Bjarne M. Iversen

Low Birth Weight Increases Risk for End-Stage Renal Disease

Case-control studies have shown an association between low birth weight and risk for renal failure. The Medical Birth Registry of Norway, which comprises data on all births in Norway since 1967, and the Norwegian Renal Registry, which comprises data on all patients who have developed ESRD in Norway since 1980, were used to examine whether birth-related variables were associated with risk for ESRD. Of the 2,183,317 children born between 1967 and 2004, 526 were found in the ESRD registry. Compared with birth weight in the 10th to 90th percentiles, births <10th percentile had a relative risk (RR) for ESRD of 1.7 (95% confidence interval 1.4 to 2.2; P < 0.001). Births with a weight for gestational age <10th percentile had an RR of 1.5 (95% confidence interval 1.2 to 1.9; P = 0.002). These associations were virtually identical after adjustment for birth-related confounders such as congenital malformations, multiple delivery, maternal age at birth, and maternal preeclampsia. Low birth weight was more strongly associated with development of ESRD during the first 14 years of life than after age 15. Low birth weight and low birth weight for gestational age were similarly associated with multiple causes of ESRD. In conclusion, in this cohort study with a maximum follow-up of 38 years, low birth weight and intrauterine growth restriction were associated with increased risk for ESRD.

Adverse Perinatal Outcome and Later Kidney Biopsy in the Mother

Strong associations of adverse perinatal outcomes have been identified with later cardiovascular disease in the mother. Few studies have addressed associations with kidney disease. This study investigated whether perinatal outcomes are associated with later clinical kidney disease as diagnosed by kidney biopsy. The Medical Birth Registry of Norway contains data on all childbirths in Norway since 1967. The Norwegian Kidney Biopsy Registry contains data on all kidney biopsies in Norway since 1988. All women with a first singleton delivery from 1967 to 1998 were included. Pregnancy-related predictors of later kidney biopsy were analyzed by Cox regression analyses. A total of 756,420 women were included, and after a mean period of 15.9+/-9.4 yr, 588 had a kidney biopsy. Compared with women without preeclampsia and with offspring with birth weight of >or=2.5 kg, women with no preeclampsia and with offspring with birth weight of 1.5 to 2.5 kg had a relative risk (RR) for a later kidney biopsy of 1.7, women with no preeclampsia and with offspring with birth weight of <1.5 kg had an RR of 2.9, women with preeclampsia and with offspring with a birth weight of >or=2.5 kg had an RR of 2.5, women with preeclampsia and with offspring with a birth weight of 1.5 to 2.5 kg had an RR of 4.5, and women with preeclampsia and with offspring with a birth weight of <1.5 kg had an RR of 17. Similar results were found in adjusted analyses and after exclusion of women with diabetes, kidney disease, or rheumatic disease before pregnancy. The same risk patterns applied to any of the specific categories of kidney disease as well as specific kidney diseases investigated. Women who have preeclampsia and give birth to offspring with low birth weight and short gestation have a substantially increased risk for having a later kidney biopsy.

Increased glomerular capillary pressure and size mediate glomerulosclerosis in SHR juxtamedullary cortex

To gain insight into the mechanisms in the development of glomerulosclerosis in juxtamedullary cortex, the degree of glomerulosclerosis, glomerular tuft diameter, glomerular capillary pressure (Pgc), and local renal blood flow (RBF) autoregulation were measured in superficial and juxtamedullary cortex of 10- and 70-wk-old spontaneously hypertensive rat (SHR), using aged matched Wistar-Kyoto (WKY) rats as controls. Pgc was measured after corticotomy by direct micropuncture of glomeruli in superficial and juxtamedullary cortex. Total RBF was measured by a transit-time flowmeter (Transonic) and local blood flow by use of laser-Doppler flowmetry. The degree of glomerulosclerosis measured by a semiquantitative histological technique was significantly increased in juxtamedullary compared with superficial cortex in all groups. The difference was most pronounced in the juxtamedullary cortex of 70-wk-old SHR. Pgc was significantly increased in juxtamedullary cortex compared with superficial cortex in 70-wk SHR (57.1 ± 2.7 vs. 46.5 ± 0.5 mmHg, P < 0.01). The corresponding data set from 70-wk WKY was 45.5 ± 0.43 vs. 41.6 ± 1.5 ( P < 0.05). The Pgc in juxtamedullary cortex of 10-wk SHR was slightly higher than in superficial cortex (45.1 ± 2.3 vs. 50.1 ± 1.2 mmHg, P = 0.05), whereas there was no difference in 10-wk WKY. Glomerular diameter was larger in juxtamedullary cortex in old animals but not significantly different in 10-wk WKY rats and 10-wk SHR. Total RBF was reset to higher perfusion pressures in hypertensive rats. Juxtamedullary and superficial blood flow autoregulation were not significantly different from total RBF autoregulation in all groups. These results suggest that hypertrophy as well as increased Pgc might contribute to the development of manifest glomerulosclerosis. Changes in local blood flow autoregulation do not seem to play a major role in the development of glomerulosclerosis.

Effects of antihypertensive drugs on autoregulation of RBF and glomerular capillary pressure in SHR

The relationship between systemic blood pressure and glomerular capillary pressure (Pgc) in spontaneously hypertensive rats (SHR) during treatment with antihypertensive drugs is still unclear. The effects of an angiotensin-converting enzyme inhibitor (enalapril), two calcium channel antagonists (nifedipine and verapamil), and an alpha1-receptor blocker (doxazosin) on renal blood flow (RBF) autoregulation, Pgc, and renal segmental resistances were therefore studied in SHR. Recordings of RBF autoregulation were done before and 30 min after intravenous infusion of the different drugs, and Pgc was thereafter measured with the stop-flow technique. When the mean arterial pressure (MAP) was reduced to approximately 120 mmHg by infusions of doxazosin or enalapril, the lower pressure limit of RBF autoregulation was reduced significantly. Nifedipine or verapamil abolished RBF autoregulation. Doxazosin did not change Pgc (43.6 +/- 1.4 vs. 46.7 +/- 1.5 mmHg in controls, P > 0.5), enalapril lowered (41.3 +/- 0.8 mmHg, P < 0.01), and the calcium channel antagonists increased Pgc [53.7 +/- 1.4 mmHg (nifedipine) and 54.8 +/- 1.2 mmHg (verapamil), P < 0.01]. When MAP was reduced to approximately 85 mmHg by drugs, Pgc was reduced to 43.3 +/- 1.7 mmHg after nifedipine (P > 0.2 vs. control), whereas Pgc after enalapril was 38.5 +/- 0.5 mmHg (P < 0.05 vs. control). Enalapril reduced Pgc mainly by reducing efferent resistance. During treatment with calcium channel antagonists, Pgc became strictly dependent on MAP. Monotherapy with nifedipine may increase Pgc and by this mechanism accelerate glomerulosclerosis if a strict blood pressure control is not obtained.The relationship between systemic blood pressure and glomerular capillary pressure (Pgc) in spontaneously hypertensive rats (SHR) during treatment with antihypertensive drugs is still unclear. The effects of an angiotensin-converting enzyme inhibitor (enalapril), two calcium channel antagonists (nifedipine and verapamil), and an α1-receptor blocker (doxazosin) on renal blood flow (RBF) autoregulation, Pgc, and renal segmental resistances were therefore studied in SHR. Recordings of RBF autoregulation were done before and 30 min after intravenous infusion of the different drugs, and Pgcwas thereafter measured with the stop-flow technique. When the mean arterial pressure (MAP) was reduced to ∼120 mmHg by infusions of doxazosin or enalapril, the lower pressure limit of RBF autoregulation was reduced significantly. Nifedipine or verapamil abolished RBF autoregulation. Doxazosin did not change Pgc (43.6 ± 1.4 vs. 46.7 ± 1.5 mmHg in controls, P > 0.5), enalapril lowered (41.3 ± 0.8 mmHg, P < 0.01), and the calcium channel antagonists increased Pgc[53.7 ± 1.4 mmHg (nifedipine) and 54.8 ± 1.2 mmHg (verapamil), P < 0.01]. When MAP was reduced to ∼85 mmHg by drugs, Pgc was reduced to 43.3 ± 1.7 mmHg after nifedipine ( P > 0.2 vs. control), whereas Pgc after enalapril was 38.5 ± 0.5 mmHg ( P < 0.05 vs. control). Enalapril reduced Pgc mainly by reducing efferent resistance. During treatment with calcium channel antagonists, Pgc became strictly dependent on MAP. Monotherapy with nifedipine may increase Pgc and by this mechanism accelerate glomerulosclerosis if a strict blood pressure control is not obtained.

Angiotensin II-induced contraction is attenuated by nitric oxide in afferent arterioles from the nonclipped kidney in 2K1C

Two-kidney, one-clip (2K1C) is a model of renovascular hypertension where we previously found an exaggerated intracellular calcium (Ca(i)(2+)) response to ANG II in isolated afferent arterioles (AAs) from the clipped kidney (Helle F, Vagnes OB, Iversen BM. Am J Physiol Renal Physiol 291: F140-F147, 2006). To test whether nitric oxide (NO) ameliorates the exaggerated ANG II response in 2K1C, we studied ANG II (10(-7) mol/l)-induced calcium signaling and contractility with or without the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME). In AAs from the nonclipped kidney, l-NAME increased the ANG II-induced Ca(i)(2+) response from 0.28 +/- 0.05 to 0.55 +/- 0.09 (fura 2, 340 nm/380 nm ratio) and increased contraction from 80 +/- 6 to 60 +/- 6% of baseline (P < 0.05). In vessels from sham and clipped kidneys, l-NAME had no effect. In diaminofluorescein-FM diacetate-loaded AAs from the nonclipped kidney, ANG II increased NO-derived fluorescence to 145 +/- 34% of baseline (P < 0.05 vs. sham), but not in vessels from the sham or clipped kidney. Endothelial NOS (eNOS) mRNA and ser-1177 phosphorylation were unchanged in both kidneys from 2K1C, while eNOS protein was reduced in the clipped kidney compared with sham. Cationic amino acid transferase-1 and 2 mRNAs were increased in 2K1C, indicating increased availability of l-arginine for NO synthesis, but counteracted by decreased scavenging of the eNOS inhibitor asymmetric dimethylarginine by dimethylarginine dimethylaminohydrolase 2. In conclusion, the Ca(i)(2+) and contractile responses to ANG II are blunted by NO release in the nonclipped kidney. This may protect the nonclipped kidney from the hypertension and elevated ANG II levels in 2K1C.

Previous preeclampsia and risk for progression of biopsy-verified kidney disease to end-stage renal disease

BACKGROUND A recent study has shown that preeclampsia is an important risk marker for end-stage renal disease (ESRD), but the underlying mechanisms are unclear. The present study investigated whether previous preeclampsia was associated with progression of established kidney disease. Material and methods. Data from the Norwegian Kidney Biopsy Registry and the Medical Birth Registry of Norway were linked. We included women who, after their last pregnancy, had had a representative kidney biopsy in 1988-2005. Women were followed up for the development of ESRD using data from the Norwegian Renal Registry. Baseline was set at the time of biopsy and Cox regression statistics were performed. RESULTS Of the 582 included women, 76 developed ESRD 3.9 ± 3.4 years (range, 0.08-16 years) after diagnosis. Mean age at first birth was 24.0 ± 4.8 years and at the time of diagnosis 41.3 ± 9.7 years. Women with clinically diagnosed preeclampsia in their first pregnancy had a relative risk of ESRD of 1.2 (95% CI, 0.63-2.4) and women with preterm birth had a relative risk of 2.1 (95% CI, 1.2-3.9). After extensive adjustments for clinical and histopathological variables at the time of diagnosis, the relative risks were 1.1 (95% CI, 0.50-2.6) and 2.4 (95% CI, 1.2-4.6), respectively. Compared to women with a first term birth without preeclampsia, women with term preeclampsia were diagnosed at a younger age (36 vs 42 years) and women with preterm birth without preeclampsia had a lower estimated glomerular filtration rate at diagnosis (48 vs 64 ml/min/1.73 m(2)). CONCLUSION In women with kidney disease diagnosed at kidney biopsy, previous preeclampsia does not seem to be a risk marker for progression to ESRD.

Exaggerated Ca2+ signaling in preglomerular arteriolar smooth muscle cells of genetically hypertensive rats

Experiments were conducted to gain insight into mechanisms responsible for exaggerated renal vascular reactivity to ANG II and vasopressin (AVP) in spontaneously hypertensive rats (SHR) during the development of hypertension. Cytosolic calcium concentration ([Ca2+]i) was measured by ratiometric fura 2 fluorescence and a microscope-based photometer. Vascular smooth muscle cells (SMC) from preglomerular arterioles were isolated and dispersed using an iron oxide-sieving method plus collagenase treatment. ANG II and AVP produced rapid and sustained increases in [Ca2+]i. ANG II elicited similar dose-dependent increases in [Ca2+]iin SMC from SHR and Wistar-Kyoto rats (WKY). In contrast, AVP caused almost twofold larger responses in afferent arteriolar SMC from SHR. ANG II effects were inhibited by the AT1 receptor antagonist losartan. AVP action was blocked by the V1receptor antagonist [d(CH2)5,Tyr(NH2)9]AVP. In SMC pretreated with nifedipine, neither ANG II nor AVP elicited [Ca2+]iresponses. Poststimulation nifedipine reversed elevated [Ca2+]ito basal levels. Short-term reductions in external [Ca2+]i(EGTA) mimicked the nifedipine effects. Our study shows that AT1 and V1 receptors stimulate [Ca2+]iby a common mechanism characterized by preferential action on voltage-gated L-type channels sensitive to dihydropyridines. Calcium signaling elicited by AT1receptors does not differ between SHR and WKY; thus the in vivo exaggerated reactivity may be dependent on interactions with other cell types, e.g., endothelium. In contrast, AVP produced larger changes in [Ca2+]iin arteriolar SMC from SHR, and such direct effects can account for the exaggerated renal blood flow responses.

Renal hemodynamics during development of hypertension in young spontaneously hypertensive rats.

Background/Aims: Cross-transplantation studies between animals with genetic hypertension and normotensive animals indicate a key role of the kidney in development of hypertension, and studies in young spontaneously hypertensive rats (SHR) have shown reduced glomerular filtration rate (GFR) and renal blood flow (RBF) for a short period at the age of 4–6 weeks during blood pressure increase. We tested the hypothesis that a decline in GFR during development of hypertension in SHR might be more pronounced in juxtamedullary cortex than other cortical zones. Methods: By use of the aprotinin method, total and zonal cortical GFR was measured in anaesthetized Wistar-Kyoto (WKY) rats and SHR at the ages of 2, 4, 6, 8 and 10 weeks. RBF was measured by a transit time flowmeter. Results: Body and kidney weights in SHR and WKY were not significantly different in any age group (p >0.05). Mean arterial blood pressure (MAP) was not different at the age of 2 weeks (79 ± 6 mm Hg in SHR and 74 ± 5 mm Hg in WKY, p > 0.05), but was significantly higher in 4-week-old SHR (104 ± 1 mm Hg) compared to 4-week-old WKY (77 ± 3 mm Hg) (p < 0.01). The difference in blood pressure increased with age from 4 to 10 weeks. RBF, total GFR, and outer, middle, and inner cortical GFR increased with age but were not different in SHR and WKY in any age group (p >0.05). Renal vascular resistance was increased from 4 weeks of age in SHR (21.5 ± 1.8), significantly higher than WKY (14.4 ± 0.9 mm Hg·ml–1·min·g) (p < 0.01) and stayed at higher values in older age groups (p ≤ 0.01). Conclusion: RBF, total and zonal GFR are not significantly different in anaesthetized SHR compared to WKY at ages from 2 to 10 weeks and GFR in juxtamedullary cortex is not decreased in SHR during onset of hypertension. The results from the present study indicate that development of hypertension cannot be explained by a temporary decline in RBF or total or zonal GFR.

Arterial damage precedes the development of interstitial damage in the nonclipped kidney of two-kidney, one-clip hypertensive rats.

Background: The progression of damage in the renal cortex has not been investigated in the nonclipped kidney of the two-kidney, one-clip model of renal hypertension. In other hypertensive models, damage has been found to progress from the juxtamedullary cortex (JMC) and outward, which has been attributed to early vascular effects. Method: The present study investigated the relation between perivascular deposition of collagen and structural damage after 16 and 24 weeks of hypertension in the nonclipped kidney in rats. Results: Periarterial collagen density in the kidney was significantly increased already 16 weeks after clipping, at that time tubulointerstitial damage was not evident. After 24 weeks of clipping, periarterial collagen was further increased, and tubulointerstitial damage had developed in the JMC, whereas the outer cortex was protected. Interstitial collagen was not significantly increased in any cortex part during the course of the experiment. Collagen type I a1 mRNA was increased in the JMC after 24 weeks, and &agr; smooth muscle actin histochemistry and collagen type I a2 in-situ hybridization identified myofibroblasts around the arteries after 16 and 24 weeks as the major source of this increase. Conclusion: Fibrosis in the nonclipped kidney of renal hypertensive rats starts around the juxtamedullary resistance vessels and then progresses in the JMC, whereas the outer cortex is protected. This suggests that pressure-induced injury to the vasculature attracts or activates fibroblasts in the perivascular area, which may allow damage to progress by impairing vessel function.

Clinical Outcome of Patients with Wegener’s Granulomatosis Treated with Plasma Exchange

We report the clinical course of 29 patients with Wegener’s granulomatosis (WG) treated with plasma exchange (PE) in Norway in the period from 1988 to 1999. Median follow-up was 41.5 months. The mean number of exchanges was 8.5 ± 5.8 (range 2–32). Median serum creatinine concentration was 400 µmol/l (range 90–1,356) and 17 patients were dialysis dependent at presentation. Two- and five-year patient survival was 75 and 71%, respectively, and renal (ESRD-free) survival was 74 and 54%, respectively. Seven (50%) of the 14 patients alive in the dialysis group had discontinued dialysis within the first month, and 6 (50%) of 12 patients alive at follow-up had independent renal function. No patients, however, had normal serum creatinine concentration. Median time until development of ESRD for patients presenting with a need for dialysis was ∼32 months. The development of ESRD in 79 patients treated with immunosuppression alone was significantly lower, but when adjusted for serum creatinine there was no difference between patients treated with or without PE. Although a considerable fraction of patients with WG and severe renal involvement regain independent renal function, few will have normal serum creatinine concentration at follow-up, despite the addition of PE as adjunctive therapy.