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Post-transplant diabetes mellitus (PTDM) is a common problem among solid organ transplant recipients contributing to morbidity and affecting patient as well as graft survival adversely. It can occur at any period following transplantation, but maximum incidence is observed in the first few months, with a second peak after a few years after transplantation. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells and insulin resistance. Both nonpharmacologic and antidiabetic therapies are important for adequate glycemic control. This point of view article provides a short review on PTDM in solid organ transplantation (SOT) recipients from a general physician’s perspective. Solid organ transplantation is currently the best choice of treatment for most patients suffering from end-stage organ failure. Successful organ transplantation offers enhanced quality and duration of life with lower morbidity and mortality. Innovations in SOT, advances in surgical techniques, progress in immunosuppressive regimens, and critical care have greatly improved both the patient and graft survival in last several decades. The discovery of calcineurin inhibitors (CNIs) represents a milestone event in the history of immunosuppression and it has revolutionized transplant medicine; further breakthrough in immunosuppressive regimens is the cornerstone for existing successful transplant program. The current 5-year graft survival is about 80% for kidney and heart transplants, and 70% for liver and lung transplants (UNOS-OPTN and SRTR registry data). Cardiovascular disease (CVD), infections, and drug toxicity play an important role in the long-term morbidity and mortality of this patient population. This risk is not only due to presence of underlying pre-existing comorbidities, but also results from adverse effects of the immunosuppressive drugs such as hypertension, dyslipidemia, and PTDM. The risk of PTDM after SOT varies from 10 to 40% during the first 1 year. This risk depends on several factors including the type of transplanted organ [10–20% of kidney transplant recipients (KTRs) and 20–40% of patients with heart, liver, and lung transplants]. Post-transplant diabetes mellitus is widely studied in KTRs, but the risk factors and pathophysiology seem to be similar in all kinds of SOT. Post-transplant diabetes mellitus [previously termed, new-onset diabetes mellitus after transplantation (NODAT)] results in a remarkable proportion of SOT recipients and contributes to increased risk of CVD and infections, leading to significant mortality and morbidity. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells as well as reduced sensitivity to insulin. Consensus guidelines and proceedings from international consensus meeting on PTDM updated its recommendations in 2014, preferred to call it as PTDM rather than NODAT, as few patients could have undiagnosed diabetes prior to transplantation. New-onset diabetes mellitus after transplantation simply indicates exclusion of pretransplant diabetes and it is found that around 10% of KTRs have undetected diabetes prior to transplantation.1 Hence, PTDM represents timing of diagnosis in post-transplant period rather than time of occurrence of disease. The gold standard method to diagnose PTDM is the oral glucose tolerance test (OGTT). Post-transplant diabetes mellitus typically presents with postprandial hyperglycemia [impaired glucose tolerance (IGT)] rather than impaired fasting glucose (IFG). International consensus guidelines for PTDM recommend standard diagnostic criteria by American Diabetes Association (ADA) and World Health Organization (WHO) for the diagnosis of PTDM and these are almost same as to those used for type II diabetes mellitus (T2DM) in the general population with few exceptions (Table 1).2 Following transplantation, there is increased turnover of red blood cells due to perioperative blood loss and regain of renal function in case of kidney transplantation with normal erythropoietin production. The immunosuppressant drugs can have a negative effect on red cell proliferation in the bone marrow. Hence the glycated hemoglobin (HbA1c) can be erratic and accurate interpretation is not possible in the first 2–3 months, and is not a recommended test to identify PTDM in early post-transplant period. After 3 months post-transplant, HbA1c is reliable and ADA cut-off can be followed to diagnose PTDM. As per ADA guidelines, “prediabetes” is diagnosed with OGTT if fasting plasma glucose is 100–125 mg/dL (IFG) or 2-hour plasma glucose is 140–199 mg/dL (IGT). American Diabetes Association and WHO criteria differ with respect to normal ranges of fasting plasma glucose. American Diabetes Association criteria are more sensitive in detecting transplant candidates at risk for PTDM as its threshold value is lower.3 Impaired fasting glucose is diagnosed if fasting plasma glucose is ≥100 mg/dL by the ADA and ≥110 mg/dL by the WHO. Oral glucose tolerance test is more sensitive for detecting prediabetes as IGT is more commonly seen than IFG. The incidence of PTDM is higher in the first year, with a second peak after a few years following transplantation. Early peak is usually the result of metabolic adverse effects of immunosuppressive drugs, whereas late peak is due to post-transplant weight gain, obesity, metabolic syndrome, and insulin resistance. There is a great variability in the prevalence and incidence rates in the published literature. This is due to differences in the proposed diagnostic criteria, definitions used, organs transplanted, timing from transplantation, follow-up duration, population genetics, geographical differences, immunosuppressive drug regimens, and other risk factors. The prevalence of PTDM varied from 15 to 55% in the literature.4–8 It is identified that up to one-third of nondiabetic KTRs develop impaired glucose metabolism by 6 months following transplantation. Currently, the prevalence of PTDM appears to be reducing, mainly due to use of lower doses of immunosuppressive drugs targeting lower trough levels to prevent drug toxicity.9 Transient hyperglycemia is highly prevalent in the early post-transplant period; it can be identified in ~90% of KTRs in the first few weeks. It can result from use of higher doses of immunosuppressive drugs, antirejection therapy, stress, infections, sepsis, and other critical conditions. While detecting transient post-transplantation hyperglycemia is crucial as it is a predisposing factor for consequent PTDM, universally labeling all of them as PTDM in the early post-transplant setting is not acceptable. The diagnosis of PTDM should be delayed until the recipient is clinically stable, with stable allograft function, and is on lower doses of immunosuppression without acute infections. To avoid overdiagnosis, few authors proposed to define PTDM as a long-term (usually more than 3 months) need for antihyperglycemic therapy. The common predisposing factors for the occurrence of PTDM are side effects of immunosuppression and their effect on glucose metabolism, infections especially due to certain viruses, and hypomagnesemia, along with traditionally identified predisposing factors seen with T2DM (Table 2). Risk factors for PTDM should be analyzed during the pretransplant period to prevent or delay the development of PTDM. Some of these include older age, high-risk race or ethnic groups, obesity or metabolic syndrome, prediabetes prior to transplant, gestational diabetes, first degree relative with diabetes, nonalcoholic steatohepatitis, polycystic kidney disease, higher human leukocyte antigen (HLA)—mismatches, acute rejection episodes, cadaver donor, cytomegalovirus (CMV) and hepatitis C virus (HCV) infections, and use of immunosuppression.8 Induction with basiliximab may predispose patients to PTDM as concluded in a study from North India.10 Glucocorticoids induced PTDM seems to be dose-dependent. It is characterized mainly by insulin resistance and higher postprandial blood glucose levels. Although, it could be dose-dependent, there is no evidence that steroid withdrawal prevents or reduces PTDM incidence.11,12 Calcineurin inhibitors have toxic effect on islet cells of pancreas and alter insulin secretion pattern.13 Calcineurin inhibitors by causing hypomagnesemia, precipitate PTDM. Diabetes Incidence after Renal Transplantation: Neoral C Monitoring Versus Tacrolimus (DIRECT) study observed a greater risk of PTDM with tacrolimus than cyclosporine (CsA).14 In the Efficacy Limiting Toxicity Elimination (ELITE) study, low-dose tacrolimus (8.4%) was more diabetogenic at 1 year than standard-dose CsA (6%), low-dose CsA (4.2%), and low-dose sirolimus (6.6%).15 Various meta-analyses also concluded that tacrolimus is more diabetogenic than CsA.16,17 Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus can also induce PTDM. Conversion from one of the CNIs (either tacrolimus or CsA) to sirolimus resulted in worsening of glycemic control and insulin resistance as shown in a study.18 Antimetabolites such as mycophenolate mofetil (MMF) and azathioprine seem to be nondiabetogenic and may not contribute to the pathogenesis of PTDM. The combination immunosuppressive drug regimens were assessed in some s t u d i e s . O n e s t u d y f o u n d t h a t t h e combination of CNI and sirolimus has a greater risk of PTDM than the combination of CNI and MMF.19 Some other drugs such as renin-angiotensin-aldosterone system (RAAS) blockers [angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)], co-trimoxazole and statins may reduce the risk of PTDM.20,21 Hepatitis C virus infection was associated with almost fourfold higher risk of acquiring PTDM than those who were not infected in a meta-analysis among KTRs. 22 The pathogenesis of HCV-induced PTDM seems to be multifactorial including abnormal glucose metabolism, insulin resistance, and beta-cell dysfunction. Anti-HCV treatment and sustained virological remission in pretransplant period may prevent the development of PTDM. A large North Indian retrospective study compared long-term outcomes of HCV-infected and noninfected KTRs and concluded greater risk of PTDM in the HCV-infected group (~40 vs 19%). In the same study, anti-HCV therapy was given to all infected recipients before transplantation.23 Hepatitis C virus-associated PTDM is usually noticed in liver transplant recipients, especially in cases with hepatic steatosis. Association of PTDM with CMV infection is unclear. There was a fourfold greater risk of PTDM in patients with asymptomatic CMV infection in a study.24 Prediabetes before transplantation can predispose to PTDM. A percentage of 35% of KTRs with PTDM had pretransplant IGT in one study.25 Risk adaptive approach and tailoring of immunosuppression seems to be the fundamental concept to delay and prevent the occurrence of PTDM, especially in those with greater risk for PTDM. Transient hyperglycemia is widely prevalent in early post-transplant period; though it can predispose the recipient to PTDM, it should not be considered as an expression of PTDM. The contribution of transient hyperglycemia to the risk of PTDM was assessed in the past. Around 29% of recipients with postoperative transient hyperglycemia progressed to develop PTDM within 1 year, in a study.26 In another similar study, 46.7% of recipients with early transient hyperglycemia developed PTDM. There was a fourfold higher risk of PTDM in patients with transient hyperglycemia.27 Post-transplant diabetes mellitus, due to its predisposition to infections and CVD, adversely affects graft and overall patient survival. Cardiovascular disease is the most common cause of death and poor patient survival in SOT recipients, and PTDM has a correlation with CVD mortality.28 There is also an adverse effect of PTDM on graft survival independent from excessive mortality. Various factors implicate in death-censored graft loss due to PTDM. Some of these include development of de novo diabetic nephropathy in the renal allograft, excessive risk for infections such as pneumonia, urinary tract infection, and viral infections including CMV.29 Also it could be due to reduced immunosuppression for glycemic control resulting in excessive risk for graft rejection and ultimately graft loss. The treatment of PTDM should be multidisciplinary as it predisposes to various complications including CVD and it is usually associated with other post-transplant complications. The risk for PTDM needs to be assessed during pretransplant assessment by taking thorough history, physical examination, evaluating for metabolic syndrome and prediabetes, and assessing for any other associated cardiovascular risk factors. All SOT recipients should be closely monitored for glycemic control postoperatively while on immunosuppression. Generally, blood sugars are monitored at regular intervals such as every week for initial 4 weeks, then at 3 and 6 months, and annually thereafter. Glycated hemoglobin is not reliable in early post-transplant period, but can be advised 3 months after transplant. Stringent glycemic control is not advisable in majority of SOT recipients as they are at high risk for CVD. Hence, management should target at achieving fair control of blood sugars to near normal glycemic targets without increasing risk for hypoglycemia. Glycated hemoglobin target of

Conventionally, major histocompatibility complex (MHC)-encoded human leukocyte antigens (HLAs) of a donor are considered as the principal targets of the recipient's immune system in renal transplantation (RT), and the clinical significance of anti-HLA allo-antibodies (Abs) is well established. In contrast, the importance of non-HLA immunity in RT is being increasingly recognized. Majority of non-HLA immune targets are the non-MHC-encoded proteins on vascular endothelial cells and exist as cryptic autoantigens. The synergistic triad of tissue injury, anti-HLA, and non-HLA immunity is involved in many cases of graft rejection and loss. The exact mechanisms by which the non-HLA auto-Abs are produced and induce graft injury are still speculative and under research. Understanding them enables the development of novel diagnostic assays and therapeutic strategies and thereby improves long-term graft outcomes. In this review, we discuss the pathobiology and novel mechanisms of non-HLA immunity in RT.

Mantle cell lymphoma (MCL) is a rare aggressive lymphoproliferative disorders (LPD) of B-cell lymphoma, which usually presents in advanced stages at initial diagnosis. Renal involvement in MCL is very rare, especially the combined presence of both glomerular and interstitial disease. We report on a patient with lymphomatous interstitial nephritis (LIN) coexistent with paraneoplastic crescentic membranoproliferative glomerulonephritis (MPGN), subsequently diagnosed to have disseminated MCL with bone marrow and lymph nodal infiltration. He was treated with rituximab-based chemotherapy and went into complete renal remission at 6-months of follow up.

Diabetic nephropathy (DN) is characterized by gradually progressive renal failure and proteinuria. Various types of nondiabetic kidney diseases may superimpose on DN, and affect the natural course, prognosis, and management. Collapsing glomerulopathy (CG) is a form of glomerular proliferative injury, characterized by rapid progression and associated with poor prognosis. CG may be idiopathic or secondary to other causes, and it has also been described with other forms of glomerular diseases. The association of CG with DN has not been reported widely. We report on a patient with DN who has undergone renal biopsy due to massive proteinuria and rapid loss of renal function. Renal biopsy was suggestive of CG superimposed on DN. He was treated conservatively, however, progressed to end-stage renal disease rapidly.

Background Isolated renal mucormycosis (IRM) is a potentially fatal disease affecting immunocompromised hosts. IRM affecting apparently immunocompetent patients is rare, with few previous reports, mostly from India. We describe 10 cases of bilateral IRM with no underlying risk factors. Methods We performed a retrospective analysis of cases of IRM from our hospital information system admitted between 2009 and 2016. We analyzed the data of this cohort of IRM, including epidemiological characteristics, clinical presentation, diagnostic procedures, treatment details and outcome. Results In all, 10 cases of bilateral IRM were identified. All of them were males with a mean age of 24.7 years (range 10–42). Most patients were initially managed as acute bacterial pyelonephritis with acute kidney injury. A total of eight patients were diagnosed antemortem. Diagnostic clues include sepsis not controlled with broad-spectrum antibiotics and enlarged kidneys with or without hypodensities on ultrasound/computed tomography imaging. Three patients also gave a specific history of passing white flakes in their urine. Eight patients received specific antifungal therapy with amphotericin B with or without posaconazole. Three patients in whom the disease was apparently confined to the pelvicalyceal system underwent local irrigation with Amp-B. One patient underwent bilateral nephrectomy. Four patients succumbed to the disease while five patients were successfully treated. One patient was discharged against medical advice. Conclusions IRM is a rare, life-threatening disease associated with high mortality even in immunocompetent individuals. Typical clinical and radiological findings and a high index of suspicion may help in early diagnosis, but definitive diagnosis requires histopathological and/or microbiological confirmation. Early and rapid diagnosis along with aggressive multidisciplinary management including initiation of specific antifungal therapy with or without surgical debridement is vital for a successful outcome.

Background Proteinuria and renal dysfunction is common in diabetic patients and may occur due to variety of causes. Nondiabetic renal diseases (NDRD) account for 30% of the renal biopsies, and idiopathic membranous nephropathy (iMN) is a common non diabetic glomerular disease that can exist alone or in combination with diabetic nephropathy (DN). Immunosuppressants used in iMN may be associated with complications of worsening glycemic control and recurrent infections. There is a paucity of literature on the clinical course, outcomes and treatment adverse effects of patients with iMN and diabetes. Methods We retrospectively analyzed the data of all diabetics, evaluated for NDRD and found to have iMN, between January 2000 and June 2015 in our institute. Results A total of 134 patients with diabetes were biopsied for NDRD and 16 patients had iMN. Mean ± standard deviation age was 54 ± 11.77 years and the median duration of diabetes was 9.4 years. Twelve patients had isolated iMN and four patients had iMN coexisting with DN. Response rates of 18%, 35.71% and 63.63% were seen with Modified Ponticelli (MP) regimen, tacrolimus and mycophenolate mofetil (MMF), respectively. Five patients developed treatment-related adverse effects significant enough to necessitate a treatment change. Worsening glycemic control was the most common side effect. Adverse effects were less with the MMF compared with the MP regimen and tacrolimus. Conclusion Patients with iMN coexisting with diabetes exhibit a poor response to the MP regimen. Treatment-related toxicity is less common with MMF in comparison with the MP regimen and tacrolimus-based regimen. An almost similar response was noted with MMF and tacrolimus-based regimen but there was more withdrawal from treatment due to toxicities observed in the latter.

Emphysematous pyelonephritis (EPN) is a rare gas forming, necrotizing infection of the renal parenchyma. It is potentially lethal, if not recognized and treated promptly. EPN-affecting renal allografts has been reported infrequently. We report a case of 34-year-old male renal allograft recipient presented with urosepsis and acute graft dysfunction, found to have EPN. He was treated conservatively with antibiotics and ureteral stenting along with reduction of immunosuppression, with complete recovery.

Concurrent thrombotic and hemorrhagic manifestations are uncommon in patients with Antiphospholipid Syndrome.A 10-year-old girl with fever, edema, rash and joint pains, who later developed deep venous thrombosis (DVT), stroke, thrombotic microangiopathic hemolytic anemia and pulmonary hemorrhage. Investigations confirmed Antiphospholipid syndrome associated with systemic lupus erythematosus.She went into complete remission with intravenous immunoglobulins, plasmapheresis, immunosuppression and anticoagulation.Thrombotic microangiopathic hemolytic anemia and anti-phospholipid syndrome can be the presenting manifestations of systemic lupus erythematosus.

A 53-year-old diabetic man, with end-stage renal disease and on maintenance hemodialysis through arteriovenous fistula since 6 months, presented with a 6-week history of fever, multiple swellings over chest and lower limbs, cough, and dyspnea. On examination, multiple fluctuant swellings with palpable crepitus were noted over anterior chest wall and lower limbs (Figure 1). Chest X-ray showed massive left pleural effusion. On thoracocentesis, empyema was noted; cultures grew methicillin-resistant Staphylococcus aureus (MRSA). Aspiration of the swellings over his chest and foot also showed MRSA infection. Blood cultures and sputum cultures were also positive for MRSA. Computed tomography (CT) of the chest was suggestive of large loculated left pleural effusion and thick-walled collections involving right sternoclavicular and manubriosternal joints, which were subluxated with air pockets within the collections and extended retrosternally abutting major vessels (Figure 2). In view of disseminated MRSA infection with bacteremia, an echocardiogram was performed, which was suggestive of endocarditis with vegetations over posterior leaflet of aortic valve. The patient was treated with vancomycin and amikacin, left-sided pleural drain, and drainage of abscesses with subsequent improvement that was confirmed on repeat echocardiogram and chest CT. This patient illustrates the high infectious risk associated with hemodialysis, which is a common cause of mortality in these patients. Early diagnosis and aggressive treatment are required.