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Question: ‘Should Vitamin 25(OH)D levels be measured in CKD patients and should this be supplemented in the patients who are already on active vitamin D supplements?’

A primary care colleague asked this excellent question.

Vitamin D has been found to have role not only in bone and mineral metabolism but also in a wide range of other systems like cardiovascular diseases, diabetes, hypertension and immune system. Vitamin D insufficiency (less than 30ng/ml) and deficiency (less than 15ng/ml) is prevalent in CKD (Chronic Kidney Disease) patients, especially in patients who are african-american, older, with diabetes and hypoalbuminema. A recent study estimated that 79% of ESRD patients on hemodialysis had vitamin D deficiency.

In patients with CKD, there is a progressive loss of renal 1 α hydroxylase activity, which is responsible for the conversion of calcidiol (Vitamin 25OH D) to the active form calcitriol  (Vitamin (1,25) OH D3). Lack of calcitriol leads to secondary hyperparathyroidism and subsequent bone and mineral derangements. Hence, active Vitamin D( calcitriol and its analogues) supplementation is routinely done in CKD patients to treat secondary hyperparathyroidism. Several studies have shown that administering active vitamin D leads to significant reduction in mortality in CKD patients and the benefit was much more than treating hyperparathyroidism alone.

There is an ongoing debate regarding the role of concurrent 25(OH)D repletion in CKD patients already treated with calcitriol or its analogues. Since, CKD 3-4 patients have some residual renal 1 α hydroxylase activity, these patients should be screened and treated for Vitamin 25 OH D insufficiency/deficiency to treat secondary hyperparathyroidism.

However, for patients with more advanced CKD (Stage 5) including dialysis patients, it has not been established that vitamin D (ergocalciferol or cholecalciferol) will be effective, since the ability to generate adequate levels of 1,25(OH)2 D3 is markedly reduced. Lately, there has been evidence that 1α hydroxylase enzyme is found in many other sites except the kidneys (such as the parathyroids, pancreas, adrenal medulla, endothelium, smooth vascular cells, skin, and cerebellum), which are intact in CKD patients. This locally produced 1,25(OH)2D is suspected to have “autocrine or paracrine” effects and most likely responsible for the roles for vitamin D, beyond its classical functions in mineral metabolism.

A study reported in the current volume of CJASN shows that vitamin d 25 OH (cholecalciferol) supplementation is safe and cost-effective in dialyisis patients and  ‘allows reduction of vitamin D deficiency, better control of mineral metabolism with less use of active vitamin D, attenuation of inflammation, reduced dosing of erythropoiesis-stimulating agents, and possibly improvement of cardiac dysfunction’. However this was a small, short term, nonrandomized study which did not look at outcomes of mortality.Large, long term, prospective studies need to be done in future to prove its beneficial effect and the dose .

Although the evidence is not strong, but since the therapy is relatively safe (side effects being hypercalcemia and hyperphosphatemia), Vitamin 25 OH D levels should be evaluated and correction of 25(OH) D deficiency/insufficiency should probably be done in CKD 5 patients also, similar to the general population as suggested by the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations.

Bottomline:

  1. Vitamin D insufficiency and deficiency is highly prevalent in CKD patients
  2. Vitamin D 25 OH (either ergocaliciferol or cholecaliferol) should be given to treat vitamin d deficiency/insufficiency in CKD3-4 patients just like the general population.
  3. Stage 5 CKD patients can also be treated with vitamin D 25 OH for vitamin D deficiency, although the evidence is not strong and long-term studies are not available.
  4. These CKD patients should be monitored closely for adverse effecs like hypercalcemia and hyperphosphatemia while on vitamin D therapy.

Defining Acute Kidney Injury

Question: “Can you help with the definition of acute renal failure.  I know in the last few years I have seen greater use of the term, acute kidney injury and there are more than one set of guidelines.  It would be nice to have a simple explanation that one could remember while doing those 3am admits.”

The other day I received this question in an email from a colleague. This is a great question but the truth is that there is not a whole lot of consensus even amongst the nephrologists about the definition of acute kidney injury.

Traditionally, acute renal failure (ARF) has been broadly described as a sudden decline in kidney function leading to the accumulation of urea and other nitrogenous waste products and the disturbances in volume, electrolytes and acid-base balance. The lack of a universally recognized definition of ARF has posed a significant limitation in early and appropriate diagnosis and even in interpreting epidemiological studies.

To resolve these limitations, the Acute Dialysis Quality Initiative (ADQI) proposed the RIFLE criteria. This consists of three graded levels of injury (Risk, Injury, and Failure) based upon either the magnitude of elevation in serum creatinine or urine output, and two outcome measures (Loss and End-stage renal disease). More recently the Acute Kidney Injury Network (AKIN), modified the RIFLE criteria recognizing that even very small changes in SCr (≥0.3 mg/dL) adversely impact clinical outcome. In addition, the term acute kidney injury (AKI) was proposed to represent the entire spectrum of acute renal failure from subclinical disease to complete organ failure. They defined AKI as

‘an abrupt (within 48 hours) absolute increase in the serum creatinine concentration of ≥0.3 mg/dL (26.4 micromol/L) from baseline, a percentage increase in the serum creatinine concentration of ≥50 percent, or oliguria of less than 0.5 mL/kg per hour for more than six hours.’

The staging system for AKI is comprised of three stages of increasing severity, which correspond to risk (stage 1), injury (stage 2), and failure (stage 3) of the RIFLE criteria (see Table)

The above criteria require at least two creatinine values within 48 hours. It is assumed that the diagnosis based on the urine output criterion alone will require exclusion of urinary tract obstructions or other easily reversible causes of reduced urine output. The above criteria should be used in the context of the clinical presentation and following adequate fluid resuscitation.

The RIFLE and AKI criteria have correlated with prognosis in a number of studies. But, there is an inherent confusion within these criteria as to whether prerenal and obstructive etiologies of ARF are included in the definition of AKI. The exact clinical utility of these criteria are yet to be proven and in the coming years may be revised.

So, while there is no simple definition of AKI, here’s the bottom line:

1. Acute kidney injury (AKI) has replaced the term Acute Renal Failure (ARF)

2. AKI is defined as an abrupt (within 48 hours):

  • absolute increase in the serum creatinine concentration of ≥0.3 mg/dL (26.4 micromol/L) from baseline,
  • ≥50 percent increase in the serum creatinine or,
  • oliguria of less than 0.5 mL/kg per hour for more than six hours.

Question: Why do some dialysis patients with failed renal transplants remain on immunosuppressants?

This was a question asked by my hospitalist colleagues, when we were taking care of a patient who had recently started dialysis after a failed renal transplant.

Over the last few decades, renal transplant outcomes have significantly improved, but we still have a substantial number of patients who end up transitioning to dialysis as their renal allografts have failed. Most of these allografts are left in place as long as they are not causing any systemic inflammatory response or acute rejection. The idea is to avoid transplant nephrectomy in such patients with a lot of comorbidities and the dilemma is whether to withdraw immunosupressants.

Intuitively it may seem reasonable to withdraw immunosuppression as soon as possible to avoid its complications (like infection, cardiovascular complications or adverse effects of long-term steroid therapy). However, withdrawal of these agents may lead to acute rejection, requiring transplant nephrectomy. Symptoms resulting from rejection include graft tenderness, fever, hematuria, localized edema, and occasionally infection. Less fulminant rejection may present with unusual symptoms, such as weight loss, anemia, fatigue, gastrointestinal complaints, and neurologic disturbances. The other, although less common complication is the risk of secondary adrenal insufficiency. It has also been found that a longer taper of immunosuppression may preserve some residual renal function. Another argument is that removal of the graft leads to immunoreactivity and increased panel-reactive antibodies, which may not be desirable in patients for subsequent transplant. Hence, the most common current practice is to withdraw the anti-metabolite (cellcept or azothioprine), reduce the calcineurin inhibitor and prednisone dose; and then taper them slowly over 3 to 6 months.

A recent study (Ayus etal ) presents a contrarian view, suggesting that allograft nephrectomies should be done more routinely and that they have a 32% lower adjusted relative risk for all cause death than the current management strategies. This retrospective study has the potential of changing our current approach to failed renal allografts, but the benefits are yet to be proven in a randomized trial. So let us see which way evidence will take us in future!

Bottomline (for now):

1)   Tranplant nephrectomies should be performed in patients who have evidence for systemic inflammatory response or acute rejection.

2)   Immunosuppressive drugs should be tapered slowly (as tolerated )in patients with failed renal transplants.

ACE in CKD

Question: How much of an increase in serum creatinine is acceptable in patients who are started on angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs)?

ACEIs and ARBS are important drugs in the treatment of patients with chronic kidney disease. In proteinuric CKD, these drugs are used not only for blood pressure control (JNC VII) but also for reducing proteinuria. They are also the drug of choice to slow down the progression of proteinuric CKD.

Initiation (or dose increase) of ACEIs and ARBs may cause an increase in serum creatinine in some patients. A 20-30% increase in serum creatinine within 1-2 weeks is generally acceptable, as long it stabilizes. This may even be a good thing as indicated by a study by Bakris and Weir, where they reviewed 12 clinical trials, and found that an acute increase in serum creatinine of up to 30% was strongly associated with long-term preservation of renal function.

If the serum creatinine concentration rises by more than 30%, one should stop or reduce the dose and consider whether the patient has a high-renin state such as hypovolemia or uncompensated heart failure. ACEIs should be given a second trial if there is a reversible state like hypovolemia. Another potential cause of elevated serum creatinine levels could also be bilateral renal artery stenosis which should be considered in patients who are smokers or have extensive atherosclerotic cardiovascular disease.

Also these drugs may sometimes increase the serum potassium levels. A potassium level of up to 5.5 mEq/L is generally considered safe as long as it is stable and the patient is following a potassium restricted diet and is not taking any medications which can excacerbate hyperkalemia like NSAIDs and aldosterone antagonists. Diuretics can be used to promote potassium excretion.

Bottomline:

1. Serum creatinine and potassium should be checked within a week of starting ACEIs or ARBS and then should be monitored frequently.

2. A rise of 20-30% in serum creatinine is acceptable as long as it is stable.

Gaodolinium and CKD

Question: At what creatinine level is it unsafe to give Gadolinium contrast in patients with kidney disease? Can dialysis prevent the complications?

Gadolinium based contrasts are widely used for MRI and until recently were considered relative nontoxic and a good alternative to iodinated contrast agents, especially in patients with kidney disease. However in the last few years, there has been a lot of literature indicating that gadolinium exposure causes a dermal fibrosing condition called ‘Nephrogenic Systemic Fibrosis’ (NSF). It first affects the skin as dermal hardening with tethering to deep dermal tissues giving the skin a wooden texture. These patients typically present with skin tightness, pruritus, arthralgias, and myalgias in affected areas. In advanced cases, it can lead to debilitating joint catractures and also involve skeletal muscle, bone, lungs, pleura, pericardium, myocardium, renal tubules, and dura mater. Diaphragmatic or pulmonary fibrosis may be implicated in respiratory failure and may cause features of restrictive lung disease. Interestingly all cases of NSF have been reported in patients having kidney disease, with nearly 80% in patients with ESRD on dialysis, and the rest with AKI, Stage 4 and stage 5 CKD. There seems to be little or no risk for patients with stages 1 through 3 CKD and patients with normal kidney function have no risk for NSF. The diagnosis is made on the basis of clinical findings, advanced renal dysfunction and temporal association with gadolinium exposure. Skin biopsy can be done to support the diagnosis.

There is no specific therapy for preventing or treating NSF. It has been found that in some cases, NSF improved with return of kidney function to normal. Studies have shown that 68% of gadolinium is eliminated after a 3-hour dialysis session and approximately 98% could be removed after three consecutive dialysis sessions. So intuitively, it would make sense to initiate dialysis in such patients after gadolinium exposure. But, most of the available evidence suggests that dialysis is not effective in preventing gadolinium-induced contrast injury. The reason behind this could be, that the Gd3+ ion dissociated from the parent dye compound deposits in tissue within dialysis-inaccessible compartment.

Bottomline:

1.Gadolinium should be avoided in patients with Stage 4-5 CKD (GFR under 30ml/min) , AKI and ESRD patients.
2.In patients, who absolutely need the imaging, informed consent should be obtained explaining the risk-benefit profile.
3.Contrast exposure should be minimal and preferably chelated gadolinium compounds (Gadoteridol in USA) , should be used.
4. Consider performing hemodialysis after the exposure (and the next 2 days) in patients who are already maintained on hemodialysis, recognizing that there are no data that support prevention of NSF with this modality.

If you want to read more, here are the links to two articles at CJASN and Nephrology Rounds

The idea

As I started my practice as a nephrologist in Charlotte, I got a lot of questions from my hospitalist and primary care physician colleagues about latest evidence and protocols in nephrology to help them manage their patients better.
It is hard for me as a nephrologist to stay on top of latest developments in the field. For non-nephrologists who have to deal with kidney related issues of patients, the challenge is even greater.
That was the seed of the idea of this blog. To create a forum for non-nephrology physicians to stay updated and find answers around kidney related issues, that will help them in patient management.
I will collect the questions that I am asked by my colleagues and readers, and try my best to answer them. Wherever appropriate I will cite the latest evidence or a good review article for further reading. I shall begin by answering a few questions that I had accumulated over the past three months and I hope I will soon have a lot of questions from you all.
So here it is, the informal vision of this blog. Let us see where it evolves from here. It should be a fun journey in a new medium.

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