Central diabetes insipidus and pain medications – a risky combination

Background Central Diabetes Insipidus (CDI) results from decreased production of antidiuretic hormone (ADH) leading to an inability to concentrate urine. CDI is treated with desmopressin (DDAVP). Rarely reported in the literature, opioids and non-steroidal anti-inflammatories (NSAIDs) can induce hyponatremia in individuals treated for CDI. Case presentation A 10-year-old boy with septo-optic dysplasia and CDI was treated with DDAVP 1.6 mg orally TID maintaining normal sodium levels. Post admission for a femur fracture, he was discharged on ibuprofen and hydromorphone. Sodium was 136 mmol/l two days before discharge. He returned to the ED after having a seizure at home. He was euvolemic and mildly lethargic. Sodium was low at 108 mmol/l. DDAVP and hydromorphone were held and he was fluid restricted, but the sodium remained low. Sodium began to rise when Ibuprofen was stopped. Intermittent small doses of DDAVP were given to facilitate gradual correction of hyponatremia. At discharge, sodium had normalized. Conclusion Hyponatremia has occasionally been described as a side effect of opioids and rarely of NSAIDs in patients with CDI. Stimulation of the thirst centre may play a role with opioids while a decrease in urine output may be the mechanism with NSAIDs.

Deletion of Cdh-16 Ksp-cadherin leads to a developmental delay in the ability to maximally concentrate urine in mouse

Ksp-cadherin (Cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system of the mammalian kidney. The principal aim of the present study was to determine if Ksp-cadherin played a critical role in the development and maintenance of the adult mammalian kidney by generating and evaluating a mouse line deficient in Ksp-cadherin. Ksp-null mutant animals were viable and fertile, and kidneys from both neonates and adults showed no evidence of structural abnormalities. Immunolocalization and Western analyses of Na/K-ATPase and E-cadherin indicated that Ksp-cadherin is not essential for either the genesis or maintenance of the polarized tubular epithelial phenotype. Moreover, E-cadherin expression was not altered to compensate for Ksp-cadherin loss. Plasma electrolytes, total CO2, BUN, and creatinine levels were also unaffected by Ksp-cadherin deficiency. However, a subtle but significant developmental delay in the ability to maximally concentrate urine was detected in Ksp-null mice. Expression analysis of the principal proteins involved in the generation of the cortico-medullary osmotic gradient and the resultant movement of water identified misexpression of Aquaporin-2 in the inner medullary collecting duct as the possible cause for the inability of young adult Ksp-cadherin deficient animals to maximally concentrate their urine. In conclusion, Ksp-cadherin is not required for normal kidney development but its absence leads to a developmental delay in maximal urinary concentrating ability.

Prevalence of various forms of diabetes insipidus and its complications in the Republic of Uzbekistan

Background. Central diabetes insipidus is characte­rized by the inability of the kidneys to reabsorb water and concentrate urine, which is due to the defect in the synthesis or secretion of vasopressin and is manifested by severe thirst and excretion of large amounts of diluted urine. The purpose of the study is to assess the prevalence of various forms of diabetes insipidus and its complications, the quality of diagnosis and treatment according to the data of regional endocrinological dispensaries of the Republic of Uzbekistan. Materials and methods. The study used data from the register of patients with diabetes insipidus registered in regional endocrinological centers in all regions of the Republic of Uzbekistan and the Republic of Karakalpakstan in 2018, as well as our own observations. It was found that by the end of 2018, 1,237 children and adolescents with diabetes insipidus were registered in the Republic of Uzbekistan and the Republic of Karakalpakstan. Of these, data of 397 patients with diabetes insipidus were analyzed. Their average age was 5.6 ± 2 years. Results. The idiopathic form of diabetes insipidus was observed predominantly — in 214 individuals (55.8 %), the second most common form was central diabetes insipidus — 129 patients (40.9 %), while the renal and hereditary forms of the disease were less common — 26 (3.3 %) and 3 (0.2 %), respectively. The majority of patients (48.9 %) did not associate the onset of the disease with any factor. However, in 20.4 % of individuals, diabetes insipidus developed after a skull injury. In 4.8 % of patients, the cause of the disease was tumors of the hypothalamic-pituitary region, and in 14.5 % — neuroviral infection. Hereditary predisposition was observed in 0.4 % of patients. Conclusions. In the regions of the Republic of Uzbekistan and the Republic of Karakalpakstan, two forms of diabetes insipidus were most common: idiopathic — 214 (55.8 %) and central — 129 cases (40.9 %). Most of the patients — 85 children (22.9%) — were aged 0 to 9 years. The average age of ill children and adolescents was 7.6 years. The disease was more often detected in males (51.1 %).

Pathophysiological Relevance of Renal Medullary Conditions on the Behaviour of Red Cells From Patients With Sickle Cell Anaemia

Red cells from patients with sickle cell anaemia (SCA) contain the abnormal haemoglobin HbS. Under hypoxic conditions, HbS polymerises and causes red cell sickling, a rise in intracellular Ca2+ and exposure of phosphatidylserine (PS). These changes make sickle cells sticky and liable to lodge in the microvasculature, and so reduce their lifespan. The aim of the present work was to investigate how the peculiar conditions found in the renal medulla – hypoxia, acidosis, lactate, hypertonicity and high levels of urea – affect red cell behaviour. Results show that the first four conditions all increased sickling and PS exposure. The presence of urea at levels found in a healthy medulla during antidiuresis, however, markedly reduced sickling and PS exposure and would therefore protect against red cell adherence. Loss of the ability to concentrate urine, which occurs in sickle cell nephropathy would obviate this protective effect and may therefore contribute to pathogenesis.

Hipernatremia dan Penatalaksanaanya

Hypernatremia could be caused by loss of water (increased loss or decreased intake), and although rarely, due to over intake of natrium. Patients who are at risk of hypernatremia are those with disturbance of thirst or limited access of water. Several factors that could cause hypernatremia especially among geriatric patients are, as follows: change of thirst stimuli, decreased ability to concentrate urine, and decreased total body water. Clinical signs of hypernatremia are usually not specific, however, patients tend to become symptomatic if hypernatemia occurs acutely. Hypernatremia clinical signs are mostly neurological related to the severity and the change of serum sodium concentration. Complications of hypernatremia are inter alia shrinkage of brain tissue due to the movement of water from intracellular to extracellular fluid which results in injury of brain vessels, bleeding in the brain, and a variety of neurological signs due to brain involovement which could lead to death. Management of hypernatremia has to be carried out accurately and thoroughly because inaccurate or too-rapid correction could risk the occurrence of cerebral edema.Keywords: hypernatremia, total body water Abstrak: Hipernatremia dapat disebabkan oleh kehilangan air (peningkatan kehilangan atau penurunan asupan) dan, walaupun jarang, karena kelebihan asupan natrium. Yang berisiko tinggi untuk hipernatremia ialah mereka dengan gangguan mekanisme rasa haus atau keterbatasan akses terhadap air. Berbagai faktor dapat menyebabkan hipernatremia terutama pada geriatri seperti perubahan rangsangan haus, berkurangnya kemampuan pemekatan urin, dan berkurangnya total body water. Gejala klinis hipernatremia biasanya tidak spesifik namun pasien cenderung menjadi simtomatik saat hipernatremia terjadi secara akut. Gejala hipernatremia terutama bersifat neurologik terkait dengan tingkat keparahan dan kecepatan perubahan konsentrasi natrium serum. Komplikasi hipernatremia ialah antara lain penyusutan otak akibat perpindahan cairan intrasel ke ekstrasel yang dapat merobek pembuluh darah otak, pendarahan otak, dan berbagai gejala neurologik akibat keterlibatan otak, yang dapat berakhir fatal. Penatalaksanaan hipernatremia perlu dilakukan dengan cermat karena penanganan yang tidak tepat atau koreksi yang terlalu cepat dapat berisiko terjadinya edema serebri.Kata kunci: hipernatremia, total body water

Convergent evolution of increased urine concentrating ability in desert mammals

One of the most celebrated textbook examples of physiological adaptations to desert environments is the unique ability that desert mammals have to produce hyperosmotic urine. Commonly perceived as an adaptation mainly observed in small rodents, the extent to which urine concentrating ability has independently evolved in distinct lineages, including medium-sized and large desert mammals, has not previously been assessed using modern phylogenetic approaches. Here, we explicitly test the general hypothesis that desert-dwelling mammals have evolved increased ability to concentrate urine compared to non-desert species, controlling for body mass and other covariates. Phylogenetic generalized least-squares models show that the mean aridity index of a species distribution range largely predicts its urine concentrating ability, even when accounting for body mass differences and phylogenetic correlations. In contrast, we find much weaker correlations between mass-adjusted basal metabolic rate and environmental variables.

GENETICS IN ENDOCRINOLOGY Pathophysiology, diagnosis and treatment of familial nephrogenic diabetes insipidus

For an endocrinologist, nephrogenic diabetes insipidus (NDI) is an end-organ disease, that is the antidiuretic hormone, arginine-vasopressin (AVP) is normally produced but not recognized by the kidney with an inability to concentrate urine despite elevated plasma concentrations of AVP. Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. For a geneticist, hereditary NDI is a rare disease with a prevalence of five per million males secondary to loss of function of the vasopressin V2 receptor, an X-linked gene, or loss of function of the water channel AQP2. These are small genes, easily sequenced, with a number of both recurrent and private mutations described as disease causing. Other inherited disorders with mild, moderate or severe inability to concentrate urine include Bartter’s syndrome and cystinosis. MAGED2 mutations are responsible for a transient form of Bartter’s syndrome with severe polyhydramnios. The purpose of this review is to describe classical phenotype findings that will help physicians to identify early, before dehydration episodes with hypernatremia, patients with familial NDI. A number of patients are still diagnosed late with repeated dehydration episodes and large dilations of the urinary tract leading to a flow obstructive nephropathy with progressive deterioration of glomerular function. Families with ancestral X-linked AVPR2 mutations could be reconstructed and all female heterozygote patients identified with subsequent perinatal genetic testing to recognize affected males within 2 weeks of birth. Prevention of dehydration episodes is of critical importance in early life and beyond and decreasing solute intake will diminish total urine output.

Severe Polyhydramnios with Consistent Fetal Full Bladder: A Novel Sign of Antenatal Bartter's Disease

Bartter's disease, an inherited renal tubular disorder is due to a defect in ion transport across the ascending limb of the loop of Henle leading to failure of the ability of kidneys to concentrate urine and hence polyuria. We present three fetuses of mothers with severe polyhydramnios with normal maternal blood sugar profile, routine Toxoplasma, Rubella, Cytomegalovirus, Herpes (TORCH) serology. The ultrasound showed no structural anomaly in the fetus, but consistent overdistended bladder with severe polyhydramnios was observed without any evidence of obstructive uropathy. The biochemical test on amniotic fluid was suggestive of Bartter's disease in case 1 and borderline in case 2, and next-generation sequencing confirmed a mutation of KCNJ1 associated with Bartter's disease Type II in case 1 and a mutation in SLC21A1 in case 2. Amniotic fluid biochemistry was inconclusive in case 3. A consistent full bladder with severe polyhydramnios with onset around 24 to 25 weeks was a novel finding which was observed due to fetal polyuria and can be used as a clue to investigate cases with severe polyhydramnios with no structural anomaly. Antenatal diagnosis will help in the proper management of child and genetic counseling for the next pregnancy.

Urinalysis in Great Dane Puppies from Birth to 28 Days of Age

Urinalysis, a common test in infants, could represent a suitable non-invasive clinical tool in puppies. In dog neonates, urine is easily collected by stimulating the somato-vesccal reflex. Information on urine characteristics during the neonatal period is missing. Beside instrumental laboratory analyses, the dipstick was proven useful for rapid urinalysis to evaluate specific gravity (SG), pH, leukocytes, nitrites, glucose, proteins, ketones, urobilinogen, bilirubin, and blood. The present study aimed to describe urinalysis features by the dipstick test and refractometer along the neonatal period. Urine samples (n = 624) were collected by manual stimulation from 48 healthy Great Danes, daily from birth to seven days, then twice a week until 28 days, to assess age-related changes (ANOVA, p < 0.05) and the possible effects of gender and litter (T-test, p < 0.05). The SG and pH significantly changed during the neonatal period. Other parameters did not vary significantly in relation to age. No significant differences were observed either among litters or between genders. The present study confirmed that canine kidneys are able to concentrate urine from the second week of age when the urinary SG started to be similar to adults, while pH still increased towards the typical values of adults at 28 days. Significant glucosuria and proteinuria were never detected. Dipstick urinalysis represents a useful first-line complementary tool in newborns clinical examination, providing information about systemic homeostasis.

Lillian Mary Pickford. 14 August 1902—14 August 2002

Mary Pickford was an experimental physiologist who carried out pioneering work on the actions of the hormones (oxytocin and vasopressin [ syn. antidiuretic hormone, ADH]) secreted by the posterior pituitary gland, which is part of the brain. She provided understanding of how the secretion of these hormones is controlled to regulate body fluid composition, specifically the maintenance, through actions on the kidneys, of normal osmolarity and Na + concentration, and hence blood volume and pressure. Using the water-loaded dog model she showed that vasopressin is the only hormone that regulates the excretion of water, by stimulating the kidneys to concentrate urine; she found that oxytocin could stimulate excretion of Na + . She showed that acetylcholine is an excitatory neurotransmitter in the hypothalamus, stimulating the neurons that produce vasopressin to secrete—the first evidence for acetylcholine action in the brain. The principles that Mary established have been extensively confirmed; hence, she was important in the establishment of the concepts and discipline of neuroendocrinology, which is about the bidirectional interactions between hormones and the brain. Using human and animal models, in her later work Mary focused on possible roles of interactions between female sex hormones and vasodilating actions of oxytocin in the perimenopausal problem of ‘hot flashes’ (or ‘hot flushes’) experienced by many women. She faced, but overcame, entrenched gender prejudice during her career; she was the first woman to be elected to the Pharmacological Society, and the first woman appointed to a chair in the Edinburgh Medical School.