Tubular secretion of creatinine in autosomal dominant polycystic kidney disease: consequences for cross-sectional and longitudinal performance of kidney function estimating equations.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal tubular cell proliferation and dedifferentiation, which may influence tubular secretion of creatinine (CCr[TS]). STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: We therefore investigated CCr(TS) in patients with ADPKD and controls and studied consequences for the performance of glomerular filtration rate (GFR) estimating equations. INDEX & REFERENCE TESTS: In patients with ADPKD and healthy controls, we measured GFR as (125)I-iothalamate clearance while simultaneously determining creatinine clearance. OTHER MEASUREMENTS: 24-hour urinary albumin excretion. RESULTS: In 121 patients with ADPKD (56% men; mean age, 40 ± 11 [SD] years) and 215 controls (48% men; mean age, 53 ± 10 years), measured GFR (mGFR) was 78 ± 30 and 98 ± 17 mL/min/1.73 m(2), respectively, and CCr(TS) was 15.9 ± 10.8 and 10.9 ± 10.6 mL/min/1.73 m(2), respectively (P < 0.001). The higher CCr(TS) in patients with ADPKD remained significant after adjustment for covariates and appeared to be dependent on mGFR. Correlation and accuracy between mGFR and CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) estimated GFR (eGFR) were 0.95 and 99%, respectively; between mGFR and MDRD (Modification of Diet in Renal Disease) Study eGFR, they were 0.93 and 97%, respectively. Values for bias, precision, and accuracy were similar or slightly better than in controls. In addition, change in mGFR during 3 years of follow-up in 45 patients with ADPKD correlated well with change in eGFR. LIMITATIONS: Cross-sectional, single center. CONCLUSIONS: CCr(TS) in patients with ADPKD is higher than that in controls, but this effect is limited and observed at only high-normal mGFR. Consequently, the CKD-EPI and MDRD Study equations perform relatively well in estimating GFR and change in GFR in patients with ADPKD.

Effects of preexistent hypertension on blood pressure and residual renal function after donor nephrectomy.

BACKGROUND: Living kidney donor selection has become more liberal with acceptation of hypertensive donors. Here, we evaluate short-term and 1- and 5-year renal outcome of living kidney donors with preexistent hypertension. METHODS: We compared outcome of hypertensive donors by gender, age, and body mass index with matched control donors. Hypertension was defined as predonation antihypertensive drug use. All donors had glomerular filtration rate (I-iothalamate) and effective renal plasma flow (I-hippuran) measured 4 months before and 2 months after donation. A subset of donors had serum creatinine measured 1 year after donation or a renal function measurement 5 years after donation. RESULTS: Included were 47 hypertensive donors and 94 control donors (both 53% male; mean age, 57±7 years; and body mass index, 28±4 kg/m). Pre- and early postdonation, systolic blood pressure, and mean arterial pressure were significantly higher in hypertensive donors. Control donors showed a rise in diastolic blood pressure after donation, and thus the predonation difference was lost postdonation. Both at 1 year (29 hypertensive donors, 58 controls) and 5 years after donation (13 hypertensive donors and 26 controls) blood pressure was similar. Renal function was similar at all time points. DISCUSSION: In summary, hypertensive living kidney donors have similar outcome in terms of blood pressure and renal function as control donors, early and 1 and 5 years after donation.

Performance of MDRD study and CKD-EPI equations for long-term follow-up of nondiabetic patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) typically extends over decades. Longitudinal monitoring of kidney function in CKD is thus of great importance. Here, we retrospectively evaluate use of the Modification of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations to monitor long-term course of kidney function and to identify individuals with progressive kidney function loss. METHODS: Patients were selected from our outpatient clinic for having four glomerular filtration rate measurements (mGFR, (125)I-iothalamate) and at least ≥ 4 years of follow-up. Renal function slopes were obtained by within-individual linear regression. RESULTS: Sixty-five nondiabetic CKD patients (40 male, mean baseline age 44 ± 12 years) with a median (range) of 9 (4-16) mGFR measurements and a median follow-up of 11 (4-33) years were included. Both equations significantly underestimated mGFR/(BSA) at baseline and at the end of follow-up. mGFR slope was significantly underestimated by the MDRD study but not by CKD-EPI equation (slopes -1.41 ± 2.06, -1.07 ± 1.72 and -1.39 ± 1.77 mL/min/1.73 m(2)/year, respectively). Sensitivity and specificity to identify progressive kidney function loss (mGFR/(BSA) slope > 1.5 mL/min/1.73 m(2)/ year, n = 23) were 78 and 88% for the MDRD study and 91 and 80% for CKD-EPI equation. In the subgroup of progressors, both MDRD study and CKD-EPI equation underestimated the rate of mGFR loss (P < 0.05) CONCLUSIONS: Long-term course of mGFR is reasonably well estimated by CKD-EPI and slightly underestimated by MDRD study equation. Patients with progressive kidney function loss may, however, not be reliably identified, so caution is warranted when using these equations in clinical practice.

Renal function equations before and after living kidney donation: a within-individual comparison of performance at different levels of renal function.

BACKGROUND AND OBJECTIVES: The Modification of Diet in Renal Disease (MDRD) study equation and the Cockcroft-Gault (CG) equation perform poorly in the (near-) normal range of GFR. Whether this is due to the level of GFR as such or to differences in individual characteristics between healthy individuals and patient with chronic kidney disease (CKD) is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated the performance of MDRD, CG per BSA (CG/(BSA)) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations compared with measured GFR (mGFR; I-iothalamate) at 4 months before and 2 months after donation in 253 consecutive living kidney donors. RESULTS: mGFR declined from 103 ± 15 to 66 ± 11 ml/min per 1.73 m(2) after donation. All equations underestimated mGFR at both time points. Arithmetic performance analysis showed improved performance after donation of all equations, with significant reduction of bias after donation. Expressed as percentage difference, mGFR-estimated GFR (eGFR) bias was reduced after donation only for CG/(BSA). Finally, in 295 unselected individuals who were screened for donation, mGFR was below the cutoff for donation of 80 ml/min per 1.73 m(2) in 19 individual but in 166, 98, and 74 for MDRD, CDK-EPI, and CG/(BSA), respectively. CONCLUSIONS: A higher level of GFR as such is associated with larger absolute underestimation of true GFR by eGFR. For donor screening purposes, eGFR should be interpreted with great caution; when in doubt, true GFR should be performed to prevent unjustified decline of prospective kidney donors.

Early renal abnormalities in autosomal dominant polycystic kidney disease.

BACKGROUND AND OBJECTIVES: Potential therapeutic interventions are being developed for autosomal dominant polycystic kidney disease (ADPKD). A pivotal question will be when to initiate such treatment, and monitoring disease progression will thus become more important. Therefore, the prevalence of renal abnormalities in ADPKD at different ages was evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Included were 103 prevalent ADPKD patients (Ravine criteria). Measured were mean arterial pressure (MAP), total renal volume (TRV), GFR, effective renal plasma flow (ERPF), renal vascular resistance (RVR), and filtration fraction (FF). Twenty-four-hour urine was collected. ADPKD patients were compared with age- and gender-matched healthy controls. RESULTS: Patients and controls were subdivided into quartiles of age (median ages 28, 37, 42, and 52 years). Patients in the first quartile of age had almost the same GFR when compared with controls, but already a markedly decreased ERPF and an increased FF (GFR 117 +/- 32 versus 129 +/- 17 ml/min, ERPF 374 +/- 119 versus 527 +/- 83 ml/min, FF 32% +/- 4% versus 25% +/- 2%, and RVR 12 (10 to 16) versus 8 (7 to 8) dynes/cm(2), respectively). Young adult ADPKD patients also had higher 24-hour urinary volumes, lower 24-hour urinary osmolarity, and higher urinary albumin excretion (UAE) than healthy controls, although TRV in these young adult patients was modestly enlarged (median 1.0 L). CONCLUSIONS: Already at young adult age, ADPKD patients have marked renal abnormalities, including a decreased ERPF and increased FF and UAE, despite modestly enlarged TRV and near-normal GFR. ERPF, FF, and UAE may thus be better markers for disease severity than GFR.

Differential ACE expression among tissues in allele-specific Wistar rat lines.

In humans, the insertion/deletion polymorphism in the angiotensin converting enzyme (ACE) gene accounts for half of the variance in plasma ACE activity. The deletion allele is associated with high plasma ACE activity, cardiovascular disease, and renal disease. In rat, a similar association is found between the B and L alleles of a microsatellite marker in the ACE gene. We identified the B/L variation in the Wistar outbred rat and bred two lines homozygous for the two alleles (WU-B and WU-L). ACE activity was measured in serum, heart, kidney, and aorta homogenates. Immunohistochemistry and ACE mRNA expression were performed in heart, kidney, and aortic tissue. Aortic rings were collected and stimulated with AngI, AngII, and AngI with Lisinopril to measure ACE functional activity by vasoconstrictor response. Serum, heart, and kidney ACE activity and kidney mRNA expression were two-fold higher in WU-B. Kidney staining showed a clear difference in tubular ACE expression, with more staining in WU-B. While in aorta ACE activity and mRNA expression was twofold higher in WU-L, functional conversion of AngI was higher in WU-B, indicating either a functional difference in AngI to AngII conversion between the two alleles due to different splicing or the presence of other factors involved in the conversion that are differentially expressed as the result of differences in the ACE alleles. The newly developed WU-B and WU-L lines show tissue-specific differences in ACE expression and activity. This provides an experimental tool to study the pathophysiologic consequences of differences in ACE alleles in renal and cardiovascular disease.

Renal hemodynamics in overweight and obesity: pathogenetic factors and targets for intervention.

Weight excess is a risk factor for progressive renal function loss, not only in subjects with renal disease or renal transplant recipients, but also in the general population. Considering the increasing prevalence of obesity worldwide, weight excess may become the main renal risk factor on a population basis, all the more so because the risk is not limited to morbid obesity, but is already apparent in the overweight range. The mechanism of the renal risk is multifactorial. In addition to the role of comorbid conditions such as hypertension and diabetes, current evidence supports a pathogenetic role for renal hemodynamics, specifically glomerular hyperfiltration, and also glomerular hypertension. Weight excess is associated with an elevated glomerular filtration rate and a less pronounced rise in renal plasma flow, resulting in an elevated filtration fraction. This suggests glomerular hypertension due to afferent-efferent dysbalance, which impairs glomerular protection from systemic hypertension. Data in renal transplant recipients support the pathogenetic role of elevated glomerular pressure for long-term renal prognosis. Blockade of the renin-angiotensin-aldosterone system can reverse the renal hemodynamic abnormalities. The obesity-associated renal risk is unfavourably affected by high sodium intake. This may be due to the effects of sodium on blood pressure, which is often sodium-sensitive in obesity, but direct renal effects are also present. Interestingly, sodium restriction ameliorates overweight-associated hyperfiltration in overweight subjects. More focus on weight excess as a renal risk factor is warranted. Preventive measures should focus on weight excess as well as on specific protection against renal damage, by renin-angiotensin-aldosterone system-blockade and moderate sodium restriction.