Case 92: Answer and Discussion

The prevalence of non dipping of blood pressure increases with loss of renal function.

— Kenar Jhaveri (@kdjhaveri) September 27, 2018

Nondipping is more prevalent in CKD than in non-CKD patients or patients with essential HTN.  The prevalence of non dipping does increase as GFR declines. The prevalence of  reverse-dippers also increases progressively as stage of CKD progresses.

Reference: https://www.ncbi.nlm.nih.gov/pubmed/23595357
 

Clinical Case 91: Answer and Discussion

A twitter poll question I had asked


https://twitter.com/kdjhaveri/status/1033699053043949568

Which one of these interferes with plasma and urine catecholamines assay?

— Kenar Jhaveri (@kdjhaveri) August 26, 2018

The answer is all of the above. There are several agents that interfere the workup for pheochromocytoma and can interfere with the catecholamine and dopamine pathway. The comprehensive list is listed below.

Tricyclic antidepressants, phenoxybenzamine, labetelol can affect the measurement of both catecholamines and metanpehrines

Monoamine oxidase inhibitors and buspirone affects mainly the metanephrine measurements

Caffeine, L-Dopa, Carbidopa mainly affect the catecholamine assays

Case 90: Answers and Summary

Which of the following is a risk factor for bleeding post kidney biopsy?

This is a tough question. Traditionally, many have thought that ASA is a known risk factor for bleeding post kidney biopsy. A recent large study states otherwise. In a large observational study published in CKJ, >2000 patients were reviewed. The incidence of major bleeding was 2.2%.  The risk factors as assessed by statistics were need for emergent biopsy as oppose to elective renal biopsy. No major risk was noted with ASA use and BMI.  There is data from prior studies suggesting no major risk with amyloidosis unless there is a factor XII deficiency associated with the amyloidosis. Emergent need for a kidney biopsy seems to be the major risk factor more than the others. 

Clinical Case 89: Answers and Summary

Which is NOT a known renal complication of Bariatric surgery?

The renal risks of bariatric surgery are pre renal AKI, and long-term risks of nephrolithiasis and oxalate nephropathy. AKI is fairly common after bariatric surgery, with reports ranging from 2.9% to 8.5% in published studies, which have used varying definitions of AKI. Risk factors for AKI after bariatric surgery include higher BMI, lower eGFR, preoperative use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and intraoperative hypotension. Bariatric surgery patients may be prone to dehydration and higher risk for prerenal AKI in the long term, although this risk has not been quantified.  FSGS is a known secondary cause of Obesity but not related to bariartic surgery.

 A recent article in KI reports summarizes AKI related to bariatric surgery

http://www.kireports.org/article/S2468-0249(17)30012-8/fulltext

Clinical Case 89: Answers and Summary

Which anti melanoma therapy can lead to immune mediated hyponatremia?

Ipilimumab(CTLA-4 inhibitor) has also been associated with electrolyte disturbances. Two cases of ipilimumab-induced hyponatremia due to panhypopituitarism from ipilimumab related hypophysitis have been reported. The incidence of hypophysitis in patients treated with this agent is close to 17% in clinical trials. Mechanistically, a loss of adrenocorticotrophic hormone-secreting corticotrophs leads to a secondary adrenal insufficiency and loss of regulatory effects of cortisol on arginine vasopressin. This could be the mechanism leading to the hyponatremia. While FDA reporting system has mentioned hyponatremia in PD1 inhibitors(nivolumab and pembrolizumab) and BRAF inhibitors(vemurafenib and dabrafenib), it is at a lower incidence and likely not immune mediated. 

http://www.karger.com/Article/FullText/455014

http://jamanetwork.com/journals/jamaoncology/article-abstract/2342045

Clinical Case 88: Answers and Summary

Which one of these immune check point inhibitors leads to loss of transplanted kidney?

The correct answer is nivolumab or PD-1 inhibitors.  Several cases of kidney injury have now been reported when the immune check point inhibitor use in kidney transplant patients. While Lipson et al had initially reported successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma without any rejection, they recently reported a case of tumor regression but allograft rejection after administration of   pembrolizumab.  In addition, three cases of rejection were reported with use of nivolumab  in renal transplant patients with melanoma. 

https://www.ncbi.nlm.nih.gov/pubmed/26752406

https://www.ncbi.nlm.nih.gov/pubmed/26951628
https://www.ncbi.nlm.nih.gov/pubmed/26988410
Based on the 6 cases, it appears that PD-1 inhibitors are more prone to causing rejection in the transplanted kidney compared to CTLA-4 antagonists , especially when the  patients  have received anti CTLA-4 agents prior to PD-1 inhibitor treatment.  Graft tolerance might be minimized and hence rejection ensues.

B cell malignancies and the Kidney

B cell malignancies and the Kidney from kdj200

Clinical Case 87: Answers and Summary

34 y old Indian Male with IgA nephropathy, crt is 2.4mg/dl and 2.5gm of proteinuria: treatment?

RAAS blockade only

  6 (12%)

 

RAAS blockade and Fish oil

  9 (19%)

 

Steroids with RAAS blockade

  19 (40%)

 

Treatment depends on Biopsy Oxford Classification of IgA Nephropathy

  13 (27%)

 

The KDIGO recommends no specific guidance for treatment with steroids in IgA nephropathy patients when they present with GFR between 30-50cc/min. A recent study published in JASN in 2015 looked at steroid use in IgA Nephropathy patients. It is called the VALIGA study.  A retrospective study that studied over 140 patients with IgA nephropathy from European registry and classified based on Oxford classification MEST score.   46% received immunosuppresive agents and of them 985 were steroids.  The ones who were treated had all the features of clinical progression( rising crt, or proteinuria).  All also received RAAS blockade.  The patients who got steroids had a significant reduction in proteinuria, a slower rate of renal function decline and greater chance of not being on dialysis.  While, initially we had thought that the benefit of such treatment was only in patients with mild- moderate AKI, this study found benefit even in the GFR<50cc/min cohort with levels of proteinuria.  

So in the above patient, the best answer would be Steroids with RAAS blockade. If the biopsy did show crescentic GN, the treatment ofcourse would be with cytotoxic agents in addition. 

Clinical Case 86: Answers and Summary

Which one of the following chemotherapy agents cause solitary hypophosphatemia?(select more than 1)

cisplatin	7 (38%)
sorafenib	2 (11%)
imatinib	7 (38%)
lenalidomide	4 (22%)

While many chemotherapy agents cause electrolyte disorders, hypophosphatemia is a rare occurrence.

Let’s take each chemotherapy agent at a time that is listed above.

Cisplatin classically is known to cause AKI and proximal tubular damage and hypomagnesemia but sole hypophosphatemia is rarely reported. Usually, a classic Fanconi syndrome has been described. 
So, choice A is less likely to cause solitary hypophosphatemia.

Sorafenib, a multikinase inhibitor targeting the c-Kit, RAF, VEGF and PDGF pathways, is approved for the treatment of patients with hepatocellular carcinoma and renal cell carcinoma, with a broad spectrum of activity also including selected sarcoma subtypes, thyroid cancers and melanoma. Sorafenib induces pancreatic exocrine dysfunction, leading to vitamin D malabsorption and secondary hyperparathyroidism. Patients receiving sorafenib can develop hypophosphatemia and vitamin D deficiency.

Of the 4 listed above, imatinib has been most well described with this electrolyte disorder. In NEJM, Berman and colleagues reported their findings regarding the development of hypophosphatemia and associated changes in bone and mineral metabolism in patients with either chronic myelogenous leukemia or gastrointestinal stromal tumors who are taking imatinib. A nice review article discusses the effect of all tyrosine kinase inhibitors such as imatinib and sorafenib and their effects on bone health. By inhibiting platelet-derived growth factor receptors expressed on osteoclasts, these agents cause a subsequent decrease in bone resorption and decreased calcium and phosphate egress from the bone. As a result, PTH levels increase and phosphaturia follows.

Lenalidomide and hypophosphatemia has been described in conjunction with other therapies and sole effect. It appears to be a potential renal loss mechanism. It is hard in this drug as myeloma is the primary cancer and the cancer itself can cause this electrolyte disorder. A Fanconi syndrome has also been described. 

Clinical Case 85: Answers and Summary ( iron use in ESRD)

ESRD patient with anemia, Fe sats of 12%, Ferritin 450 needs IV iron. Patient has bacteremia.

A. Proceed to give IV iron as anemia and low Fe sats demands it.  (2%)

B. Given active infection, do not give IV iron till 2 weeks after infection resolved (73%)

C. Given active infection, do not give IV iron till 4 weeks after infection resolves. (24%)

There have been no clinical trials of adequate sample size and duration to provide us sufficient understanding of the safety of intravenous iron. Is bolus iron better or continuous form? Is iron infusion pose an infection risk?

Brookhart et al. retrospectively studied patients on dialysis treated at Davita Inc. dialysis facilities and found that patients receiving 200mg intravenous iron per month had an increased risk for hospitalization or death because of infection. They also found that bolus dosing was more associated with infection. More recently, A CJASN study by Miskulin et al. found a increased risk for infection-related mortality when cumulative iron dose exceeded 1050 mg over 3 months or 2100 mg over 6 months( not statistical but a trend). In an accompanying editorial to the Miskulin study, Fishbane et al (must read) discuss what the USRDS data suggests. As the mean serum ferritin of United States patients on dialysis approximately doubled from 1993 to 2001, the rate of bacteremia/sepsis increased approximately by 40%. From 2001 to 2010, serum ferritin stabilized, and soon enough the bacteremia/sepsis rate also stabilized. In light of these above findings, it is advisable to hold iron infusions in setting of active bacteremia.  

What about other active infections such as cellulitis or pneumonias? No data exists for those at this point. How long do we wait is a good question. Most likely choice is 2 weeks but data for that is not clear. Some of you chose 4 weeks: might also be a reasonable choice.  Another concern might be catheter use.  Infection risk as stated by the Brookhart study that risks are largest among patients with a catheter and the ones with a recent infection. 

Clinical Case 84: Answers and Summary

What is the pathology seen in the kidney in Mesoamerican nephropathy?

Chronic glomerular damage	1 (5%)
Chronic tubulo interstitial damage	13 (72%)
Chronic thrombotic microangiopathy	0 (0%)
Chronic nodular sclerosis	4

The correct answer is tubulo interstitial disease.  The best summary of this entity was recently discussed in the online nephrology journal club ( NephJC).  

http://www.nephjc.com/hyperosmolarity-ckd/ is the full link

This link also goes over the discussion re this entity on twitter. 

https://storify.com/nephondemand/meso-american-nephropathy

Clinical Case 83: Answer and Summary

Which one of these drugs is the most common culprit in acute allergic interstitial nephritis now?

Amoxicillin 13%
Omeprazole 37%
Ciprofloxacin 24%
Ibuprofen 24%

Classically, drug induced AIN has been most commonly linked with antibiotics and NSAIDS. Recently, PPIs have emerged as a more common cause of AIN than the other drugs. This might be due to the massive use of these agents for almost all patients that are admitted to the hospital for ulcer ppx.  A recent study from Mayo Clinic looked at biopsy proven AIN in a single center retrospectively and identified the culprits. Drugs were 70% of the causes followed by autoimmune diseases. The most common class of drugs were antibiotics followed by PPI and then antibiotics. But overall, the top 3 causes were omeprazole, amoxicillin and then ciprofloxacin.  Patients with PPI induced AIN were older, not as symptomatic and had longer duration of drug exposure till getting kidney biopsy. 

Clinical Case 82: Answers and Summary

Which oral magnesium preparation has the highest amount of elemental magnesium content?

Milk of magnesia

  4 (11%)

 

Magnesium citrate

  7 (19%)

 

Magnesium oxide

  13 (36%)

 

Magnesium chloride

  5 (13%)

 

Magnesium lactate

  3 (8%)

 

Magnesium carbonate

  4 (11%)

 

Magnesium oxide  has the highest ( 61%) elemental magnesium; 242mg in a 400mg tablet

Milk of Magnesia Or Magnesium Hydroxide  has the second highest ( 42%).

Mg Carbonate has 24%

Mg Citrate has 16% elemental Mg

MgCl has 12%

Mg lactate has 10%

Other ones not listed are Mg gluconate that has 5% elemental Mg, Mg aspartate HCl that has 10%
Mg glycerophosphate that has 10% as well.

Check out a nice review article in AJKD by Ayuk and Gittoes on management of hypomagnesemia. 

Clinical case and answers 81

What leads to hyponatremia in adrenal crisis?

Pre renal state due to low cortisol	5 (26%)
CRH release leads to hyponatremia	2 (10%)
Cortisol normally suppresses ADH and in adrenal insuff, this doesn't happen	11 (57%)
The mechanism is not known	6 (31%)

The hypersecretion of ADH seen in low cortisol states may be due in part to the reductions in blood pressure and cardiac output. However, a more important mechanism may be that cortisol deficiency lead to increase CRH production leading to increase ADH state.  Cortisol feeds back negatively on CRH and ACTH, an inhibitory effect that is removed with adrenal insufficiency. In addition, cortisol appears to directly suppress ADH secretion. Thus, ADH levels increase when plasma cortisol levels are low.  Alternatively, the hypersecretion of ADH induced by aldosterone deficiency is caused by renal salt wasting with resultant volume depletion. Many studies support the concept that hyponatremia in patients with hypopituitarism is mainly caused by failing inhibition of ADH secretion because of hypocortisolism.

http://jasn.asnjournals.org/content/17/7/1820.long is an amazing reference from JASN that looks at water homeostasis in adrenal disorders. 

Clinical Case 80: Answers and Summary

Which statement best describes the relationship of microalbuminuria and cardiovascular disease?

Microalbuminuria causes cardiovascular disease Atherothrombosis causes microalbuminuria A common risk factor causes both microalbuminuria and cardiovascular disease A common pathophysiological process such as endothelial dysfunction might lead to  both microalbuminuria and cardiac disease

Most of you got this one correct. The age old question is " is microalbuminuria cardio toxic?" This is tough. Is it a surrogate marker of inflammation as some believe it is the ESR for the kidney or is it truly a risk factor for cardiac disease?  A paper in JASN many years ago looked at 4 potential mechanism of how these two might be related. The 4 mechanisms are listed above as your 4 choices. 

There is no direct evidence that supports statement " microalbuminuria causes cardiovascular disease".  The second statement may be partially true based on the authors argument but not many times hence atherothrombosis causing microalbuminuria might not be the problem either. Clearly common risk factors do exist with these two condition such as insulin resistance and or metabolic syndrome, and no one has looked at whether the association of the two conditions disappears when adjusted for insulin resistance and or other variables that are common risk factors. 

Hence, the most likely statement that makes sense is a common process that leads to endothelial damage leads to both microalbuminuria and cardiac disease.  Endothelial damage makes most sense as we as nephrologist see this all the time:- both diabetics get proteinuria and then the SLE patients with endothelial damage and then the pre eclamptics with endothelial damage. 

Clinical Case 79: Answers and Summary

Which one of these agents are potential treatment options for sarcoidosis induced hypercalcemia?

Steroids	41 (78%)
ACTH	8 (15%)
Ketaconazole	7 (13%)
Hydroxychloroquine	4 (7%)
Pamidronate	9 (17%)

In a earlier study in JAMA years ago, it was established that the hypercalcemia in sarcoidosis is 1,25 vitamin d production mediated.  Classically, for 1,25 Vitamin D mediated hypercalcemia such as in lymphoma, TB. etc, steroids are the mainstay of treatment. A dose of 15-25mg/day of prednisone is usually effective.  Ketoconazole is the next line of treatment for patients who cannot tolerate steroids.  Since its an imidazole antifungal that inhibits enzymes in steroid synthesis, it works well. Hydrocholoroquine also causes inhibition of 25(OH), D3 1 alpha hydroxylase and can be used in some patients that have side effects to prior two meds.  MTX and Azathioprine can be used to treat systemic disease that might have effect on calcium as well. ACTH has not been studied in this arena.  Pamidronate has been used in case reports but the mechanism of hypercalcemia doesn't really support the use of that agent. 

References:

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)08251-8/fulltext

http://www.ncbi.nlm.nih.gov/pubmed/6287893?dopt=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/3755800?dopt=Abstract

Clinical Case 78: Answers and Summary

Which one of the following are items to assess when solute clearance per session in HD is marginal?

Adequacy of the blood flow from the access	14 (63%)
Dialysate flow rate	8 (36%)
Dialyzer surface area	10 (45%)
Duration of dialysis	18 (81%)
Blood pump speed	8 (36%)
Serum potassium pre dialysis level	2 (9%)
Dialysate pathway stagnation	4 (18%)
Serum sodium pre dialysis concentration	2 (9%)

All the above need to be assessed to see if the clearance is good for HD session. Serum K and Na pre dialysis has not been evaluated to have any clearance related benefit. Access, dialysis flow rate, blood flow rate, duration of dialysis being the most important followed by blood pump speed, pathway stagnation, fiber bundle clotting, dialyzer surface area are also important components. Check out the free access HD core curriculum in AJKD 2013 for an excellent review on this topic. Watch out for an eAJKD quiz on this topic coming soon as well.

Clinical Case 77 Answers and Summary

A 56 y old on PD presents with PD peritonitis and bacteremia as well likely related to the peritonial infection. How would you treat?

The role of IV antibiotics in PD peritonitis has always been questions. A recent Cochrane review was done on this topic. They identified 36 studies (2089 patients): antimicrobial agents (30); urokinase (4), peritoneal lavage (1) intraperitoneal (IP) immunoglobulin (1). No superior antibiotic agent or combination of agents were identified. Primary response and relapse rates did not differ between IP glycopeptide-based regimens compared to first generation cephalosporin regimens, although glycopeptide regimens were more likely to achieve a complete cure (3 studies, 370 episodes: RR 1.66, 95% CI 1.01 to 3.58). IP antibiotics were superior to IV antibiotics in reducing treatment failure (1 study, 75 patients: RR 3.52, 95% CI 1.26 to 9.81). Based on one study, IP administration of antibiotics is superior to IV dosing for treating PD peritonitis. Intermittent and continuous dosing of antibiotics are equally efficacious.
What about bacteremia in addition to the PD peritonitis?  This is a hard question that hasn’t been looked at. A study did analyze the incidence rates and risks of bacteremia and HD and PD. Placement of a permanent access (fistula, graft, or PD catheter) prior to initiation of dialysis, smoking cessation, and better nutritional status (i.e. higher serum albumin) were associated with a reduced risk of bacteremia in dialysis patients. Higher serum albumin was also associated with a reduced bacteremia-associated mortality.
Two cases reports have looked at treating cases of peritonitis and bacteremia. Most used IP only but some had combo treatment. The jury is still out.
http://www.pdiconnect.com/content/31/3/366.long
http://www.pdiconnect.com/content/30/3/381.long

Clinical Case 76: Answer and Summary

A 35 y old male with BMI of 38 has microalbuminuria. He has hyperlipidemia and no history of DM or HTN. What do you do next?

Start ACEI/ARB	8 (10%)
Weight loss and observe microalbuminuria	63 (79%)
Observer microalbuminuria	6 (7%)
Kidney biopsy	2 (2%)

With 79 responses, most of you would just recommend weight loss( given BMI) and observe the microalbuminuria. Close second was starting ACEI/ARB.  Given no DMII or HTN, many thinkers in nephrology on "microalbuminuria" say that observing might be a better option. Chronic illnesses such as obesity, hyperlipidemia, rheumactic illnesses, etc. all can lead to microalbuminuria. In other words, it can thought of as "ESR" test rather than real renal disease. Observing is important as if rises to significant proteinuria, then certain action might be needed ( as new disease might have developed or meds might be indicated). Data on this is still skim and perhaps we shall hear about this soon in the literature.

Clinical Case Answers and Summary 75

What is the mechanism of injury of carfilzomib induced renal injury?

Carfilzomib (Kyprolis, Onyx) is a next-generation epoxyketone proteasome inhibitor that is approved for the treatment of relapsed refractory multiple myeloma. The phase 2 trial  that initially raised interest in this agent was a single-arm study of patients with refractory multiple myeloma who received carfilzomib 20 mg/m2 intravenously twice weekly for 3 weeks in cycle 1 and  then 27 mg/m2 for subsequent cycles. Increased serum creatinine was the most frequently reported renal adverse event, affecting 25% of the 266 patients in this study.

Case report and discussions with experts suggests its more likely to be a pre-renal insult. Glomerular disease is less likely the cause of the renal toxicity. In a patient who has multiple myeloma with renal involvement, nephrotoxicity caused by the disease can be hard to distinguish from nephrotoxicity caused by an agent.