Consult Rounds: eDKA with GLP-1R Agonists

Euglycemic diabetic ketoacidosis (DKA) is a rare but serious condition characterized by ketoacidosis without significant hyperglycemia. We have seen this complication and heard about it in SGLT2i. Apparently, this can occur in patients using GLP-1 receptor agonists as well. 

GLP-1 (glucagon-like peptide-1) agonists enhance glucose-dependent insulin secretion, suppress inappropriate glucagon release, slow gastric emptying, and promote satiety. Euglycemic DKA is rare but has been reported in patients on GLP-1 agonists, particularly in combination with other diabetes medications like SGLT2 inhibitors. Why and when:- especially in type 1 diabetes (even if undiagnosed), severe illness, surgery, dehydration, and reduced insulin doses. Dehydration and changes in diet or medication regimens can also precipitate euglycemic DKA.

FAERS reporting system study confirmed this association. Using the FAERS database, The authors extracted the number of DKA reports from the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019 and calculated proportional reporting ratios (PRRs). They then examined each FAERS file from Q1 2004 to Q4 2020 to gather detailed information on DKA reports. During the period from Q1 2004 to Q4 2019, there were 1,382 DKA cases (and 1,491 ketosis cases) linked to GLP-1RA in the FAERS database. After excluding the influence of SGLT2 inhibitors, Type 1 diabetes, and insulin, there was a slightly disproportionate reporting of DKA associated with overall GLP-1RA (PRR 1.49, 95% CI 1.24-1.79, p < 0.001). This disproportionality disappeared when GLP-1RA was combined with insulin. When GLP-1RA is not combined with insulin, there was a disproportionality of DKA reports associated with GLP-1RA. The authors's analysis of the FAERS database provides evidence and highlights the potential association between DKA adverse events and GLP-1RA therapy, which clinicians may often overlook.

Here is a case report. This case report is with GLP-1RA and SGLT2i use. Here is a summary from the UK agency. 

Diagnosis requires a high index of suspicion in diabetic patients presenting with typical DKA symptoms but normal or mildly elevated blood glucose.

Let's observe to see if we see more of these cases as more and more prescriptions are being given out in the general medicine, cards and renal community. 

CONSULT ROUNDS: NELL-1 MEMBRANOUS NEPHROPATHY

 After PLA2R, NELL-1 related membranous nephropathy(MN) seems to be the second most common MN.  Initially, the studies had pointed towards a cancer-related cause for NELL-1 MN. In recent years and most recently, 2 papers published in 2024 highlight the role of complementary medications.  

A study from India investigates the clinical outcomes of NELL1-associated MN compared to unidentified antigen-associated MN. Among 46 NELL1 and 36 unidentified antigen-associated MN patients, a significant history of complementary and alternative medicine (CAM) use was noted particularly in the NELL1 group. NELL1-associated MN patients showed a lesser need for immunosuppression, attributed partly to CAM intake, with similar remission rates observed in both groups. The study highlights the distinct clinical features of NELL1-associated MN, including its association with CAM, and suggests a potential for spontaneous remission in these patients. Despite limitations like small sample size and short follow-up, findings indicate CAM's role in NELL1-associated MN and underscore the need for further research in this entity. 

A study spanning three institutions in the USA reviewed NELL1 associated MN cases, revealing that 53% of the 70 patients were male, with a median age of 66 and proteinuria of 5.9 grams/day. Associations included lipoic acid (36%), heavy NSAID use (27%), autoimmune diseases (23%), and malignancy (33%). At a median 11-month follow-up, 72% achieved remission, notably 91% in lipoic acid-associated cases with ≥6 months follow-up. Primary NELL1 MN and greater tubular atrophy and interstitial fibrosis predicted lower remission rates, while lipoic acid use correlated with higher complete remission rates, suggesting its discontinuation as a primary treatment strategy.

I have revised my concept map for NELL-1 MN based on this study to really highlight the CAM and Lipoic acid components. ( created using bio-render).

Consult Rounds: Hypophosphatemia and Tumor Genesis Syndrome

What is this entity? Tumor Genesis Syndrome compared to Tumor Lysis Syndrome.

Tumor lysis syndrome (TLS) is a critical medical condition that can arise in leukemias and lymphomas either as an initial presentation or after the initiation of anti-neoplastic treatments. Conversely, tumor genesis syndrome (TGS) is a rare occurrence associated with specific malignancies, particularly those characterized by a high neoplastic burden with rapid proliferation, resulting in the excessive uptake of phosphorus from the serum and leading to hypophosphatemia. Interestingly, a subset of patients may experience a combination of TLS and TGS concurrently, resulting in hypophosphatemia instead of the hyperphosphatemia typically seen in TLS.

From a nephrology perspective, this presents a potential differential diagnosis in leukemic patients. Differentiating hypophosphatemia from TGS is crucial, especially when considering other causes of severe hypophosphatemia related to neoplasms, such as tumor-induced osteomalacia. In this scenario, increased fibroblast growth factor-23 production leads to renal phosphate wasting, mimicking the hypophosphatemia seen in TGS.

In their literature review, Chan et al. highlighted an uncommon presentation involving severe hypophosphatemia, hypokalemia, acute renal failure, and acute respiratory failure in a 16-year-old patient with acute leukemia and significant leukocytosis. Conversely, Zakaria et al. reported a case of a 14-year-old boy with acute T-cell lymphoblastic leukemia who exhibited normal serum biochemistry except for marked hypophosphatemia and elevated LDH levels. Intriguingly, the child showed no symptoms related to low phosphate levels. Additionally, Radi and Nessim described a case of severe hypophosphatemia in an 82-year-old patient with lymphoma, attributing the cause to neoplastic intracellular phosphate uptake. Similarly, Aderka et al. presented a case of a 49-year-old patient with acute myelogenous leukemia experiencing hypokalemia, hypocalcemia, and severe hypophosphatemia (<1 mg/dL) leading to extreme weakness. The hypophosphatemia developed post-chemotherapy initiation and blast lysis, mainly due to the excessive phosphate uptake by leukemic blasts. Recently, another case was described with normal potassium and calcium levels, and despite very low phosphate levels, the patient did not show signs of acute respiratory failure. Additionally, low glucose, elevated LDH, and in some cases elevated lactate may be noted, which may or may not be directly related to TGS but could be a separate effect of leukemia.

Tumor Genesis Syndrome is a rare syndrome that needs to be considered in the differential diagnosis of hypophosphatemia. 

Consult Rounds: BK in non renal solid organ transplantation

What is the incidence of BK viremia, and BK Nephropathy in non renal solid organ transplants?

Not much that I could find in the literature.

In this retrospective study from 2021, the authors investigated the clinical characteristics, pathological findings, and outcomes of BK viremia and nephropathy in non-renal solid organ transplant patients (NRSOT) who sought nephrology consultation over a five-year period. Among liver, heart, and lung transplant recipients referred to Nephrology, 14% were diagnosed with BK viremia, with a median peak serum BK viral load of 35,500 copies/ml (ranging from 250 to 21,100,000 copies/ml). Notably, BK viremia resolved in six out of seventeen patients (35%), but four out of five biopsied patients exhibited BK virus (BKV) nephropathy. Furthermore, eleven out of the seventeen patients with BK viremia progressed to advanced stages (stage 4 or 5) of chronic kidney disease. Additionally, four patients experienced rejection of their solid organ transplant within the first year following the detection of BK viremia after reducing immunosuppressive treatments. This may be a sign of just net immunosuppression.

Another study back in 2019 had looked at literature systematically on report of BK disease in native kidneys. In their review at that time, in heart transplant recipients, 13 cases of BKV nephropathy had been reported, with most occurring in males (10 out of 13), and the mean age being 36.6 years. In lung transplant patients, six cases of BKV nephropathy were identified, with a mean diagnosis age of 47.3 years. Only one case of BKV nephropathy was reported in a liver transplant recipient, and one in a pancreas transplant recipient. More have been reported since their report. The average time from transplant to BKV nephropathy diagnosis in the solid organ transplant population was 2.88 years. For patients who had undergone hematopoietic cell transplantation (HSCT), 19 cases of BKV nephropathy were found, with a mean diagnosis age of 30.6 years. In cases with demographic information, 58% were males, and half of these patients required renal replacement therapy, with a mortality rate of 63.2%. Ten cases of BKV nephropathy were reported in the context of hematologic malignancies, with an average time from malignancy diagnosis to BKV nephropathy diagnosis of 3.06 years. Ten cases of BKV nephropathy were reported in HIV-infected patients, all in males, with a mean age of 34.5 years. Three of these patients required renal replacement therapy, and mortality at the time of publication was 30%. Additionally, individual cases of BKV nephropathy were described in various other clinical settings, such as rheumatoid arthritis, Hyper IgM immunodeficiency syndrome, pulmonary tuberculosis, diabetes mellitus, prostate cancer, and an immunocompromised patient with an unclear medical history. This is fascinating to note that this entity has been ignored in the recent non renal transplant literature. 

In a meta-analysis evaluating the frequency and risk factors for BK viruria and viremia in NRSOT patients, Viswesh et al found a relatively high rate of viruria (8%-52%) but infrequent progression to viremia (3%-7%) and BKV nephropathy (1 biopsy-proven case in an heart transplant recipient). Among those NRSOT patients who did have progression to viremia and BKV nephropathy, heart transplants patients represented the majority of cases. This finding might be due to the proposed “double-hit” hypothesis, which suggests that the cumulative insult of immunosuppression and renal hypoperfusion secondary to cardiac allograft dysfunction causes clinical progression to BKV nephropathy.  

Should implementing a systematic BK screening program could effectively identify and manage this issue in the NRSOT population and or HCT patients?

Consult Rounds: Differential Diagnosis of Asterixis

 The differential diagnosis of asterixis is important for a Nephrologists- It is not always Uremia...

Metabolic causes-- Uremia, Liver failure and hypercapnia 
Neuro drugs--Anticonvulsants, Benzos-- classic is phenytoin, carbamazepine, gabapentin, valproic acid, lithium
Antibiotics-- Cefepime, and other cephalosporins
Electrolyte disorders-- Hypomagnesemia, hypokalemia( never seen it there)
Bilateral brain lesions
**Unilateral brain lesions cause unilateral asterixis

Consult Rounds: Hyponatremia and AKI- need CRRT- what do we do??

 

Hyponatremia correction is challenging but manageable.
Offering and prescribing CRRT in the ICU is also doable by most nephrologists.

Here comes the challenge.

You are called, “ anuric patient, Na 110, K 5.4, BUN 90, Crt 6.0mg/dl) and altered mental status”
Now you are confronted with correcting the Na slowly and providing good dialytic clearance as well given anuria and hyperkalemia.

CRRT has advantages in its ability to correct plasma sodium values in a predictable and slow manner. Compared with standard hemodialysis machines, where the lowest dialysate sodium concentration is 130 mEq/l, CRRT solutions can be customized to any desired sodium level, allowing for personalized therapy. 

To act on these advantages and prescribe CRRT to target an increase in serum sodium no >6 mEq/L per day, there are three options: either (1) customize the CRRT circuit or (2) customize CRRT solutions. (3) add D5W infusion separate line with standard CRRT

So how is this rate calculated if we were to use Method 3( the easiest of the 3 options)

If D5W rate will be used – the formula is (140 -- target Na value)/( 140 X clearance)
So if we take 110 meq/L as the starting Na value and goal is in 24 hours to be 118. Given the patient was symptomatic, using 3% saline bolus- we get him to 112-113meq/L range. Then if we do 30cc/kg/hour clearance of CVVHDF, that would be roughly 2.4 liters/hour and hence the rate of D5W would need be 375cc/hour. If we use clearance of 25cc/kg/hour- then around 300cc/hr of D5W would be needed.

In an article by Rosner et al, in CJASN, method 1 is well discussed using this figure- changing the post filter fluid or replacement fluid to sterile water( d5W) and rate calculated similarly as stated above.

For method 2: Adding sterile water to commercial dialysis solutions to achieve a desired final sodium concentration would be next way. For instance, if a 5-L bag of replacement solution has a sodium concentration of 140 mEq/L, then the addition of 1 L of water would result in a final sodium solution of the replacement solution of 116.7 mEq/L. 

An important caveat, once desired Na is reached, D5W needs to be changed back to standard replacement fluids and or D5W drip discontinued. 

Consult Rounds: Hyponatremia from Anti depressants

 As nephrologists we often get called on SIADH from medications. Anti depressants a class of agents that we do consider to cause hyponatremia. Which ones are more likely vs others has always been interesting to know? A study from Denmark has a detailed look into this matter. 

The odds of developing hyponatremia in one large study was the highest in clomipramine, followed by nortriptyline, citalopram, paroxetine, duloxetine, venlafaxine, sertraline and amitriptyline. It had the least odds of association with mirtazapine, mianserin and escitalopram. The development was highest in the first 2 weeks of starting treatment( with the highest incidence of hyponatremia in the first 2 weeks in citalopram and lowest in mianserin. 

So, SSRI had the most association, SNRIs had slightly lower and non adrenergic specific serotogenic antidepressants had the least association. 

Consult Rounds: Causes of Osmotic Demyelination unrelated to hyponatremia correction

Osmotic Demyelination syndrome (ODS) is classically been associated with rapid correction of hyponatremia. But sometimes, in some rare cases, we observe other causes of this syndrome.
Here is a list that encompasses other known causes of ODS

Hyperglycemia
Hypernatremia( acute formation)
Hypoglycemia
Hypokalemia( this is well known entity causing it)
Alcoholism( This is probably the most important one)
Liver disease and liver transplantation
Malnutrition( another important one)
Hypophosphatemia
Use of CNI( not sure of the mechanism of this one)
Lithium use

This article from AJKD is an amazing reference.

Consult Rounds: Novel Sofosbuvir based Hep C agents and AKI

Can the novel agents used to treat hepatitis C cause AKI?

Most of the novel agents used to treat Hep C now in the current era are Sofosbuvir based. It has low rate of drug-drug interaction but kidney excretes over 70% of it’s major metabolite. This metabolite know as GS-331007 increases by ten fold in patients with renal dysfunction.

To my knowledge, no initial trials had any cases of AKI reported with this agent. Based on some recent trials using this agent, AKI might happen in 1-15% of patients treated with this agent.  Higher incidences were seen ( 45%) in liver transplant patients getting this agent. 

https://www.ncbi.nlm.nih.gov/pubmed/26923436

https://onlinelibrary.wiley.com/doi/full/10.1111/apt.14117

When?- 9-22 weeks of treatment.
Risk factors:- CKD, NSAID use, other nephrotoxic agent, DMII and ascites

Pathology:- what is the mechanism? There are only 4 published cases of kidney biopsy findings. We had published the first case of this in 2016 that showed AIN.  Subsequently, 3 other cases with AIN have been published and in one case ATN was also reported. It appears that the most likely mechanism is interstitial disease. In 2 of the 4 cases, 8 weeks was the time frame of injury, in remaining was 14 and 22 weeks of injury. It seems to be reversible in most cases.

https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/phar.1803

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496585/

https://europepmc.org/abstract/med/28656492

This is an interesting trend to watch. As we see less and less of Hep C induced renal disease, it is more likely we may see more treatment induced renal disease now.

A recent review of this topic is a good read.

Consult Rounds: High Dose IV Insulin and new avenues of treatment..

Traditional therapies for beta-blockers or calcium channel blocker toxicity are:
Glucagon, Calcium, Atropine and Vasopressors.

What I learned is that now high-dose insulin therapy has emerged as a preferred treatment of cardiogenic shock induced by calcium channel blockers or beta blockers. When used at doses 10 times that of the normal antidiabetic dose, insulin has positive inotropic effects even in the presence of beta-blocker or calcium channel blocker toxicity. What insulin dose at these high doses is improve hemodynamic stability and improve response to pressors. This takes almost 30 min to take effect.

There is a toxicology guidelines for this listed below: Consensus recommendations for the management of calcium channel blocker poisoning in adults. There is a  linear dose-response curve where increasing doses of insulin produce increasing positive hemodynamic effects. Goals for treatment can be a heart rate of at least 50 beats per minute and a systolic blood pressure of at least 100 mmHg. Obviously, one has to give dextrose to combat the severe hypoglycemia that might result of this and monitor K and phos levels s well.

Interestingly, this is being used commonly in beta blocker toxicity as well. In one large study looking at using high dose insulin in beta blocker and CCB toxicity, median insulin bolus was 1U/kg and peak infusion was 8 Units/kg/h.  Interestingly and expectedly, hypokalemia occurred in close to 30% of patients and hypoglycemia in 30% of patients.

 This is an interesting concept and a creative use of a common agent.

Consult Rounds: Heavy Chain Deposition Disease

Heavy-chain deposition disease (HCDD) is the least common non-organized monoclonal immunoglobulin deposition disease (MIDD), with close to 50 documented cases in world literature to date. The existence of this entity was postulated for many years until the first case was reported by Tubbs et al. in 1982 followed by another report by Aucouturier et al. in 1993.

It is mostly characterized by γ-heavy chain(HC), and occasionally α-HC, μ--HC,  or δ-HC deposits. Nearly half of HCDD cases were in patients without a symptomatic B-cell disorder, a condition now referred to as monoclonal gammopathy  of renal significance (MGRS).  A constant biochemical characteristic of deposited HC is the deletion of the first constant domain (CH1), which is required for the secretion of an isolated free HC. Other pathologic and clinical features differ from those of LCDD, including the higher frequency of nodular glomerulosclerosis, hypertension, hematuria, and serum hypocomplementemia in g-HCDD.

Recent studies have confirmed that the heavy chain with complement components, mostly C3 and C1q, is frequent in γ 3- and γ 1-HCDD with hypocomplementemia. These findings have been attributed to the capacity of IgG3 and, to a lesser extent, IgG1, to activate the complement classic pathway through C1q binding to the CH2 domain. Whether local and/or systemic complement classic pathway activation is involved in the pathogenesis of γ -HCDD remains unclear.

So what really happens?

When there is the CH1 domain lacking in the heavy chain, this doesn’t allow for the heavy chain binding to it’s chaperone protein in the endoplasmic reticulum, resulting in a truncated heavy chain by the B cell or plasma cell clone. This then starts depositing as it has a higher affinity to tissue- mainly the kidney! Even a small amount of it can cause damage. Hence, most of these cases didn’t have full blown myeloma but bone marrow showed in most as MGUS or smoldering myeloma.  Interestingly, in this latest study by Bridoux et al in 2017, they showed that in over 60% of the cases they reported, there was an abnormal serum free light chain ratio and a positive free light chain immunofixation as well. Interestingly, free light-chain assay levels correlated with disease response in the majority of patients. This suggests that the underlying B- or plasma cell clone produces a monoclonal light chain in addition to the pathogenic heavy chain, and thus the serum-free light-chain assay can be useful in HCDD diagnosis and monitoring after treatment.

Earlier studies had shown that there is a grim prognosis for HCDD. I think this might have been before MGRS was defined and many of them never got treated with anti-plasma cell agents. In the post bortezomib era, the newer data suggests otherwise. Bridoux et al from France data suggests that the outcomes were not that grim and the response to proteasome inhibitors were excellent. Recent mouse models have shown that this efficient response to proteasome inhibitors mostly relies on the presence of the isolated truncated heavy chain that sensitizes plasma cells to bortezomib through an elevated unfolded protein response.

So in summary

HCDD is rare but is a form of MIDD

Most commonly associated with MGUS or smoldering myeloma

The most common HC involved is γ and IgG3 specific

It is not unusual to see hypocomplementemia with this entity

Nodular sclerosis is the pathology finding on light microscopy

Response to proteasome inhibitors appears promising

Consult Rounds: Cisplatin induced AKI, can we predict?

Cisplatin is a well known nephrotoxic agent. But here is a scenario. You have a 51 y old man with no history of HTN, baseline serum creatinine of 1.1mg/dl, well nourished now diagnosed with laryngeal cancer. He is planned to get cisplatin. What is the risk of AKI post first dose of cisplatin for this individual?

Prediction models are helpful in such instances to guide the oncologists and nephrologists. Similar to the prediction of AKI and need for dialysis post contrast as done by Mehran et al, Motwani et al developed a prediction model for cisplatin based AKI.

The predictive model demonstrated reasonably good discrimination and calibration. The multivariate model was developed using a large cohort of patients and internally and externally validated. Its uses age, HTN, albumin and dose of cisplatin as the major coordinates.

Identification of high-risk individuals may facilitate appropriate preventative options such as more frequent laboratory monitoring, avoidance of concurrent use of other renal tubular toxins, and careful evaluation of dosing and administration of additional intravenous fluids. This study also suggests that baseline kidney function measured by creatinine may not be a good predictor of the risk of cisplatin induced AKI after the first course. 

I summarized the scoring the investigators designed and validated. 

Score Assigned	Age
0	<=60
1.5	61-70
2.5	71-90
	HTN
2	Yes
0	No

Score Assigned	Cisplatin Dose(mg)
0	<= 100
1	101-150
3	>=151
	Serum ALBUMIN(g/dl)
0	>3.5
2	1.3-3.5

So if score is 0-3 your risk of AKI is 3-8%, if score is 3.5-6, 15% and >6, risk is 28-39%

So in our case example, if the patient were to get 88mg of cisplatin and his albumin was 4.5g/dl, his risk scores for Cisplatin-AKI after the first course would be as follows: age < 60 years = 0; dose < 100 mg = 0; no hypertension = 0; and albumin > 3.5 g/dL = 0. Therefore, his total risk score would be 0 and his predicted probability of developing C-AKI would be 3%

Another example, A 69-year old man with a medical history of type 2 diabetes mellitus, hypertension, has new gastric cancer and is cisplatin-based adjuvant chemotherapy with a dose of 200 mg. His baseline creatinine is 1.0 mg/dL and her serum albumin is 2.8 g/dL. His risk scores for cisplatin AKI after the first course would be as follows: age 61 to 70 years = 1.5; hypertension = 2; dose > 150 mg = 3; albumin < 3.5 g/dL = 2. Therefore, his total risk score would be 8.5 and his predicted probability of developing AKI would be 28-39%.

A very helpful tool indeed for all of us to use.

Consult Rounds: Cryoglobulins and paraproteinemias

What is the connection of cyroglobulins(cyro) with paraproteinemias or myelomas?

Cryoglobulins are Igs that reversibly precipitate at temperatures <37°C. The precipitation results in symptoms that are seen in vasculitis: rash, ischemia, ulcers, joint pains, fatigue, and glomerulonephritis. The pathogenesis of cryoglobulin-induced injury involves two main mechanisms, hyperviscosity and immune complex deposition, that activate complement and induce vascular inflammation. Classically, in the renal community, we see this in Hep C association and other infections. In the “Harvoni” era of Hep C treatment, cyro associated MPGN from Hep C is likely on a downtrend.

What about with paraproteinemias?

In the largest case series of type 1 cryoglobulinemia associated with MM, six of seven patients were men 28–69 years of age, and all had stage 1 indolent myeloma. Three patients had an IgGκ monoclonal protein, three had an IgGλ monoclonal protein, and one had an IgMλ monoclonal protein. Skin changes and rheumatologic failure were the most common presenting symptoms. Renal manifestations were reported in two patients who presented with nephrotic syndrome and AKI.

Pathology usually shows an MPGN pattern of injury on LM and hyaline thrombi within glomerular capillaries. IF may reveal staining for various Igs within hyaline thrombi and the subendothelial space, and monoclonal light chain restriction may be observed in types 1 and 2 cryoglobulinemia. On EM, cryoglobulins may appear as paired, curved microtubules with a diameter of 20–30 nm), although it should be noted that this feature is observed in only a subset of patients.

In patients with cryoglobulinemia associated with a lymphoproliferative disorder, treatment should focus on the underlying hematologic malignancy that is producing the cryoglobulin. Fludarabine- and rituximab-based regimens have been used to treat type 1 cryoglobulinemia associated with MGUS, Waldenstrom macroglobulinemia(WM), and NHL. Antimyeloma therapies, including bortezomib, thalidomide, and lenalidomide, have shown efficacy in the treatment of type 1 cryoglobulinemia associated with MM.  With WM, besides AL amyloidosis, cyro MPGN is commonly seen as the GN manifestation.

High index of suspicion is required to connect the dots and many times the bone marrow and testing might be negative. As we have learnt, the clone might not be that large but it is noxious to the kidney.

Check out this recent CJASN review from few years ago on Paraprotein associated GNs

Consult Rounds: Low Urinary Na

Urinary Na concentration is a very useful urinary test that we use in clinical practice to decide the volume status of the patient. It is also very useful in helping decide pre renal vs intrinsic renal disease. 

There are several causes of AKI where urine Na concentration and fractional excretion of Na may be initially low, only to increase later. They are listed below

1.       Radiocontrast agent induced AKI- due to AngII increase and ischemic damage

2.       Sepsis- activation of AngII leads to initial vasoconstriction and low levels of urinary Na

3.       NSAIDs- unopposed vasoconstriction from Ang II

4.       Rhabdomyolysis- mechanism unclear

5.       Acute obstruction( initial phase)- again activation of AngII

6.       Acute GN- cytokines that lead to decrease GFR causing lowering of filtered Na load

7.       Acute rejection- similar to GN

A recent article in CJASN reviews the use of urinary studies in diagnosis of kidney diseases.

Consult Rounds: Adipsic Hypernatremia

When one encounters really high Na levels- 170-200meq/L range, adipsic hypernatremia should be in the differential; especially if they are asymptomatic. The key question to ask is “ are you thirsty?” Once called essential hypernatremia, this disorder is now called adipsic diabetes insipidus or central diabetes insipidus with deficient thirst or easier to call them adipsic hypernatremia. The most common reasons for these are lesions that affect the thirst center in the brain- craniopharyngiomas, CNS sarcoidosis, germinomas and clipping or rupture aneurysms of the anterior communicating artery of the circle of Willis. 

Tight regulation of water balance is accomplished via the thirst mechanism and ADH. Both are crucial to maintaining a remarkably narrow range of plasma osmolarity of 282–298 mOsm/kg. Osmoregulation of ADH is mediated by osmoreceptors located in the anteromedial hypothalamus near the neurohypophyseal cell bodies in the supraoptic nucleus. These osmoreceptors are extremely sensitive to changes in osmotic pressure. For example, an increase in osmolarity of 1 to 2 percent increases ADH secretion. However, ADH secretion alone is not adequate to prevent dehydration, and an intact thirst mechanism is vital for water homeostasis. Thirst is regulated by hypothalamic osmoreceptors that are sensitive to changes in effective osmotic pressure of body fluids. The osmotic threshold at which the thirst mechanism is activated begins approximately 5–10 mOsm higher than the threshold for ADH release. These two systems work together to maintain plasma osmolality. With both systems intact, hypernatremia is a rare development, but can occur in patients who have lost their ability to maintain or increase free water intake, for example hospitalized patients and particularly the geriatric population. 

There are four variants of adipsic hypernatremia. Type A adipsia is characterized by an upward setting of the osmotic threshold for both thirst and vasopressin release, sometimes called essential hypernatremia. Type B adipsia is characterized by subnormal thirst and vasopressin responses to osmotic stimuli. This is due to partial destruction of the osmoreceptors. Complete destruction of these receptors is classified as type C adipsia, and these patients have complete absence of ADH release and a lack of thirst mechanism. Type D is an extremely rare form that manifests as only a thirst mechanism failure with an intact ADH production.

In all patients with adipsic hypernatremia, a careful neurologic and radiologic evaluation should be performed, looking for a possible treatable disease (such as a benign tumor) that might restore osmoreceptor function. 

Forced drinking to make patients eunatremic is the treatment—that is, scheduled water drinking because there is no thirst mechanism, with some desmopressin if need be—is usually what helps. Surgical correction of the cause will be helpful in cases where it is possible. 

An old case of detective nephron that discusses this in a fun way at ASN Kidney News.

Consult Rounds: Toxic alcohol ingestions

A summary of all potential alcohol toxicities ( Renal perspective)

Name	Metabolic Acidosis	Osmolar Gap	Anion Gap	Ketones	Ca Oxolate Stones	Reduced Vision
Alcohol	Yes	Yes	Yes( lactate also)	Yes	No	No
Methanol	Yes	Yes( earlier on and then disappears)	Yes	No	No	Yes
Ethylene Glycol	Yes	Yes	Yes	No	Yes	No
Isopropyl Alcohol	No	Yes	No	Yes	No	Yes
Propylene Glycol	Yes	Yes(initially)	Yes(converted to lactate)	No	No	No