Urinary Concentration Capacity Research Articles

Dehydration associates with lower urinary tract symptoms in progressive multiple sclerosis.

Lower urinary tract symptoms (LUTS) are common in persons with progressive multiple sclerosis (pwPMS), who may consequently limit their fluid intake. We aimed to investigate the hypothesis that LUTS associate with objective evidence of inadequate hydration status in pwPMS. In this prospective study, 55 pwPMS were studied over 2 years. A 6-monthly first-morning urine specimen was analysed for urinary osmolality and sodium as hydration markers. LUTS symptom severity in three categories (urgency, voiding and discomfort) was assessed and quantified using a questionnaire. Correlation between LUTS severity and hydration was assessed within subjects and between subjects, controlling for age. Some 274 urine samples with accompanying LUTS data from 55 participants were analysed. Biochemical data showed the expected loss of urine-concentrating capacity with increasing age. Inadequate hydration was observed in 47% of participants. LUTS were very common (87% reported urgency and 89% voiding symptoms). Voiding and discomfort, but not urgency severity, were correlated with hydration markers, both within and between participants. LUTS are very common in pwPMS, and associate with inadequate hydration. The causes and consequences of inadequate hydration in MS need further study, since (i) this will focus greater attention on LUTS management in pwPMS and (ii) dehydration has been associated with reversible cognitive dysfunction and physical underperformance.

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

Association of the Urine-to-Plasma Urea Ratio With CKD Progression

The urine-to-plasma (U/P) ratio of urea is correlated with urine-concentrating capacity and associated with progression of autosomal dominant polycystic kidney disease. As a proposed biomarker of tubular function, we hypothesized that the U/P urea ratio would also be associated with progression of more common forms of chronic kidney disease (CKD). Observational cohort study. 3,723 adults in the United States with estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m2, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. U/P urea ratio, calculated from 24-hour urine collections and plasma samples at baseline. Associations of U/P urea ratio with eGFR slope, initiation of kidney replacement therapy (KRT), and CKD progression, defined as 50% decline in eGFR or incident KRT. Multivariable linear mixed-effects models tested associations with eGFR slope. Cox proportional hazards models tested associations with dichotomous CKD outcomes. The median U/P urea ratio was 14.8 (IQR, 9.5-22.2). Compared with participants in the highest U/P urea ratio quintile, those in the lowest quintile had a greater eGFR decline by 1.06 mL/min/1.73 m2 per year (P< 0.001) over 7.0 (IQR, 3.0-11.0) years of follow-up observation. Each 1-SD lower natural log-transformed U/P urea ratio was independently associated with CKD progression (HR, 1.22 [95% CI, 1.12-1.33]) and incident KRT (HR, 1.22 [95% CI, 1.10-1.33]). Associations differed by baseline eGFR (P interaction= 0.009). Among those with an eGFR≥30 mL/min/1.73 m2, each 1-SD lower in ln(U/P urea ratio) was independently associated with CKD progression (HR, 1.30 [95% CI, 1.18-1.45]), but this was not significant among those with eGFR<30 mL/min/1.73 m2 (HR, 1.00 [95% CI, 0.84-1.20]). Possibility of residual confounding. Single baseline 24-hour urine collection for U/P urea ratio. In a large and diverse cohort of patients with common forms of CKD, U/P urea was independently associated with disease progression and incident kidney failure. Associations were not significant among those with advanced CKD at baseline.

Erythropoietin prevented the decreased expression of aquaporin1-3 in ureteral obstructive kidneys in juvenile rats.

Urinary tract obstruction is associated with impaired renal urinary concentration; even after the release of the obstruction, patients still suffer from polyuria. It has been reported that the decreased expression of aquaporins (AQPs) is associated with postobstructive polyuria, and erythropoietin (EPO) can promote the recovery of decreased AQP2 expression induced by bilateral ureteral obstruction. However, whether EPO can promote the recovery of the expression of AQP1-3 after the release of unilateral ureteral obstruction (UUO) has not yet been reported. To investigate the effects of EPO treatment on the expression of renal AQP1-3 after the release of UUO. UUO was established in rats by 24-h temporary unilateral obstruction of renal ureters. Three days following EPO treatment, the kidneys were removed to determine the expression levels of AQP1-3, NLRP3, caspase-1, and IL-1β via semiquantitative immunoblotting and immunohistochemistry. EPO inhibited the expression of NLRP3, caspase-1, and IL-1β; reduced plasma creatinine and urea; and promoted the recovery of AQP1-3 expression in UUO rats. EPO treatment prevented the decreased expression of renal AQPs and the development of impaired urinary concentration capacity after the release of UUO, which may partially occur by way of anti-inflammasome effects. EPO treatment could prevent the decreased expression of renal water transporter proteins AQP1-3 and the development of impaired renal functions, which may be associated with its anti-inflammasome effects. EPO regulated the expression of renal water transporter proteins AQP1-3, which could provide the potential for the treatment of postobstructive polyuresis. EPO treatment could be one of the effective methods by participating in multiple dimensions for patients with obstructive nephropathy.

Peripheral Resistance to Arginine Vasopressin and Its Relationship with Plasmaosmolarityinaged Population

Background: The causes of age-related poor urine concentration capacity favouring low-grade chronic dehydration in aged populations are not well understood. Objectives: To explore links between age and plasma and urine osmolarity levels and a possible picture of peripheral resistance to arginine vasopressin (R-AVP) in an aged population. Design: observational cross-sectional study. Study population: communitydwelling subjects aged 70 years and older. Data collection: Blood and urine samples collected after 10 hours night fasting were analysed for osmolarity and copeptin levels (AVP surrogate). R-AVP was established based on a urinary osmolarity/copeptin ratrio&lt;35. Results: 237 subjects were recruited (mean age 75.7 years, 52.7% women). Plasma osmolarity was similar between the sexes and age groups (70-79 and ≥80 years); whereas urine osmolarity was lower in women and in the older age group. Plasma hyperosmolarity (&gt;295 mOsm/L) was present in no women and in 4.5% of men, and was significantly 14 times greater in the older group. R-AVP prevalence was 12.7% in the younger group vs 20.7% in the older group (p=0.252). Subjects with R-AVP, compared to without R-AVP, presented higher plasma osmolarity (287.6 vs 285.4 mOsm/L; p=0.023) and higher prevalence of plasma hyperosmolarity (8.7% and 0.7%; p=0.053). R-AVP was also related with IL-6 and creatinine levels and with loop diuretic use. Conclusions: Urine concentration capacity decreases and plasma hyperosmolarity increases after the age of 80 years. Fourteen percent of ≥70 year’s old population present R-AVP, which greatly increases the risk of plasmahyperosmolarity and is related with loop diuretic use, and IL-6 and creatinine levels.

Desmopressin oral lyophilisate in young children: new insights in pharmacokinetics and pharmacodynamics

ObjectiveTo study the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of desmopressin (dDAVP) oral lyophilisate in children below the age of 8 years with special emphasis on age-related and size-related differences in bioavailability.DesignOpen...

Use of the Urine-to-Plasma Urea Ratio to Predict ADPKD Progression.

Predicting disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) poses a challenge, especially in early-stage disease when kidney function is not yet affected. Ongoing growth of cysts causes maximal urine-concentrating capacity to decrease from early on. We therefore hypothesized that the urine-to-plasma urea ratio, as a reflection of the urine-concentrating capacity, can be used as a marker to predict ADPKD progression. The urine-to-plasma urea ratio was calculated by dividing concentrations of early morning fasting spot urine urea by plasma urea. First, this ratio was validated as surrogate marker in 30 patients with ADPKD who underwent a prolonged water deprivation test. Thereafter, association with kidney outcome was evaluated in 583 patients with ADPKD with a broad range of kidney function. Multivariable mixed-model regression was used to assess association with eGFR slope, and logarithmic regression to identify patients with rapidly progressive disease, using a cutoff of -3.0 ml/min per 1.73 m2 per year. The urine-to-plasma urea ratio was compared with established predictors, namely, sex, age, baseline eGFR, Mayo Clinic height-adjusted total kidney volume class, and PKD gene mutation. The maximal urine-concentrating capacity and urine-to-plasma urea ratio correlated strongly (R=0.90; P<0.001). Next, the urine-to-plasma urea ratio was significantly associated with rate of eGFR decline during a median follow-up of 4.0 (interquartile range, 2.6-5.0) years, both crude and after correction for established predictors (β=0.58; P=0.02). The odds ratio of rapidly progressive disease was 1.35 (95% confidence interval, 1.19 to 1.52; P<0.001) for every 10 units decrease in urine-to-plasma urea ratio, with adjustment for predictors. A combined risk score of the urine-to-plasma urea ratio, Mayo Clinic height-adjusted total kidney volume class, and PKD mutation predicted rapidly progressive disease better than each of the predictors separately. The urine-to-plasma urea ratio, which is calculated from routine laboratory measurements, predicts disease progression in ADPKD in addition to other risk markers. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_01_27_CJN10470620_final.mp3.

Association of Renal Glomerular and Tubular Function With Renal Outcome in Patients With Posterior Urethral Valves

ObjectiveTo analyze renal glomerular and tubular function and their association in patients operated for posterior urethral valves and to prognosticate the risk for end-stage kidney disease (ESKD) MethodsSixty-three previously treated patients were evaluated for renal function during 1987-1991. The patients’ age at evaluation was 11 years (range 2-24). Glomerular function was assessed by measuring glomerular filtration rate (GFR) and urine albumin excretion. Tubular function was determined by measuring urine concentration capacity and excretion of electrolytes (Na, K, Cl, Ca, P, Mg) and β-2-microglobulin. Additionally, the prevalence of hypertension and serum parathyroid hormone and aldosterone values were registered. Tubular function was compared with GFR and the risk of developing ESKD before November 2018. ResultsTwenty of the study patients (32%) had decreased GFR. In addition, 19% had proteinuria and 56% were hypertensive. Those without proteinuria or hypertension had better GFR values (P < .01 for both). There was a significant correlation between GFR and all the tubular function (P < .05) variables (except excretion of chloride) measured. Compared to the patients with favorable renal outcome, the patients (n = 10) who later developed ESKD had significantly (P < .01) lower GFR and reduced urinary excretion of all measured electrolytes except calcium. Consistently, urine β-2 microglobulin and serum parathyroid hormone and aldosterone values were significantly higher in the patients who developed ESKD (P ≤ .01). ConclusionBoth glomerular and tubular function decline was common and several parameters were likely to predict ESKD in posterior urethral valves patients.

Syndromes de Bartter–Gitelman

Bartter–Gitelman syndromes are rare inherited autosomal recessive salt-losing tubulopathies characterized by severe and chronic hypokalemia associated with metabolic alkalosis and secondary hyperaldosteronism. Bartter syndrome results from a furosemide-like defect in sodium reabsorption in the Henle's loop leading to hypercalciuria and defect in urinary concentration capacity. The antenatal Bartter syndrome is defined by polyhydramnios and an infantile polyuria with severe dehydration whereas classic Bartter syndrome appears during childhood or adulthood. Gitelman syndrome is a thiazide-like salt-losing tubulopathy. It is associated with hypomagnesemia, hypocalciuria without defect in urinary concentration capacity. The diagnosis is most often made in adolescents or adults. Clinical symptoms include tetany, delay in the height-weight growth curves, chronic tiredness, muscle weakness, myalgia and vertigo. Nephrocalcinosis in Bartter syndrome could lead to chronic kidney disease. Antenatal Bartter syndrome requires hospitalization in intensive care unit to manage the severe newborn dehydration. Chondrocalcinosis is the major complication in the Gitelman syndrome. The corner stones of treatment is the fluid and electrolyte management Bartter and Gitelman syndromes need lifelong oral supplementations of potassium, salt (Bartter) and magnesium (Gitelman). Indomethacin is efficient to reduce water and electrolyte loss in Bartter. In Gitelman, potassium-sparing diuretics may be helping for severe hypokaliemia but they will reinforce hypovolemia.

Tubular Acidification Defect in Adults with Sickle Cell Disease.

Metabolic acidosis is a frequent manifestation of sickle cell disease but the mechanisms and determinants of this disorder are unknown. Our aim was to characterize urinary acidification capacity in adults with sickle cell disease and to identify potential factors associated with decreased capacity to acidify urine. Among 25 adults with sickle cell disease and an eGFR of ≥60 ml/min per 1.73 m2 from a single center in France, we performed an acute acidification test after simultaneous administration of furosemide and fludrocortisone. A normal response was defined as a decrease in urinary pH <5.3 and an increase in urinary ammonium excretion ≥33 µEq/min at one or more of the six time points after furosemide and fludrocortisone administration. Of the participants (median [interquartile range] age of 36 [24-43] years old, 17 women), 12 had a normal and 13 had an abnormal response to the test. Among these 13 participants, nine had normal baseline plasma bicarbonate concentration. Plasma aldosterone was within the normal range for all 13 participants with an abnormal response, making the diagnosis of type 4 tubular acidosis unlikely. The participants with an abnormal response to the test were significantly older, more frequently treated with oral bicarbonate, had a higher plasma uric acid concentration, higher hemolysis activity, lower eGFR, lower baseline plasma bicarbonate concentration, higher urine pH, lower urine ammonium ion excretion, and lower fasting urine osmolality than those with a normal response. Considering both groups, the maximum urinary ammonium ion excretion was positively correlated with fasting urine osmolality (r2=0.34, P=0.002), suggesting that participants with sickle cell disease and lower urine concentration capacity have lower urine acidification capacity. Among adults with sickle cell disease, impaired urinary acidification capacity attributable to distal tubular dysfunction is common and associated with the severity of hyposthenuria. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_12_10_CJN07830719.mp3.

Antidiuretic Hormone and Serum Osmolarity Physiology and Related Outcomes: What Is Old, What Is New, and What Is Unknown?

Although the physiology of sodium, water, and arginine vasopressin (AVP), also known as antidiuretic hormone, has long been known, accumulating data suggest that this system operates as a more complex network than previously thought. English-language basic science and clinical studies of AVP and osmolarity on the development of kidney and cardiovascular disease and overall outcomes. Apart from osmoreceptors and hypovolemia, AVP secretion is modified by novel factors such as tongue acid-sensing taste receptor cells and brain median preoptic nucleus neurons. Moreover, pharyngeal, esophageal, and/or gastric sensors and gut microbiota modulate AVP secretion. Evidence is accumulating that increased osmolarity, AVP, copeptin, and dehydration are all associated with worse outcomes in chronic disease states such as chronic kidney disease (CKD), diabetes, and heart failure. On the basis of these pathophysiological relationships, an AVP receptor 2 blocker is now licensed for CKD related to polycystic kidney disease. From a therapeutic perspective, fluid intake may be associated with increased AVP secretion if it is driven by loss of urine concentration capacity or with suppressed AVP if it is driven by voluntary fluid intake. In the current review, we summarize the literature on the relationship between elevated osmolarity, AVP, copeptin, and dehydration with renal and cardiovascular outcomes and underlying classical and novel pathophysiologic pathways. We also review recent unexpected and contrasting findings regarding AVP physiology in an attempt to explain and understand some of these relationships.

Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the Gdnf-Axis in Kidney Development.

The mammalian kidney develops through reciprocal inductive signals between the metanephric mesenchyme and ureteric bud. Transcription factor 21 (Tcf21) is highly expressed in the metanephric mesenchyme, including Six2-expressing cap mesenchyme and Foxd1-expressing stromal mesenchyme. Tcf21 knockout mice die in the perinatal period from severe renal hypodysplasia. In humans, Tcf21 mRNA levels are reduced in renal tissue from human fetuses with renal dysplasia. The molecular mechanisms underlying these renal defects are not yet known. Using a variety of techniques to assess kidney development and gene expression, we compared the phenotypes of wild-type mice, mice with germline deletion of the Tcf21 gene, mice with stromal mesenchyme-specific Tcf21 deletion, and mice with cap mesenchyme-specific Tcf21 deletion. Germline deletion of Tcf21 leads to impaired ureteric bud branching and is accompanied by downregulated expression of Gdnf-Ret-Wnt11, a key pathway required for branching morphogenesis. Selective removal of Tcf21 from the renal stroma is also associated with attenuation of the Gdnf signaling axis and leads to a defect in ureteric bud branching, a paucity of collecting ducts, and a defect in urine concentration capacity. In contrast, deletion of Tcf21 from the cap mesenchyme leads to abnormal glomerulogenesis and massive proteinuria, but no downregulation of Gdnf-Ret-Wnt11 or obvious defect in branching. Our findings indicate that Tcf21 has distinct roles in the cap mesenchyme and stromal mesenchyme compartments during kidney development and suggest that Tcf21 regulates key molecular pathways required for branching morphogenesis.

Comparative short-term variation of urine concentration among three sigmodontine rodent species from contrasting habitats

We compared urine concentration capacity among three phylogenetically closed sigmodontine rodent species that occur in two distinct habitats: Necromys lasiurus (xeric), Akodon cursor and Akodon lindberghi (mesic). Water conservation ability was evaluated in 30 h-trials, with urine collected every 6 h. A control (I- water and food ad libitum) and a test (II- food and water deprivation) were conducted for each species. Body mass loss (BML), urine volume (UV), urine relative volume (UVr) and urine concentration (UC) were compared between experiments I and II for each species and among species. Changes in urine osmolality between experiments were modeled using exponential and sine functions. Circadian variation of urine concentration was obtained by sine functions fit to the experiments I. Best fit was achieved for sine functions with an accumulation term for experiments II, showing that even in stressful conditions the circadian variation is still present. Highest UC and lowest BML were obtained from Necromys lasiurus individuals, which achieved them at faster rates. The lowest UC with highest BML were obtained for A. cursor individuals at slower rates and values than A. lindberghi, which were intermediate. Necromys lasiurus is more adapted for xeric habitats achieving higher urine concentration in shorter time and faster rate than species of genus Akodon.

Renal Evaluation in Common Variable Immunodeficiency.

Introduction Common variable immunodeficiency (CVID) comprises a heterogeneous group of disorders characterized by impaired antibody production. Kidney involvement in CVID is described in isolated and sporadic case reports. The objective of this study was to study the renal function pattern in CVID patients through glomerular and tubular function tests. Methods Study of 12 patients with CVID diagnosis and 12 healthy control individuals. Glomerular filtration rate (GFR), fractional excretion of sodium (FENa+) and potassium (FEK+), urinary concentration, and acidification capacity were measured. In addition, microalbuminuria and urinary monocyte chemoattractant protein-1 (MCP-1) were evaluated as markers of selectivity of the glomerular barrier and inflammation, respectively. Results In relation to glomerular markers, all CVID patients had normal GFR (>90 mL/min/1.73 m2), and microalbuminuria and urinary MCP-1 levels were also similar to those of controls. Interestingly, CVID patients had reduced urinary concentration capacity, as demonstrated by lower U/POsm ratio, when compared to controls. Also, while all control subjects achieved a urinary pH less than 5.3, no CVID patients showed a decrease in urinary pH to such levels in response to acid loading with CaCl2, characterizing impaired urinary acidification capacity. Conclusion Patients showed a trend towards an elevated prevalence of tubular dysfunction, mainly related to urinary acidification and concentration capacities.

Kidney function and plasma copeptin levels in healthy kidney donors and autosomal dominant polycystic kidney disease patients.

Plasma copeptin, a marker of arginine vasopressin, is elevated in patients with autosomal dominant polycystic kidney disease and predicts disease progression. It is unknown whether elevated copeptin levels result from decreased kidney clearance or as compensation for impaired concentrating capacity. Data from patients with autosomal dominant polycystic kidney disease and healthy kidney donors before and after donation were used, because after donation, overall GFR decreases with a functionally normal kidney. Data were obtained between October of 2008 and January of 2012 from healthy kidney donors who visited the institution for routine measurements predonation and postdonation and patients with autosomal dominant polycystic kidney disease who visited the institution for kidney function measurement. Plasma copeptin levels were measured using a sandwich immunoassay, GFR was measured as (125)I-iothalamate clearance, and urine concentrating capacity was measured as urine-to-plasma ratio of urea. In patients with autosomal dominant polycystic kidney disease, total kidney volume was measured with magnetic resonance imaging. Patients with autosomal dominant polycystic kidney disease (n=122, age=40 years, men=56%) had significantly higher copeptin levels (median=6.8 pmol/L; interquartile range=3.4-15.7 pmol/L) compared with donors (n=134, age=52 years, men=49%) both predonation and postdonation (median=3.8 pmol/L; interquartile range=2.8-6.3 pmol/L; P<0.001; median=4.4 pmol/L; interquartile range=3.6-6.1 pmol/L; P<0.001). In donors, copeptin levels did not change after donation, despite a significant fall in GFR (from 105 ± 17 to 66 ± 10; P<0.001). Copeptin and GFR were significantly associated in patients with autosomal dominant polycystic kidney disease (β=-0.45, P<0.001) but not in donors. In patients with autosomal dominant polycystic kidney disease, GFR and total kidney volume were both associated significantly with urine-to-plasma ratio of urea (β=0.84, P<0.001; β=-0.51, P<0.001, respectively). On the basis of the finding in donors that kidney clearance is not a main determinant of plasma copeptin levels, it was hypothesized that, in patients with autosomal dominant polycystic kidney disease, kidney damage and associated impaired urine concentration capacity determine copeptin levels.

Renal function evaluation in patients with American Cutaneous Leishmaniasis after specific treatment with pentavalent antimonial

BackgroundRenal evaluation studies are rare in American Cutaneous Leishmaniasis (ACL). The aim of this study is to investigate whether specific treatment reverts ACL-associated renal dysfunction.MethodsA prospective study was conducted with 37 patients with ACL. Urinary concentrating and acidification ability was assessed before and after treatment with pentavalent antimonial.ResultsThe patients mean age was 35.6 ± 12 years and 19 were male. Before treatment, urinary concentrating defect (U/Posm <2.8) was identified in 27 patients (77%) and urinary acidification defect in 17 patients (46%). No significant glomerular dysfunction was observed before and after specific ACL treatment. There was no reversion of urinary concentrating defects, being observed in 77% of the patients before and in 88% after treatment (p = 0.344). Urinary acidification defect was corrected in 9 patients after treatment, reducing its prevalence from 40% before to only 16% after treament, (p = 0.012). Microalbuminuria higher than 30 mg/g was found in 35% of patients before treatment and in only 8% after treatment. Regarding fractional excretion of sodium, potassium, calcium, phosphorus and magnesium, there was no significant difference between pre and post-treatment period.ConclusionAs previously described, urinary concentrating and acidification defects were found in an important number of patients with ACL. Present results demonstrate that only some patients recover urinary acidification capacity, while no one returned to normal urinary concentration capacity.

Effect of Chronic Inhibition of Converting Enzyme on Renal Handling of Salt and Water: A Study on a Pediatric Population

Background/Aims: The effect of angiotensin-converting enzyme inhibition (ACEi) is amply documented in several pathological conditions. However, there are few reports about the effect of chronic ACEi on salt and water balance. The present work evaluates the effect of chronic ACEi on salt and water balance in a population of children receiving enalapril chronically in order to reduce albuminuria elicited by a uremic hemolytic syndrome. Methods: Nine children aged from 9 to 19 years with normal glomerular filtration rate, normotension and with urinary concentration capacity preserved were treated with enalapril with doses ranging between 0.1 and 0.30 mg/kg/day. Diuresis, urinary absolute and fractional excretion of Na⁺, K⁺ and urea, creatinine clearance, osmolal clearance and tubular water reabsorption were measured under three experimental procedures: (1) with free access to water; (2) with a water load and (3) with water restriction. In the last group urinary antidiuretic hormone (ADH) was measured. These tests were performed in a paired way, just before starting ACEi treatment and after 6 months of enalapril treatment. Results: Enalapril treatment diminished the urinary concentration capacity without affecting Na⁺ and K⁺ urinary excretion. Creatinine clearance was not modified except in the condition of water load where a fall in it was found after ACEi. ADH increased after enalapril treatment in children under water restriction. Conclusion: In these children chronic ACEi decreases urinary concentration capacity.

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

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][1]). However, many ADPKD patients with GFRs indistinguishable from normal are unable to increase the

Tissue injury after lithium treatment in human and rat postnatal kidney involves glycogen synthase kinase-3β-positive epithelium

It was hypothesized that lithium causes accelerated and permanent injury to the postnatally developing kidney through entry into epithelial cells of the distal nephron and inhibition of glycogen synthase kinase-3β (GSK-3β). GSK-3β immunoreactivity was associated with glomeruli, the thick ascending limb of Henle's loop, and collecting ducts in the developing and adult human and rat kidney. In rats, the abundance of inactive, phosphorylated GSK-3β (pGSK-3β) protein decreased during postnatal development. After feeding of dams with litters lithium [50 mmol Li/kg chow, postnatal (P) days 7-28], the offspring showed plasma lithium concentration of 1.0 mmol/l. Kidneys from lithium-treated rat pups exhibited dilated distal nephron segments with microcysts. Stereological analysis showed reduced cortex and outer medullary volumes. Lithium increased pGSK-3β and the proliferation marker proliferating cell nuclear antigen (PCNA) protein abundances in the cortex and medulla. After lithium treatment, pGSK-3β-immunopositive cells exhibited restricted distribution and were associated primarily with subsets of cells in dilated and microcystic segments of cortical collecting ducts. After 6 wk of lithium discontinuation, adult rats exhibited attenuated urine concentration capacity and diminished outer medullary volume. Histological sections of two nephrectomy samples and a biopsy from three long-term lithium-treated patients showed multiple cortical microcysts that originated from normally appearing tubules. Microcysts were lined by a cuboidal PCNA-, GSK-3β-, and pGSK-3β-immunopositive epithelium. The postnatal rat kidney may serve as an experimental model for the study of lithium-induced human kidney injury. The data are compatible with a causal relationship between epithelial entry of lithium into cells of the aldosterone-sensitive distal nephron, inactivation of GSK-3β, proliferation, and microcysts.

Karl Peter’s fundamental contribution to the structural organization of the kidney

Karl Peter provided the first detailed description of the structure and morphology of the human kidney and defined at least 9 major segments of the tubules. He showed that the nephrons were heterogeneous in their structure and could be divided in 2 categories: the short-looped and the long-looped ones. Peter's scheme of the human nephrons was published in many journals and textbooks. Another contribution was the demonstration of a relationship between the relative occurrence of long thin loops (versus short loops) and the maximal urinary concentration capacity. Peter was also the first to describe the cells of the macula densa, which are of fundamental importance in the tubuloglomerular feedback mechanism. Furthermore, Peter gave a detailed description of the principal zones of the human kidney: the cortex, the outer medulla with outer and inner stripes, and the inner medulla.