS was positively associated with liver enzymes. During follow‐up for 5.3[4.5–5.7] years, 95 recipients died (49 cardiovascular). In univariate Cox regression analyses, GGT (HR = 1.43[1.21–1.69], p < 0.001) and AP (HR = 1.34[1.11–1.63], p = 0.003) were associated with mortality, whereas ALT was not. Similar associations were found for cardiovascular mortality. Adjustment for potential confounders, including MS, diabetes and traditional risk factors did not materially change these associations. Results for nonbone AP mirrored that for total AP. ALT, GGT and AP are associated with MS. Of these three enzymes, GGT and AP are associated with mortality, independent of MS. These findings suggest that GGT and AP are independently related to mortality in RTRs.

The predictive value of renal vascular resistance for late renal allograft loss.

The renal artery resistance index (RI), assessed by Doppler ultrasonography, was recently identified as a new risk marker for late renal allograft loss. This finding requires confirmation since RI in that study was not measured at predetermined time points and ultrasonography is operator‐dependent. We investigated the predictive value of renal vascular resistance (RVR), a less operator‐dependent method as assessed by mean arterial pressure divided by renal blood flow, for the prediction of recipient mortality and death‐censored graft loss. RVR was compared to commonly used risk markers such as creatinine clearance (CrCl), serum creatinine (SCreat) and proteinuria (UProt) in 793 first‐time cadaveric renal transplant recipients at predetermined time points after transplantation using receiver operating characteristics (ROC) and Cox survival analyses. The present study showed that RVR is a prominent risk marker for recipient mortality and death‐censored graft loss. However, the predictive value of RVR for recipient mortality owed mainly to the impact of mean arterial blood pressure. In contrast, RVR constituted more than the sum of its components for death‐censored graft loss, but showed less predictive value than SCreat in univariate analysis. As the assessment of RVR is expensive and time‐consuming, we believe that RVR holds no clinical merit for the follow‐up of renal transplant recipients.

Dietary supplementation with lish oil modifies renal reserve filtration capacity in postoperative, cyclosporin A-treated renal transplant recipients

Abstract. The effect of a daily supplementation of 6 g fish oil (30% C20:5 omega‐3 = EPA and 20% C22:6 omega‐3 = DHA) for 1 month on renal function variables was investigated in a placebo‐controlled (6 g coconut oil), prospective, randomized, double‐blind study in acute postoperative cyclosporin A (CyA)‐treated renal transplant recipients. Seventeen patients ingested placebo capsules (EPA‐) and 14 patients fish oil (EPA +). Renal function tests were performed using the simultaneous determination of 1251‐iothalamate and 1311‐hippuran clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively. Renal reserve filtration capacity was assessed by dopamine infusion, amino acid infusion, and a combination of both stimuli. After 1 month there were no significant differences in rejection episodes, CyA dose, or CyA levels. In contrast to our earlier observations, serum creatinine, creatinine clearance, GFR, and ERPF did not differ between the EPA‐and EPA + groups. Filtration fraction (FF) differed significantly, being 0. 21 in the EPA‐group versus 0. 26 in the EPA+ group. To exclude the possible influence of a rejection episode, the nonrejecting patients were analyzed separately, creating the subgroups EPA + re‐and EPA‐re‐. These two groups were comparable in age, donor age, and GFR. The EPA + regroup had a significantly lower ERPF (164 ml/min per 1. 73 nr) than the EPA‐re‐group (262 ml/min per 1. 73 m2). FF was significantly higher in the EPA + re‐group (0. 26) than in the EPA‐re‐group (0. 21). Following dopamine, no significant differences in the percentage increase of GFR and ERPF between both groups were observed, while FF fell to the same extent in both groups. Following amino acids, the fish oil‐treated patients had a significantly better response on GFR (EPA + re‐15. 3 versus EPA‐re‐10. 6%; P < 0. 05). The near‐normal FF and the better response on amino acid infusion strongly suggest that at 1 month postoperatively, the CyA‐and fish oil‐treated patients have more balanced renal hemodynamics than the CyA‐and coconut oil‐treated patients.

Donor kidney adapts to body dimensions of recipient: no influence of donor gender on renal function after transplantation.

Female kidneys and kidneys from small donors have been suggested to perform worse after kidney transplantation. Here, we evaluate the impact of gender and body dimensions on posttransplantation GFR in living donor transplantation. Two hundred and ninety‐three donor–recipient pairs, who were transplanted at our center were evaluated. All pairs had detailed renal function measurement (125I‐iothalamate and 131I‐hippuran) 4 months predonation in the donor and 2.5 months posttransplantation in donor and recipient. For 88 pairs, 5 years of recipient follow‐up was available. Delta GFR was calculated as (recipient GFR–donor single kidney GFR). Recipients of both male and female kidneys had similar renal function at early and long term after transplantation. Male recipients had higher ERPF, ΔGFR and ΔERPF at both time points. Kidneys of donors smaller than their recipient had higher ΔGFR and ΔERPF than kidneys of larger donors at both time points (p < 0.05). In multivariate analysis, ΔGFR was predicted by donor/recipient BSA‐ratio together with transplantation related factors (R2 0.19), irrespective of donor and recipient gender. In conclusion, in living donor transplantation, female kidneys perform as well as male donor kidneys. Kidneys adapt to the recipients body size and demands, independent of gender, without detrimental effects in renal function and outcome up to mid‐long term.