Nursing Care Study Of A Patient With Nephrogenic Diabetes Insipidus

ASSESSMENT OF PATIENT

1.0 Introduction 

Assessment is the first phase of the nursing process. Assessment involves the gathering of information about the health status of the patient, analysis and synthesis of the data, and the making of a clinical judgment (Weller, 2014). According to Stonehouse (2017), information gathered can be either subjective or objective and primary or secondary. Subjective is information that the patient tells the nurse about how he or she is feeling, the levels and sensation of pain perceived. Objective information is that which can be measured, such as blood pressure or weight. Primary information is that which is gained from the patient themselves, whereas secondary data is information from other sources, such as family members.  Assessment tools such as interviews, physical examination and observations were used to obtain information in order to assess the health outcome of the patient. These information were received from patient herself as well as her family members.    

Nursing care study is an academic assessment course programme.  The care rendered is based on the nursing process which is a systematic approach in identifying patient’s problems and taking the necessary nursing action to provide solutions based on the scientific principles.  The nursing care rendered to Mr. G. A started on the 26th January, 2022, when he was admitted to the male medical ward. Upon assessment, he was diagnosed as having nephrogenic diabetes insipidus by Dr B.  Interaction with patient and family was terminated on 17th

February, 2022. I introduced myself as a final year student of Wisconsin international University College, Accra-Ghana and requested his consent to use him for my patient/family care study. He agreed to cooperate and gave assistance that was needed. He was encouraged and made aware that all information regarding him and his family will be kept confidential. Mr. G. A stayed on the ward for 5 days and was discharged home on 31st January, 2022. Three home visits were made; the first one was while she was still on admission, the second was embarked upon after she had been discharged. 

1.1 Patient’s particulars

Mr G. A is 50 is a Ga-Dangbe and hails from Odumasi in the Eastern Region. He was born on 4th September 1971, as the second born among his five siblings to the late madam S. A and the late Mr B. A. He is dark in complexion, weighs 65kg and 5.6ft tall. He speaks Twi, Dangbe, Ewe and English. Mr G. A currently stays at Nkwanta with his wife who is a trader. He is a commercial Driver and has four children of which one is dead and the two of them are working and the last born and still going to school and living with him. He said he completed his elementary education at Hohoe and could not further his education due to financial instability of his parent.

Mr G. A is a devoted Christian and worship with the Pentecostal church at Nkwanta. His next of kin is his first son, Mr D. A

1.2 Family Medical History  

Mr G. A said the family has history of nephrogenic diabetes insipiduswhich his father died of about fifteen years ago, but no family history of any hereditary diseases such as leprosy, hypertension and epilepsy. Minor ailments like headache, abdominal pain and malaria usually occur among the family members. But when this happens, they usually seek for treatment from Nkwanta south Hospital and sometimes they buy drugs from pharmacy shops. Sometimes they are treated with traditional medicine from traditional medical practitioners in the community. There is a no known allergy in his family. 

1.3 Socio Economic History

Mr G. A is a driver who drives his own transport bus (trotro). He depends on it for his daily income for survival, thus cater for his nuclear family. His wife also support the home with her trading business. He has neither registered himself nor his family with the National Health Insurance scheme, this is because he said it’s has inadequate benefits.

1.4 Patient Developmental History

He was born on the 4th September 1971 to Mr S.A and Mrs B.A all of blessed memories at Hohoe in the Volta region. He was born in the house by a Traditional Birth Attendant. He said per what his late mother told him, he was delivered through spontaneous vaginal delivery with no congenital abnormalities. He also said he never suffered any childhood illnesses e.g.; measles and polio. According to Mr G.A he had no difficulty in his developmental stages, like crawling, sitting or talking. He added that his mum made sure he was immunised in his childhood to prevent diseases and he has a mark on his right upper arm which shows clearly that he was immunised. At the age of seven months in his childhood, he crawled, at 8months then later walked at 11months with no support. According to Mr G. A he started experiencing his adolescent changes at age 12, thus deeper voice, broad chest and development of public hair. He completed his elementary education at Hohoe and due to financial difficulties he was not able to further his education. He is married to Mrs M.A at 24 years and gave birth to the first child at 25 years. He currently has three children, two girls and a boy. He started working at age twenty. He wants to give his children the necessary support they need in their education. He emphasized that all the three children were delivered at the hospital by a qualified health personnel.

1.5 Patient’s Hobby /Lifestyle.

Mr G.A goes to bed around 10pm every day and wakes up at 4.30am, excluding Sundays which he wakes up at 6.00am because that is his off duty day. He said he does not sleep with light on because it interrupts his sleep. He read his bible and does morning devotion with his family before they step out of bed. He said he brushes his teeth once day in the morning with maxam paste and pepsodent brush.  He then empty his bowel and take his bath. He said he often take “Hausa koko” with “koose” without sugar since he is a known nephrogenic diabetes insipidus patient, every morning before going to work. According to Mr G. A he eat three time daily. He said his  favourite food is fufu with groundnut soup, and because his wife knows his underlying condition (DM) so she make sure to add more plantain and less cassava when pounding his fufu. He also said he is able to drink three litres of water everyday mostly “ice cool”.  On Sundays since he does not go to work he wakes up a bit late (6am) and as usual read his bible and does morning devotion with his family and then prepares for church. He attend church of Pentecost Nkwanta central, close from church between 12:30pm to 1pm. When he get home with his family he eat lunch relaxes and watch television. Mr G. A is a very decent, calm and sociable man. He said he has few friends and does not smoke or abuse his wife but drinks occasionally. He attends social gathering if he gets the chance. His source of clean water at home is a borehole next to their house.

1.6 Past Medical History

According to Mr G. A he never suffered any condition which requires hospitalization until 2years ago, he had severe headache and was urinating frequently. It was abnormal for him so he decided to go for a check-up at Battor clinic and he was diagnosed of nephrogenic diabetes insipidus and was put on some analgesics and tab metformin 500mg bd.

1.7 Present Medical History 

According to Mr. G. A, he was very strong and active until a days ago when he felt dizzy, general body pains and general body weakness. He visited the nearest drug store and was given (gebedol). They later realized that the symptoms still persisted. At about 8:45am on January 26, 2022, his condition became serious. He was then rushed to the Nkwanta South Hospital, where he was seen by the doctor on duty and was later admitted to the male ward with the diagnosis of nephrogenic diabetes insipidus.

1.8 Admission of the Patient

Mr G. A. was admitted to the male medical ward of the Nkwanta south Hospital through the Outpatient Department on 26th January, 2022 at 10am by Doctor B. and team with complaints of excessive urination, abdominal discomfort and general body weakness. Upon arrival, patient and relatives were welcomed and offered a seat at the nurses’ station and patient’s folder were collected. Patient was identified and confirmed in relation to his name from his folder. Patient arrived in a semi-conscious state and a quick assessment was made in reference to the patient general condition. He came in with an intravenous peripheral line on the left distal arm for the administration of the prescribed intravenous fluid. Patient was received into an already prepared bed. His relatives were assured of competent nurses and medical team. Patient’s vital signs was checked and recorded as follows;

Temperature - 38.0oC

Pulse - 130bpm

Respiration - 24bpm

Blood pressure - 131/86mmHg.

SpO2                             -            98%

Blood glucose            -            26mmol/L (patient was placed on the Alberti’s regimen)

Relevant history and information about patient was obtained from relatives instead of patient because of his level of consciousness. During interaction with relatives, it was found that Mr G. A. was not on the national health insurance scheme thus it was agreed that any form of treatment given will be paid for using the cash and carry system. Admission papers were filled out with the necessary information in the nurse’s notes, admission and discharges book and daily ward state. Mr G. A. relatives were informed of the visiting hours and the various routines on the ward and the items that will be required (toiletries). He was managed on IV fluids (normal saline), one litre over next 30mins then one litre over next 2hour then one litre over next 4hours,

Check random blood glucose every 1hour then give insulin (soluble) SC 5units every hour until random blood sugar<=11mmol/l. Switch to sliding scale if random blood sugar <=11mmol/l, then check random blood sugar every 4hours,

 Intravenous fluid 5% dextrose one litre tds X 24hrs, 

Intravenous Paracetamol 1g 8hourly X 24hours, Intravenous ciprofloxacin 400mg bid x 24 hours, 

Intravenous Nos-pa 80mg stat. 

Tablet metformin 500mg bid x 30days, 

Tablet zinnat 500mg x 7 days

Laboratory investigations requested are blood urea and creatinine, full blood count, blood film for malaria parasite, urine for culture and sensitivity test Fasting plasma glucose, Haemoglobin AIC and Lipid profile test. I introduced myself as a Final year nursing student of Wisconsin international university college. I explained the essence of the patient and family care study and my intention to use him for the study. He was assured of adequate confidentiality. He and his family agreed and assured me of their full cooperation and support.

1.9 Patient’s Concept of His/her Illness

Mr G. A. attributes his illness to the fact that he eats late at night and sleep afterwards and that he eats a lots of sweets. He believe such calamity could befall anybody and that he would regain his health with God on his side and also with the help of excellent medical and nursing care from the doctors and nurses. Furthermore he believes that if he complies with the treatment plan prescribed for him there will be a massive improvement in his condition.

1.10 Literature Review on the Disease Condition

Nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus (NDI) results from failure of the kidneys to concentrate urine. Patients with this disease typically produce around 12 l of urine per day. Assuming a bladder volume of 500 ml, this volume of urine will necessitate voiding approximately once per hour throughout the day and night. Moreover urinary fluid losses need to be replenished by constant fluid intake. The disease has a substantial impact on quality of life as sleep is frequently interrupted and patients must plan their daily activities with logistics for frequent voiding and access to drinking water.  Primary and secondary forms of NDI exist. Paediatricians typically see patients with primary inherited forms of the disease, mostly boys presenting in the first year of life with failure-to-thrive and vomiting. By contrast, in adults acquired NDI is much more common than primary NDI. Medical treatment can ameliorate the symptoms of NDI and as understanding of the underlying pathophysiology improves, new potential treatment options arise. In this Review we consider the clinical, diagnostic and therapeutic aspects of NDI in the context of the physiology of renal water handling to enable a molecular understanding of the disease. We also discuss recent insights into the regulation of water permeability and their consequences with respect to diagnosis and new treatment options. 

Physiology of urine concentration 

Healthy adult kidneys produce approximately 180 l of primary glomerular filtrate per day.1 The vast majority of this filtrate is reabsorbed in the proximal tubule, which is freely permeable to water owing to the constitutive expression of aquaporin (AQP)-1 water channels.2 As solutes are reabsorbed in the proximal tubule, water follows passively along the osmotic gradient. The remaining urine is thus still isotonic when it enters the loop of Henle, the key segment for counter-current concentration (Figure 1). Urine concentration begins in the thin descending limb (TDL). Mechanisms of concentration include AQP1-mediated exit of water into the medullary interstitium.3 However, data from several rodent models show that Aqp1 expression is mainly restricted to the first 60% of the TDL rather than to the deeper papillary parts in which the steepest part of the osmotic gradient is generated.4 Concentration of the tubular fluid in these innermost parts of the TDL might occur via passive sodium influx,5 but no substantial sodium permeability has been observed.6 Thus, the exact mechanism of urinary concentration in the innermost part of the medulla remains to be elucidated. 

Urine subsequently enters the thick ascending limb (TAL, also known as the diluting segment), which is impermeable to water but actively removes sodium chloride via the co-transporter solute carrier family 12 member 1 (SLC12A1,  also known as NKCC2), thereby diluting the urine.7 The accumulation of solutes in the interstitium generates the driving force for the removal of water from the TDL (in long-looped nephrons) and the entry of sodium chloride (in short-looped nephrons), completing the counter-current multiplier. 

Further removal of sodium chloride occurs in the distal convoluted tubule via SLC12A3 (also known as NCC). At entry into the arginine vasopressin (AVP)sensitive connecting tubules and collecting ducts, urine osmolality is typically around 50–100 mOsm/kg. The final osmolality of the urine is solely dependent on the availability of water channels. If these channels are present, water exits the tubule following the interstitial concentration gradient and the urine is concentrated. If no water channels are present, dilute urine will be excreted. 

Vasopressin-regulated water permeability 

Vasopressin secreted by hypothalamic neurons in response to changes in soma volume (Figure 2) is the key regulator of the water permeability of the collecting ducts. The key cell type that mediates this regulated water permeability is the principal cell, which constitutively expresses AQP3 and AQP4 on the basolateral side.2 The water permeability of the apical membranes of the principal cell is determined by the availability of AQP2 water channels. In the absence of AVP signalling, these channels are located in intracellular vesicles and no apical water permeability exists.8  Binding of AVP to the vasopressin V2 receptor (AVPR2) initiates a signalling cascade that ultimately leads to the insertion of AQP2 channels into the apical membrane(Figure 3). AVPR2 is a G-protein-coupled receptor and binding of AVP leads to the release of stimulatory G-protein, which in turn activates the neighbouring adenylyl cyclase.9 The resulting increase in levels of cAMP activates protein kinase A (PKA). 

The cytoplasmic carboxy-terminal tail of AQP2 has five canonical PKAphosphorylation sites: Thr244, Ser256, Ser261, Ser264 and Thr269 (Ser269 in mice).10 Upon administration of the vasopressin analogue 1-desamino-8-Darginine vasopressin (DDAVP), phosphorylation of AQP2 at Ser256, Ser264 and Ser269 is abundantly increased, whereas phosphorylation at Ser261 is decreased;10 specific phosphorylation of these residues might serve distinct physiological roles. In a mammalian cell line (LLC-PK1) transiently transfected with AQP2, phosphorylation at Ser256 was essential for trafficking of the water channel to the plasma membrane,11 whereas in Xenopus oocytes,  phosphorylation of at least three subunits of the AQP2 tetramer at Ser256 was required for redistribution from storage vesicles to the apical plasma membrane.12 The critical role of Ser256 in AQP2 function was confirmed by the identification of mutations that impair phosphorylation at this site in patients with NDI.13, 14 In vitro studies demonstrated the failure of such mutants to reach the apical membrane.13, 14  AVP also induces phosphorylation of AQP2 at Ser269, but this action is delayed and requires prior phosphorylation at Ser265.15 Phosphorylation at Ser269 might increase retention of AQP2 at the apical plasma membrane and interactions of AQP2 with proteins participating in the endocytic machinery.16 By contrast, AQP2 phosphorylated at Ser261 is found mainly in intracellular vesicles; phosphorylation at this site is thought to stabilize ubiquitination of AQP217 at Lys270.18 Ubiquitination might, therefore, mediate the endocytosis of AQP2 from the plasma membrane in the absence of AVP stimulation. This mechanism leads to a limited tenure of AQP2 in the apical membrane of principal cells; endocytosis of this water channel enables the cells to return to their waterimpermeable state. The role of AQP2 phosphorylation at Thr244 is unknown. 

The actions of cAMP might not only be mediated via the classical PKA/cAMPdependent protein kinase pathway, but also by guanine nucleotide-exchange factors such as exchange protein directly activated by cAMP (Epac).19  Like PKA, Epac contains an evolutionally conserved cAMP-binding domain that senses intracellular cAMP levels and acts as a molecular switch to control diverse biological functions.20  Epac might be involved in the long-term regulation of AQP2 abundance, whereas PKA has independent short-term effects. 

In addition to an acute role in AQP2 localization, AVP-mediated increases in cAMP promote AQP2 expression via PKA-mediated phosphorylation of the cAMP responsive element binding protein, which subsequently stimulates transcription from the AQP2 promoter.22-24 The change in localization of AQP2 occurs within minutes, whereas the increase in transcription requires hours to take effect.25,26 

Congenital NDI 

In 1992 the AVPR2 gene that encodes the AVP2 receptor was cloned and mutations in this gene were identified in patients with X-linked NDI (Figure 4).2730 The AQP2 gene was cloned in 199331, 32 and in 1994 mutations in AQP2 were found to underlie autosomal recessive NDI.33 The discovery of these two key genes—AVPR2 and AQP2—has enabled genetic testing of affected patients. Mutations in either of these genes are identified in almost all patients with a clear clinical phenotype of congenital NDI.34, 35 

AVPR2 mutations 

Approximately 90% of patients with inherited NDI have a mutation in AVPR2.36, 37  As this gene is located on the X-chromosome, AVPR2 mutations have an Xlinked pattern of inheritance; consequently the majority of patients with NDI are male. Occasionally, female patients with NDI due to AVPR2 mutations have been described.34, 35, 38-41 In one study, 16 of 64 (25%) female carriers of AVPR2 mutations showed polyuric symptoms and four of these patients (6%) were diagnosed with complete NDI rather than the milder partial NDI phenotype described below.34 Skewed X-inactivation is thought to cause symptoms in some female carriers of AVPR2 mutations, although these symptoms do not necessarily correlate with the X-inactivation patterns observed in leukocytes.42 Presumably, X-inactivation patterns can differ between tissues, so the pattern in leukocytes might not reflect that in the kidney. In our experience at Great Ormond Street Hospital, London, UK, two female relatives in 20 families with AVPR2 mutations have been diagnosed with complete NDI (unpublished data). One of these women was the index case in her family, but not all female carriers have been systematically investigated. Partial NDI symptoms were observed in two other female carriers in one family.43 A few AVPR2 mutations have been identified recurrently owing to a founder effect. For example, the Hopewell mutation (Trp71X)—derived from an Ulster Scot immigrant who arrived in Halifax, Canada on the ship Hopewell in 1761— has been identified in >40 North American patients.44, 45 Another recurrent mutation is the Cannon mutation (Leu312X), which is named after a large pedigree with ?38 affected patients in Utah.45 Most patients, however, have individual mutations; to date >250 different AVPR2 mutation have been described in >300 families (46 and our unpublished data). Interestingly, most of these mutations are missense and, when assessed in vitro, seem to encode functional but misfolded receptors, which are retained and degraded in the endoplasmic reticulum (ER).47 

AQP2 mutations 

Approximately 10% of cases of congenital NDI are due to loss-of-function mutations in the AQP2 gene located on chromosome 12.45,34, 48 These mutations are typically inherited in an autosomal recessive fashion, although a few mutations have been described to cause autosomal dominant disease.13, 49-51 AQP2 is a homotetramer; four subunits assemble to form the water channel. Dominant mutations typically affect amino acids in the C-terminus, leading to aberrant trafficking; mutant AQP2 subunits are able to oligomerize with wildtype protein to form tetramers, but exert a dominant-negative effect on trafficking of these assembled tetramers.52 Interestingly, specific mutations direct AQP2 trafficking to distinct cellular compartments, such as the Golgi complex,13 late endosomes and lysosomes49 or the basolateral membrane.51, 53 These findings have provided insights into the intracellular trafficking motifs of AQP2. 

Epidemiology  

Few population-based data on the incidence of congenital NDI exist, but estimates can be made. In 2000 we assumed that we had complete ascertainment of all the patients with AVPR2 mutations who were born in the province of Quebec, Canada between 1988 and 1997.35 Indeed, in the subsequent 18 years, no patients with AVPR2 mutations born in the province during this period have emerged. Based on these data, we estimated the incidence of Xlinked NDI in the general population of Quebec to be four in 454,629 or approximately 8.8 per million (SD 4.4 per million) male live births. This estimate might be representative of the general world population. However, owing to chance population genetic events, such as a founder effect, the incidence of NDI is elevated in certain regions. For example, in the Canadian maritime provinces of Nova Scotia and New Brunswick, we estimate the incidence of the Hopewell mutation to be 58 per million male live births.35 A higher incidence of NDI is also found in Utah due to the prevalence of the Cannon mutation.44  Based on the families referred to us for genetic testing, we estimate that the incidence of NDI secondary to AQP2 mutations is five to ten times lower than that of NDI secondary to AVPR2 mutations. The incidence of this type of congenital NDI might, however, be increased in populations with a high degree of consanguinity; we have found an over-representation of the Val71Met AQP2  allele in patients of Pakistani descent.54 

Secondary inherited forms of NDI 

In addition to primary forms of congenital NDI a few cases of secondary inherited NDI have been reported.55, 56 These patients have Mendelian diseases that affect tubular function with NDI as a secondary complication. In some such patients the NDI symptoms dominate the clinical picture, leading to an initial misdiagnosis, with the true underlying cause of disease subsequently identified.55, 57 Most of the primary diseases associated with secondary NDI, such as Bartter syndrome and apparent mineralocorticoid excess, are associated with hypokalaemia and hypercalciuria. These associations might provide clues to the aetiology of NDI, as both hypokalaemia and hypercalciuria are associated with decreased AQP2 expression.58, 59 Hypercalciuria has been suggested to cause a urinary concentration defect mediated by the calcium-sensing receptor, which is expressed on the luminal side of collecting duct cells and is thought to affect AQP2 trafficking by altering cAMP levels.60, 61 

Acquired NDI 

In adult nephrology practice the majority of patients who present with NDI have acquired this disease, with lithium treatment being the predominant cause.62-64 Reports of NDI among patients treated with lithium vary widely but the incidence of this adverse effect has been reported to be as high as 85%.63, 65 As 0.25–0.77% of the general population aged >65 years are prescribed lithium, it is not surprising that lithium-induced NDI is fairly commonly.66, 67 Indications for lithium treatment include bipolar disorder, schizoaffective disorder, depression, alcoholism and cluster headaches.64 Cessation of lithium therapy can resolve the symptoms of NDI, but this approach is not an option in most cases because the beneficial effects of the drug on the psychiatric disorder outweighs the negative impact of the polyuric complications on quality of life. 

In rats, chronic lithium administration (>4 weeks) led to epithelial remodelling in the collecting duct and a dramatic reduction in the number of principal cells.68 Moreover, in the mouse collecting duct cell line mpkCCD, lithium exposure decreased Aqp2 abundance independent of cAMP levels.69 Consistent with these data, decreased urinary excretion of AQP2 has been observed in patients with lithium-induced NDI.70 The exact mechanism of lithium toxicity on the principal cell remains to be elucidated, but robust data suggest that lithium exerts its effect after entering the cell through epithelial sodium channels (ENaCs), which have a high permeability for lithium.10 Consequently, treatment with ENaC blockers, such as amiloride, can increase urine osmolality and ameliorate polyuria in lithium-induced NDI.71-73  

Other acquired causes of typically transient NDI include hypercalcaemia, hypercalciuria and obstructive uropathy. In patients with obstructive uropathy, NDI is thought to result from direct suppression of AQP2 expression, which might be mediated by hydrostatic pressure. Animal studies have shown decreased Aqp2 expression in the setting of bilateral ureteric obstruction,74 whereas in unilateral obstruction a marked decrease in Aqp2 is seen only in the obstructed kidney.75 This down-regulation of Aqp2 persists up to 30 days after release of obstruction, perhaps explaining the diuresis often observed after release of severe obstruction in patients.9 

Initial presentation 

Most patients with congenital NDI present with failure to thrive during the first few months of life, whereas those with acquired NDI typically present later in life with polyuria and or polydipsia. In patients with congenital NDI the antenatal history is typically normal with no polyhydramnios, which helps to distinguish NDI from other polyuric disorders, such as Bartter syndrome. Parents often report that the baby sucks vigorously but vomits shortly afterwards. This vomiting is thought to occur because intake of large fluid volumes causes gastrooesophageal reflux. 

NDI is a rare disease so does not feature prominently on the diagnostic radar of frontline medical staff. Families seeking medical attention for their yet undiagnosed baby might, therefore, be sent home without further investigations because the attending professionals are falsely reassured by the large urine output. Laboratory investigations in such instances would show the typical picture of hypernatraemia with inappropriately dilute urine, the biochemical “fingerprint” of diabetes insipidus. If blood tests are obtained and hypernatraemia is noted without consideration of a urinary concentration defect, inappropriate treatment with 0.9% saline might be instigated because of concerns regarding too rapid correction of the hypernatraemia. Unfortunately, given the imbalance between the sodium concentration of the administered fluid (154 mmol/l) and the urine (usually <10 mmol/l), this approach will result in even higher plasma sodium concentrations. 

Diagnosis 

In patients who present with hypernatraemic dehydration and dilute urine, a DDAVP test can help to distinguish between cranial diabetes insipidus (which is normally the result of disease of the hypothalamus or surrounding tissues) and NDI. In patients with suspected diabetes insipidus who present with polyuria and normal plasma biochemistries, a water deprivation test might first be performed to challenge urinary concentration. 

DDAVP test 

As DDAVP has high specificity for AVPR2 it can be used to assess the renal response whilst avoiding AVPR1-mediated vasoconstriction. DDAVP is available in formulations suitable for oral, intranasal, subcutaneous or intravenous (IV) administration. After DDAVP administration a urine osmolality >800 mOsm/kg is usually considered normal and excludes a diagnosis of NDI, whereas a urine osmolality below plasma osmolality indicates AQP2 deficiency and is consistent with the diagnosis. Care needs to be taken in the interpretation of intermediate results, especially in infants, as full urinary concentrating ability develops during the first year of life.76 Other causes for submaximal values include interstitial renal disease, use of loop diuretics, partial NDI, washout of the interstitial medullary concentration gradient or technical failure of the test, for example as a result of incomplete DDAVP absorption. 

Various protocols for the DDAVP test exist, but we prefer to use IV administration to enable the most reliable absorption of the polypeptide.77 The DDAVP dose (0.3 mcg/kg) used in this test is the same as that used to boost factor VIII concentration in patients with mild haemophilia or von Willebrand disease.78, 79 The key risk of the test is the development of hyponatraemia in patients who respond to DDAVP and keep drinking. The physiological suppression of thirst from reduced plasma osmolality prevents this complication in the vast majority of responders, but patients with habitual polydipsia and babies who keep receiving feeds from their carer are at risk. Strict observation of fluid balance is required to prevent this potentially serious complication and patients should only be allowed to receive a fluid volume equivalent to their ongoing losses. 

A key advantage of IV administration is the short half-life of DDAVP in blood, which necessitates an observation time of only 2 h, thus minimizing the burden of the test. Other advantages include a low risk of test failure owing to incomplete absorption and the ability to distinguish between X-linked and autosomal-recessive forms of NDI, as AVPR2 mediates haemodynamic and coagulation factor changes in response to high-dose DDAVP.77 This response is abrogated in patients with defective AVPR2 function, yet retained in those with mutations in AQP2. The low plasma levels of DDAVP achieved with other forms of administration make detection of these subtle changes virtually impossible. 

Spectrum of clinical disease  

Mental impairment 

As with most inherited diseases a wide spectrum of severity of clinical disease is observed in NDI. The most severe consequences are seen in patients who have not received adequate treatment and have experienced repeated episodes of hypernatraemic dehydration, leading to brain damage and impaired mental development.39, 80, 81 In some such patients, intracranial calcifications can be observed. These calcifications are thought to result from endothelial cell necrosis during severe dehydration and thus might represent a radiological correlate to brain damage from recurrent hyperosmolar stress associated with  hypernatraemic dehydration.82 

Fortunately, cases of severe mental impairment in patients with NDI are now virtually non-existent in countries where modern health care is available. Nevertheless, impaired school performance and behavioural abnormalities are often reported among patients with NDI. In a Dutch study, 8 of 17 participants were diagnosed with attention deficit hyperactivity disorder.83 This diagnosis might be partly related to the constant craving for water and need to void. Some data, however, suggest that behavioural abnormalities might be an intrinsic aspect of the disease. Vasopressin (and oxytocin) act as neurotransmitters that modulate the autonomic fear response84 and vasopressin has been described to enhance aggressiveness, anxiety and stress levels in an animal model.85 Raised vasopressin levels might also potentially affect long-term behaviour in patients with NDI. 

Flow uropathy 

Dilatation of the urinary tract is a recurrently noted complication of NDI and patients with poor voiding habits are especially at risk.39, 86, 87 In those with hydronephrosis, anatomic causes of obstruction should also be considered. Such obstructions are potentially remediable and even minor impediments to urine flow can cause severe dilatation in this polyuric disorder.88 Obstructive nephropathy can be seen in cranial diabetes insipidus and NDI, and if untreated can lead to obstructive end-stage renal disease. 

Partial NDI 

Some patients with congenital NDI have a mild phenotype; they present after infancy with normal development, often for the assessment of polyuria or enuresis, and typically show intermediate urine osmolality after DDAVP administration (greater than plasma osmolality but <800 mosm/kg). Patients with partial NDI typically carry mutations that result in partial function of either AVPR2 43, 89 or AQP2.90, 91 The first mutation to be associated with partial NDI was the Asp85Asn mutation in AVPR2.89 Interestingly, another missense mutation, Val88Met, has been associated with partial NDI in some patients and complete NDI in others.43, 92, 93 The underlying disease mechanism in patients with these missense mutations is ER retention of the mutant protein, but degree to which the mutant protein can escape from this retention and traffic to the cell membrane seems to differ between individual patients. 

Treatment 

Current treatment approaches for congenital NDI focus on amelioration of the symptoms rather than curing the disease. If possible, treatment of acquired NDI should   target the underlying cause, such as relief of urinary obstruction or amiloride therapy in lithium-associated NDI.73 If such approaches are not possible, treatment of congenital NDI is comparable to that of primary NDI. 

Management of hypernatraemic dehydration 

Most emergency protocols for any patient with hypernatraemic dehydration suggest initial treatment with 0.9% saline, owing to concerns about lowering plasma sodium levels too rapidly. The situation differs, however, in patients with NDI because of the ongoing losses of essentially pure water with the urine; infusion of 0.9% saline will result in excess sodium chloride administration and thus worsen the hypernatraemia. In these patients, isotonic fluids should be reserved only for acute intravascular volume expansion in hypovolaemic shock, which is an exceedingly rare complication, as extracellular fluid volume is usually sufficiently preserved in hypernatraemia. Thus, patients with NDI should be treated with hypotonic fluids, either enterally (using water or milk) or if necessary intravenously (using 5% dextrose in water). Hypotonic fluids must never be administered as an intravenous bolus; instead, the infusion rate should only slightly exceed the urine output. The aim is to provide just enough water to safely normalize plasma sodium concentration at a rate of <0.5 mmol/l per h (<10–12 mmol/l per day ). The main risk of a rapid decrease in plasma sodium is cerebral oedema and potentially death.94-97 Consequently, careful fluid balance and frequent monitoring of clinical state and biochemistries is key to safe treatment and requires a clinical environment with sufficient experience in the treatment of complicated electrolyte disorders. Fluids should be taken orally as soon as feasible, to enable the thirst physiology to properly regulate fluid intake. As dextrose in water provides no osmotic load (Box 1), urine output can decrease substantially, highlighting the importance of ongoing monitoring and fluid balance to avoid rapid swings in plasma sodium concentrations. 

Diet 

Dieticians have a key role in the management of patients with NDI, especially in the first year of life when intake of fluid and calories is coupled. Minimizing the osmotic load (Box 1), whilst providing the recommended caloric and protein intake to enable normal growth and development is a cornerstone of paediatric 

NDI management. 

Thiazide diuretics 

The use of diuretics in polyuric disorders seems counterintuitive. The therapeutic potential of these agents in NDI was discovered more or less serendipitously, but reported in patients as early as 1905.98 This observation was confirmed in the 1950s when administration of hydrochlorothiazide was shown to reduce urine output in experimental animals with diabetes insipidus by as much as 50%.99 An early study in patients with NDI showed a small reduction in urine volume with concomitant increases in urine osmolality and sodium shortly after commencing hydrochlorothiazide treatment.100 After 3 days of treatment, sodium excretion had decreased to less than baseline, whereas urine output had decreased to ~50% of baseline. These changes were associated with reductions in plasma volume and body weight. The researchers astutely concluded that the initial increase in urine osmolality was related to inhibition of urinary dilution, mediated by decreased salt reabsorption through the thiazidesensitive co-transporter SLC12A3 in the distal tubule, and that the loss of sodium led to a reduction in plasma volume with subsequent enhanced proximal reabsorption of the glomerular filtrate, so that less water was presented to the collecting duct and lost in the urine. A SLC12A3-independent mechanism of thiazide-mediated reductions in urine output was proposed based on studies in Slc12a3 knock-out mice with lithiuminduced NDI.101 A marked reduction in urine volume with unchanged urine osmolality was observed in these mice after hydrochlorothiazide administration. The researchers speculated that this reduction might be mediated by inhibition of carbonic anhydrase in the proximal tubule, resulting in reduced proximal sodium uptake and consequently—via tubuloglomerular feedback—to decreased glomerular filtration. They also found that in mpkCCD cells treated with lithium, hydrochlorothiazide administration led to an increase in Aqp2 abundance at the apical membrane.101 However, the finding that lithium-treated and control SLC12A3 knock-out mice had similar urine osmolality after  hydrochlorothiazide administration suggests that this effect is negligible in vivo. The hypothesis of impaired proximal sodium reabsorption as a mechanism for reduced urine volume in NDI101 is surprising and in direct contrast to the earlier hypothesis that enhanced proximal sodium uptake leads to enhanced proximal water reabsorption.100 To what degree these apparently opposing mechanisms occur in patients remains to be determined. 

Prostaglandin synthesis inhibitors 

An effect of prostaglandins on epithelial water permeability was noted soon after their discovery.102 With the advent of inhibitors of prostaglandin synthesis, such as indomethacin, experiments showed a synergistic effect of these new drugs with AVP.103 An early study in an animal model of diabetes insipidus demonstrated that indomethacin reduced water diuresis independent of AVP.104 

A similar effect of prostaglandin synthesis inhibitors was noted in patients with NDI. 

Prostaglandin synthesis inhibitors have become essential components in the treatment of NDI, particularly in the first years of life when management is the most complicated. The effect of these drugs can be quite marked when first initiated. Indeed, hyponatraemic seizures associated with rapid lowering of plasma sodium levels as a result of commencement of indomethacin and hydrochlorothiazide have been reported.109 In our experience, urine osmolality is unchanged after indomethacin treatment, suggesting that the drug acts mainly by enhancing the proximal reabsorption of salt and water.110 

Gene discovery 

Since the discovery of the two known NDI disease genes, AVPR2 and AQP2, in the 1990s (Figure 4) no additional causative genes have been reported. Mutations in AVPR2 or AQP2 are not, however, found in all patients. Between 2003 and 2013, the Montreal laboratory performed genetic testing for NDI in 208 families and identified causative mutations in AQP2 in 18 families and in AVPR2 in 119 families (D. Bichet unpublished data). In some of the samples, mutations in genes causing renal disorders with secondary forms of NDI, such as Bartter syndrome were found, whereas in others, the phenotype was not detailed enough to clearly establish a diagnosis of NDI.56 In a Japanese study no mutations were identified in 7 of 62 (11%) families with clinical NDI,34 suggesting that genes other than AQP2 and AVPR2 might be involved. However the phenotypes of these patients were poorly described and not further investigated by the referring physicians.  

In our clinical experience very few patients with a convincing NDI phenotype have no identified mutation. In our Great Ormond Street cohort, we have identified three such patients from two families (unpublished data). The results of our linkage analyses in these families were, however, consistent with the presence of mutations in AVPR2 or AQP2. Thus, if additional NDI disease genes are identified, they are likely to be causative only in a small subset of patients. 

Novel treatments 

The promise of molecular medicine is that through improved understanding of specific molecular defects in individual patients, we can develop targeted, rational treatments.111 Unfortunately, progress has been slow at best. Although several novel treatment approaches for patients with congenital NDI have been suggested, little clinical data are available. These novel approaches focus on restoring AVP signalling upstream of AQP2 so are not applicable to patients with AQP2 mutations.  

PR2 antagonists 

A new treatment strategy for NDI focuses on the fact that most patients carry missense mutations in AVPR2 that result in misfolding of AVPR2 and its retention in the ER.47 If proper folding is induced using a molecular chaperone, the mutant receptor can escape the ER, traffic to the cell membrane and provide normal AVP signalling. 

Cell-permeable AVPR2 antagonists are molecular chaperones that fit into the AVP binding pocket of AVPR2 and induce proper folding of the receptor. In patients with suitable mutations, these antagonists might provide a new treatment approach for NDI. The problem with this strategy is that the tighter the AVPR2 antagonists fit into the binding pocket, the better they promote surface expression of the receptor, but the less likely they are to diffuse off the receptor and enable normal AVP signalling. Conversely, compounds with low affinity for AVPR2 are less efficient at promoting surface expression, but are more likely to diffuse off the receptors that traffic to the cell surface. Antagonists with intermediate affinity have the best overall efficacy, but one such agent, the orally active, nonpeptide AVPR1A antagonist SR49059, only moderately reduced urine volume in five patients with X-linked NDI.112 SR49059 is no longer provided by the pharmaceutical company because of the possibility of idiosyncratic increases in liver enzymes (these increases were not observed in patients with NDI who received the drug) and no further clinical data on this treatment approach have been published. 

AVPR2 agonists 

Cell-permeable agonists that stimulate AVPR2 independent of AVP are another potential treatment approach for patients with NDI. As these agents do not block AVPR2 signalling they could potentially be a more effective treatment approach than AVPR2 antagonists.  

Vasopressin analogues 

A mutation-specific treatment strategy has also been suggested for patients with the Asn321Lys mutation in AVPR2.113 The mutant receptor seems to have normal cell surface expression in vitro, but severely decreased affinity for vasopressin and DDAVP. AVP signalling via this receptor could reportedly be rescued using the vasopressin analogue Val4-desmopressin. Clinical data on the use of this compound in patients with NDI bearing this mutation have not yet been reported. 

Prostaglandin receptor agonists 

Another novel treatment approach for patients with AVPR2 mutations focuses on enhancing cAMP production in the principal cells independent of AVPR2, for example via stimulation of prostaglandin E2 receptors coupled to adenylyl cyclase (Figure 3). Such a strategy would not benefit patients with the autosomal form of NDI, as AQP2 mutations result in a defect downstream of cAMP production. 

In a mouse model of X-linked diabetes insipidus with conditional deletion of the Avpr2 gene, administration of a prostaglandin E2 receptor EP4 subtype (EP4 receptor) agonist resulted in an increase in urine concentration.114 The peak increase in urine concentration (from 150 mOsm/kg to a maximum of 500 mOsm/kg) was short lived (3 h), possibly due to down regulation of EP4 receptors in response to the high osmolality, but with mini-pump constant infusions a sustained increase in urine osmolality from 200 mOsmol/kg to 300 mOsmol/kg was observed. 

Doubling of urine osmolality in patients with NDI would halve urine output (to ~6 l daily in adults) so would constitute successful treatment. In a rat model of NDI secondary to the administration of the AVPR2 antagonist, butaprost, an EP2 receptor agonist approximately doubled urine osmolality.115 To date, no clinical data on the use of prostaglandin receptor agonists in patients with NDI have been reported. Moreover, given the proven efficacy of prostaglandin synthesis inhibitors in NDI treatment, doubts remain as to whether this approach would be a viable treatment option.116

Secretin receptor agonists 

The secretin receptor is a G-protein coupled receptor expressed in principal cells. Stimulation of this receptor can increase cAMP levels.117 Infusion of secretin and fluvastatin resulted in doubling in urine osmolality in mice with conditional deletion of the Avpr2 gene.118 If appropriate scientific and ethical permission was obtained, short-term therapy with a combination of secretin and fluvastatin could potentially be tested in humans with X-linked NDI. Long-term secretin treatment might be limited by adverse effects of the drug.  

cGMP phosphodiesterase inhibitors 

Increased levels of cyclic guanosine monophosphate (cGMP) have been shown to enhance trafficking of AQP2 to the luminal membrane and induce a short-lived increase in urine osmolality in Brattleboro rats (a model of cerebral diabetes insipidus with deficient vasopressin production by the hypothalamus).119 This finding suggests a potential role of cGMP phosphodiesterase inhibitors, such as sildenafil, in the treatment of patients with NDI resulting from AVPR2 mutations. 

Gene therapy 

Genome editing of somatic tissue or embryos is of considerable recent interest to correct defective genes in humans but the ethics, especially of embryo editing is controversial 120  121.. Currently, no such endeavours have reached the clinical arena. We anticipate that the ethical governance, safety and long term effects of such editing therapies will be determined possibly within the next two decades so that patients with hereditary disorders, such as NDI will benefit from them.

Dietary Management

Diet is a major factor in the control of nephrogenic diabetes insipidus. The dietary plan should indicate the number of calories required each day and the portions allocated to carbohydrate, protein and fat. The amount of calories is determined by the patient’s weight, age, activity level and previous dietary intake. Total caloric intake needs to be controlled to maintain or attain a reasonable body weight and control blood glucose levels. 

1. Patient should not fast 

2. Eat 3 meals a day 

3. Snack can be taken PRN 

Suggested Diet 

50 – 30% carbohydrate 2/5 carbohydrate 

20 – 30%  fats 2/5 fruits and vegetables 

10 – 20% protein 1/5 protein 

Complex sugars are advised because they gradually breakdown and reduce the risk of sudden rise in blood glucose level. 

Insoluble fibres – bread, cereals, whole grain, brown rice, beans, fresh fruits and vegetables 

1. Alcohol may be taken but remind patient of the danger of hypoglycaemia especially patients on insulin, this is because alcohol decreases the normal physiologic activities that produce glucose. Therefore, patient must eat before drinking alcohol. 

2. Avoid tobacco

3. Reduction in fat (saturated fat and cholesterol) intake in order to decrease cardiovascular disease risk.

4. Less fruit and  more vegetable intake e.g. watermelon, carrots

5. High protein diet to aid in achieving weight loss and blood glucose level control.

6. Intake of high fibre diet which slows the rate of glucose absorption into the bloodstream.

7. Take small amount of food/meals at frequent intervals(preferably 4 hourly)

Refined sugars .e.g. sweets, cakes, doughnuts, honey, jam, ice cream, soft drinks, malted beverages (Milo) should not be eaten

Sweeteners may be used; 

1. Saccharine 

2. Aspartame 

3. Sucralose 

4. Acesulfame 

Exercises

This is very important in the management of nephrogenic diabetes insipidus because it;

1. Improves the action of insulin in the body by increasing insulin receptor sites. 

2. It facilitates reduction of weight and proper weight maintenance

3. Lowers blood pressure and decreases risk of cardiovascular diseases 

4. Increases uptake of glucose by body muscles and improves insulin utilization

5. It  improves circulation and muscle tone and maintains a feeling of well being

6. It alters blood lipids by increasing levels of HDL reducing risk of peripheral vascular complications.

Precautions for exercising

1. Do not inject insulin into the body part to be exercised

2. Exercise about 1 to 2 hours after meals 

3. Drink plenty of water before and after exercise to prevent thirst. 

4. Exercise as can be tolerated 20-30 minutes 3 times daily. 

5. Get snack ready to be taken after exercising to prevent hypoglycaemia 

6. Wear comfortable shoes during exercises (e.g. sneakers and cotton socks)

7. Check blood glucose level before, during and after exercises (do not exercise if  blood glucose > 250mg/dl)

8. Exercise should be regular and  not sporadic 

9. Do moderate exercises such as; Walking, jogging, running, cycling, swimming, Dancing, skipping and playing football.

Foot care

Careful examination of feet every day with major concentration on the heels and in between the toes. Look out for possible sores, cracks, cuts, blister, color changes, corns, calluses and overgrown nails.

1. Washing of feet at least once a day

2. Use mild soap and warm water

3. Dry feet gently with a clean dry towel especially in between the toes

4. Wear socks made of cotton or wool and should not be tight

5. Avoid walking bare foot even inside the house.

6. Inspect your feet daily (top, sides, soles, heels and area between the toes)thus one can use a mirror or seek for assistance from someone when unable to inspect own feet.

7. Wash your feet everyday in warm water with mild soap.

8. Dry feet thoroughly to prevent infections from developing in moist areas.

9. If feet is rough/dry, moisturize skin but not between the toes.

10. Avoid walking barefoot to prevent injuries; wear footwear everyone one goes.

11. Trim nails across rather than in a curved fashion to prevent ingrown toe nails(do not cut into the corners)

12. Wear comfortable well fitted shoes with plenty of room (avoid tight shoes to prevent blister formation).

13. Break in new shoes slowly; wear for one hour the first day, two hours for the second day until they are comfortable to be worn for a whole day.

14. Report to health care personnel if any of the following problems are noticed ;sores, cracks, blister, boils, peeling, pain, itching, loss of feeling and swelling.

Skin care

1. Adequate personal hygiene 

2. Special attention to skin folds 

3. Avoid handling hot objects with bare hands 

4. Use sharps with special care(by placing it into a sharps container) 

5. Treat small cuts and sores promptly 

6. Avoid tattoos

7. Avoid touching very cold /hot objects with bare hands, use smitten.

8. Ensure adequate perineal care 

9. Prevent falls and injuries 

10. Treat small cuts and sores promptly

11. Use of warm water to soak and wash feet daily and dry properly especially in between toes.

12. Use skin lotions, Shea butter, and cocoa butter on your feet after cleaning but avoid inbetween toes. 

13. Wear footwear even in bedroom to prevent stepping on sharp objects.

14. . Use comfortable covered shoes that fit well and avoid tight and pointed shoes. 

15. File the tip of toe nails to prevent any form of injury.

16. Daily inspection of feet especially heel and in between toes with the use of mirror or can let someone check for them.

17. Observe for cracks, cuts, blisters, colour changes, corns, calluses, overgrown nails, numbness and tingling sensation and report for treatment.

Monitoring

1. Blood glucose level 

2. Urine for glucose/ketone ,leukocytes, protein

3. Glycosylated haemoglobin 

4. Vital signs checked 

5. Weight monitoring 

6. Fluid intake and output 

7. Caloric intake 

8. Observe for acute complications 

9. Observe for peripheral vascular impairment 

10. Signs of infections 

11. Signs of diabetic neuropathy (numbness or pain in hand and feet)

12. Delayed wound healing (observe for skin cracks/ cuts)

13. Use of sliding scale and Albertis Regime 

Patient Teaching

1. Teach patient how to do self-monitoring blood glucose using the Glucometer 

2. Educate patient on the normal glucose level which is between 4.4mmol/l  to 6.6mmol/l.

3. Educate patient on when and how to administer insulin at the right sites (the upper arm,the abdomen, mid section of the thigh)

4. Join diabetic association 

5. Educate the patient on frequent medical checkups/review and its importance.

6. Teach patient signs and symptoms of complications (blurred vision, excessive sweating etc)

7. Teach patient on the management of minor complications (if he goes into hypoglycaemia can take in some cubes of sugar or half of a sugary drink like coke to help increase the glucose level a little)

8. Educate patient on his/her diet – type, quantity ,what to avoid and when to eat(don’t skip meals, avoid high calorie diets etc) 

9.Medication dosages and times of administration 

10. Effects and side effects of drugs 

11. Wearing of diabetic identification bands/bracelets 

12. Teach on exercises and its importance and precautions to consider. 

13. Lifestyle modification – avoid alcohol, fatty diet, smoking 

14. Educate the patient to take in prescribed medications at the right time and doses and should avoid over the counter medications

Eye care

Visual impairment or disturbance is one of the complications of nephrogenic diabetes insipidus, which might lead to blindness. There should be a yearly plan or more frequent complete eye examinations by an ophthalmologist for patients with nephrogenic diabetes insipidus.

1.11 Validation

 It’s the assessment of an action, decision, plan or transaction to establish that it is correct, complete, being implemented (and/or recorded) as intended and delivering the intended outcome. Information was acquired from interaction with doctors and members of the health team, medical records, observation, investigations, clinical features and questioning of family members during the home visit to confirm information obtain from patient thus any information obtained is valid.