Urine-concentrating defects exacerbate with age in male offspring with a low-nephron endowment

Singh, Reetu R.; Denton, Kate M.; Bertram, John F.; Dowling, John P.; Moritz, Karen M.

doi:10.1152/ajprenal.00463.2011

Cited by 19 publications

(25 citation statements)

References 46 publications

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“…Studies in isolated dog kidneys have reported that furosemide administration in the presence of the anti-diuretic hormone arginine vasopressin (AVP) increases CH 2 O, which is associated with reduced water reabsorption in the collecting ducts, indicating that the collecting ducts may be desensitized to AVP in the presence of a diuretic (44). Recently, we have shown that in response to both AVP infusion and to a 30-h period of dehydration, these uni-x animals have a significantly reduced urine concentrating ability (34). This defect in concentrating ability was observed despite plasma AVP levels being similar between the treatment groups (34).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we have shown that in response to both AVP infusion and to a 30-h period of dehydration, these uni-x animals have a significantly reduced urine concentrating ability (34). This defect in concentrating ability was observed despite plasma AVP levels being similar between the treatment groups (34). AVP regulates water transport by acting on the aquaporin 2 (AQP-2) channels in the collecting duct segments, and the expression of AQP-2 is significantly reduced in the uni-x animals at 6 mo of age (34); therefore, it is possible that the increase in CH 2 O in response to furosemide in the current study is due to the decrease in the AQP-2 channels in these animals.…”

Section: Discussionmentioning

confidence: 99%

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Renal responses to furosemide are significantly attenuated in male sheep at 6 months of age following fetal uninephrectomy

Singh

Bertram²,

Denton

2012

American Journal of Physiology-Regulatory, Integrative and Comp

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We have previously shown that fetal uninephrectomy (uni-x) at 100 days of gestation (term = 150 days) in male sheep results in a 30% nephron deficit, reduction in glomerular filtration rate (GFR) and renal blood flow, and elevation in arterial pressure at 6 mo of age. Furthermore, in response to an acute 0.9% saline load, sodium excretion was significantly delayed in uni-x animals leading us to speculate that tubuloglomerular feedback (TGF) activity was reset in uni-x animals. In the present study, we induced TGF blockade by furosemide administration (1.5 mg/kg iv over 90 min) and determined GFR, effective renal plasma flow, and urine and sodium excretion responses in 6-mo-old male sheep. In response to furosemide, a significant diuresis and natriuresis was observed in the sham group; however, the response was significantly delayed and reduced in uni-x animals (both, P(treatment×time) < 0.001). Cummulative urinary and sodium output was significantly less in the uni-x compared with the sham sheep (both, P(treatment×time) < 0.001). GFR was increased in the sham but not the uni-x sheep (P(treatment×time) < 0.0001). In conclusion, the excretory response to furosemide was attenuated in the uni-x sheep, and this suggests a rightward resetting of the TGF operating point. The TGF mechanism is important in the fine tuning of sodium homeostasis and is likely a contributing factor for the dysfunction in sodium regulation we have previously observed in the uni-x animals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Renal responses to furosemide are significantly attenuated in male sheep at 6 months of age following fetal uninephrectomy

Singh

Bertram²,

Denton

2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…This will lead to tubular growth/lengthening [45] and alteration in the number or function of the ion channels/transporters in the tubule thereby contributing to the programming of hypertension. To date changes in the gene expression of sodium, calcium and water channels have been documented in several models of programmed hypertension [46][47][48][49]50 ], but as expression levels often do not indicate functional activity the impact of these adaptations require further study in programming models.…”

Section: Impaired Renal Sodium Handlingmentioning

confidence: 99%

Role of the kidney in the fetal programming of adult cardiovascular disease: an update

Singh

Denton

2015

Current Opinion in Pharmacology

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“…Interestingly, human renal donors with otherwise excellent numerical GFR values exhibit a "mild" defect in maximal urine concentration, as do uninephrectomized animals (17,18). Perhaps the most elegant model illustrating the long-term consequences of a solitary kidney is a study of uninephrectomized fetal sheep that were studied 6 months and 4 years after birth (19). Uninephrectomized animals had lower maximal urine osmolalities than normal animals after 30 hours of dehydration and supplementary infusion of AVP.…”

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Bully Renal Cysts Knock Down Urine-Concentrating Capacity in the Early Rounds

Grantham

2012

Clinical Journal of the American Society of Nephrology

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The commonly accepted manifestations of renal insufficiency are usually not recognized in patients with autosomal dominant polycystic kidney disease (ADPKD) until the fourth decade of life (1). However, many ADPKD patients with GFRs indistinguishable from normal are unable to increase the osmolality of urine above 800 mosm/kg H 2 O after overnight dehydration or after the parenteral administration of supplementary vasopressin. This "concentrating defect" can be detected in some young children and young adults decades before the GFR noticeably declines, indicating that parenchymal malfunction begins very early in the course of renal cystic disease (2). In an excellent study reported in this issue of CJASN, Zittema et al. (3) confirm that maximal urine concentration capacity is lost in ADPKD patients compared with normal controls. Still at issue is the mechanism(s) by which ADPKD impairs the maximal concentration of the urine.The baseline urine volumes, osmolar excretion rates, and plasma arginine vasopressin (AVP) and copeptin concentrations were not appreciably different between ADPKD patients and controls in this study; however, after overnight dehydration, the plasma levels of AVP and copeptin were significantly and persistently higher in the ADPKD subjects, and the urine osmolality was persistently lower than in the controls. The authors found evidence of an intact hypothalamic mechanism for the osmotic release of vasopressin, meaning that the defect must lie in the kidneys. Interestingly, ADPKD patients had higher plasma and lower urine concentrations of urea after achieving the highest elevation of urine osmolality, suggesting that urea clearance was decreased in the ADPKD patients even though eGFR was not different between study patients and control subjects. The urea excretion rate after dehydration was not reported; however, the similar baseline osmolar excretion rates make it unlikely that the urea excretion rates in the ADPKD patients were different from normal.The plasma urea levels were elevated in the ADPKD patients, possibly reflecting a decreased renal urea clearance. Because plasma sodium levels were equal in patients and control subjects, the increased urea concentration probably accounts for the consistent elevation of plasma osmolality in ADPKD patients compared with control subjects. Because urea distributes relatively freely in body water, it is unlikely that the small increase in plasma osmolality caused by increased urea concentration was responsible for the increased plasma concentrations of AVP and copeptin in the ADPKD patients. On the other hand, the restriction of water intake unquestionably increased plasma levels of vasopressin and copeptin and the reabsorption of free water in the patients, although to a lesser degree than in control subjects. A nonosmotic vasopressin releasing mechanism, e.g., extracellular fluid volume contraction, is a reasonable possibility and, in this regard, careful measurements of changes in body weight and urine volume before and after water restriction wo...

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Urine-concentrating defects exacerbate with age in male offspring with a low-nephron endowment

Abstract: Singh RR, Denton KM, Bertram JF, Dowling J, Moritz KM. Urineconcentrating defects exacerbate with age in male offspring with a lownephron endowment.

Cited by 19 publications

References 46 publications

Renal responses to furosemide are significantly attenuated in male sheep at 6 months of age following fetal uninephrectomy

Renal responses to furosemide are significantly attenuated in male sheep at 6 months of age following fetal uninephrectomy

Role of the kidney in the fetal programming of adult cardiovascular disease: an update

Bully Renal Cysts Knock Down Urine-Concentrating Capacity in the Early Rounds

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