Gadolinium Induced Acute Kidney Injury and Nephrogenic Systemic Fibrosis

16 peritoneal dialysis therapy. Approximately 90% of cases have been reported in dialysis patients and 10% of cases in 12 patients with stage 3 or 4 CKD. NSF is an indolent disease with several weeks to months of symptoms prior to diagnosis but can present as rapidly progressive disease often with 16 systemic involvement. NSF occurs in patients regardless of age, gender or race and has been reported in pediatric patients 17,18 as young as 8 years old. Fibrosis affecting skin and or 20 systemic organs dominates the clinical picture. Cutaneous Involvement NSF first affects the skin as dermal hardening with tethering to deep dermal tissue, giving a characteristic woody 20 feel. Additional skin findings are brownish hyper pigmented plagues, brawny indurations, waxy erythematous papules, and subcutaneous nodules. Extremities as well as trunk may be affected but NSF typically presents in lower extremities at calves in a symmetrical fashion. Involvement of upper extremities follows the development of disease in lower extremities. Trunk is involved late in the severe form of 15,20 the disease whereas face is usually spared. Systemic Involvement Systemic fibrosis is an important and a well recognized feature of NSF and can involve skeletal muscles, bones, lungs, pleura, pericardium, myocardium, renal tubules, 15,21 testes and duramater. NSF can lead to joint contractures due to fibrosis of periarticular structures involvement of shoulders, elbows, wrists and hands causes significant functional disability. Joint contractures of hips, knees and ankles can predispose to falls and factures. Lung involvement leading to fibrosis and diffuse diaphragmatic infiltration leading to respiratory failure is known in NSF.

peritoneal dialysis therapy.Approximately 90% of cases have been reported in dialysis patients and 10% of cases in 12 patients with stage 3 or 4 CKD.NSF is an indolent disease with several weeks to months of symptoms prior to diagnosis but can present as rapidly progressive disease often with 16 systemic involvement.NSF occurs in patients regardless of age, gender or race and has been reported in pediatric patients 17,18 as young as 8 years old.
Fibrosis affecting skin and or 20 systemic organs dominates the clinical picture.

Cutaneous Involvement
NSF first affects the skin as dermal hardening with tethering to deep dermal tissue, giving a characteristic woody 20 feel.Additional skin findings are brownish hyper pigmented plagues, brawny indurations, waxy erythematous papules, and subcutaneous nodules.Extremities as well as trunk may be affected but NSF typically presents in lower extremities at calves in a symmetrical fashion.Involvement of upper extremities follows the development of disease in lower extremities.Trunk is involved late in the severe form of 15,20 the disease whereas face is usually spared.

Systemic Involvement
Systemic fibrosis is an important and a well recognized feature of NSF and can involve skeletal muscles, bones, lungs, pleura, pericardium, myocardium, renal tubules, 15,21 testes and duramater.NSF can lead to joint contractures due to fibrosis of periarticular structures involvement of shoulders, elbows, wrists and hands causes significant functional disability.Joint contractures of hips, knees and ankles can predispose to falls and factures.Lung involvement leading to fibrosis and diffuse diaphragmatic infiltration leading to respiratory failure is known in NSF.

Etiology
No definite correlation is yet established but a possible connection with severity of renal failure, history of hyperthyroidism, thrombotic episodes, dependent edema, and vascular procedures has been reported.Many drugs including high dose erythropoietin therapy, past angiotensin converting enzyme inhibitor and sevelamer therapy, has 22,23 been implicated but not statistically proved.An Austrian study correlated NSF with Gadolinium exposure, renal insufficiency and concurrent acidosis whereas a Danish study calculated a strong link between GD exposure and subsequent onset of NSF in renal insufficiency patients with 14 or without acidosis.

Diagnosis
Often physical examination and laboratory analysis are adequate to make the diagnosis of NSF in appropriate clinical setting.Non-Gadolinum enhanced MRI may reveal skin thickening and elevated T2 signals in muscles.Skin biopsy is 20 needed in some cases to confirm diagnosis.

Nephrotoxicity (Acute Kidney Injury)
Since GBC agents have significantly lower viscosity compared to iodinated radio contrast agents and the volume used is 4-11 times less, the nephrotoxicity due to GD was 2,3 thought to be significantly less.Nephrotoxicity of GBC agents has been studied in experimental animals and minimal elevation of serum creatinine was reported when high doses 4 (>1.0 mmol/kg) were used.Nephrotoxicity of GBC agents has been studied in healthy individuals and in patients with 6,7,8,9 mild to moderate kidney disease.
Several of these studies demonstrated that GBC agents lack significant nephrotoxicity particularly in patients who have normal or 7,8 minimally elevated (<2.5mg/dl) serum creatinine.In these studies GBC associated nephrotoxicity developed in 0-5% of patients which was less than iodinated contrast (17-40%).
In contrast to these favorable studies, a number of other studies suggest that GBC's exhibit variable degrees of 9,10 nephrotoxicity.GD based contrast agents are reported to induce acute kidney injury (AKI) in a high-risk population 9 group at the usual dose for MRI and MRA examinations.This was noted more frequently in patients with elevated baseline creatinine ≥3 mg/dl) and in patients with hyperten-10 sion, diabetes mellitus and sepsis.In these studies nephrotoxicity developed in 5-50% of patients which was equal to or greater than that seen with iodinated radio contrast agents.In conclusion majority of studies suggest renal safety but GBC induced nephrotoxicity can develop.Factors which increase the risk of GBC associated nephrotoxicity are advanced CKD, higher doses, and arterial 9 injection.

Nephrogenic Systemic Fibrosis (NSF)
NSF is a rare syndrome characterized by fibrotic skin, muscle contractures, decreased range of joint motion and 14,15 organ fibrosis.The first case of NSF was reported in 1997, since then many cases and small cases series have been [12][13][14][15][16][17][18] reported.The largest series from India consists of seven 19 patients of NSF reported from Kolkata.It was initially recognized as a novel, idiopathic, progressive, scleromyxedema like fibrosing disorder of the skin but soon it was recognized that fibrosing process is not limited to skin but 15 occurs as a systemic condition.Over last decade multiple reports have revealed an associated between NSF and prior exposure to GBC agents in patient with advanced renal 15 failure.However no new case of NSF has been reported from USA after 2009.Patient, physician, hospital, product, regulatory and country considerations account for the emergence and disappearance of NSF.

Epidemiology
NSF has been exclusively reported in patients with renal disease with a glomerular filtration rate (GFR) <60 2 ml/min/1.73m .NSF has been reported in the setting of acute or chronic kidney disease, as well as in either haemo or

Histopathology of NSF
Well described pathological features of NSF include dermal thickness, increased collagen bundles, increased mucin, fibroblast proliferation and spindle shaped fibroblast.Fibrosis can extend into subcutaneous tissue, fascia and even skeletal muscles.Immunolabelling for CD 34 and procollagen I in the spindle cells of NSF may provide a sensitive and specific method of diagnosis.Scanning electron microscopy and inductively coupled mass spectrometry 15,16 identified GD in biopsies from NSF patients.

Differential Diagnosis
The closest differential diagnosis of NSF is scleromyederma in which skin thickness occur over head, neck, arms and upper trunk while as in NSF characteristic lesional distribution (acral and truncal preferences, facial sparing), raised ESR and CRP lack of inflammatory cells on histology, lack of paraproteinemia and characteristic immunohistochemistry with CD 34 and procollagen I favors the diagnosis of NSF.Systemic sclerosis may be considered as second most important differential diagnosis but serologic finding and histopathology provides the clue.Eosinophilic fasciitis is characterized by peripheral eosinophilia, hypergammaglobinemia and dermal inflammation on skin 19 biopsy and thus differentiating it from NSF.

Treatment
Physiotherapy is advised to maintain joint mobility.Many pharmacological agents have been tried to improve skin and systemic fibrosis including corticosteroids, thalidomide, cyclophosphamide, mycophenolate mofetil, intravenous immunoglobulin with variable results.Plasma exchange and plasmapheresis has been reported to improve skin fibrosis.Extracorporeal photopheresis has been shown to be more effective than others in improving fibrosis but is [24][25][26] very expensive.
To conclude it is important that the clinicians should be cognizant of GBCA's risk and benefits.NSF fears should not lead to denial of enhanced MR imaging examinations with lower risk stable GBCA's, when clinically appropriate.It is important to identify high-risk patients and closely monitor renal function after administration of GD.