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Hans H Hirsch

Publications and source records attributed to Hans H Hirsch.

At least 19 recordsLinked to original sources
PubMed2026

Benchmarking urinary cell transcriptomes for noninvasive differentiation of BK polyomavirus-associated nephropathy from T cell-mediated rejection.

BK polyomavirus-associated nephropathy (BKVN) adversely impacts kidney allograft survival and often mimics acute T cell-mediated rejection (TCMR), confounding diagnosis and management. To address this conundrum, we performed unbiased RNA sequencing of urinary cells matched to biopsies classified as BKVN with intragraft inflammation (BKVN-P), BKVN without inflammation (BKVN-N), TCMR, or no rejection (NR). BKVN-N displayed dominant host DNA replication, cell cycle, and repair programs, while BKVN-P samples exhibited expansive innate immune activation, antigen presentation, chemokine upregulation, and epithelial injury. Both BKVN subtypes shared signatures of T cell exhaustion and mature and tolerogenic dendritic cell activation but differed in immune orientation - Th1 predominance in BKVN-N versus Treg and CD8 enrichment in BKVN-P. Compared with TCMR samples, BKVN-P lacked robust TCR/CD28 signaling and was enriched for viral and innate modules; BKVN-N lacked alloimmune activation. B cell exhaustion characterized BKVN-N, while BKVN-P displayed robust B cell activation with metabolic downregulation. A ratiometric urinary cell biomarker, CXCL10 mRNA/CD3E mRNA, distinguished both BKVN subtypes from TCMR with diagnostic accuracy, replicated by quantitative reverse transcription PCR for clinical translation, and confirmed in an independent cohort. These findings demonstrate the utility of urinary cell transcriptomics for resolving viral injury from alloimmunity, enabling precision diagnostics and targeted immunomodulation in kidney transplantation.

Humans↗
PubMed2006

Once-daily directly observed therapy lopinavir/ritonavir plus indinavir as a protease inhibitor-only salvage therapy in heavily pretreated HIV-1-infected patients: a pilot study.

Lopinavir/ritonavir plus indinavir was administered once daily as directly observed protease inhibitor-only therapy in 12 heavily pretreated HIV-1-infected patients with multiple virological failures and advanced immunosuppression (CD4 cell count 95 x 10 cells/microl). The treatment was well tolerated. At weeks 12, 24 and 48, most patients on treatment achieved viral suppression of less than 400 copies/ml and a corresponding median CD4 T-cell count increase. Pharmacokinetic data indicated therapeutic concentrations for both protease inhibitors in most patients.

Adult↗
PubMed2006

Clinical validation of atazanavir/ritonavir genotypic resistance score in protease inhibitor-experienced patients.

OBJECTIVE: To develop a clinically relevant genotypic resistance score for boosted atazanavir (ATV) in protease inhibitor-experienced patients. METHODS: At baseline, 62 patients with HIV-1 RNA > 1000 copies/ml switched to a boosted ATV regimen (300 mg ATV, 100 mg ritonavir once daily); two were excluded from analysis at 3 months as they had undetectable plasma ATV. The impact of baseline protease mutations on virological response (> 1 log10 copies/ml plasma HIV RNA decrease) at 3 months was analysed using Fisher's exact test. Mutations with prevalence > 8% and P < 0.2 were retained. Cochran-Armitage's test was used to select the combination of mutations most strongly associated with reduced virological response. Robustness of the score was investigated using bootstrap resampling. RESULTS: At 3 months, 82% of patients had a virological response and 56% had RNA < 50 copies/ml. Eight mutations (10F/I/V, 16E, 33I/F/V, 46I/L, 60E, 84V, 85V and 90M) were retained in the genotypic resistance score (P = 8.67 x 10) and virological response was observed in 100%, 100%, 80%, 42%, and 0% of patients with none, one, two, three, and four/five mutations, respectively. There was 100% response in patients with a score < 2 independently of the number of active drugs, whereas in patients with a score > or = 3 there was a gradient of response according to the number of active drugs (0%, 29% and 60% with none, one and two/three active drugs, respectively). CONCLUSIONS: The occurrence of three of the eight mutations in the ATV/RTV genotypic resistance score predicted a clinically identifiable reduced response in patients.

Antiretroviral Therapy, Highly Active↗
PubMed2006

Polyomavirus-associated nephropathy in renal transplantation: critical issues of screening and management.

Polyomavirus-associated nephropathy (PVAN) is an emerging disease in renal transplant patients with variable prevalence of 1-10% and graft loss up to 80%. BK virus (BKV) is the primary etiologic agent, but JC virus (JCV) and possibly simian virus SV40 may account for some cases. Intense immunosuppression is viewed as the most important risk factor. However, the preferential manifestation in renal transplants as compared to other allografts or to autologous kidneys of other organ transplants suggests that organ determinants and immunologic factors synergize: Renal tubular epithelial cells and their compensatory proliferation to restore tubular integrity after immunologic, ischemic or toxic injury may provide the critical cellular milieu supporting polyomavirus replication while immune control is impaired due to maintenance immunosuppression, anti-rejection treatment and HLA-mismatches. Patient determinants (older age, male gender, seronegative recipient), and viral factors (genotype, serotype) may have a contributory role. The definitive diagnosis of PVAN requires allograft biopsy which is, however, challenged by (i) limited sensitivity due to (multi-)focal involvement (sampling errors); (ii) varying presentations with cytopathic-inflammatory and/or fibrotic/scarring patterns; (iii) coexisting acute rejection which is difficult to differentiate, but impacts on intervention strategies. Screening for polyomavirus replication in the urine and in the plasma complements allograft biopsy by high sensitivity and allows for noninvasive monitoring. Thus, we suggest a terminology similar to invasive fungal diseases where viruria ("decoy cells") defines patients at risk ("possible PVAN") who should be evaluated for plasma viral load. Increasing BK viremia (>10,000 copies/mL) or urine VP-1 mRNA (>6.5x10(5) copies/ng total RNA) load defines "presumptive PVAN" for which an intervention of reducing immunosuppression should be considered even if the diagnosis could not be confirmed by allograft biopsy ("definitive PVAN"). The response to intervention should be monitored using plasma DNA or urine mRNA load.

Humans↗
PubMed2006

Comparison of two dosages of thymoglobulin used as a short-course for induction in kidney transplantation.

Thymoglobulin is used effectively as an induction agent in kidney transplantation, but the optimal dose is not well established. We evaluated the degree and durability of T-cell clearances with two different thymoglobulin regimens in adult kidney transplant recipients (KTR). Seven KTR received a 3-day thymoglobulin-based induction of 1.0 mg/kg/day while nine received 1.5 mg/kg/day, in addition to maintenance immunosuppression. Lymphocyte subsets were monitored for 6 months. Renal function, infections and malignancies were monitored for 24 months. T-cell subsets were significantly lower by day 30 with the thymoglobulin 1.5 mg/kg/day regimen when compared with the 1.0 mg/kg/day regimen; this trend was sustained at 6-month (CD3(+): 438 +/- 254 vs. 1001 +/- 532 cells/mm(3), P = 0.016). Renal function between the two groups was not significantly different at 6- and 24-months post-transplant. One case of BK Virus viremia in the 1.5 mg/kg/day thymoglobulin group was detected. No acute rejection episodes, cytomegalovirus infections, or malignancies were noted in either group. Thymoglobulin induction was efficacious in both groups, but with a significantly sustained T-cell clearance in the 1.5 mg/kg/day regimen. A more profound T-cell clearance within the first 6 months postinduction therapy may translate into a decreased risk of immunological injury and improved long-term outcome after kidney transplantation.

Aged↗
PubMed2005

Rapid dynamics of polyomavirus type BK in renal transplant recipients.

BACKGROUND: Polyomavirus type BK-associated nephropathy (PVAN) is an emerging cause of early renal transplant failure. No specific antiviral treatment has been established. Current interventions rely on improving immune functions by reducing immunosuppression. In patients with PVAN, a high BK virus (BKV) load is detectable in plasma. However, the relationship between BKV replication and disease is not well understood. METHODS: In a retrospective analysis of BKV plasma load in renal transplant recipients undergoing allograft nephrectomy (n = 3) or changes in immunosuppressive regimen (n = 12), we calculated viral clearance rates and generation times and estimated the loss of BKV-infected renal cells. RESULTS: After nephrectomy, BKV clearance was fast (viral half-life [t(1/2)], 1-2 h) or moderately fast (t(1/2), 20-38 h), depending on the sampling density, but it was independent of continued immunosuppressive regimens. After changing immunosuppressive regimens, BKV was cleared with a t(1/2) of 6 h-17 days. Using the basic reproductive ratio, the efficacies of intervention ranged from 7% to 83% (mean, 28%; median, 22%). CONCLUSION: The results emphasize that high-level BKV replication is a major pathogenetic factor that may have implications for genome rearrangements, immune evasion, and antiviral resistance.

BK Virus↗
PubMed2005

Polyomavirus disease in renal transplantation: review of pathological findings and diagnostic methods.

Up to 10% of renal transplant recipients can develop polyomavirus nephropathy (PVN) in the allograft, leading to premature graft failure. Recent studies have shown that early diagnosis of PVN before there is irreversible damage to the kidney can result in marked improvement of outcome with resolution of the infection in a large proportion of patients. Early histopathologic diagnosis is complicated by the subtle beginning of the infection and its multifocal nature. This review presents a comprehensive set of guidelines for the effective clinical use of urine cytology and quantitation of viruria and viremia in conjunction with the renal biopsy findings. The morphological features of PVN are presented with specific emphasis on the patterns of PVN that are based on the histological progression of the disease and that correlate with clinical outcome. Also discussed in the context of their clinical significance are the main virological and epidemiological aspects of the BK, JC, and SV40 polyomavirus infections.

BK Virus↗
PubMed2005

Negative impact of human leukocyte antigen matching in the outcome of polyomavirus nephropathy.

Factors dependent on the host, the virus, and the allograft affect the course of polyomavirus allograft nephropathy (PVAN). Development of specific cytotoxic antiviral immunity requires recognition of host human leukocyte antigen (HLA) molecules together with viral peptides on the target cells. We correlated the number of matched HLA-A, HLA-B, and HLA-DR antigens with graft outcome in 90 patients with PVAN. Patients that maintained graft function had significantly less degrees of HLA matching (mean 1.5) in comparison to patients with graft loss (mean 2.87, P= 0.001). Markedly reduced incidence of graft loss was observed in patients with no HLA matching whatsoever in comparison to patients with any degree of matching (P= 0.003). Lack of HLA matching may impair the host's ability to mount an effective antiviral cytotoxic immune response. An adequately developed antiviral cellular immunity may lead to significant tissue damage and graft loss even if the viral infection is eventually controlled.

Graft Survival↗
PubMed2005

BK virus: opportunity makes a pathogen.

More than 70% of the general population worldwide has serological evidence of exposure to Polyomavirus hominis type 1, better known as BK virus (BKV). BKV infection typically occurs during childhood, without specific symptoms, followed by a state of nonreplicative infection in various tissues, with the urogenital tract as the principal site. Asymptomatic reactivation and low-level replication with viruria is observed in 5% of healthy individuals. Persistent high-level BKV replication is the hallmark of polyomavirus-associated nephropathy in renal transplantation and of hemorrhagic cystitis in bone marrow transplantation. Since these manifestations are rare in other types of immunocompromised patients, the presence of specific cofactors is postulated. The role of BKV in autoimmune disease and cancer is a controversial topic and is difficult to determine, because the pathology no longer depends on BKV replication. This article discusses current views of pathogenesis, diagnosis, and treatment.

BK Virus↗
PubMed2005

Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations.

Polyomavirus-associated nephropathy (PVAN) is an emerging cause of kidney transplant failure affecting 1-10% of patients. As uncertainty exists regarding risk factors, diagnosis, and intervention, an independent panel of experts reviewed the currently available evidence and prepared this report. Most cases of PVAN are elicited by BK virus (BKV) in the context of intense immunosuppression. No specific immunosuppressive drug is exclusively associated with PVAN, but most cases reported to date arise while the patient is on triple immunosuppressive combinations, often comprising tacrolimus and/or mycophenolate mofetil plus corticosteroids. Immunologic control of polyomavirus replication can be achieved by reducing, switching, and/or discontinuing components of the immunosuppressive regimen, but the individual's risk of rejection should be considered. The success rate of this intervention is increased with earlier diagnosis. Therefore, it is recommended that all renal transplant recipients should be screened for BKV replication in the urine: 1) every three months during the first two years posttransplant; 2) when allograft dysfunction is noted; and 3) when allograft biopsy is performed. A positive screening result should be confirmed in <4 weeks and assessed by quantitative assays (e.g. BKV DNA or RNA load in plasma or urine). Definitive diagnosis of PVAN requires allograft biopsy. If PVAN and concurrent acute rejection is diagnosed, antirejection treatment should be considered, coupled with subsequently reducing immunosuppression. The antiviral cidofovir is not approved for PVAN, but investigational use at low doses (0.25-0.33 mg/kg intravenously biweekly) without probenicid should be considered for refractory cases. Retransplantation after renal allograft loss to PVAN remains a treatment option for patients clearing polyomavirus replication.

Humans↗
PubMed2005

Successful outcome of progressive multifocal leukoencephalopathy in a renal transplant patient.

We report the case of a 47-year-old man who developed progressive multifocal leukoencephalopathy (PML) after receiving immuno-suppressive therapy for renal transplantation. The patient presented with a focal seizure and cognitive changes 5 months post-transplantation. He was found to have enhancing lesions in the parietal lobe and typical findings of PML in a brain biopsy. Immunosuppression was discontinued and the neurological symptoms gradually resolved over a period of 4 weeks. The patient is free of any neurological symptoms 36 months after the diagnosis of PML and imaging studies demonstrate resolution of the PML lesions. The patient returned to hemodialysis 3 months after immunosuppression was discontinued. We also present a review of the literature on PML in renal transplant recipients.

Biopsy↗
PubMed2004

BK virus-associated nephropathy in renal allograft recipients: rescue therapy by sirolimus-based immunosuppression.

BACKGROUND: BK virus nephritis (BKN) in recipients of renal allografts has reemerged during the past 5 years. Despite increased incidence, therapeutic options remain limited and progression of the disease often leads to allograft failure. METHODS: From May 2002 to July 2002, we performed protocol biopsies in 25 recipients of kidney allografts with progressive allograft dysfunction; three patients demonstrated unexpected histopathologic features of BKN. We tested the hypothesis that replacement of their lymphocytotoxic and nephrotoxic immunosuppression (combination of mycophenolate and tacrolimus) with sirolimus- and prednisone-based therapy can lead to disappearance of the virus without increasing the risk of acute rejection. RESULTS: During the median follow-up of 18 months after sirolimus and prednisone therapy, decoy cells disappeared first, followed by progressive decrease in the median plasma BK virus-DNA load, and undetectable levels at the last follow-up. Patients remained free of acute rejection, and follow-up median estimated creatinine clearance increased to 67 mL/min (range 62-75 mL/min) from 52 mL/min (range 51-54 mL/min) at the time of diagnosis. CONCLUSIONS: Further studies are needed, but at present these preliminary results offer a new direction for therapeutic intervention in recipients of renal allografts with BKN.

Adult↗
PubMed2004

Immune reconstitution in HIV-infected patients.

The prognosis of patients infected with human immunodeficiency virus (HIV) type 1 has dramatically improved since the advent of potent antiretroviral therapies (ARTs), which have enabled sustained suppression of HIV replication and recovery of CD4 T cell counts. Knowledge of the function of CD4 T cells in immune reconstitution was derived from large clinical studies demonstrating that primary and secondary prophylaxis against infectious agents, such as Pneumocystis jirovecii (Pneumocystis carinii), Mycobacterium avium complex, cytomegalovirus, and other pathogens, can be discontinued safely once CD4 T cell counts have increased beyond pathogen-specific threshold levels (usually >200 CD4 T cells/mm3) for 3-6 months. The downside of immune reconstitution is an inflammatory syndrome occurring days to months after the start of ART, with outcomes ranging from minimal morbidity to fatal progression. This syndrome can be elicited by infectious and noninfectious antigens. Microbiologically, the possible pathogenic pathways involve recognition of antigens associated with ongoing infection or recognition of persisting antigens associated with past (nonreplicating) infection. Specific antimicrobial therapy, nonsteroidal anti-inflammatory drugs, and/or steroids for managing immune reconstitution syndrome should be considered.

Antiretroviral Therapy, Highly Active↗
PubMed2004

Acute renal failure on immune reconstitution in an HIV-positive patient with miliary tuberculosis.

Immune reconstitution syndrome following HAART in human immunodeficiency virus (HIV)-infected patients is characterized by inflammatory worsening of organ functions despite improvement in HIV surrogate markers of HIV infection. We describe a patient with miliary tuberculosis and urinary shedding of acid fast bacilli who developed acute renal failure 8 weeks after initiation of antituberculosis therapy and 6 weeks after initiation of HAART. The diagnostic workup and further course of disease implicated immune reconstitution syndrome as the cause of acute renal failure.

Acute Kidney Injury↗
PubMed2004

Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load.

Polyomavirus-associated nephropathy (PVAN) is a significant cause of allograft loss. The diagnosis requires allograft biopsy, but the impact of the histological features on diagnosis and outcome has not been described. We studied the distribution and extent of PVAN in 90 patients. Viral cytopathic changes, tubular atrophy/fibrosis and inflammation were semi-quantitatively scored and classified into histological patterns. The histological findings were correlated with viruria, viremia and graft survival. PVAN lesions were random, (multi-)focal and affected both cortex and medulla. Areas with PVAN coexisted with areas of unaffected parenchyma. In 36.5% (15/41) of biopsies with multiple tissue cores, discordant findings with PVAN-positive and -negative cores were observed. However, all patients with PVAN had decoy cells in urine as well as significant viruria and viremia (mean of 2.5 x 10(8) and 2.32 x 10(7) viral copies, respectively). Biopsies showing lesser degrees of renal scarring at the time of diagnosis were associated with, more likely, resolution of the infection, in response to decrease of immunosuppression (p = 0.001). More advanced tubulointerstitial atrophy, active inflammation and higher creatinine level at diagnosis correlated with worse graft outcome (p = 0.0002, 0.0001 and 0.0006). Due to the focal nature of PVAN, correlation of biopsy results with viruria and viremia are required for diagnosis.

Biopsy↗
PubMed2004

Epstein-Barr virus load correlating with clinical manifestation and treatment response in a patient with angioimmunoblastic T-cell lymphoma.

Epstein-Barr virus (EBV)-associated lymphoma may arise secondary to angioimmunoblastic T-cell lymphoma (AITL). The prognosis is poor despite chemotherapy and experimental therapies. We report on a 40-year-old woman with AITL without obvious immunodeficiency in which EBV-associated lymphoma developed. The occurrence and size of enlarged lymph nodes correlated strongly with the EBV load in serum (EBVL). Treatment with valacyclovir at the early stage resulted in a drastic more than 3 log10 decrease of EBVL and complete remission. However, valacyclovir had to be stopped after 6 months due to side effects, and the lymphoma reoccurred 3 months later associated with increasing EBVL. Eventually started cytotoxic chemo- and anti-CD20 therapy resulted only in partial remission. The lymphoma progressed and 33 months after it was diagnosed the patient died. This case report demonstrates the close association of EBVL and AITL and a beneficial effect of antiviral therapy at an initial stage of disease manifestation.

Acyclovir↗